Idoc - Pub - Audit Checklist For Store Department
Idoc - Pub - Audit Checklist For Store Department
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:This document describes the conduct of the Management review of the quality system for G
Conformance Certification, including the conduct of an internal audit to assure the system meets
requirements of ISO Guidelines and is effectively implemented..
2.0 Objective: To Provide Documented Procedure for review of the quality system for GMP Conformance Certificat
including the conduct of an internal audit to assure the system meets the requirements.
Scope : To define role/responsibility of various functions responsible for Internal audit
4.0 Responsibility :
o Board of Internal Audit and Management Review Committee: Arranges for the internal audit
gathers all information for the Management Review.
o QA Management Committee: Provides all information as required by the Board of Internal Audit
Management Review Committee and is responsible for follow-up corrective and preventive actions
o QA Internal Auditor(s): Conduct the internal audit according to GMP.
5.0 Procedure :
The QA Management Committee, by consensus, selects three qualified individuals for the Board
Internal Audit and Management Review Committee. Members to the Committee serve until they
replaced.
The Board of Internal Audit and Management Review Committee arranges for the half yearly inte
audit to be conducted.
The date for the audit is established by mutual agreement between the Board of Internal Audit a
Management Review Committee and the General Manager Production and Asst. Manager Produc
(AMP).
The audit is conducted by any member of the board or Internal auditor qualified to participate on
Certification Board so long as the auditor is not a member of the QA Management Committee
qualified and knowledgeable in certification, auditing.
The audit must be conducted at least every 06 months.
During the audit, personnel responsible for the area audited are immediately notified of the outco
of the audit of their area.
During an audit, it is possible that a difference of opinion can arise as to the severity of
observation. It is important not to spend too much time debating the merits of the observation.
does not appear that the difference of opinion can be resolved, then the auditee should be inform
that the audit report is subject to review by the Board of Internal Audit and Management Rev
Committee and the QA Management
The draft report is issued to the Board of Internal Audit and Management Review Committee wi
14 calendar days. The Committee members review and comment on the report and a final repo
issued.
The final internal audit report is submitted to the QA Management Committee.
The QA Management committee drafts a response to the audit report that is finalized after review:
Findings, nonconformities, trends, and other opportunities for improvement are identif
investigated to determine the causes; and corrective/preventive actions are developed. These acti
are implemented as soon as possible and recorded.
The response to the internal audit report is submitted to the Board of Internal Audit and Managem
Review Committee for their concurrence.
Upon agreement on the response to the internal audit, the Board of Internal Audit and Managem
Review Committee prepares a complete Certification Program Management Review Report
includes, as appropriate,:
Results of internal and external audits
Feedback from clients and interested parties related to the fulfillment of the Certification Process
Feedback concerning impartiality
Follow-up actions from previous Certification Program Management Review Reports
The status of corrective or preventive actions
The fulfillment of objectives
Changes that could effect the management system
Appeals and complaints
The Board of Internal Audit and Management Review Committee submit their Certification Progr
Management Review Report to the QA Management Committee.
The Certification Program Management Review Report with the response to the internal aud
discussed at the next meeting of the full Board. The expected outputs of the review includes decisi
and actions related to:
Improvement of the effectiveness of the management system and its processes.
Resource needs.
Decisions and actions of the Board are documented in the Board Minutes and all o
Corrective/Preventive Actions are reviewed and their status documented at all subsequent quart
Board Meetings.
Effectiveness of completed actions is reviewed at the next Program Management Review.
6.0 Abbreviations :
GMP: Good Manufacturing Practice
QA : Quality Assurance
1.2 Reception
1.5 Maintenance
1.6 Surroundings
2. PERSONNEL:
2.1 : Or
2.2 : Qu
2.3 : Pro
Me
Fo
Fo
2.4 : Pe
Fo
Fo
2.5 : Fa
Fo
Fo
Wa
2.6 : Pe
Sh
WC
Lo
Ca
2.7 : Jo
Re
2.8 : Tra
2.9 : En
2.10 : Dr
2.11 : Sy
2.12 : Pe
c) : Intermediate ____________
3.18 : EQUIPMENT
4 MANUFACTURING CONTROL:
.
4.1 : Identification level for material under processing
5. TSE QUESTIONNAIRE:
5.1 : Have you obtained the COS Certificate from EDQM for the
Material you are supplying to us? If yes please attach the copy.
5.2 : Is any of the starting material used in the manufacturing from
Animal Origin. If yes, Please ensure to obtain the TSE free Certificate
from your supplier.
5.3 : Is the Production Line dedicated?
5.5 : Is your batch COA contains the TSE / BSE free Declaration. If no submit an
undertaking to send the batch wise TSE / BSE free Declaration for all
supplies to us?
6. RECORD KEEPING :
8. QUALITY CONROL:
CRITICAL
MAJOR
OTHER
CONCLUSION
SIGN
DATE
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1.0 OBJECTIVE: To lay down a procedure for handling of out of specification (OOS) result in
Microbiological analysis and monitoring.
2.0 RESPONSIBILITY
3.0 ACCOUNTABILITY
4.0 PROCEDURE
In all the reports the identified reason shall be written on a continuation sheet to the annexure
provided. A copy of the above investigation report shall be maintained with the batch
manufacturing records concerned to increase awareness and for any future reference
4.1.1.1The data of the microbiological monitoring of the sterility testing facility shows fault;
4.1.1.2 A review of the testing procedure used during the test in question reveals a fault;
4.1.1.4 After determination of the identity of the microorganisms isolated from the test, the
growth of this species or these species may be ascribed unequivocally to faults with respect to
the material and / or the technique used in conducting the sterility test procedure.
4.1.2 If the test is declared to be invalid it is repeated with the same number of units as in the original
test.
4.1.3 If no evidence of microbial growth is found in the repeat test the product examined complies with
the test for sterility. If microbial growth is found in the repeat test the product examined does not
comply with the test for sterility.
4.2.1 If the microbial counts are found to be more than or equal to the alert limit then
open a deviation report (annexure I) through Q.C. Head to the concerned Production head.
Production personnel shall check the working discipline, supply of air, safety measures etc.
4.2.2 If the count exceeds or reaches the action limit then the urgent notification to the Production
head and Engineering Head through Q.C. Head shall be followed by an investigation for the
same. –
- Supply of air
- Working discipline
- Review of data from the same place and others from the incubated plates
- If any of the plates does not indicate the same then no action is necessary.
- If any of the plates indicates more count then perform additional cleaning, disinfection or
fumigation and retraining to the operator shall be given.
- All activities shall be recorded as per the annexure attached with this SOP.
- More number of samplings (i.e. double the original) shall be preformed at the same location
where the counts observed were beyond or equivalent to the action limit but an additional
relevant parameter of monitoring shall also be performed which shall be incorporated with the
same annexure.
- All the batches manufactured during the said period shall be subjected to the microbial
analysis for MLT / Sterility &BET in order to ensure that the batches manufactured are in
accordance with the relevant finished product specifications. The investigation report shall be
submitted to the Q.C. - Head
4.2.3 If the bio-burden is found out of specified limit in the core areas the identification of the
organism shall be performed.
4.2.4 Stop the production immediately and check all the possible parameters, which can affect bio-
burden of the area.
4.2.5 Check the pressure differential of the area, which must be within the specified limit.
4.2.6 Check the air velocity of LAF /HEPA filters, which must be within the specified limit.
4.3 If the investigation / review of manufacturing activities (e.g. sterilization process, aseptic
filtration, environmental conditions, personnel practices) indicates failure of manufacturing
activities, then the batch shall be considered as failed to comply sterility.
If only the alert is exceeded without finding an undesirable microorganism the release of the
preparation for which this water has been used, has to be taken under hold till the result comes.
In case of the counts touching the action limit then all the batches manufactured shall be re
analyzed by taking 25 grams and making the allowance for the larger size specimen for the
analysis.
In the case of counts crossing or touching the alert limit or action limit in any type of water the
same will be intimated to the production department and maintenance department. If the result
cannot be attributed to the analytical error, sampling error, contamination in the container
sampled then the microorganism detected must be identified / differentiated by taking sample
from all other points.
4.4.1 Adequate sanitization of the system shall be ensured to eliminate the source of contamination
with a rigorous check for the same.
4.4.2 All the investigations made shall be recorded in the annexure III provided with this SOP.
4.5.2 Retest the same material/product but with a sample size of 25 grams by making allowance for
the larger size specimen.
4.5.3 Results for the same shall be intimated to the Q.A. Head for final decision.
Harmonization of format
6.0 TRAINING:
7.0 DISTRIBUTION:
ANNEXURE –I
Deviation : Parameter:
Requirement :
Results : Signature :
Name : Signature :
Date:
Repeated Sampling :
Parameter:
Result:
Signature :
ANNEXURE - II
Revision No. : 00
REF. SOP NO.: Page No.: 1 of 1
Effective Date:
Date : Deviation :
Done By : Checked
By :
ANNEXURE –III
INVESTIGATION REPORT FOR FAILURE IN TEST FOR BACTERIAL ENDOTOXIN & M.L.T
Revision No. : 00
REF. SOP NO.: Page No.: 1 of 1
Effective Date:
Sample
BET
Micro tips Test tubes Pipette
LAL reagent
Results of other samples with same conditions tested on the same day.
Result
Test repeated
Date Result
Microbiologist
ACTION TAKEN :
CONCLUSION
Microbiologist QC
Manager
Date: Date:
S. No. Questions
1.0 GENERAL INFORMATION
1.1 Name and Address of Laboratory:
3.0 PERSONNEL:
3.1 Number of Staff: No.
Q A:
Q C:
R & D Lab:
Microbiology:
Others:
3.2 No. of Approved persons:
GLP
GMP
Job training
ISO principals
By examination
GMP
cGMP
USFDA
ISO 9001:2000
By clients
By National authority
By Foreign authority
By FDA
1.
2.
3.
Name of customer
Sample quantity
Batch No.
Date
Analytical procedure?
Cleaning procedure?
Temperature
Relative Humidity
8.0 WATER:
8.1 Which type of water used for analysis?
8.2 How will you check the quality of water and it is
free of contamination?
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First Aid
Purpose: To provide a documented guideline for the first aid treatment n case of any accident.
2.0 Objective: To provide a first aid treatment.
3.0 Scope: Employees / Visitors / workmen.
4.0 Responsibility :
5.0 Procedure :
Training
First aid training shall be given to selected employees of each department.
Detail training of the first aid shall be given to some employees of the company.
The list is as follows and shall be available in each department for easy reach out
during emergency.
List of trained employees
Serial No. Department Name of Trained employees
The first aid box shall be numbered and located at identified and marked
positions as following –
Locations of first aid box
Serial No. First aid box number Location of First aid Box
Every Monday from Personnel department personnel or General Manager (Adm) shall
Review the contents of first aid box and shall replenish the required item. The
Record of review shall be kept.
urpose : To provide a documented procedure for preventing accident & Recording accident.
2.0 Objective : To maintain safety aspects
3.0 Scope : Preventing accident & Recording accident
4.0 Responsibility :
Follow up : Concern department head
Over all responsibility: Personnel & Administration Manager.
5.0 Procedure :
Accident Prevention
Workman shall engage themselves in the duties which have been assigned to them.
The execution of their duties must be in the safe manner laid down in S.O.P. for the
operation, of the machine or duty concerned.
Removal of guards or safety devices, cleaning of machines which they are
Running, etc., are expressly forbidden.
Workmen working beyond the height of 10 feet shall wear the safety belt.
If any employee / work man working beyond the height of 10 feet on ladder shall work
with one additional work man / employee to hold ladder.
Safety instructions given or posted on Notice Boards are to be followed.
Workman shall not keep sharp edge tools into their pocket.
Any employee / workman working with electricity shall wear safety shoes &
Sock proof gloves.
Any workman working with hazardous chemicals / acid shall wear the safety
Wears like goggles, gloves etc.
Speed of vehicle inside the factory premises shall not exceed 20 km / hr.
When welding work is to be carried out in closed area, extra fire extinguisher
Shall be provided.
After working with oil, floor shall be cleaned thoroughly to wipe out the oil.
Solvents shall be stored in tight closed container.
Used drums of solvent / chemicals shall be discarded by skilled workman.
Sufficient emergency light shall be provided.
Entry into transformer yard / explosive storage yard shall be restricted to selected
Personnel.
Machine which is under maintenance shall be labeled as “Under Maintenance”.
Workman shall enter into water tank, drainage, septic tank only after permission Of
Personal & Administration department.
Workman shall carry out repairing work of high pressure line / high temperature Line /
or any explosive line only after permission of Engineering In charge.
Wear earplugs near high noise area.
ecording of Accident
Accident shall be recorded into Accident Register.
The accidents are categorized as critical major and minor depending on the
Seriousness of the incident.
The First aid, if required, after the accident shall be provided at the earlier marked
Locations and trained persons are available.
The telephone no. of fire station, doctor, ambulance shall be displayed in all the
Departments to call upon in an emergency.
The affected employee shall be immediately rushed to the hospital, if needed and is
provided the required medical help.
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Purpose : To provide guideline to ensure that different production activities are carried out in compliance with
safety & cGMP requirement, at pre-determined frequency.
Objective : To provide a documented guideline to ensure that different production activities are carried out in
compliance with safety & cGMP requirement, at pre-determined frequency.
4.0 Responsibility :
5.0 Procedure :
Before starting any process in equipment make sure equipment should be cleaned and line
clearance has been given by QA.
The production area should be clean and free from dust and dirt so the intermediate and final
product could not be contaminated.
TRAINING:
All the staff shall be covered for cGMP, Safety and Job-related training as per the training
procedure.
SOP must be prepared for all activities that are quality critical or safety critical or relate to key
business areas. These SOPs must be prepared, reviewed & authorized and controlled in
accordance with Site SOP.
The SOPs must include specific maintenance instructions, lubrication details, Spares
requirements, frequency of maintenance, responsibilities for carrying out the job &
documentation, etc. as appropriate. The department activities must be reviewed to identify
operations which need preparation of SOP and the current SOPs must be updated / reviewed
as scheduled.
AUDITS:
Department audits must be carried out to monitor the production aspects of departmental
activities in regard to its impact on SHE, Energy Conservation and Quality matters.
VALIDATION:
CHANGE CONTROL:
All changes must be fully documented, assessed and authorized prior to the work being carried
out.
In line with good documentation practice, change in process must be controlled as per the
good manufacturing practices. If any Change occurs it should be reported to QA department
with reason.
n documents.
Equipment Cleaning Record: Before conducting next step in process cleaning of equipment
should be required. To follow cGMP ECR should be filled by production department before
starting every process. By checking ECR, QA department give line clearance to production
department.
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Duties:
In case of fire, necessary arrangement and provision of fire squad and systems to the
emergency spot and its neighbouring sections.
Organise necessary ambulance and medical treatment for affected persons if required.
Preserve evidence.
Organise investigation.
Before allowing re-entry to the site check if the conditions are safe (Toxicity, fire hazard,
structural stability etc.).
Re-starting of plant operations only after ensuring steps for prevention of re-occurrence.
ADVISORY TEAM
Responsibility of Advisory Team.
Remain with Emergency Leader at the emergency control center and advice him as needed.
In case Emergency Leader has to leave his post for some reasons any of the member of the
Advisory Team will take over as the Emergency Leader.
If needed Factory Manager can deputy Emergency Leader to the site to be of help to the
incident controller.
ACTION TEAM – A
Shift in-charge of affected plant.
Inform emergency control center / security about location and nature of emergency.
Shutting down the operation as per requirement and other areas as guided by the incident
controller.
Department Head
Take over the responsibilities of the shift in-charge upon arrival and proceed as
listed above.
1. As shift in charge will be involved in fire fighting operations senior chemist will ensure
that
Operations of affected area will be stopped and reactions will be stopped in safer mode
with consulting shift-in-charge.
2. Chemists and junior chemists will form fire fighting team with guidance of incident
controller start fire fighting with fire extinguishers and then with fire hydrant system if
required.
ACTION TEAM – B
Manager Electricals.
On hearing Alarm
When instructed by the Emergency Leader
Take over responsibilities from shift-in-charges and ready to shut down plant if needed.
Manager – Maintenance
Manager – Electricals.
Ensure that adequate power supply is made available for sensitive plant operation and
emergency lighting.
On hearing Alarm
Security Officer
Control traffic.
Safety Officer
Proceed to scene of Emergency
Inform with consultation with advisory team to Factory Inspector and other Authorities.
Offer any help expected, advice with First Aid render First Aid to injured person.
Doctors.
First Aiders
Stores-incharge
Proceed to the site and hospital as per decided by Emergency Leader to render assistance.
Stores-in-charge.
Arrange additional supplies of Fire Fighting or Safety equipments as required.
ACTION TEAM – E
On hearing Alarm
Get back to work places (if safe) and await instructions from supervisors.
Avoid panic
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Stability
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Analytical Validation
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Pharmacopoeias
Q4 Pharmacopoeias
Specifications
Q6A Specifications : Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances (including
Decision Trees)
Pharmaceutical Development
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Chemical industries are more prone to safety hazards, in terms of fire, explosion
etc., resulting in huge loses of resources and precious lives.
Hence, it is of utmost importance that each one, irrespective of his position in the
organization should exhibit a high sense of responsibility to safeguard the safety of
his area of operation, in his own as well as in the interest of the organization.
The hazards could be of various types, arising from chemical, mechanical, electrical
or civil in nature.
1. Chemical Hazards:
Most of the accidents occurring in chemical industries are of this nature. The
causes for the hazards can be attributed to:
i) Process deficiencies.
i) Chemical processes :
All process equipments which have bearing on the process control, such as
temperature indicators, pressure / vacuum gauges, safety / control valves etc.
should be of reliable quality and tested for performance before being installed.
There should also be a system for periodic inspection and maintenance of these
equipments.
iv) Training:
Training plays an important role in the skill development process. All the
operational persons should be adequately trained for the job.
1. All chemicals based on their chemical properties and incompatible nature with
other chemicals must be stored as stipulated in their MSDS.
3. Proper personnel safety equipments, such as apron, goggles, face shield, nose
mask, safety shoes should be worn while handling corrosive and hazardous
chemicals.
7. All electrical fittings, such as lighting, switches etc. in the storage area should be of
flame proof category.
8. it must be ensured that MSDS (Material Safety Data Sheet) for all the hazardous
chemicals being stored must be made available to the stores incharge and it is the
responsibility of the stores incharge to make sure that the storage and handling is
done in compliance to the procedures stipulated in the MSDS.
10. As a safety need, every storage room should be provided with an exit door, which
is to be properly identified and kept un-locked.
11. Good house keeping is an important requirement in storage godowns. There must
be clear passage area for free material movements.
1. There are chemicals, which remain harmless if stored in isolation, but upon
allowing coming into direct contact, could pose severe fire, explosion hazards.
iii) Acetone
Methanol vs CrO3
Glycerine
v) Sodium metal vs H 2O
In all the above cases instant fire will take place, due to the high amount of heat
produced as a result of the vigorous reaction between these compounds.
6. Dichromates (ammonium)
4. Few of the chemicals are very corrosive in nature and can cause severe blisters /
deformity / loss of vision etc, if they come into contact with human body. All
personal protective equipments such as hand gloves, apron, goggles, nose mask,
safety shoes should be worn by those handling these chemicals e.g.
4. Chloro compounds (acetyl chloride, Thionyl chloride, mono and tri-chloro acetic
acid, aluminium chloride etc.)
Based upon the degree of flammability (Flash points), flammable solvents are
classified under the following 3 categories:
1. All solvents of category A and B should be stored only in metallic containers, well
closed, in a cool place at the designated area.
2. No hot jobs such as welding, cutting or bracing is permitted inside the storage
place or in the vicinity.
8. Basic training for fire-fighting systems should be imparted to all the operating
staff.
11. Flammable solvent storage warehouse should meet the statutory requirements of
Indian Explosive Act.
One of the most hidden hazard, causing fire and explosion in chemical industry is
associated with the unique property of several solvents and organic compounds to
acquire electric charges termed as “static electricity”, which subsequently get
discharged in the form of electric spark, causing the disaster.
2. Preventive Measures
11. Allow flammable solvents to flow through metallic pipes only. These pipes should
be earthed to the ground with proper conduits.
12. While charging a solvent into a reactor/container, ensure that the liquid is not
dropped from the top to fall to the bottom. Always ensure that the liquid reaches
the bottom of the vessel, through metal pipes.
13. Avoid storage in non-conductive containers, such as those with moc PVC/PP/HDPE.
Always store only in metal containers.
14. Loading and unloading of bulk flammable solvents should be permitted only in
authorized premises (refer Petroleum Act of India). Proper earthing connections
should be provided to both the storage container and the receiver.
15. Before operating any centrifuge, ensure that it is being properly earthed to the
ground. Also, before scooping out any material from the centrifuge, ensure that the
metallic scoop is also earthed (plastic or nonconductive equipments are not
advisable for scooping material from centrifuges).
16. To avoid dust explosion, which is likely in large powder handling units, provide
adeauzte ventilation so as to prevent dust accumulation which is the cause for this
kind of hfazards.
17. Wherever possible spray water in the surroundings of large solvent storages, as
higher humidity helps to dissipate static charges (water particles are good electric
conductors).
Caution:
Never ever let any live electric cable come in contact with earthing cables, as the
consequences could be disastrous.
Handling of compressed and liquefied gases, contained in cylinders calls for special
attention, as these are of potentially high hazards, in case of any leakage or
bursting up of the container.
There are about 101 permanent, as well as liquefied gases, which are being
conveyed in specially designed cylinders and these gases are contained under high
pressures (18 kg/cm2 to 250 kg/cm2) and are identified with unique colour codes.
Some of the commonly used gases and the corresponding colour codes of the
cylinders are:
vii.1. Precautions to be observed in storage and handling.
1. Always store filled gas cylinders in a cool and ventilated and sheltered area, away
from heat and direct sunlight.
2. No hot jobs, such as welding, bracing, cutting or grinding, is permitted in the gas
storage area.
3. Always keep the cylinder properly capped. The cylinder valve is the most delicate
and vulnerable part of the cylinder. Never allow the Needle valve of the cylinder to
get damaged, while loading/unloading and shifting operations.
4. Store the cylinders in vertical position, near a solid support, properly fastened with
a metal chain to avoid their falling.
5. In case of any leakage of the cylinder, never attempt to repair the valve. Isolate
the cylinder from the main stream and keep it in an open and cool area and seek
help from the cylinder supplier.
6. The cylinder storage area should be located always, away from the main/process
building and under no circumstances should any gas cylinder be used inside the
processing areas. Gas cylinders should be kept away from corrosive acid fumes,
which could corrode the cylinder body and damage the cylinder valve.
7. Never try to apply grease on the cylinder valve/nozzle, as certain highly reactive
gases like hydrogen can ignite the organic mass, causing fire.
8. For shifting gas filled cylinders, always use cylinder trolleys and never let them roll
on their body.
9. Never try to open any cylinder without having the appropriate type of regulators.
10. As a safe practice, always store the cylinders outside the building in the proper
designated area, and draw the gases into the operational area through metal pipes
with suitable safety valve.
12. It is always preferable to keep minimum possible inventory for better handling,
especially for toxic and flammable gases.
13. Do not store incompatible gases together, as this could lead to explosion in case of
simultaneous leakage from both the cylinders.
Ammonia vs Chlorine
1. All the process equipments such as reaction kettles, pressure vessel etc. should be
properly maintained and periodically pressure tested to ascertain their capability to
withstand the optimum pressure for which they are designed.
2. Never ever subject the equipment to more pressure than the designed capacity.
All equipments where pressure reactions are carried out, should be provided with
safety pressure releasing valves.
3. The vent line of process reactors (except pressure reactors, designed for specific
services) should be vented outside the process block, preferably through a
scrubber, depending upon the nature of the effluent gases generated in the
chemical processes.
5. Ensure that all the moving parts of an equipment, such as the shaft of a drying
oven, blades of a fan, coupling of a mechanical pump, the belt of a motor fan are
provided with proper metal guards so that they do not come into contact with
human body.
7. All utility lines, conveying steam, chilled water, brine, vacuum, nitrogen etc,
should bear clear identification tags and preferably they are to be identified with
distinct colour code system.
8. As a safety measure it is highly advisable to purge nitrogen gas into the reaction
vessels before start of the process, thereby reducing the oxygen concentration
inside the reactor and thus reducing the fire risk.
1. All electric fixtures such as cables, wires, switches, electronics fittings should be of
standard quality and free from any manufacturing deficiency.
2. Overloading of any supply point by drawing more power than the recommended
norm should be totally avoided:
3. It must be ensured that all the electric fittings, fixtures, lightings, induction
motors etc, should be of flame proof quality.
4. All electric equipments and fittings should be safe guarded against moisture,
chemical fumes etc, and periodically inspected by regular maintenance systems.
5. Electric panel boxes, main control switches etc. should be properly housed in a
proper ventilated block, away from the plant and must be tagged for easy
identification.
7. Cables and electric wires used should be of single piece and should not have any
joint.
8. Never let the electric and earthing cables come in touch with each other at any
point.
11. Whenever any equipment is under maintenance / repairs, ensure that the power to
the equipment is switched off from the main panel and proper tagging is done at
the panel switch, as well as on to the equipment.
12. Only qualified and authorized personnel should be permitted to perform electrical
jobs.
INDUSTRIAL FIRE AND PREVENTIVE METHODS
a) A fuel [this can be: any organic matter; such as a solvent, oil, wood, paper, etc.].
d) Free radical reaction. The chemistry of combustion indicates that the union of
Oxygen and the fuel is not direct, but through a series of steps wherein the actual
reaction taken place between Oxygen and the free radicals liberated by the heated
fuel at the point of ignition.
2. CLASSIFICATION OF FIRES:
Basically all the type of fires can be classified into the following major categories.
a) Class A Fires:
These are fires on ordinary combustible materials, such as paper wood, rags etc.
which can be put off by the quenching and cooling effect of water. For
extinguishments of such type of fires, use of water, form or dry chemical fire
extinguishers would be effective.
b) Class B Fires:
These are fires occurring in flammable liquids such as oils, organic solvents, petro
chemicals etc., where a blanketing or smothering effect is essential to put the fire
out. Fire extinguishers like Foam, CO2, and Dry chemical are recommended for this
type of fires, which provide a blanketing effect around the fire, thus, preventing air
from coming into contact with the burning substance.
Water is effective for oil fires, only when it is used in the form of a spray or mist, but
as such is not advisable to use in fires involving solvents and oils, which are
immiscible with water.
c) Class C Fires :
These fires are associated with Electrical fittings, fixtures, such as electrical panel
boxes, electric cables, electric ad electronic equipments etc. Non conductive
extinguishing agent such as CO2 gas is the most ideal and recommended fire
extinguisher for Electric Fires.
d) Class D Fires:
These are fires in metals, such as Li, Na, K, Zn, Mg etc. and mishandling of this type
of fires can cause explosion and spread to other areas. Special attention and
training is needed to handle metal fires.
Normal fire fighting agents used for extinguishing are dry sand, dry powder,
graphite etc.
It is important to understand the meaning of some of the fire control terms and
definitions of certain critical physical characteristics of solvents which will help to
understand the degree of flammability of a particular Product.
This is the lowest temperature at which the liquid will give off enough flammable
vapours at or near its surface, such that in an intimate mixture with air and a spark
or flame, it ignites.
The flash point of a flammable liquid is usually determined by the standard method
of test for flash point with the Tag Closed Cup Tester (TCC) or with the Tag Open Cup
Tester (TOC). The results recorded with Tag Open Cup Tester (TOC) is always found
to be 5-10oF higher (less flammable) than that being recorded with Closed Cup
Tester.
The closed cup flash point value is usually several degree lower (more flammable)
than the open cup, as the test in the former case is made on a saturated vapour-air
mixture, whereas in the letter case, the vapour has free access to air and thus is
slightly this reason open cup values more nearly simulate actual condition.
This is the lowest temperature at which a mixture of air and vapour continues to
burn in an open container when ignited. It is usually above the flash point.
Wherever the flash point data is not available, fire point figures can be considered
as significant as flash point to understand the degree of flammability of the
material.
This is the temperature at which a material (solid, liquid or gas) will self-ignite and
sustain combustion in the absence of a spark or flame. This value is influenced by
factors such as the size, shape, the material of the hot surface, rate of heating etc.
etc.
4. Vapour Density:
This value expresses the ratio of the density of the vapours to the density of air.
The vapours of most of the flammable solvents are heavier tan air, with the result
that they tend to travel at ground level making them more dangerous, as the risk
will be more in case of a fire, since the vapours do not get diluted with air. Hence,
in operational areas, where such higher V.D. solvents are used, the ventilating
outlets should be at the lower level. Similarly, wherever, the liquids of low V.D. is
handled, the ventilator should be at the higher level.
This is the temperature at which the vapour pressure on the liquid surface becomes
equivalent to the atmospheric pressure and at this temperature a continuous flow of
vapour bubbles occur from throughout the liquid body and it is an indication as to
how much volatile the liquid could be.
This physical characteristic of liquids can be made use of, in preventing many
hazards like Fire, Thermal decomposition of the product etc by subjecting the
distillation process to take place under reduced pressure.
7. Chemical Formula:
In the event of lack of data regarding the flammable nature of a product, the
chemical formulation of the product can give a clue regarding its flammable nature
to a certain extent. For instance, if a product consists only of Carbon and Hydrogen
(Hydro carbon), it can be assumed to be flammable and if it is in liquid form and
having a low boiling point, it can be considered to be more flammable.
8. Flammable liquids:
FIRE PROTECTION
The two major aspects of Fire Protection are 1. Prevention and 2. Loss
minimization.
1. Prevention:
The most undisputed aspect of Fire protection is it’s prevention. Since, for a fire to
occur, all the 3 basic requirements, Fuel, Oxygen and source of Heat are needed to
combine, by avoiding any of the 3 basic requirements, Fire can be prevented. For
instance let us take an example of an industry which uses large volumes of Acetone
in an open atmosphere. Now, for a fire to happen, among the 3 requirements, two
of them i.e. Fuel and Oxygen (from air) are already available in the vicinity. The
third requirement for Fire is heat.
From the flash point data, Acetone has a Flash point of 0oF, which means that at all
temperatures above 0oF Acetone would give out enough vapours which on
combining with Oxygen of air, can form a flammable mixture in case if it comes into
contact with a spark, flame or a hot surface or any other source of ignition. Thus, in
an installation using Acetone, following avenues are available from Fire Protection
point of view:
1. The working temperature (ambient) should be kept less than the Flash point,
0oF of Acetone, so that the vapour pressure of acetone at that temperature is
lowered to considerable extent and consequently it does to give out enough
vapours for the Fire to take place.
2. The supply of atmospheric oxygen must be cut off. This is possible in two
ways.
i) By applying vacuum in the processes which taken away the air from the liquid
surface.
ii) By providing a continuous stream of Nitrogen gas flow over the surface of the
liquid (also termed Nitrogen blanketing).
ii) Hot operations, such as welding, gas cutting, bracing should not be carried out in
and around the operational area.
iii) All the electrical fittings and fixtures and electric motors used in the process area
should be Flame proof in nature.
4. The area must be ventilated so that even though acetone gives off enough
vapour to form a flammable mixture with air, the vapour will be drawn out of
the area by means of the fume exhaust as rapidly as it is formed, thus
preventing the accumulation of vapour concentration.
Below is a brief account of the 3 essential supporters of fire and the means to
reduce their influence for Fire Protection.
A) OXYGEN:
Although under certain specific conditions, chemicals can initiate fire even in the
absence of oxygen for short duration (e.g. Fires associated with sulphur /
phosphorous chlorine, hydrogen etc.), for sustained propagation of Fire, oxygen is
very essential. Also the higher the concentration of oxygen in the atmosphere,
more would be the intensity of fire. In industrial atmosphere it is difficult to
manipulate the oxygen concentration in the working area, particularly since a
concentration of oxygen, far below normal to keep fires from starting, would also be
too low to support human life.
When it becomes necessary to work with such products, which by mere contact with
air of atmosphere, can initiate a Fire, following steps are recommended for their
safe handling.
i) Isolate such products, such as sodium azide, sodium hydride etc. which are
highly reactive with atmospheric oxygen from the main stream of materials and
store them in containers under vacuum, or follow the guidelines for storage as
mentioned in their respective MSDS.
ii) Keep such products under a blanket of inert gas such as nitrogen, helium or
argon.
B) HEAT:
In industrial fires the most easily overlooked fact is that all the major Fires that had
occurred, had a modest beginning in the initial stages, which might have gone
unnoticed and hence uncontrolled. Then, since fires are by definition exothermic,
the very small fire started by a tiny heat source, supplies to its surroundings more
heat than it absorbs, thus enabling it to ignite more fuel and oxygen mixture, and so
on until very quickly there is more heat available than is needed to propagate a
large Fire.
The heat for the initial Fire to start might have been provided by various sources of
ignition such as high environmental (ambient) temperatures, hot surfaces,
mechanical friction, spark from a switch, static electric discharge, an open flame or
from a jot job, like welding, gas cutting etc.
It is worthwhile here to look into the various aspects of the “ignition source” and
find ways to effectively curtail them.
a) Open flames:
b) Electrical sources:
Some of the common source of electric heating are from non certified lightings,
cables, switches, starters, electric motors, digital electronic indicators, overloading
of supply point, poor earthing systems etc. As a matter of safety, it is advisable to
have all electrical switches and electric panel board properly housed in a separate
block, away from the main plant / operating premises.
c) Over heating:
Processes which need high pressure steam and involve high temperature reactions,
runaway reactions, special processes, etc. should be identified and these are to be
segregated from the relatively safer processes. HAZOP study should be undertaken
before the implementation of such processes and special attention has to be paid in
training the persons operating such plants.
i. Hot surfaces:
The most common hot surfaces in a chemical industry are equipment like, drying
oven, boiler, steam line, hot oil system etc. These equipments must be housed in a
quarantined location preferably away from the operating area (boiler / thermo pack
and electrically) heated drying oven in any case should be way from the process
block). All the supply lines conveying steam, hot oil, hot water, hot air etc. should
be properly insulated and maintained. It must be remembered that Flammable
solvents, having the auto ignition temperature, lower than any of these hot
surfaces, can get ignited themselves in case of their contact.
Many fires are caused by the heat of reaction produced when chemicals,
incompatible in their chemical characteristics come into contact with each other,
which are further accelerated by external source of heat and air. Few of such
commonly used chemicals, having incompatibility with each other are:
v) Sodium hydride, elements like sodium, potassium lithium etc. with water.
Many of fire investigations have proved beyond doubt that the cause of fire in most
of the cases was due to neglect, poor house keeping practices, accumulation of
flammable wastes such as cotton rags, residual oil and grease etc.
iii) Sparks:
Sparks may be produced from various sources, such as from electric motors,
switches, loose electric connections or by static electric discharges. Sparks are also
generated from friction between mechanical parts, by hammering and chiseling
etc. to avoid electric sparking, some of the recommended precautions are:
i) All the electrical fittings, such as switches, lighting, induction motors etc. should
be flameproof in nature.
ii) Electric panels, main control switches etc must be away from the process block.
iii) Electric cables/wires connected to equipments should be of the right quality and
should be in one piece (there should not be any joints on the cable).
iv) Proper earthing should be provided to all equipments, storage vessels etc.
i) All moving parts of the mechanical equipment, such as the shaft of the gear box,
shaft of the fan in a drying oven, clutches of a centrifuge etc must be greased and
maintained in good condition.
ii) Hammering and chiseling should be avoided as far as possible inside the
process plant.
If at all they have to be done, use hammers / chisles made of brass or gun metal,
which does not produce sparks on hammering.
a) Static Electric Discharge:
This is a phenomena in which certain products, mostly of organic liquids and non-
polar solvents get electrically charged on their surface, by virtue of factors, such as
high speed discharge, fall from heights, separation at a higher speed, prolonged
storage etc. Causes for fire in many industries especially chemical and paper, are
attributed to this unique phenomena. Most of these occur during the months when
the atmospheric humidity is low and artificial heating is don(droplets of water in a
humid atmosphere acts as a suitable conduit to carry away the acquired electric
charges from the liquid surfaces, thus preventing a spark to generate by static
discharge). Maintaining a humidity of 40 to 50% in rooms where flammable
solvents are being handled, will greatly help to reduce the risk of a spark due to
static discharge. Electrical grounding of storage tanks, process equipments,
discharge pipings etc. are mandatory as per Indian Petroleum Act and it must be
strictly enforced.
In all the equipments as far as possible the use of belts should be avoided and the
use of metallic chains or direct shaft driven systems should be encouraged.
i. Friction:
One of the major causes for industrial Fire can be attributed to the heat / spark
generated by friction from the moving parts of mechanical equipments, e.g. fan
blades rubbing the sides of outer casting, poorly lubricated bearings of a rotating
body like hydro extractor, uncooled mechanical seal of a reactor etc.
ii. Fuel
Combustion takes place most easily between oxygen of air and a fuel in its vapour
or finely divided particle state. As solid chemicals need preheating for their
transformation from solid stage to liquid stage they are relatively safe, particularly if
their melting points are high. But in case of liquids, most of them give out sufficient
amount of vapours even at lower temperatures which can form a flammable mixture
with air and ignite themselves.
As a matter of safety and fire prevention, all solvent storage tanks above ground
level should have dikes constructed out of bricks and cement so that in the event of
any leakage or fire, it can be contained within a limited area, thus preventing it from
spreading.
It is also worth probing when a new process is developed that, whether or not it is
possible to substitute Flammable and Hazardous chemicals with non-flammable/less
flammable and non-hazardous chemicals. If cost is the prime factor in favour of a
flammable solvent other indirect benefits, such as savings in installation of high cost
safety devices, training cost, high insurance premium etc. should be assessed by
substituting with a non-flammable solvent. However in any event, usage of
flammable solvents in a chemical process cannot be avoided irrespective of the
quantum.
Dust Explosion:
Like static electric discharge, another lurking industrial hazard is dust explosion.
Practically any flammable material in the form of the particles or dust, mixed with
air at the right proportion, when comes into contact with a spark (mostly generated
by static discharges), flame or heat will burn so rapidly as to cause a severe
explosion which is termed as Dust Explosion. This kind of hazard commonly occurs
in industries handling, plastic, grain, flour, coal dust, metal powders, fertilizers,
wood dust, powdered milk, detergent powder, paper dust and industries handling
sulphur and phosphorous powders. Some of recommended precautions to minimize
dust explosion are:
c) Do not allow the dust to accumulate to alarming proportions. This can be achieved
by providing effective exhaust system.
d) All the dust particles generated in the process, should be taken out through metal
ducts, and the vent of such ducts must be outside the block, preferably, taken to a
distant location.
e) Proper earthing should be provided to the pulverizing / dust generating
equipments / ductings etc.
h) The use of compressed air to blow the dust off the equipments/floors etc, thus
helping the formation of dangerous dust clouds is totally FORBIDDEN.
k) As in the case of Flammable solvents, any kind of source of ignition, such as open
flame, smoking, welding/cutting, grinding, electric sparks from loose contacts or
from static discharges, should be avoided.
l) Use of inert gas like nitrogen, in closed vessel operations has been found very
effective and rewarding in preventing Fire and Explosions.
LOSS (CONTROL)
One of the equally important aspects of Fire protection is also to devise various
alternates/methods to minimize the loss, in case of a major fire. There have been
major Fires all around, and loss of precious human lives and properties. Although
investigations help to identify to some extent the cause of Fire, in most events they
are inconclusive or doubtful, as most the live evidences of fire gets destroyed or
distorted in the fire itself and the findings of the investigations normally are based
on assumptions and hypothesizes.
What is more important is how to prevent a Fire totally from happening and how
best maximum salvage could be done in case of any such unfortunate incident.
Caution:
It must be ensured that there should not be any holes or cracks on the fire wall.
Every hole made on the wall to permit utility pipes / electric cable trays etc. to pass
through must be properly sealed with cement, so that no flammable vapour could
pass through such holes.
3. In many Fire incidents, it has been observed that the Fire Exit Doors provided
in the process blocks, to enable the persons trapped to escape safely, in the
event of fire, had caused more damage than any use, because of the reason
that either they were not maintained regularly for proper functioning, or the
path to the Exit Door were blocked with materials, storage drums etc. as a
result of which access to the door became difficult and the very purpose of
the door was defeated.
It is of utmost importance that the Fire Doors should be greased regularly and must
be tried for smooth functioning atleast once in a day and a record should be
maintained. No materials whatsoever should be stored on the pathway to the Exit
Door, and the approach way should be clearly highlighted with painting.
There should also be proper indicators to locate the Exit Doors and the most
importance caution to be observed is that these doors should never ever be bolted
tightly or locked.
4. Ensure that in the process blocks, the inventory of flammable solvents is kept
to the minimum possible level and the bunks, lids etc of all the storage drums
/ tanks are tightly closed. There should be clear space for movement
between the storage drums and in the event of Fire, these are to be moved
out of the building depending upon the situation. In case if it is not
accessible to reach the drums, they should be kept cool, by spraying a jet of
water from the Fire Hydrant system.
In case there are more than one plant/module, it is suggested that the Fire alarm
system from each of the module may be connected to one main Fire Alarm Display
board located at a central location preferably at the “Time Office / Security Office”.
Similarly, the fire display board should be provided with suitable indicator system to
identify the exact location of fire.
6. Needless to mention, there must be adequate Fire fighting equipments, easily
accessible in the case of emergency. Location of the Fire fighting equipments
is also equally important, so that they must be easily accessible.
8. One of the most important aspects in Fire Protection is to prevent the Fire
from spreading from floor to floor in a multistoreyed building. Mostly the fire
spreads through open staircases, elevators, cutouts for future installations
etc. not only that the fire spreads through these `ventilators’, these also get
choked with fumes, hot air, noxious gases etc. and the stair cases often
become real death traps. One way to prevent this kind of hazard, is to
provide proper enclosures to stair cases and elevators at each floor with self
closing doors. It is important to remember that these doors should have self
closing arrangement, as there is always a tendency among people to keep
the door open. Similarly, all open cut-out on the floors, must be closed with
brick and cement.
10.However, the most effective way to prevent fire damages can be achieved
only through educating and training the operating staff n regular basis and to
inculcate a sense of ownership and alertness.
FIRE FIGHTING
As already discussed earlier, to extinguish a fire it is essential that at least one of
the three components of fire viz., Fuel, Air (oxygen) or Heat is cut off from the
system or its concentration is drastically reduced.
Although cutting the fuel supply is the best option to contain the Fire, in many cases
either it is difficult or not practicable, but in case the Fire is on a large storage tank
or a big reactor, and it has a pumping system connected to a far off storage vessel,
then the solvent can be pumped out from these containers to the safe storage
vessel as the Fire blazes only on the surface of the liquid. It is also important to
keep the burning tank cool with a jet of high pressure water so that the temperature
is brought down below the ignition temperature of the liquid.
1. Water:
The most commonly used fire extinguishing agent is water. It is the cheapest and
most effective media, especially when applied in the form of a fine spray. It has a
blanketing effect on the fire if sprayed, as the fine droplets of water act as a barrier
to prevent the air ingression to the fire point. More importantly it cools down the
fire surroundings below the autoignition temperature of the liquid, which results in
the extinguishing of the fire.
However, water has certain limitations too. It is good, as describedc earlier, for fires
with materials like wood, paper, cellulose, liquids miscribe with it, etc. but not
suitable for items like Oil, Petrol, Organic solvents having lower density than water,
Liquids immiscible with it, fires in metals etc. etc.
Water is not recommended for oil fires, and fires involving immiscible organic
solvents etc as these being lighter than water will float on the water surface and
also due to the impact of the water jet, will scatter all around carrying the fire along
with it. In such cases blanketing will also be difficult as the fire will be floating
around with water. The consequence could be disastrous, if this floating fire goes
down to the Gutter and Sewerage, as this could result in more spread of the fire,
affecting other plants as well.
Explosions have also been reported inside open gutters resulting in massive loss to
property and human lives.
This kind of extinguishers are operated by inverting them and directing the nozzle
of the hose towards the base of the flame. Int his type, a small bottle of con. H 2SO4
is kept around a saturated solution of sodium bicarbonate inside a metal cylinder,
having an outlet connected to a small rubber-hose. When it is overturned, the acid
comes into direct contact with sodium bicarbonate present in the water, generating
CO2 gas, which in turn pressurizes the water to come out of the extinguishers under
pressure. Such extinguishers need to be recharged once in a year, irrespective of
the fact whether they have been used or not. This type of extinguishers are useful
for ordinary type of fires on paper, wood, cotton, waste rags etc.
In this type, there will be a small high pressure CO2 cylinder inside the body of the
extinguisher, surrounded with fine sodium carbonate powder. When the
extinguisher is put into operation, the CO2 cylinder gets punctured and due to the
high gas pressure generated, the soda powder is driven out through the nozzle of
the cylinder. These are equally effective as the soda-acid extinguishers has a good
blanketing effect on the Dire. These also need annual replacement of the sodium
carbonate powder, as it has a great tendency for cake formation on prolonged
storage.
Despite the limitations, for fighting uncontrollable fire, water is the most effective
fire extinguishing agent and in fact there is no substitute for water. One of the most
effective ways of fire protection is to install a suitable fire hydrant system, having
access for high pressure water at all the crucial locations. In this system sufficient
quantity of water is stored in an underground tank exclusively built for Fire fighting
purpose and from this tank water is circulated through 4” to 6” dia metal pipes laid
underground by a powerful mechanical pump. At all the crucial locations tapping is
provided from the main line and these are connected to the Fire hoses. It is
important to ensure that the pump is maintained regularly by a systematic
maintenance schedule and the hose reel is free from defects. As a good safety
practice, it is suggested that the fire hydrant system should be activated at least
once in a week and checked for the performance.
Some other type of Fires which though not common, are equally disastrous and all
preventive steps must be taken to avert their occurrence.
a) Gas Fires:
This type of fires can be put out with the use of fire extinguishers of CO 2 dry
chemicals and in certain cases with water also, but the most important step should
be to turn off the gas valve from the source. If source of supply is far away, ad
likely to take time to reach there, the best way to fire fight is to keep the
surrounding area cool by spraying water continuously, till the gas valve is closed
and in the meantime utilizing the Fire extinguishers at the fire.
Caution: On some occasions though the fire is extinguished successfully, people
forget to close the supply valve for long periods, with the result the gas
concentration can increase to explosive limit leading to explosion.
b) Metal:
Fires on metals is very dangerous and often difficult to extinguish. Ordinary Fire
fighting agents may not be suitable, depending upon the type of the metal and the
volume. Normal metal Fires are associated with metals, such as sodium, potassium,
Lithium, Magensium, Zinc etc. Fire fighting agents such as sodium chloride, sodium
bicarbonate, graphite, magnesium carbonate, magnesium oxide are found effective
for controlling the Fire.
Caution: Water should never be used to extinguish metal fires, as this can result in
explosion which would further spatter burning metal particles to great distances,
thus helping the fire spread.
STORAGE AND HANDLING
OF
HAZARDOUS MATERIALS.
a) Explosive chemicals:
These are chemicals which under certain conditions of heat, pressure, shock etc.
undergo rapid decomposition, evolving large volumes of gas and heat, which in
turn further heats up the surrounding air to expand so rapidly that the entire
process ends up in what is called explosion.
Storage and handling of this type of materials should be done with extreme caution.
1. all type of chemicals falling under this category, such as nitrates, chlorates, per
sulphates, per iodates, azides, perioxides etc should be stored in a separate block,
away from the main buildings and human habitation.
4. Avoid storage for prolonged periods. FIFO system should be followed in the
warehouse.
6. Rough handling, dragging of the containers, stacking at higher levels thus creating
more strain on the bottom containers, etc should be totally avoided.
7. No attempt should be made to scrap out the material with any metal object nor
should it be pulverized or powdered.
8. Disposal of explosive chemicals should be done only as per the procedure laid
down in the MSDS or as per the maufacturer’s instructions.
a) Flammable chemicals:
Combustible materials can be of all the 3 types viz; solids, liquids, or gases,
although the rate of Fire propagation is different for each type. The propagation is
least in the case of solids, as the vapour pressure being very low at ambient
temperatures, it takes much longer time for the solids to get heated up to produce
sufficient vapours to get ignited. However, the rate of propagation is much faster in
the case of liquids and still faster in case of gases. As a matter of fact in case of
vapour Fires, the rate of propagation is so fast that they normally end up in
explosions aggravating the situations.
1. All flammable solvents must be stored in a cool place, under shelter with proper
ventilations. The storage store should be away from the main building.
3. No hot jobs, such as welding, gas cutting, grinding or any other source of ignition
such as naked flame, smoking etc should be allowed in and around the storage
area.
4. As far as possible electrical equipments and fixtures, such as lighting fans, water
coolers, air conditioners etc must be avoided in the storage block and if at all they
are to be installed, it must be ensured that they should be flameproof in nature.
9. Movement in solvent farm area and in flammable solvent storage blocks, should
be restricted and only authorised personnel should be allowed to operate in these
areas.
10. Proper colour coding should be implemented for correct identification of the
solvents and also all the pipe lines conveying these solvents shold have proper
identification tags.
11. Regular training should be imparted to the staff by competent personnel on fire
fighting and salvage techniques.
a) Oxidising agents:
Since oxidizing agents are capable of generating oxygen, by way of heat, chemical
decomposition or by interaction with other incompatible materials, they help fire to
ravage, even in the absence of atmospheric air or oxygen. Following categories of
chemicals are considered to be most powerful oxidizers and these are to be handled
very cautiously.
As a general rule, all flammable solvents must be stored away from oxidising
chemicals and these should never be allowed to come into contact with each other.
e.g. Instant Fire will take place if Chromic acid comes into contact with organic
solvents such as acetone, alcohols, hydrocarbons etc. Equally dangerous is the
interaction between potassium permanganate and con. Sulphuric acid which would
also result instantaneous fire.
Similarly potassium permanganate or chromic acid can set ablaze poly hydric
alcohols such as glycerol, if they come into contact with each other.
Also it is advisable to store the oxidizing chemicals in a separate store, away from
the operational areas, having adequate ventilation and cooling arrangement, since
most of these chemicals are susceptible to thermal decomposition.
There are many chemicals which undergo decomposition upon contact with water
and the rate of some of the decomposition processes is so fast that it results in
explosion and Fire.
ii) metal salts such as hydrides, nitrides, sulphides, carbides, borides, acid
anhydrides, concentrated mineral acids.
iii) Organic chloro compounds such as acetyl chloride, Thionyl chloride etc.
These compounds are to be stored in water proof storage rooms, in air tight
containers preferably on dry sand beds, which normally acts as good adsorbant, in
case of any leakage.
As these are very reactive with water, steam etc., a caution board in bold letters
should be displayed outside the storage room, strictly prohibiting the use of water in
that area, in case of any fire.
Only recommended fire fighting agents, such as Drypowder, CO2 should be used in
the affected area.
c) Toxic chemicals:
These chemicals can be both Organic or Inorganic, as well as in all the 3 forms viz.
solids, liquids or gases.
1. Store these chemicals, especially if they are in the liquid form, in well closed
containers in a cool place with adequate ventilation. This is more relevant, if the
material is low in its boiling point.
2. Ensure that as far as possible they are not allowed to come into contact with
atmospheric oxygen, moisture etc. as many of the otherwise harmless chemicals
become toxic due to chemical degradation, with air and moisture. (Chemicals such
as chloroform, carbon tetrachloride etc., can produce the highly toxic gas phosgene,
by their interaction with atmospheric oxygen and moisture, particularly when stored
in mild steel containers).
3. Ensure that toxic chemicals are not stored along with other chemicals, particularly
with those meant for human consumption such as IP/BP grade products.
4. There must be proper identification tags on toxic chemicals, clearly indicating the
route through which they enter human body and severity of toxicity.
5. All safety aids, such as hand gloves, nose masks, fresh air masks, goggles etc
should be available handy and use of these equipments should be strictly enforced,
through proper education and training.
d) Corrosive chemicals:
Some of the common corrosive chemicals, being used in chemical industries are:
As corrosive chemicals can cause severe injuries to human body, including loss of
vision or damage to limbs, causing permanent deformity, it is very important that of
safety aids, such as goggles, face shields, nose and fresh air masks, aprons, hand
gloves, safety shoes etc. should be utilized while handling such hazardous products.
e.g. strong alkalis like sodium hydroxide, potassium hydroxide, liquor ammonia
solution can damage the eye permanently, if there is a splash and they come into
contact with eye. No alkaline material should be handled without goggles and
handgloves.
Contact any part of the body by concentrated mineral acids such as Sulphuric and
nitric acids, can cause severe burns and blisters. Always wear protective aids such
as gloves, goggles, aprons and safety shoes while handling these chemicals.
Hydrofluoric acid:
Dimethyl sulphate:
It is colourless and odourless liquid and contact of this chemical on the skin will not
cause any feeling of discomfort or irritation for hours together, but later on there
would be intense pain and irritation on the affected part of the body causing painful
blisters. Make sure that safety aids like goggles, gloves, aprons and safety shoes
are used while handling this product.
e) Compressed gases:
There are several liquefied and natural gases used in chemical industry for
manufacturing purposes. These are conveyed in specially designed cylinders with
unique colour codes for easy identification.
2. carbon dioxide
3. air compressed
4. chlorine
5. Fluorine
6. Helium
7. Hydrogen
8. Mono methylamine
9. Nitrous oxide
10.Nitrogen
11.Oxygen
These gases can be flammable, toxic or corrosive in nature and extreme care should
be taken in their storage and handling.
a) keep the full cylinders always in a vertical position, near a solid support like the
wall of the building, duly fastened to the wall with metal chains, to prevent them
from falling down.
b) The storage place should be located away from the main building and should be
provided with suitable cover, so as to avoid direct sun rays falling on to these
cylinders.
c) The storage block should be adequately ventilated so that the vapour
accumulation is minimum in case of leakage.
d) Keep the cylinders capped and take all precaution to ensure that the needle valve
of the cylinder is not damaged during transportation from one place to another.
f) Use the recommended gas regulators while using the cylinder and never try to
repair the valve of a leaking cylinder. In case of leakage remove the leaking
cylinder to an isolated area in a cool place and let the gas bleed off slowly and in
case it is toxic or corrosive, inform the authorized dealer immediately,
g) Always use cylinder trolleys for shifting the cylinders from one place to another
and never drag or roll the cylinders on hard surface.
h) Do not apply any grease or lubricants on the cylinder nozzles, as gases like
hydrogen oxygen etc. can ignite the organic matter.
HEALTH & SAFETY INFORMATION
Risk Phrases
R10 Flammable
and if swallowed.
inhalation.
with skin.
Cons. Nitric acid Acetic acid, Aniline, Chromic acid, flammable liquids and
gases
Substances which give rise to highly exothermic reactions in contact with other
substances, particularly flammable substances.
Flammable
Extremely flammable liquids have a flash point less than 0C and a boiling point less
than or equal to 35C.
Explosive
Substances which may explode under the effect of flame or heat or which are more
sensitive to shock of friction than dinitrobenzene.
Toxic
Corrosive
Substances which destroy living tissue
Substance which, were they to enter into a environment, would present or might
present an immediate or delayed danger for one or more components of the
environment.
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Validation of QC Chemist
Calculation in QC department
VALIDATION OF INCUBATORS
OPERATION OF CENTRIFUGE
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Anis Mustafa
5 EP5 Communication 01
PURPOSE
SCOPE
THIS PROCEDURE COVERS ALL ACTIVITIES, SERVICES AND PRODUCTS OF THE MPPL.
PROCEDURE
0.0 Scope
This procedure describes the responsibilities and methods for determining aspects,
impacts and their significance of MPPL operations.
1.0 Purpose
This procedure exists to ensure that MPPL significant environmental aspects and impacts are
identified in order that the EMS may address them.
2.0 Responsibilities
- The Director is responsible for ensuring that all managers & supervisors are aware of those
aspects & impacts, which are generated by their work.
3.0 Procedure:
- energy consumption
- resource consumption
The Director determines the aspect and impacts using an input – output process model ,
recording the resources used and products developed .
Having determined these, the Director then determines the impacts of these aspects and
impacts under normal conditions.
3.2 Significance criteria test
Having determined an impact, the Director then uses the criteria test to determine whether or
not an aspect of MPPL operations is environmentally significant. The questions are listed in
order of priority.
5. Does the process consume more than 5% of the company’s energy requirements ?
The significant aspects are rated on from 4.3.1 F1(appendix-1), in order of significance. The
greater the number of yes answers, the more significant the aspect.
The list of significant , ranked impacts is then used as a trigger for setting the objectives and
targets.
2.0 Purpose:
This procedure outlines the responsibilities for supervising the implementation of legislation
relating to the environment .
3.0 Responsibility:
The MR is responsible for maintaining the register of legislation and other requirements, and for
implements any changes triggered by new regulations.
4.0 Procedure:
MPPL operates under a number of different consents imposed by the environment authorities.
The Director holds copies of the COMPANY (ies ) are
These are supported by other acts, statutory regulations. This must be adhered to the
requirements.
All relevant legislation is maintained in a register of legislation and other requirements which is
held in Appendix 2, on Form EPF -R1 (appendix 2) Legal register of key processes ,
legislations, Releases and environmental impacts.
Cross reference:
This procedure is applicable for setting and reviewing the objectives & targets for MPPL
2.0 Purpose:
The aim of this procedure is to define new objectives and targets, and to review and update
objectives and targets . Targets should be quantifiable where possible and relate to the
objectives contains in the environmental policy.
3.0 Responsibility:
4.0 Procedure:
4.1 On an annual basis the operations Director is responsible for co-coordinating the objectives
and targets within the context of:
ü Emerging legislation
1.1 The MR is responsible for ensuring that objectives and quantified targets are set for reducing
waste, and energy use in all production departments.
1.2 The MR is responsible for ensuring that any relevant technical objectives and target are set e.g.
development of new procedures, improved management of environmental impacts.
1.3 The maintenance Supervisor is responsible for ensuring that relevant objectives and targets
are set for maintenance activities.
1.4 The Director is responsible for setting relevant objectives and targets, e.g. looking for
environmentally friendly alternatives for hazardous materials, and establishing a phase – out
schedule.
4.2 In addition to the annual objectives and target setting, objectives and targets may also be
set by managers when necessary , e.g. in case of new legislation or incidents . These must be
communicated to the Director.
4.3 The Director is responsible for consolidating environmental objectives and target provided
by the managers and for ensuring that targets are consistent with the environmental policy and
objectives
4.4 The Director is responsible for presenting the consolidated objectives and targets for
Management review and for communicating approved targets to relevant personnel.
4.5 Director is responsible for rotating an up to date list of objectives and targets together with
any superseded list and corrective actions.
Cross reference:
EP : 4 Communication
1.0 Scope :
2.0 Purpose:
Purpose of this procedure is to establish effective communication between internal & external
customer so that effective Environmental Management System can be established in MPPL.
4.0 Procedure:
EP 5: Waste management
5.0 Scope :
6.0 Purpose:
All waste management activities are conducted in accordance with the requirements of relevant
legislation , regulations and other statutory codes .
Consistently high standards of waste management are observed at all times and in all places
7.2 SUPERVISOR:
8.0 Procedure
Any waste that is produced at MPPL is appropriately stored treated and disposed off some waste ,
such as scrap & other cloths waste( such as copper’ iron gun cloths powder etc.) several key
steps must be incorporated from waste production through to final disposal viz.
All controlled wastes should be identified and recorded in a waste inventory. the inventory
should as a minimum contain details of :
The disposal method employed , i.e. waste carrier and skip type
where possible the inventory should the approximate quantities of each waste produced , per week
cans per month etc.
An example of a waste inventory and a blank pro-forma are included in the appendices of this
procedure .
investigate if the waste requires segregation due to the potential effects of any mixing of wastes.
All waste contractors employed to remove waste materials must be in the list of approved
supplier.
Where waste transfers a repetitive and consists of general waste only an annual transfer note shall
be acceptable.
EP 6 Effluent Monitoring
1. Scope
This procedure defines the responsibilities and actions to ensure that the company complies
with all the requirements of all trade effluent discharge consent.
2. Responsibilities
The Director is responsible for ensuring compliance with trade effluent discharge consents, and
communicating with Waste control ( AMC ) & control of pollution) authority.
Production Manager is responsible for informing the Director of any planned change in process ,
which may result in change to the nature , and composition of a trade effluent.
3. Procedure
3.1 The company must comply with the relevant consent limits at all times .
3.2 Trade effluent must only be discharged from the specified points as detailed on individual
consents.
3.3 Monitoring points at all times without prior notification for the purpose of inspecting ,testing or
sampling effluent.
Cross reference:
1.0 Scope
This procedure describes the responsibilities for, and the action to be taken , for the disposal ,
storage and handling of cloths waste and prevention of pollution.
2.0 Purpose
This procedure exists to ensure the safe and effective handling and storage of cloths waste, in
order to prevent pollution
3.0 Responsibilities
All personnel involved in the disposal , handling and storage of cloths waste, have a responsibility
for following this procedure .
Relevant seniors are responsible for ensuring all personnel under their jurisdiction are fully aware of
this procedure .
4.0 Procedure
cloths waste must be stored in the designated areas prior to use these are :-
4.2.1 all waste cloths waste should be stored in designated storage area having three ( 3’ ) feet
boundary.
4.2..2 Related person should wear long shoes & equipped with long fork for handling the
scrape.
5.0 GENERAL:
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1.0 INTRODUCTION
Pharmaceutical Ltd. recognizes the importance of formalized training programs to
impart training to all employees of various levels.
This “Training Manual” is prepared at the beginning of calendar year to enhance the
effectiveness of training procedure existing in the company.
Training Manual includes the various Types of training and cGMP training schedules
for each department, which identifies the name of the topic, targeted audience &
trainer to conduct the training in all organized manner.
“SOP” training is not included in the Manual, since it will be covered in the change
management system, via a separate SOP. Whenever a new SOP is made (or)
existing SOPs is revised, the respective dept. personnel are trained to make them
familiar with the activities mentioned in the SOPs to make them effective.
2.0 OBJECTIVE
To ensure that all the employees working in Pharmaceutical Ltd., are capable to
perform the duties as per the cGMP, SOPs and procedures and each employee of
Pharmaceutical Ltd., shall improve the relevant knowledge, expertise and to
consolidate the same to discharge their duties effectively. cGMP advises that
appropriate training is required to perform the jobs effectively, which in turn helps in
maintaining the quality system.
3.0 SCOPE
This procedure applies for training of all levels of employees and permanent
workers, working in
Pharmaceutical Ltd.
4.0 RESPONSIBILITIES
Departmental heads are responsible to ensure that the training programs are
conducted as per the schedule in respective departments.
Personnel & administration department is responsible to coordinate with the trainer,
trainee and departmental heads and to monitor the schedules, to organize the
trainings and to keep the training records, department wise and individually.
Trainer should prepare / refer the (training) course material and a questionnaire will
be prepared for each topic in consultation with the departmental heads / seniors.
After completion of each session, trainer should evaluate feedback. If some body
needs retraining it should be organized in coordination with the personnel and
administrative department.
Each trainee should sign in their departmental training log after attending the
training program.
Each employee is responsible to attend the training / retraining as per the schedule
communicated to him.
QA shall verify whether the Training program is carried out as per the schedule
during their audits.
5.0 PROCEDURE
TYPES OF TRAINING:
A training Manual for the next calendar year may be prepared in the month of
March or in advance as appropriate.
Training Manual should be approved by D.G.M – Q.A/Q.C and Authorized by Sr. G.M–
Mfg. prior to issuance and implementation.
A copy of the training Manual shall be issued to personnel dept and Personnel
Department will circulate a copy of the departmental training schedules to the
respective head of departments.
A master copy of training Manual shall be retained at Q.A and controlled copy
circulated to Executive – P & A.
Each new employee from supervisory and above will be given induction training in the
following aspects:
Introduction about the company’s code of conduct and job responsibilities.
Importance of GMP and its compliance, key elements of GMP and GLP (Good
laboratory practices) as appropriate.
An induction program will be arranged by Executive – P & A, where the new person
will be made familiar with the contact people in each dept. and the activities that are
being carried out in those departments.
Each new employee will be given induction training in the following aspects by
Executive – P&A.
Trainer shall write the remark that participants were “trained”, head of department
review shall be carried out and review comments shall be recorded in the same
format.
On job training shall be documented only in the format “Department Training Log”.
Schedules are prepared by head of department for on job training and the same will
be complied to make the employees pertinent to their relevant jobs that they carried
out.
GMP training schedules are prepared as part of training Manual by each dept. Head,
reviewed by Manager – personnel, Approved by D.G.M - Q.A / Q.C, and Authorized by
Sr. G.M - Manufacturing.
The understanding about the topic on which participant was trained will be
assessed by the percentage of marks obtained. The trainee should obtain more
than 80% Marks. The trainee who scores less than 80% will be retrained. Suitable
method of departments can adopted for oral assessments.
Validations.
Regulatory aspects.
6.1 All the employees training details are recorded in Training Card
maintained at Personnel dept. and in the respective “Log Book” for
Training. .
6.2 Training needs shall be identified by the respective department heads, before
preparation of schedules to be included in subsequent calendar year training
Manual.
6.3 All the training related formats are specified in the Annexure. Each training
shall be recorded as in the Annexure as Indicated below.
ANNEXURE-I
(Executive – P & A)
1.
2.
Designation
Title Of Training
Topics Covered
Head - Q.A
Topic: Date :
NAME
: DATE OF
JOINING:
DEPARTMENT
:
DESIGNATION:
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Training course material should be prepared / referred for each training class or
relevant SOP Procedures, Quality Manuals, Quality Policy and instructions ICH
guidelines.
10.1 Production
10.2 Stores
10.3 Engineering
10.5 Personnel
We at our company are dedicated to supply quality products with above mentioned
High Quality Testing Equipment, Highly qualified technical staff, in-house tool room,
checking & packing we are confident of handling your requirements.
Title: Scope of the Quality Section: QM 2.0
Management System
Scope of the Quality Management System for ISO 9001: 2000 Standard Implementation is as
Under :
The Following Clauses of ISO 9001:2000 Standard are not applicable in purview with the Scope
of the Organization:
The organization is manufacturing as per the IP (31431-39-7), USP and B.P. and doesn’t have its
own design hence this clause is not applicable.
The company has established, documented, implemented and maintained a quality management
system to continually improve its effectiveness in accordance with ISO 9001:2000 QMS
standards
The process needed for quality management system and their applications throughout the
organization are identified.
The sequences and interaction of these processes are determined and documented in respective
sections of this manual and in respective documents. Also a Flow chart of interaction of these
processes is prepared.
The criteria and methods needed to ensure that both operation and control of these processes are
effective are determined.
Availability of resources and information necessary to support the operation and monitoring of
these processes are ensured.
These processes are monitored, measured and analyzed.
Action necessary to achieve planned results and continual improvement of these processes are
implemented.
These processes are managed by company in accordance with the requirements of ISO
9001:2000
Nitration process is outsourced and the same is controlled through outgoing and incoming
quality checks and the reports for the same are being maintained.
4.2 DOCUMENTATION
4.2.1 General
The Quality Management System Documentation includes:-
Quality records
ACTIVITY REFERENCE:
PROCEDURE MANUAL- MANAGEMENT REPRESENTATIVE
Title: Management Responsibility Section: QM 5.0
The company commits itself to the development and implementation of quality management
system and continually improves its effectiveness. Regular meetings wherein the importance of
meeting customer requirements and feedback are communicated to employees whenever
necessity arises will achieve this. The administrative personnel are briefed regularly about the
statutory and regulatory requirements in meeting.
The quality policy is established and the text of the Quality Policy is given in 5.3
The Quality Policy is supported by tangible Quality Objectives as given in 5.3
Management Reviews are conducted regularly to ascertain effectiveness of QMS (refer 5.6)
The company ensures that adequate resources are made available to meet customer requirement,
Quality System requirements as well as statutory and regulatory requirements.
The Company has belief in the philosophy that, CUSTOMER is the purpose of its business.
Employees are regularly trained on customer focus. The feedback from customer in terms of
quality, delivery, quality complaints etc. are accorded top priority and their cause and preventive
measures are immediately implemented.
Customer Satisfaction is enhanced through regular meeting with customer/representatives and
fulfilling their targets in terms of quality, delivery lead-time and price expectations. Periodically
customer feedback form is sent to ascertain their needs and expectations.
ACTIVITY REFERENCE:
PROCEDURE MANUAL - MANAGEMENT REPRESENTATIVE AND MARKETING
Considering the needs and expectations of customers and our company’s business strategy, Top
Management has formulated the quality policy:
The quality policy of the company is defined, documented and made known to all the employees
by way of display at prominent places and emphasizing its intents in regular training at all level.
The policy is regularly reviewed in management review meeting for its continuing suitability and
revised as and when necessary.
ACTIVITY REFERENCE:
QUALITY POLICY
5.4.1 QUALITY OBJECTIVES
The quality objective is segmented department wise and the measures to evaluate its
achievements are defined. These objectives are periodically reviewed, updated and MR identifies
actions for implementation.
ACTIVITY REFERENCE:
QUANTIFICATION OF QUALITY OBJECTIVES
The Management Representative ensures that the quality management system is planned with
defined responsibility and authorities, which is documented in Quality Activities. The system is
planned to meet the requirements of clause 4.1 and quality objectives as defined in clause 5.4.1
of the manual.
The integrity of the QMS is ensured by way of review of the system, when the scope of the
system is enhanced or when new product lines are introduced. Quality Manual and Quality
Activities are reviewed for changes as and when required.
Internal audit results are reviewed and the corrective actions are standardized in the quality
system Documents.
Product configuration changes are reviewed and product related documents are updated as
applicable.
Corrective and preventive actions are reviewed and the changes are standardized in appropriate
documents.
The result of internal and external audit is reviewed and appropriate corrective and preventive
actions are initiated.
The organogram chart included in Section 09.0 of this manual shows the relationships between
the respective functions.
All employees are responsible for the quality of their own work and for advising their
responsible Manager or supervisor of any conditions that are adverse to the quality of the work
being produced or adverse to the satisfactory operations of the quality system.
Managers and supervisors are responsible, and have the authority within their defined areas of
control for:
The responsibilities and authorities of the organization chart are described as below:
TOP MANAGEMENT
Responsibility:
a) Overall business development of the organization
b) Financial Management of the organization
c) Recruit executives in Managerial Cadre
d) Formulate quality policy with objectives for the organization
e) Overall responsible for implemented quality management system
Authority:
a) Make key decisions and can supercede decisions taken by others
b) Approve purchase of capital goods
c) Approve the formulated quality management system
d) Final authority in all policies of the company
HOD– OPERATIONS
Responsibility:
a) Maintain Harmonic cultures in the company
b) Liaison and handling prospective customers
c) Recruitment of personnel at works
d) Handling and resolving customer complaints
e) Execution of work orders in time
f) Procurement of all material and services required for the organization
g) Manage supplier development
h) Overall responsible for processes of the organization
i) To implement on-line inspection stage wise
j) To plan production and manpower
k) Impart regular training at shop floor
l) To maintain plant and machinery and general house keeping
m) Co-ordinate with Materials, QC&I and Design department
Authority:
a) Approve all purchases of material and services
b) Approve recruitment personnel at works
c) Sanction commercial transactions at work
d) Approve the formulated quality management system
SUPERVISOR
Responsibility:
a) To Inspect, approve, reject all incoming material
b) To Inspect, approve, reject process activity
c) For final inspection of the product
d) Co-ordination with third party for inspection
e) Co-ordination with production dept. for product quality improvement
f) Co-ordination with MR for QMS implementation
Authority:
a) Approve deviation in production processes
b) To prepare dispatch documents
c) Control of material at shop floor
d) Recruit workers required for production activity
Review of document & data control, making current version available, precludes use of
obsolete documents, identifying nature of change.
Conducting the internal quality audit as per schedule, recording non-conformities, and
verification of effectiveness of corrective action against non-conformities.
Conducting the Management Review Meeting and reporting the finding of IQA to Top
Management.
Customer Feed Back: Meetings, Letters, Emails, Feedback form & proactive actions
5.6.1 General
Top Management with all HODs will conduct Management Review Meeting once in every six
months or as when required. The purpose of the meeting is to ensure that Quality System meets
or exceeds the requirement of ISO 9001 : 2000 standard. In addition it will assess the Quality
System’s continued suitability with respect to achieving company’s Quality Policy and
Objectives and opportunity for improvement in quality management system, quality policy and
quality objectives.
The MR records review inputs in agenda for management review. Review outputs are recorded
in minutes of MRM and communicated to all concerned.
To implement and maintain the quality management system and continually improve its
effectiveness.
The resource needs are identified through activities such as product planning, internal
audit, management reviews and review of quality objectives.
6.2.1 General
The Company ensures that personnel performing work affecting product quality are competent
on the basis of appropriate education, training, skills and experience.
ACTIVITY REFERENCE:
PROCEDURE MANUAL - MANAGEMENT REPRESENTATIVE
6.3 INFRASTRUCTURE
Infrastructure needs are assessed on the basis of the resource requirement and business plan.
The infrastructure such as building and amenities for the operators are provided.
Tools & Tackles, Testing Instruments, Testing facilities are provided on the basis of quality plan.
Need for supporting services such as logistics, computer support, etc. are provided.
The Company plans the requirement of quality and identifies the controls of the process,
inspection and test methods, measurement needs and standards of acceptability, acquisition of
any controls, equipment, etc.
The quality planning also includes the compatibility of product/process, establishment inspection
and test activities, development of newer measurement methods, identification of inspection and
testing requirement, identification and preparation of quality records.
For each product line, such controls are defined in quality plan and are used as a means of
controlling quality. Quality Plan is prepared for final approval of equipment
The Company identifies the requirements specified by customer though work order inputs and
application details provided by customer, delivery schedules desired b customers and feedback
on products supplied.
Requirements not specified by customer, who is required for intended use are identified by
Departmental Head.
Statutory and regulatory requirements related to the products are identified through customer
communication
Any additional requirements related to the products are identified based on the organization’s
experience in supplying products to similar application
The Company ensures to review the requirements related to the product as follows:-
Product specification/application is reviewed during the order processing and any mismatch or
incompatibility is reported to the customer. Order requirements are reviewed and recorded.
Delivery requirements are reviewed and recorded.
During this review, if any product or order requirements are deviating from those previously
expressed, they are resolved
After review it is ensured that confirmation to customer is established to prove ability to meet
customer requirements.
Where the customer requirements are communicated verbally, the customer requirements are
confirmed in review documents as above, prior to acceptance.
When the product requirements are changed, the amendments are reviewed and the changes are
incorporated on all relevant internal documents.
The document changes are made known and communicated to relevant functions.
7.2.2 Customer Communication
Order handling, queries and amendment handling are carried out by Marketing Personnel and
communicated to customers.
Customer feed back and complaints are analyzed and communicated to them.
ACTIVITY REFERENCE:
PROCEDURE MANUAL - MARKETING
EXCLUDED
7.4 PURCHASING
The Quality System Activities ensure that products, Raw material & Packaging Material are
purchased form approved sources only
Any new source of product / make shall approve based of evaluation and/or trial production,
which shall access the ability of the source to meet the company’s quality and delivery
requirements.
The extent of control on the source of supply is based on the product criticality. This is defined in
product quality plan.
The results of supplier performance in terms of adherence to quality and delivery requirements
are monitored. The data is reviewed by HOD Purchase and Top Management and the supplier are
evaluated once in a year.
Records of evaluation, re-evaluation and ratings are maintained.
Where specified by customer or when required by the company, the verification may be
done at supplier’s premises by company or by Customer.
The verification method may include product evaluation, Supplier Quality System Audit.
In such case, purchasing information shall specify the method of verification and sub-sequent
product release.
ACTIVITY REFERENCE:
PROCEDURE MANUAL – PURCHASE
The selection of the Instruments and test equipments is done in such a way that measurement
uncertainty is known and is consistent with accuracy required.
To control, calibrate and maintain inspection, measuring and test equipment to provide evidence
of conformity of product to specified requirements the procedure for calibration and
Maintenance of Instrument is followed.
It is also ensured that monitoring and measurements are carried out and in a manner that is
consistent with the monitoring and measurement requirements.
For this purpose, list of measuring and test equipment is prepared.
To ensure valid results, measuring equipment is Calibrated at specified intervals, or prior to use,
against measurement standards traceable to international or national measurement standards;
where no such standard exists, the basis used for calibration or verification is recorded.
ACTIVITY REFERENCE:
PROCEDURE MANUAL – PRODUCTION & QUALITY CONTROL
8.1 GENERAL
The Company plans and implements the monitoring, measurement, analysis and improvement
process as follows:-
The frequency and duration of an audit is determined based on the volume of activity,
importance of the activity.
The Company ensures that products, which do not conform to product requirements, are
Identified and controlled to avoid inadvertent use or delivery. Activity for non-conforming
products describes the controls involved in segregating non-conforming products, quarantine
areas for non-conforming products, the responsibilities and authorities for evaluation,
notification and disposal of non-conforming products.
The methods of dealing with non-conforming products are :-
Required actions such as rework, to eliminate the detected non-conformity
By taking action to scrap after due care that the scrapped products do not find its way to
the original intended use.
The Company determines the data to be collected, analyzed to demonstrate suitability and
effectiveness of quality management system and to effect continual improvement.
The various data collected are:
Measurement data
Defect data
Supplier performance
Tools and techniques such as graphs, charts, brainstorming etc. are used in the analysis of
data
8.5 IMPROVEMENT
Management review
The Company takes appropriate action to eliminate the potential cause of non-conformities in
order to prevent occurrence. The preventive actions will be appropriate to the effects of non-
conformities.
Activities for preventive action ensures the following requirements are defined :-
1.0 OBJECTIVE : To lay down a procedure for sampling and testing of packing materials.
2.0 RESPONSIBILTY
3.0 ACCOUNTABILITY
4.0 PROCEDURE
4.1 Collect the intact packs of Bottles / ROPP caps / Inner caps or any other primary packing
materials (Annexure-1) from the consignment and transfer to Microbiology laboratory. Carry out
sampling under laminar air flow in MLT area. Seal the containers properly and send it back to
warehouse.
4.2 Prepare 3x100ml of 0.9% of NaCl solution and sterilize by autoclaving ,for sample of each
consignment of packaging material (for small items like caps ,rubber stoppers used for oral
packaging material etc) .
4.3 Open the sample under LAF and submerge 20units in the prepared solution and swirl it for 10
min.
4.4 Transfer the solution in sterile filtration unit & filter the solution with 0.45mm filter membrane of
100ml each.
4.5 Then transfer the filter membrane in sterile SCD agar plate and incubate at 35°C for 72 hrs
,for bacteria,
SDA agar plate, for fungi, and incubate at 20-25°C for 120 hrs and note the observations, for
pathogens submerge the filter membrane in 100ml of sterile SCD Medium and proceed for the
testing of pathogens as per SOP
Formula : No. of cfu in each unit=Number of cfu observed on filter membrane / 6 (unit)
Limit: Bacteria NMT 5 cfu / unit, Fungi NMT 1 cfu / unit and pathogens nil / unit.
4.6 For vials and bottles used for oral packaging material pour 5 ml of sterile solution into
each of the 15 containers with the help of sterile pipette and thoroughly wet the inner walls and
filter the solution in sterile 0.45mm filter membrane.
4.7 Then pour rinsed solution from 5 vials in each three sterile 0.45mm membrane filter assembly
and filter the solution.
4.8 Then transfer the filter membrane in sterile SCD agar plate and incubate at 35°C for 72 hrs ,
(for total bacterial count), SDA agar plate, (for total fungal count) , and incubate at 20-25°C for
72 hrs and note the observations ,for pathogens submerge the filter membrane in 100ml of
sterile SCD Medium and proceed for the testing of pathogens as per G.P No.-
Formula : No. of cfu in each unit =Number of cfu observed on filter membrane / 5 (unit)
4.9 For pathogen testing test for S aureus , Pseudomonas , E. coli and Salmonella as per SOP
No. K/QC/059.
4.10 Limit (for oral packing materials: for bottles or vials): For bacteria: 100 cfu / unit , For
fungi: 10 cfu / unit., pathogens: Nil / unit
4.11 Limit (for injectable packing materials, Like vials, rubber-stoppers etc ): For
bacteria.
NMT 10 cfu / unit , For fungi. <1 cfu / unit , pathogens: Nil / unit
4.11 Foils( Aluminum, PVC / PVDC Films)- Cut (three replicates) inner 20 x 20 cm with sterile
tools and use contact plate (RODAC plate) for sampling
Formula :No. of cfu in 100cm2 =Sum of the number of cfu observed on three RODAC
plates/ 3x 19
5.0 ABBREVIATIONS :
cfu – Colony forming unit
°C – Degree centigrade
ANNEXURE – 1
Rubber plugs, Caps – 20 Nos.
Vials – 20 Nos.
ANNEXURE –II
MEDIA PREPERATIONS:
MEDIA NAME MEDIA BATCH NO. STERILI. CYCLE MEDIA LOT PREPAR
NO.
Dil. ® +ve -ve Cfu / plate +ve -ve control Cfu / plate
control control control
Ist day
2nd day
3rd day
4th day
5th day
Calculation:
MEDIA PREPERATIONS:
Cetrimide agar
S.aureus
Pseudomonas
E. coli
Salmonella
INFERENCE: The above sample complies / does not complies the test.
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Microbiologist / Executive
3.0 ACCOUNTABILITY
4.0 PROCEDURE
4.1 Ensure that the instrument is clean & free from dust.
4.3 Ensure that the marker is connected to either right or left side of the instrument.
4.5 Switch on the power button. The internal light will be flashed ‘ON’ and the digital screen will
show ‘0000’ figure in red. Again pressing this button will turn the power.’ OFF’.
4.7 Now, mark each and every colony one after the other by pressing the tip of the marker.
4.8 The number of colonies will automatically get displayed on the screen can be reset to 0000 by
pressing the RESET button.
4.9 The counting can be done manually by pressing the MANUAL button.
4.10 Switch ‘OFF’ the instrument and put under cover when not required.
Harmonization of format.
6.0 TRAINING:
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2.0 RESPONSIBILTY
Microbiologist / Executive
3.0 ACCOUNTABILITY
4.0 PROCEDURE
4.2 Switch on the main switch of microscope so that bulb will glow.
4.3 Adjust the low power objective, by rotating the revolving nose piece in position.
4.6 Place the slides on the stage, set the objective at the closest position w.r.t slide then slowly lift
the objective with coarse adjusting screw, while observing through the eye piece, till the field
appears clearly ( if the oil immersion objective is in use, place on drop of immersion oil on the
slide before placing it on the stage and then lower the objective just to touch the oil drop.
4.7 Make the field clearer with the help of fine adjustment and then observe the slide.
4.8 Slide can be moved in left, upper and lower direction to observe the complete smear area with
help of slide stage screw and coarse adjustment.
4.9 After completion of observation, remove the slide, clean the objective lens and condenser with
cotton soaked in xylene. Bring the 10x objective in the active position. Lower down the
condenser and place low power objective in position.
6.0 TRAINING:
7.0 DISTRIBUTION:
1.0 OBJECTIVE: To lay down a procedure for handling of out of specification (OOS) result in
Microbiological analysis and monitoring.
2.0 RESPONSIBILITY
3.0 ACCOUNTABILITY
4.0 PROCEDURE
In all the reports the identified reason shall be written on a continuation sheet to the annexure
provided. A copy of the above investigation report shall be maintained with the batch
manufacturing records concerned to increase awareness and for any future reference
4.1.1 If evidence of microbial growth is found, the product to be examined does not comply with
thetest for sterility, unless it can be clearly demonstrated that the test was invalid for causes
unrelated to the product to be examined .The test may be considered invalid only when one or
more of the following conditions are fulfilled:
4.1.1.1The data of the microbiological monitoring of the sterility testing facility shows fault;
4.1.1.2 A review of the testing procedure used during the test in question reveals a fault;
4.1.1.4 After determination of the identity of the microorganisms isolated from the test, the
growth of this species or these species may be ascribed unequivocally to faults with respect to
the material and / or the technique used in conducting the sterility test procedure.
4.1.2 If the test is declared to be invalid it is repeated with the same number of units as in the original
test.
4.1.3 If no evidence of microbial growth is found in the repeat test the product examined complies with
the test for sterility. If microbial growth is found in the repeat test the product examined does not
comply with the test for sterility.
4.2.1 If the microbial counts are found to be more than or equal to the alert limit then
open a deviation report (annexure I) through Q.C. Head to the concerned Production head.
Production personnel shall check the working discipline, supply of air, safety measures etc.
4.2.2 If the count exceeds or reaches the action limit then the urgent notification to the Production
head and Engineering Head through Q.C. Head shall be followed by an investigation for the
same. –
- Supply of air
- Working discipline
- Review of data from the same place and others from the incubated plates
- If any of the plates does not indicate the same then no action is necessary.
- If any of the plates indicates more count then perform additional cleaning, disinfection or
fumigation and retraining to the operator shall be given.
- All activities shall be recorded as per the annexure attached with this SOP.
- More number of samplings (i.e. double the original) shall be preformed at the same location
where the counts observed were beyond or equivalent to the action limit but an additional
relevant parameter of monitoring shall also be performed which shall be incorporated with the
same annexure.
- All the batches manufactured during the said period shall be subjected to the microbial
analysis for MLT / Sterility &BET in order to ensure that the batches manufactured are in
accordance with the relevant finished product specifications. The investigation report shall be
submitted to the Q.C. - Head
4.2.3 If the bio-burden is found out of specified limit in the core areas the identification of the
organism shall be performed.
4.2.4 Stop the production immediately and check all the possible parameters, which can affect bio-
burden of the area.
4.2.5 Check the pressure differential of the area, which must be within the specified limit.
4.2.6 Check the air velocity of LAF /HEPA filters, which must be within the specified limit.
4.3 If the investigation / review of manufacturing activities (e.g. sterilization process, aseptic
filtration, environmental conditions, personnel practices) indicates failure of manufacturing
activities, then the batch shall be considered as failed to comply sterility.
If only the alert is exceeded without finding an undesirable microorganism the release of the
preparation for which this water has been used, has to be taken under hold till the result comes.
In case of the counts touching the action limit then all the batches manufactured shall be re
analyzed by taking 25 grams and making the allowance for the larger size specimen for the
analysis.
In the case of counts crossing or touching the alert limit or action limit in any type of water the
same will be intimated to the production department and maintenance department. If the result
cannot be attributed to the analytical error, sampling error, contamination in the container
sampled then the microorganism detected must be identified / differentiated by taking sample
from all other points.
4.4.1 Adequate sanitization of the system shall be ensured to eliminate the source of contamination
with a rigorous check for the same.
4.4.2 All the investigations made shall be recorded in the annexure III provided with this SOP.
4.5.2 Retest the same material/product but with a sample size of 25 grams by making allowance for
the larger size specimen.
4.5.3 Results for the same shall be intimated to the Q.A. Head for final decision.
6.0 TRAINING:
7.0 DISTRIBUTION:
ANNEXURE –I
Deviation : Parameter:
Requirement :
Results : Signature :
Corrective action in Production Department:
Name : Signature :
Date:
Repeated Sampling :
Parameter:
Result:
Signature :
ANNEXURE - II
Date : Deviation :
Done By : Checked
By :
ANNEXURE –III
INVESTIGATION REPORT FOR FAILURE IN TEST FOR BACTERIAL ENDOTOXIN & M.L.T
Revision No. : 00
REF. SOP NO.: Page No.: 1 of 1
Effective Date:
Sample
BET
Micro tips Test tubes Pipette
LAL reagent
Results of other samples with same conditions tested on the same day.
Result
Test repeated
Date Result
Microbiologist
ACTION TAKEN :
CONCLUSION
Date: Date:
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1.0 OBJECTIVE: To lay down a procedure for Media Fill operation in the sterile dry powder Filling
facility..
2.0 RESPONSIBILTY
3.0 ACCOUNTABILITY
4.0 PROCEDURE
PRE-START UP:
4.0 Ensure that all the equipments, HVAC system, water system and other utility services of the
facility are validated.
4.1 Ensure that the Gamma irradiation certification report of the lactose + SCDM (Soyabean
Casein Digest) mixture (3:1) from BARC and sterility test report (done in-house) is available.
4.2 Ensure that solubility test report and growth promotion/inhibition test report of sterile
4.3 Ensure that solubility test report and growth promotion/inhibition test report of sterile
lactose+SCDM mixture is available. [Solubility should be NLT 1gm/10 ml of WFI].
4.4 Ensure that freshly distilled WFI to be used for filling, is autoclaved and the sample given for
sterility test.
4.5 Ensure that all the contact parts of Dry Powder Filling machine are duly cleaned and
sterilized or sanitized.
4.6 Ensure that the last Environmental Control Reports of the area are conforming to the
acceptance standard.
4.7 Ensure that the Liquid Filling machine is done inside the sterile filling area on the previous day
after autoclaving /sanitization.
4.8 Ensure by manometer readings, that the pressure balancing of the sterile area is as per
requirement.
4.9 Ensure that the cleaning, sanitization and fumigation of the area is done on the previous day.
START UP
4.9 Enter the sterile area as per SOP using gowns sterilized 4days back.
4.12 Check and confirm the temperature and RH of liquid filling room is as per the requirement.
4.13 Assemble the Liquid Filling machine.Ensure that that filling of liquid and liquid can be done
simultaneously.
4.14 Measure the nonviable particulate count of filling cabinet and filling room.
OPERATION
4.15 Bring the autoclaved WFI container near the liquid filling assembly.
4.16 Transfer sterile SCDM liquid from the container in to liquid hopper.
4.17 Transfer sterile dried rubber stoppers (sterilized 4 days back) in to the hopper of stoppering unit.
Send sample for sterility testing simultaneously.
4.18 Put the inlet suction tube of Liquid Filling Assembly into the WFI container.
4.19 Set the Liquid Filling machine for the respective dose.
4.20 Remove the Liquid Filling Assembly and all the contact parts. Disinfect it, clean it and get it
sterilized/sanitised.
4.21 Ensure that all the left over rubber stoppers are given outside the sterile area for destruction.
CLEANING:
4.23 Ensure that all the tools and accessories containers etc. used during media fill are given for
cleaning/sanitization/sterilization.
4.24 Follow the cleaning and sanitization SOP for cleaning of sterile area.
4.25 Do the extra cleaning and sanitization of the floor/walls/machine after media fillrun with 10%
Bacillocide and Lysol solution
ACCEPTANCE CRITERIA:
4.26 Initial validation: During initial validation, it should qualify all three consecutive media fill run i.e.
during each run there should not be growth in more than two vials.
4.27 Revalidation: Only one media fill run in which there should not be any growth in more than two
vials.
4.28 Persons involved in media fill should be medically examined and declared fit within last one year.
4.29 Persons should be trained on general hygiene and current gowning procedure, and the present
health condition should be O.K.
NOTES
In case of any positive growth in any vial during the incubation period.\
4.32 If the isolated organism is other than the house flora, thorough investigation shall be carried out
by Quality Assurance and Production.
4.34 When there is no assignable cause, media fill shall be repeated three times and production
should commence only after all the three runs meet the acceptance criteria.
4.35 When there is assignable cause, after rectification of the cause, repeat the media fill run
once.
4.36 Before and during media fill run no special cleaning shall be carried out.
4.37 Normal production can resume only after minimum one day of environmental monitoring
compliance report.
4.38 Batches filled before the final result of the media fill run shall not be released to the market till the
media fill run passes in case of initial validation.
4.39 The routine environmental monitoring plates shall be kept for 14 days (in case of any growth) to
help in investigation of any positive growth in the media filled vials.
4.40 If for any reason the media fill run is considered invalid vials shall not be incubated.
4.41 Media fill runs can be aborted for the same reason that a product lot would be aborted. All
media filled units filled before an incident that would cause an aborted fill must be incubated.
4.42 During media fill all the Operators, Officers& Maintenance staff who are authorized to do the
sterile filling, supervision and maintenance must be involved in media fill trial.
4.43 The volume of liquid filled must be sufficient to wet all surfaces including the closure and
to facilitate inspection.
4.44 The line must be run at a slower speed than normal production run to give greater
exposure time.
4.45 Total duration of the routine media fill must be the same or more as the longest process
conducted on that line.
4.45 The incubation temperature of the filled containers must be sufficient to promote
microbial growth at 30-35oC. for 336hrs(stored upright) followed by 20-25oC. for 336 hrs.
(stored upside down).
4.47 Personnel that conduct the inspection of incubated media fills must have training on
basic microbiological concepts ,concepts of media fill and examples of contaminated container
showing various stages of growth.
4.48 Filled incubated vials should be optically checked by microbiologist and certified.
4.49 Incubate the vial samples with no growth approximate 5 vials for 14 days with normal house flora
and 5 vials with organisms used for the sterility test growth promotion for 14 days.
4.5 Temp. range for incubation 1st two week at30 to 35o C. (vials stored upright).
ANNEXURE - I
These are the activities which are performed during normal working in the sterile filling area:
5) Picking unstoppered vials from the outfeed back to conveyor for stoppering.
6) Adjustment of separator.
21) Running the machine at a slower speed than actual production run.
22) Covering the working shift usually 12 hours and shift Change over
ANNEXURE - III
ACCEPTANCE CRITERIA FOR MEDIA FILL SIMULATION
MAXIMUM
NO.OF
PERCENTAGE BATCH SIZES
REJECTED
OF FAILURE
VIALS
ACCEPTABLE
AT 95%
CONFIDENCE
LEVEL
62911 62911
1.0 OBJECTIVE : To lay down a procedure for disposing of microbiological culture media.
2.0 RESPONSIBILTY
3.0 ACCOUNTABILITY
4.0 PROCEDURE
4.1 INTRODUCTION:
4.1.1 Bacteriological culture media contains all the nutritive sources which favors rapid growth of
different types of Micro-organisms. Some selective media’s are used for cultivating specific type
of Pathogenic organisms. The micro-organisms grown either on enriched or selective
media’s if not disposed or destroyed in proper way can cause contamination of the
environment which in turns is very hazardous.
4.2 METHOD:
4.2.1 Collect all the used semi solid media’s in plastic bag containing about 50 ml of 2.5% Savlon
solution and close the opening tightly with a tag or rubber-band and transfer the it to the
incinerator.
4.2.2 For liquid media add 2.5% disinfectant (savlon), to the liquid media ,mix it well ,hold for half an
hour and then discard them in a stream of running tap water.
4.2.3 The plates & test tubes are then thoroughly washed with soap water and sterilized by
autoclaving.
4.3.1 INTRODUCTION
GMP require the standard procedure for glassware cleaning used in microbiological
work. This procedure provides Guidelines for proper cleaning of glassware in micro
section.
4.3.2.1Keep all the glassware’s used in microbiology in the cupboard of the tables used by the
Microbiologists to work.
4.3.2.2Do not use these glass wares in chemical
testing.
4.3.2.3Rinse all the glass wares with tap water two to three times.
4.3.2.4Dip all the glass wares in 2% v/v solution (prepared in D.M water)of teepol or liquid soap for at
least 4 hours, for depyrogenation dip it into 2.5% NaOH solution.
4.3.2.6Rinse twice with D.M water followed by rinsing once with W.F.I
4.4 ABBREVIATIONS
W.F.I= Water For Injection, NaOH= Sodium hydroxide, %=Percentage, v/v =Volume by volume
D.M water= De mineralized water
Harmonization of format.
6.0 TRAINING:
7.0 DISTRIBUTION:
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1.0 OBJECTIVE: The objective of this SOP is: to lay down a procedure for preparation of plates
that can be used as settling plates and in various microbiological analysis.
2.0 RESPONSIBILITY
The Microbiologist shall be responsible for preparation of settle plates, their pre-incubation and
related documentation.
3.0 ACCOUNTABILITY:
4.0 PROCEDURE:
4.1 Media with the content of agar can be used for the preparation of settle plates like.
i) Soyabean Casein Digest Agar (SCDA) - For enumerating Bacteria and Fungi (required for
Environmental monitoring and Microbial limit tests.)
ii) Sabarauds Dextrose Agar (SDA) – For estimation of fungi.( Required for Microbial limit
tests. )
4.3 Follow the gowning procedure and enter the M.L.T Room by following SOP.
4.4 Clean the LAF with 70% I.P.A and wait till drying.
4.5 Switch on LAF and UV lamp 15 min. before pouring the plates.
4.6 Open the containers containing sterile petri-dishes (That are previously sterilized by
Autoclaving) and place on the working surface table of L.A.F.
4.7 Open the containers containing sterile petri-dishes and place them on the working table of
LAF.
4.8 Take out the cotton plug of conical flask containing agar medium.
4.9 Sterilize the mouth of the conical flask by flaming it and start pouring about 20-25 ml of
medium to each petri-dish quickly .
4.10 Cover the plates and keep under LAF, till they are solidified.
4.11 After getting solidified, preincubate the plates to the incubator at 30-35°C for 48 hrs to check
any accidental contamination.
4.12 Check each and every plate under colony counter before exposure to the environment for
monitoring.
5.0 TRAINING :
Trainees -- Microbiologists
6.0 DISTRIBUTION:
The available regulatory guidance provides useful definitions and general comments
about degradation studies. However, guidance concerning the scope, timing, and best
practices for degradation studies is very general. Various issues related to stress testing
are addressed in numerous guidance documents but not always in the context of stress
testing. For example, the available guidance discusses issues such as stereo chemical
stability, degradation product identification thresholds, polymorphism and crystal forms,
stability of (parenteral) combination products, and mass balance but does not address
these issues in the context of degradation studies.
The FDA and International Conference on Harmonization (ICH) guidance provides very
little information about strategies and principles for conducting forced degradation
studies, including problems of poorly soluble drugs and exceptionally stable
compounds. In particular, the issue of how much stress is adequate in stress testing is
not addressed specifically. Overstressing a molecule can lead to degradation profiles
that are not representative of real storage conditions and perhaps not relevant to
method development. Therefore, stress-testing conditions should be realistic and not
excessive. In this regard, it is the amount of stress that is important and not necessarily
the extent of degradation. Indeed, some compounds may not degrade significantly after
considerable exposure to stress conditions. Also somewhat unclear is what should be
done at each development phase from both a regulatory and a scientific perspective.
Although FDA does not require degradation studies for an investigational new drug
(IND) application, prelimi-nary degradation studies are useful for the development of the
stability-indicating methods that will be used during the clinical trials.
This article provides a practical interpretation and summary of the available guidance
and some suggestions for best practices for conducting forced degradation studies.
Drug product-The guidance specifies the following for degradation studies of the drug
product at the time of registration:
● challenge methods intended for monitoring the stability of the drug product with the
degraded samples or with the drug substance spiked with a mixture of known
degradation products
● isolation and characterization of significant degradation products, if possible. The
identity and chemical structure, procedure for isolation and purification, mechanism of
formation (including order of reaction), and chemical and physical
properties should be reported, if available. These degradation products include any drug
substance–related compounds such as drug substance degradation products, drug
substance–excipient degradation products, drug substance– extractive degradation
products, and so forth.
● distinction between degradation products that are related to drug substances and
those related to non–drug substances
● photolysis of the drug product in excess of ICH light conditions
Experimental approach
The experimental protocol for degradation studies of new drug substances and drug
products ideally will result in samples that either have been degraded 10% or have been
exposed to an amount of energy that slightly exceeds that supplied under accelerated
storage conditions (e.g., 400C for 6 months).
Forced degradation studies should be conducted whenever a stability-indicating method
is required. Studies may need to be repeated as methods, processes, or formulations
change. Alternatively, methods can be developed with a mixture of the known
degradation products, if available. Forced degradation studies should be performed on
each unique formulation before formal stability studies begin.
Table I shows a general outline for degradation studies of new drug substances and
drug products that was endorsed at the workshop. Sufficient exposure of a drug
substance or drug product is achieved when the drug substance has degraded 10%
from its initial amount or after an exposure in excess of the energy provided by
accelerated storage (e.g., 400C for 6 months), whichever comes first. Application of this
rule of thumb may result in no degradation in some cases. The goal is to generate
degradation in profile that mimics what would be observed in formal stability studies
under ICH conditions.
The duration of storage required at a given temperature can be estimated by making
conservative kinetic assumptions. The energy of activation, Ea, represents the
quantitative relationship between reaction rate and temperature. The range of activation
energies for most drug substances is 12–24 kcal/mole with an average of about 19–20
kcal/mole.
Assuming activation energy of 12 kcal/ mole affords nearly a doubling of the reaction
rate for every 100C increase in temperature. (Recognize that this is a conservative
estimate and that activation energy of 20 kcal/mole affords about a 2.5- to 3-fold
increase in reaction rate for every 10 0C increase in temperature.) With this relationship,
one can calculate the amount of time a sample should be stored at a specified
temperature to achieve the energy equivalent of exposure at accelerated stability
conditions (e.g., 400C for 6 months). A sample of bulk drug substance stored at 80 0C
would be stored for 12 days. Thus, for a compound that degrades with Ea -12
kcal/mole, storage at 800C for 12 days is kinetically equivalent to storage at 40 _C for 6
months.
Suggested equipment and exposure levels for photo stability stress testing are
described in ICH and FDA guidance. Light storage should be in sufficient excess of ICH
light conditions. The guidance states that solution-phase degradation studies of a drug
substance can be carried out in solution or in suspension. The use of inert organic
cosolvents may be indicated in cases in which drug substances are extremely insoluble
but recognize the potential of any organic co solvent to react with the drug substance
under a given set of stress conditions.
For drug products, non–drug substance related peaks should be distinguished from
drug substance related compounds. This process can be accomplished through
comparative analysis of stressed samples of drug substance alone, of drug substance
plus excipients, and of excipients alone. Stressing drug substance and/or excipient
blends instead of final dosage forms may be adequate for the determination of
degradation pathways of a drug product. However, there may be significant differences
in degradation profiles observed between blends and actual drug products.
Consideration also should be given to the possibility of a reaction between the drug
substance and components of a film-coating or capsule shell. For combination
parenteral or aerosol products, the guidance recommends an investigation of the
chemical compatibility or stability of multiple actives that will be combined before
administration. By extension, any combination product should be stressed to examine
for drug–drug interactions potentially manifested by accelerated degradation and/or new
degradation pathways and products. Early investigation can facilitate development of an
optimum formulation as well as stability-indicating methodology. Consideration may be
given to stereochemical stability, mass balance, and crystal-form stability.
Stereoisomers should be treated like any other potential degradation product. Failure to
observe an increase in stereoisomers during forced degradation studies may be
sufficient justification to eliminate testing for stereoisomers during stability studies.
Investigation of the mass balance in degraded samples can reveal the adequacy of the
analytical methods to examine for degradation products. Assessing mass balance is the
process of adding the assay value and levels of degradation products to see how
closely these add to 100% of the initial value, with due consideration of the margin of
analytical error. In cases in which substantial mass loss is observed, efforts to account
for the missing mass should be made such as consideration of response factors or the
formation of highly retained or volatile degradation products. FDA recognizes that mass
balance may not be obtained in all cases and instead emphasizes the thoroughness of
the investigation to determine the specificity of the assay and the pathways of
degradation. The chemical and physical stability of crystal forms, if relevant, should be
investigated. This analysis could include evaluation of stressed solid-state samples for
changes in crystallinity or crystal form.
Method specificity for the active ingredient can be established by peak purity
experiments using hyphenated techniques such as liquid chromatography (LC)–MS,
LC–UV (photodiode array detection), and LC–NMR or orthogonal methods. If needed,
degradation product structure elucidation can be accomplished with hyphenated
techniques (e.g., LC–MS, LC–UV, and LC–NMR) or by synthesis and/or isolation.
Structure elucidation may be postponed until the drug demonstrates safety and efficacy.
A decision to isolate and/or characterize a degradation product should be based
primarily on results obtained from formal stability studies of the drug substance and
drug product whenever possible. The guidance provides the identification thresholds for
degradation products in drug substances and drug products found in formal stability
studies.
Summary
Forced degradation studies of new drug substances and drug products are essential to
help develop and demonstrate specificity of stability-indicating methods and to
determine the degradation pathways and degradation products of the active ingredients.
They also can be useful in the investigation of the chemical and physical stability of
crystal forms, the stereochemical stability of the drug substance alone and in the drug
product and mass-balance issues, and for differentiating drug substance–related
degradation products in formulations. Procedures for the preparation of specific
degradation products needed for method validation often emerge from these studies.
Knowledge gained from these studies can be used to guide formulation development
and improve manufacturing and packaging processes.
For marketing applications, current FDA and ICH guidance recommends inclusion of the
results, including chromatograms of stressed samples, demonstration of the stability-
indicating nature of the analytical procedures, and the degradation pathways of the drug
substance in solution, solid state, and drug product. The structures of significant
degradation products and the associated procedures for their isolation and/or
characterization also are expected to be included in the filing. The experimental protocol
for degradation studies will depend on the active ingredients and formulation involved
because the chemistry of each compound is different. A target of the lesser of 10%
degradation of the active ingredient or exposure to energy in slight excess of
accelerated storage is recommended. A compound may not necessarily degrade under
a given stress condition. No further stressing is advised in these cases.
References
1. FDA, “International Conference on Harmonization: Stability Testing of New Drug
Substances and Products,” Federal Register 59 (183), 48753–48759 (22 September
1994) (ICH Q1A).
2. FDA, “International Conference on Harmonization: Draft Revised Guidance on Q1A(R)
Stability Testing of New Drug Substances and Products,” Federal Register 65 (78),
21446–21453 (21 April 2000) [ICH Q1A(R)]. This revised guideline reached Step 4 of
the ICH process on 8 November 2000. Implementation as of this writing — EU: adopted
by CPMP, November 2000, issued as CPMP/ICH/2736/99.MHW: to be notified. FDA: to
be notified.
3. FDA,“Draft Guidance for Industry, Stability Testing of Drug Substances and Drug
Products,” Federal Register (Notices) 63 (109), 31224–31225 (8 June 1998)
(combination of ICH Q1A-Q1C and Q5C, draft).
4. FDA, “INDs for Phase II and III Studies of Drugs, Including Specified Therapeutic
Biotechnology Derived Products,” Federal Register (Notices) 64 (76), 19543–19544 (21
April 1999).
5. FDA, Center for Drug Evaluation and Research, “Submitting Documentation for the
Stability of Human Drugs and Biologics” (Rockville, MD, February 1987).
6. FDA, “International Conference on Harmonization: Guideline for the Photostability
Testing of New Drug Substances and New Drug Products,” Federal Register 62 (95),
27115–27122 (16 May 1997) (ICH Q1B) and References 1 and 2.
7. FDA, “International Conference on Harmonization: Guideline on Impurities in New Drug
Substances,” Federal Register (Notices) 61 (3), 371–376 (4 January 1996) (ICH Q3A)
and FDA, “International Conference on Harmonization: Draft Revised Guidance on
Impurities in New Drug Substances,” Federal Register (Notices) 65 (140), 45085–
45090 (20 July 2000) [ICH Q3A(R)]. ICH Q3A(R) currently is at Step 3.
8. FDA, “International Conference on Harmonization: Guideline on Impurities in New Drug
Products,” Federal Register (Notices) 62 (96), 27453–274561 (19 May 1997) (ICH Q3B)
and FDA, “International Conference on Harmonization: Draft Revised Guidance on
Impurities in New Drug Products,” Federal Register (Notices) 65 (139), 44791–44797
(19 July 2000) [ICH Q3B(R)]. ICH Q3B(R) currently is at Step 3.
9. A,“Draft Guidance for Industry on Analytical Procedures and Methods Vaidation
Chemistry, Manufacturing, and Controls Documentation,” Federal Register (Notices) 65
(169), 52776–52777 (30 August 2000).
10.FDA, “International Conference on Harmonization: Guideline on the Validation of
Analytical Procedures: Methodology, Availability, Notice,” Federal Register 62 (96),
27463–27467 (19 May 1997).
11.A. Conners, G.L.Amidon, and V.L. Stella, Chemical Stability of Pharmaceuticals (Wiley
and Sons, New York, New York, 2d Ed., 1986), p. 19 and Reference 3.
12 FDA,“International Conference on Harmonization: Guidance on Q6A Specifications: Test
Procedures and Acceptance Criteria for New Drug Substances and New Drug Products:
Chemical Substances,” Federal Register (Notices) 65 (251), 83041–83063 (29
December 2000) (ICH Q6A) and FDA, “International Conference on Harmonization:
Draft Guidance on Q6A Specifications: Test Procedures and Acceptance Criteria for
New Drug Substances and New Drug Products: Chemical Substances,” Federal
Register (Notices) 62 (227), 62889–62910 (25 November 1997) (ICH Q6A). PT
VALIDATION OF ANALYST
1.0 OBJECTIVE
2.0 RESPONSIBILITY
3.0 ACCOUNABILITY :
4.0 PROCEDURE
4.1.1 Samples of known analytical values shall be identified by the Quality Control Manager.
4.1.2 The analytical value(s) of sampler(s) along with acceptable limit(s), AR no., and code no.
shall
be recorded by Quality Control Manager in a register maintained for this purpose.
4.1.3 All the coded samples shall be kept in sealed vials in the refrigerator and shall be
used within
the period specified on the label.
4.1.3 The necessary information required for analysis of coded samples shall be disclosed to the
analyst.
4.2 The analyst shall be undergone validation for either one or more of following areas of
analysis.
4.2 The Analyst validation shall involve use of one or more of the following instruments.
4.2.1 HPLC
4.2.2 UV Spectrophotometer
4.2.3 Auto-apparatus ( Titrator , KF Titrator )
4.2.4 Melting point apparatus
4.2.5 IR Spectrophotometer
4.2.6 The results of analyst shall be checked for cGlp compliance and compared with expected
values.
4.2.7 The capability to perform tests by Analyst shall be considered satisfactory if the results reported
by the Analyst are within the acceptable limits , and documentation as per the
requirement.
4.2.8 The analyst shall be revalidated once in two years.
4.2.9 The details like calculations, chromatograms, strip charts alongwith comments of Quality
Control Manager shall be filed in training file of analysts.
Spectra.
Melting range should be within the range
4.3 ABBREVIATIONS
6.0 TRAINING:
7.0 DISTRIBUTION:
8.0 ANNEXURES:
Nil
Validation of QC Chemist
General concept
Three consecutive validations will be performed to prove that the method is validated.
Whenever a new product is introduced, equipment usage and nature of potential contaminant
will be studied to assess whether it poses a challenging study for cleaning validation.
If the new product represents worst case, study/ identify/develop method of cleaning to be
employed. Simultaneously develop Analytical method for cleaning and validate the same.
Revalidation Policy.
Level of cleaning:
Levels of cleaning during processing depends on:
o Equipment usage (e.g. dedicated or not)
o Stages of manufacturing
o Nature of contaminant (e.g. solubility, toxicity, color etc.)
Our policy is to carry out cleaning after the end of each process, so that the equipment is clean
and ready for the next use.
Elements of cleaning validation:
Cleaning validation study includes:
Cleaning Procedure
o Identification of equipment
o Characterization of products
o Determination of cleaning agents
Analytical method and its validation
Sampling procedure
Establishment of acceptance criteria
Validation protocol
Validation Reports
Cleaning Procedure:
Prior to developing cleaning validation study, evaluate the following:
o Identification of Equipments:
Identify equipments to be cleaned.
Identify difficult to clean areas
Check for ease of dismantling
o Characterization of products:
Study activity/toxicity, solubility of the active substance of current batch and dosage and batch
size of next product to be taken on the equipment.
o Determination of Cleaning Agents:
Identify cleaning agents to be used
Identify number of cleaning cycles
Identify equipments / materials to be used for cleaning.
o Based on above, prepare detailed written cleaning procedures for each equipment.
Analytical Methods and its validation:
In order for the analytical testing of the cleaning validation samples to yield meaningful results,
the analytical methods used should be validated.
Analytical method validation for cleaning should include limit of detection, limit of
quantification, acceptance criteria and rationale for setting the specified limits.
Sampling Procedure:
Sampling plan for validation study should be drawn which includes:
Sampling technique: Type of Sampling methods to be used are,
o Direct surface sampling by swab.
o Rinse water sampling (for equipment cleaning).
o Plate exposure (for area cleaning).
Sampling Locations:
o Two easy to clean and two hard to clean areas should be clearly defined in Protocol.
Sampling Procedure:
o Should mention how many samples are to be taken
Swab samples should be taken separately for chemical and microbiological studies
For each of chemical and microbiological analysis take 2 swabs from easy to clean hard to clean
locations
How the samples are to be taken
Sample Numbering:
o Swab samples should be numbered numerically and sequentially like 01, 02 etc for
identification.
Establishment of Acceptance Criteria:
o Based on the data available calculate acceptance criteria for both Pharmacological dose method
and limiting the level of product to 10 ppm which appear in the following product.
o Of these two, choose the criterion with stringent limits and detectable by analytical
method.
o Microbiological limit is 50 CFU/100 cm2. Per swab
Validation Protocol
Validation protocol defines protocol number.
Protocol defines a validation team that will be responsible for carrying out validation studies.
Validation team comprises of at least one responsible person from production, QC & QA
department.
Responsibilities of team member are:-
o Production – Carrying out cleaning methods & implementing validation protocol.
o Quality Control – Developing analytical method for cleaning, sampling, testing & recording the
results.
o Quality Assurance – Issuing & reviewing of protocol, supervision of validation activities.
Validation protocol given details location, product manufactured, profile of active ingredient,
cleaning agents used, testing equipment to be used, sampling points, sampling procedures, limit
of detection acceptance calculation, surface area, validation report etc.
Responsible persons from Production, QC and QA should formally approve the cleaning
validation protocol.
After approval Validation protocol is issued to QC Department.
QC will perform validation studies in accordance with protocol and record results in validation
report.
Validation Procedure:
After completion of the manufacturing process, workman will clean the equipment.
If the cleaned equipment is listed in the protocol, production person will inform QC Department
to collect samples for testing and QA department for supervision.
QA/QC chemist will first check visually for cleanliness of equipment.
If it observed not clean, instruct for re-cleaning.
If it observed visually cleaned, collect samples separately for both chemical and microbial
analysis (if required) from locations given in the protocol as per sampling procedure.
Samples are carried to QC, where testing of the samples will be done using validated Analytical
method.
Validation Report:
QC will record the results of testing in the protocol.
QC will return the protocol with documented results and attachments like work sheet, graphs,
chromatograms etc. to QA for review.
After completion of documented studies, QA will write conclusions regarding acceptability of
the results and status of procedures considered for validation.
Any recommendations based on the documented results will be mentioned.
References to the procedures used for cleaning, sampling and testing should be mentioned in the
validation report.
All the members of validation team should approve conclusion
In cases where it is unlikely that further batches of the product will be manufactured for a period
of time, it is advisable to generate interim reports on batch-to-batch basis till such time the
cleaning validation study is complete.
If the results of validation of any of the three studies are non-conforming to set limits of
acceptance criteria, QC should inform immediately to QA.
Further manufacturing process on the equipment/in the area should be suspended.
Re-validation should be performed.
Prior to re-validation, cleaning methods/procedures, sampling methods/ procedures and
analytical procedures employed should be re-checked and reviewed.
Re-validation Policy:
Revalidation of validated cleaning procedures will be considered –
o Once in a year, three replicate studies will be performed.
o In case of changes in equipment/process of product
If the new product represents worst-case challenge
1.0 The result of inadequate cleaning procedures is that any of a number of contaminants may be
present in the next batch manufactured on the equipment such as:
o Precursors to the Active Pharmaceutical Ingredient
o By-products and/or degradation products of the Active Pharmaceutical
Ingredient
o The previous product
o Solvents and other materials employed during the manufacturing process.
o Micro-organisms
This is particularly the case where microbial growth may be sustained by the product.
o Cleaning agents themselves and lubricants
2.0 Cleaning techniques to be evaluated
o Manual cleaning
o CIP (Clean-in place)
o COP (clean-out-of-place)
o Semi automatic
o Automatic
o Time considerations
o Number of cleaning cycles.
1.0 OBJECTIVE :
To establish a procedure for swab sampling for validation of test surface to evaluate cleaning efficacy.
2.0 RESPONSIBILITY:
3.0 ACCOUNTABILITY:
4.0 PROCEDURE
FOR CHEMICAL EVALUATION:
4.1 SWAB : A clean room laundered polyurethane foam swab molded into a
polypropylene stick.
TRANSPORT : Capped test tubes made of glass.
CONTAINER
4.2.2 Remove a swab from its protective bag using a clean latex hand glove.
4.2.4 Transfer the swab in transport container (test tube)containing 10ml of sampling solvent and allow the
swab to soak completely.
4.2.5 Take out the swab from sampling solvent and squeeze the tip against inner surface of test tube to
remove excess solvent in such a manner that excess sampling solvent drips inside the test tube.
4.2.6 Hold the stem of swab without touching the head of the swab.
4.2.7 Using one side of moistened swab wipe the test surface of 2” x 2” with 10 firm horizontal strokes as
illustrated in Fig. 1.
4.2.9 Turn the swab over to its other side, wipe the test surface of 2” x 2” with 10 firm vertical strokes as
illustrated in figure no.2.
4.2.10 At the end of each stroke, lift the swab carefully.
4.2.11 Hold the steam of the swab without touching the head of the swab and let the swab drop into the
transport container. Cap the transport container and send for analysis after labeling the same.
4.3.2. Make the swab with (1) sampling point and (2) Date on outer cover.
4.3.3 Put on the clean latex hand gloves and disinfect the same with 70% IPA.
4.3.4 Take out the sterile swab carefully from the outer cover and swab the complete selected area (10
x 10cm).
4.3.5. Replace the swab immediately inside the cover, close if and send for analysis.
4.4. ABBREVIATIONS:
6.0. TRAINING:
Trainer -- Head – Quality Control
Trainees-- Quality Control Chemists
Period -- One day
7.0. DISTRIBUTION:
8.0. ANNEXURES:
Nil.
9.0. REFERENCES
In-house.
1) PROCESS VALIDATION
prospective validation
concurrent validation
prospective validation
2) cleaning validation
3) change control
4) Re- validation
Cleaning validation
Documented evidence to establish that cleaning procedures are removing residues to
predetermined levels of acceptability, taking into consideration factors such as batch size, dosing,
and toxicology and equipment size.
Validation
Action of proving and documenting that any process, procedure or method actually and
consistently leads to the expected results.
Process validation
Documented evidence which provides a high degree of assurance that a specific process will
consistently result in a product that meets its predetermined specifications and quality
characteristics
Concurrent validation
Validation carried out during routine production of products intended for sale.
Prospective validation
Validation carried out during the development stage on the basis of a risk analysis of the
production process, which is broken down into individual steps; these are then evaluated on the
basis of past experience to determine whether they may lead to critical situations.
Retrospective validation
Involves the evaluation of past experience of production on the condition that composition,
procedures, and equipment remain unchanged.
- The sources of data for this validation may include batch documents, process control chart,
maintaince logbook, records of personnel change process capability studies, fp data and stability
results.
Validation report (VR)
A document in which the records, results and evaluation of a completed validation programme
are assembled and summarized. It may also contain proposals for the improvement of processes
and/or equipment.
Approaches to validation
5.1.1 There are two basic approaches to validation—one based on evidence obtained through
testing (prospective and concurrent validation), and one based on the analysis of accumulated
(historical) data (retrospective validation). Whenever possible, prospective validation is
preferred. Retrospective validation is no longer encouraged and is, in any case, not applicable to
the manufacturing of sterile products.
5.1.2 Both prospective and concurrent validation, may include:
• extensive product testing, which may involve extensive sample testing (with the estimation of
confidence limits for individual results) and the demonstration of intra- and inter-batch
homogeneity;
• simulation process trials;
• challenge/worst case tests, which determine the robustness of the process; and
• control of process parameters being monitored during normal production runs to obtain
additional information on the reliability of the process.
5.2 Scope of validation
5.2.1 There should be an appropriate and sufficient system including organizational structure and
documentation infrastructure, sufficient personnel and financial resources to perform validation
tasks in a timely manner. Management and persons responsible for quality assurance should be
involved.
5.2.2 Personnel with appropriate qualifications and experience should be responsible for
performing validation. They should represent different departments depending on the validation
work to be performed.
5.2.3 There should be proper preparation and planning before validation is performed. There
should be a specific programmed for validation activities.
5.2.4 Validation should be performed in a structured way according to the documented
procedures and protocols.
5.2.5 Validation should be performed:
— for new premises, equipment, utilities and systems, and processes and procedures;
— at periodic intervals; and
— when major changes have been made. (Periodic revalidation or periodic requalification may
be substituted, where appropriate, with periodic evaluation of data and information to establish
whether requalification or revalidation is required.)
5.2.6 Validation should be performed in accordance with written protocols. A written report on
the outcome of the validation should be produced.
5.2.7 Validation should be done over a period of time, e.g. at least three consecutive batches (full
production scale) should be validated, to demonstrate consistency. Worst case situations should
be considered.
5.2.8 There should be a clear distinction between in-process controls and validation. In-process
tests are performed during the manufacture of each batch according to specifications and
methods devised during the development phase. Their objective is to monitor the process
continuously.
5.2.9 When a new manufacturing formula or method is adopted, steps should be taken to
demonstrate its suitability for routine processing. The defined process, using the materials and
equipment specified, should be shown to result in the consistent yield of a product of the
required quality.
5.2.10 Manufacturers should identify what validation work is needed to prove that critical
aspects of their operations are appropriately controlled. Significant changes to the facilities or the
equipment, and processes that may affect the quality of the product should be validated. A risk
assessment approach should be used to determine the scope and extent of validation required.
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method will be developed and validated for use to analyze samples during the early
development of an active pharmaceutical ingredient (API) or drug product. As drug
development progresses from phase 1 to commercialization, the analytical method
will follow a similar progression. The fi nal method will be validated for its intended
use for the market image drug product and transferred to the quality control laboratory
for the launch of the drug product. However, if there are any changes in the
manufacturing process that have the potential to change the analytical profi le of the
drug substance and drug product, this validated method may need to be revalidated
to ensure that it is still suitable to analyze the API or drug product for its intended
purpose.
General Concepts
The discussion of the validation of analytical procedures is directed to the four most
common types of analytical procedure:
Identification tests
Quantitative tests for impurities content
Limit tests for the control of impurities
Quantitative tests of the active moiety in samples of drug substance or drug product or
other selected components in the drug product.
Typical validation characteristics which should be considered are:
Accuracy
Precision
Specificity
Quantitation Limit
Linearity and Range
Robustness
Method Validation Parameter for the assay of Mebendazole:
Linearity: Mebendazole to be analyzed as per proposed method. The results obtain is used to
statistically evaluate for coefficient of determination (r 2), standard error of estimate and y
intercept.
Precision: Precision of the chemical method is ascertained by carrying out the analysis as per the
procedure and as per normal weight taken for analysis. Repeat the analysis five times.
Calculate the % assay, mean assay, % Deviation and % relative standard deviation and
%RSD.
Accuracy: Accuracy of the method is ascertained by standard addition method at 3 levels.
Standard quantity equivalent to 80%, 100% and 120% is to be added in sample.
Method Validation Parameter for residual solvent by GC for Mebendazole:
Specificity: Resolution of the analyte peak from the nearest peak: Solution of each of the analyte
was injected separately and their retention time is noted. The standard working solution
containing a mixture of the component being analyze is also injected and each of
analyte peaks is check for its resolution from the nearest.
Precision:
Repeatability: Six replicate injections of standard solution for system precision should
analyze as per the proposed method and from the chromatograms obtained the
percentage % RSD is calculated.
Intermediate precision: The purpose of this test is to demonstrate the intermediate
precision of the method when method is executed by a different analyst and on different
day. Results obtained will be compared.
Linearity and Range: Solution of analyte solvent, having different concentration
should make separate from L.O.Q. concentration, which is 50% to 150%. The result
obtained is statistically evaluated for coefficient of determination (r 2), standard error of
estimate and y intercept.
LOD & LOQ:
The limit of Detection (L.O.D.) was calculated as per below equation:
LOD = 3.3 X SD
Slope
METHOD REVALIDATION
There are various circumstances under which a method needs to be revalidated.
Some of the common situations are described below:
1. During the optimization of the drug substance synthetic process, signifi cant
changes were introduced into the process. To ensure that the analytical method
will still be able to analyze the potentially different profi le of the API, revalidation
may be necessary.
2. If a new impurity is found that makes the method defi cient in its specifi city,
this method will need to be modifi ed or redeveloped and revalidated to ensure
that it will be able to perform its intended function.
3. A change in the excipient composition may change the product impurity
profi le. This change may make the method defi cient in its specifi city for the
assay or impurity tests and may require redevelopment and revalidation.
4. Changes in equipment or suppliers of critical supplies of the API or fi nal drug
product will have the potential to change their degradation profi le and may
require the method to be redeveloped and revalidated.
TABLE OF CONTENTS
-- Table of content 1
1.0 Objective 2
2.0 Scope 2
3.0 Responsibility 2
Conclusion 11
1.0 OBJECTIVE:
To perform long term stability study on production batches to evaluate and justify
the recommended shelf life. Storage conditions and desired packing.
2.0 SCOPE:
Long term stability studies: A minimum of one batch per year for long term
stability study and any batch where a process change is made which will affect the
stability and quality of the product.
3.0 RESPONSIBILITY:
The recommended shelf life, storage conditions, and desired packaging should be
accompanied by the results of the testing.
Batches details:
1 DESCRIPTION:
2 IDENTIFICATION (IR)
3 ASSAY
4 MELTING POINT
5 LOSS ON DRYING
6 CLARITY
7 RESIDUE ON IGNITION
All of the analytical methods used for carrying out the above mentioned tests are
the same as those described in European Pharmacopoeia – Annexure-I.
Temperature: 25°C 2° C
Relative 60% 5%
humidity:
3 Months
6 Months
9 Months
12 Months
18 Months
24 Months
36 Months
48 Months
60 Months
The following Test methods were applied to verify product integrity during the
time period tested as per Specification.
DESCRIPTION
DENTIFICATION (IR)
LOSS ON DRYING
MELTING POINT :
CLARITY :
RESIDUE ON IGNITION:
ASSAY :
o Results of tests
o Conclusion:
Annexure-II
Product name :
Batch No :
Manufacturing date :
Batch size :
Sr. Test Limit Analysis (after months)
No. s
0 3 6 9 12
1 DESCRIPTION:
2 IDENTIFICATION (IR)
CHROMATOGRA-PHIC .
3
PURITY
4 MELTING POINT
5 LOSS ON DRYING
6 CLARITY
7 RESIDUE ON IGNITION
Sr. No. Test Limits Analysis (after months)
0 3 6 9 12
8. ASSAY
Results of Long term testing at Temperature 25°C 2° C & Relative
Humidity 60% 5%
Product name :
Batch No :
Manufacturing date :
Batch size :
1 DESCRIPTION:
2 IDENTIFICATION (IR)
CHROMATOGRA-PHIC
3
PURITY
4 MELTING POINT
5 LOSS ON DRYING
6 CLARITY
7 RESIDUE ON IGNITION
8. ASSAY
Conclusion:
One of the biggest computer validation challenges facing pharmaceutical manufacturers is the
large corporate system. This book provides practical information and advice on good IT practice
and validation principles. Written by experts, it includes case studies on EDMSs, EAM systems,
LIMSs, and MRP II systems. Topics include paper- and peopleless plants, GxP compliance,
integrating manufacturing systems,electronic signatures, validating asset management systems,
enterprise/manufacturing planning systems, lab information management systems, and Local &
Wide Area Networks, compliance for IT Infrastructure, IT system maintenance and support, and
auditing suppliers, software Integrators, and hardware manufacturers.
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s:
There are many reasons for the need to validate analytical procedures. Among them
are regulatory requirements, good science, and quality control requirements. The
Code of Federal Regulations (CFR) 311.165c explicitly states that “ the accuracy,
sensitivity, specifi city, and reproducibility of test methods employed by the fi rm shall
good science to demonstrate that the analytical method used had demonstrated
quality control unit would defi nitely want to ensure that the analytical methods that
the department uses to release its products are properly validated for its intended
General Concepts
Validation is the act of demonstrating and documenting a procedure that operates effectively.
The discussion of the validation of analytical procedures is directed to the four most common
types of analytical procedure:
Identification tests
Quantitative tests of the active moiety in samples of drug substance or drug product or other
selected components in the drug product.
Precision
Specificity
Quantitation Limit
Robustness
Linearity: Mebendazole to be analyzed as per proposed method. The results obtain is used to statistically
evaluate for coefficient of determination (r2), standard error of estimate and y intercept.
Precision: Precision of the chemical method is ascertained by carrying out the analysis as per the
procedure and as per normal weight taken for analysis. Repeat the analysis five times.
Calculate the % assay, mean assay, % Deviation and % relative standard deviation and %RSD.
Accuracy: Accuracy of the method is ascertained by standard addition method at 3 levels. Standard
quantity equivalent to 80%, 100% and 120% is to be added in sample.
Specificity: Resolution of the analyte peak from the nearest peak: Solution of each of the analyte was
injected separately and their retention time is noted. The standard working solution containing a
mixture of the component being analyze is also injected and each of analyte peaks is check for
its resolution from the nearest.
Precision:
Repeatability: Six replicate injections of standard solution for system precision should analyze
as per the proposed method and from the chromatograms obtained the percentage % RSD is
calculated.
Intermediate precision: The purpose of this test is to demonstrate the intermediate precision
of the method when method is executed by a different analyst and on different day. Results
obtained will be compared.
Linearity and Range: Solution of analyte solvent, having different concentration should make
separate from L.O.Q. concentration, which is 50% to 150%. The result obtained is statistically
evaluated for coefficient of determination (r2), standard error of estimate and y intercept.
LOD = 3.3 X SD
Slope
LOQ = 10 X SD
Slope
Accuracy / % Recovery (By Standard Addition Method): Accuracy of the method was
ascertained by standard addition method at 3 levels.
Standard solution quantity equivalent to 50%, 100% and 150% are added in sample.
The solutions amount is analyzed by the proposed method and chromatogram obtained.
The amount recover by the method is compared to the amount added. Percent deviation is
calculated at each levels and a grand average across all the levels are also calculated.
Robustness:
The evaluation of robustness should be considered during the development phase and
depends on the type of procedure under study. It should show the reliability of an analysis with
respect to deliberate variations in method parameters.
If measurements are susceptible to variation in analytical conditions, the analytical condition
should be suitably controlled or a precautionary statement should be included in the procedure.
One consequence of the robustness should be that a series of system suitability parameters
(e.g. resolution test) is established to ensure that the validity of the analytical procedure is
maintained whenever used.
detailed validation report that will conclude the success or failure of the validation
exercise. Depending on the company ’ s strategy a summary of the validation data may also be
generated. Successful execution of the validation will lead to a final analytical procedure that
can be used by the laboratory to support future analytical work for the drug substance or drug
product.
METHOD REVALIDATION
1. During the optimization of the drug substance synthetic process, signifi cant
changes were introduced into the process. To ensure that the analytical method
will still be able to analyze the potentially different profi le of the API, revalidation
may be necessary.
2. If a new impurity is found that makes the method defi cient in its specifi city,
profi le. This change may make the method defi cient in its specifi city for the
product will have the potential to change their degradation profi le and may
1) PROCESS VALIDATION
prospective validation
concurrent validation
prospective validation
2) cleaning validation
3) change control
4) Re- validation
Cleaning validation
Documented evidence to establish that cleaning procedures are removing residues to
predetermined levels of acceptability, taking into consideration factors such as batch size, dosing,
and toxicology and equipment size.
Validation
Action of proving and documenting that any process, procedure or method actually and
consistently leads to the expected results.
Process validation
Documented evidence which provides a high degree of assurance that a specific process will
consistently result in a product that meets its predetermined specifications and quality
characteristics
Concurrent validation
Validation carried out during routine production of products intended for sale.
Prospective validation
Validation carried out during the development stage on the basis of a risk analysis of the
production process, which is broken down into individual steps; these are then evaluated on the
basis of past experience to determine whether they may lead to critical situations.
Retrospective validation
Involves the evaluation of past experience of production on the condition that composition,
procedures, and equipment remain unchanged.
- The sources of data for this validation may include batch documents, process control chart,
maintaince logbook, records of personnel change process capability studies, fp data and stability
results.
Validation report (VR)
A document in which the records, results and evaluation of a completed validation programme
are assembled and summarized. It may also contain proposals for the improvement of processes
and/or equipment.
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General concept
Three consecutive validations will be performed to prove that the method is validated.
Whenever a new product is introduced, equipment usage and nature of potential contaminant
will be studied to assess whether it poses a challenging study for cleaning validation.
If the new product represents worst case, study/ identify/develop method of cleaning to be
employed. Simultaneously develop Analytical method for cleaning and validate the same.
Revalidation Policy.
Level of cleaning:
Levels of cleaning during processing depends on:
o Equipment usage (e.g. dedicated or not)
o Stages of manufacturing
o Nature of contaminant (e.g. solubility, toxicity, color etc.)
Our policy is to carry out cleaning after the end of each process, so that the equipment is clean
and ready for the next use.
Elements of cleaning validation:
Cleaning validation study includes:
Cleaning Procedure
o Identification of equipment
o Characterization of products
o Determination of cleaning agents
Analytical method and its validation
Sampling procedure
Establishment of acceptance criteria
Validation protocol
Validation Reports
Cleaning Procedure:
Prior to developing cleaning validation study, evaluate the following:
o Identification of Equipments:
Identify equipments to be cleaned.
Identify difficult to clean areas
Check for ease of dismantling
o Characterization of products:
Study activity/toxicity, solubility of the active substance of current batch and dosage and batch
size of next product to be taken on the equipment.
o Determination of Cleaning Agents:
Identify cleaning agents to be used
Identify number of cleaning cycles
Identify equipments / materials to be used for cleaning.
o Based on above, prepare detailed written cleaning procedures for each equipment.
Analytical Methods and its validation:
In order for the analytical testing of the cleaning validation samples to yield meaningful results,
the analytical methods used should be validated.
Analytical method validation for cleaning should include limit of detection, limit of
quantification, acceptance criteria and rationale for setting the specified limits.
Sampling Procedure:
Sampling plan for validation study should be drawn which includes:
Sampling technique: Type of Sampling methods to be used are,
o Direct surface sampling by swab.
o Rinse water sampling (for equipment cleaning).
o Plate exposure (for area cleaning).
Sampling Locations:
o Two easy to clean and two hard to clean areas should be clearly defined in Protocol.
Sampling Procedure:
o Should mention how many samples are to be taken
Swab samples should be taken separately for chemical and microbiological studies
For each of chemical and microbiological analysis take 2 swabs from easy to clean hard to clean
locations
How the samples are to be taken
Sample Numbering:
o Swab samples should be numbered numerically and sequentially like 01, 02 etc for
identification.
Establishment of Acceptance Criteria:
o Based on the data available calculate acceptance criteria for both Pharmacological dose method
and limiting the level of product to 10 ppm which appear in the following product.
o Of these two, choose the criterion with stringent limits and detectable by analytical
method.
o Microbiological limit is 50 CFU/100 cm2. Per swab
Validation Protocol
Validation protocol defines protocol number.
Protocol defines a validation team that will be responsible for carrying out validation studies.
Validation team comprises of at least one responsible person from production, QC & QA
department.
Responsibilities of team member are:-
o Production – Carrying out cleaning methods & implementing validation protocol.
o Quality Control – Developing analytical method for cleaning, sampling, testing & recording the
results.
o Quality Assurance – Issuing & reviewing of protocol, supervision of validation activities.
Validation protocol given details location, product manufactured, profile of active ingredient,
cleaning agents used, testing equipment to be used, sampling points, sampling procedures, limit
of detection acceptance calculation, surface area, validation report etc.
Responsible persons from Production, QC and QA should formally approve the cleaning
validation protocol.
After approval Validation protocol is issued to QC Department.
QC will perform validation studies in accordance with protocol and record results in validation
report.
Validation Procedure:
After completion of the manufacturing process, workman will clean the equipment.
If the cleaned equipment is listed in the protocol, production person will inform QC Department
to collect samples for testing and QA department for supervision.
QA/QC chemist will first check visually for cleanliness of equipment.
If it observed not clean, instruct for re-cleaning.
If it observed visually cleaned, collect samples separately for both chemical and microbial
analysis (if required) from locations given in the protocol as per sampling procedure.
Samples are carried to QC, where testing of the samples will be done using validated Analytical
method.
Validation Report:
QC will record the results of testing in the protocol.
QC will return the protocol with documented results and attachments like work sheet, graphs,
chromatograms etc. to QA for review.
After completion of documented studies, QA will write conclusions regarding acceptability of
the results and status of procedures considered for validation.
Any recommendations based on the documented results will be mentioned.
References to the procedures used for cleaning, sampling and testing should be mentioned in the
validation report.
All the members of validation team should approve conclusion
In cases where it is unlikely that further batches of the product will be manufactured for a period
of time, it is advisable to generate interim reports on batch-to-batch basis till such time the
cleaning validation study is complete.
If the results of validation of any of the three studies are non-conforming to set limits of
acceptance criteria, QC should inform immediately to QA.
Further manufacturing process on the equipment/in the area should be suspended.
Re-validation should be performed.
Prior to re-validation, cleaning methods/procedures, sampling methods/ procedures and
analytical procedures employed should be re-checked and reviewed.
Re-validation Policy:
Revalidation of validated cleaning procedures will be considered –
o Once in a year, three replicate studies will be performed.
o In case of changes in equipment/process of product
If the new product represents worst-case challenge
1.0 The result of inadequate cleaning procedures is that any of a number of contaminants may be
present in the next batch manufactured on the equipment such as:
o Precursors to the Active Pharmaceutical Ingredient
o By-products and/or degradation products of the Active Pharmaceutical
Ingredient
o The previous product
o Solvents and other materials employed during the manufacturing process.
o Micro-organisms
This is particularly the case where microbial growth may be sustained by the product.
o Cleaning agents themselves and lubricants
2.0 Cleaning techniques to be evaluated
o Manual cleaning
o CIP (Clean-in place)
o COP (clean-out-of-place)
o Semi automatic
o Automatic
o Time considerations
o Number of cleaning cycles.
You might also like:
Validation of QC Chemist
Analytical Method Validation
SWAB SAMPLING FOR CLEANING VALIDATION
VALIDATION OF INCUBATORS
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1. GENERAL:
1.5 Maintenance
1.6 Surroundings
2. PERSONNEL:
2.1 : Or
2.2 : Qu
2.3 : Pro
Me
Fo
Fo
2.4 : Pe
Fo
Fo
2.5 : Fa
Fo
Fo
Wa
2.6 : Pe
Sh
WC
Lo
Ca
2.7 : Jo
Re
2.8 : Tra
2.9 : En
2.10 : Dr
2.11 : Sy
2.12 : Pe
c) : Intermediate ____________
3.18 : EQUIPMENT
4 MANUFACTURING CONTROL:
.
4.1 : Identification level for material under processing
4.2 : Written Manufacturing Procedure
5. TSE QUESTIONNAIRE:
5.1 : Have you obtained the COS Certificate from EDQM for the
Material you are supplying to us? If yes please attach the copy.
5.2 : Is any of the starting material used in the manufacturing from
Animal Origin. If yes, Please ensure to obtain the TSE free Certificate
from your supplier.
5.3 : Is the Production Line dedicated?
5.5 : Is your batch COA contains the TSE / BSE free Declaration. If no submit an
undertaking to send the batch wise TSE / BSE free Declaration for all
supplies to us?
6. RECORD KEEPING :
8. QUALITY CONROL:
CRITICAL
MAJOR
OTHER
CONCLUSION
VALIDATION OF INCUBATORS
1.0 OBJECTIVE
Microbiologist / Executive.
3.0 ACCOUNTABILITY
4.0 PROCEDURE
4.1.3 The incubator is set for desired temperature with the knob on control panel of
incubator
4.1.4 Wait till the temperature reaches at set point & note down the temp. displayed on
the small screen of incubator and compare this temp. with standard thermometer
kept near the RTD probe.Likewise check the temperature after every 15 minutes up
to one hour and note down the readings on the format.
4.1.5 Record any difference between the displayed temp. & temp. showed by standard
thermometer and set the incubator accordingly
4.2.1 Keep all the apparatus wrapped thrice with aluminum foil inside DHS
as locations shown
in the diagram.
4.2.2 Keep the Spore loaded strips (having spore of B subilis) & Endotoxin
indicator indicators
having 10,000EU/vial in DHS(hot air oven) kept in 30ml vial wrapped thrice with
aluminum foil at locations shown in the diagram keep one vial unbaked as PPC.
Set the hot air oven at 250C ,wait till the temperature reaches upto the set
temperature.
4.2.3 After reaching the set temperature, note the time & temperature, hold for one hour
4.2.4 After completion of depyrogenation cycle ,switch off the power supply
and take out
4.3.1 Take out the baked endotoxin loaded vial from the DHS.
4.3.2 Reconstitute 1ml of LRW in the baked vial and transfer 100l of
sample to the
4.4.1 Transfer (spore loaded) strip from backed vials and are inoculated in100ml
sterile SCD
media and incubate at 30 – 350C for 7 days to observe for any turbidity, if any,
report to Manager QC..
Harmonization of format.
6.0 TRAINING:
7.0 DISTRIBUTION:
8.0 ANNEXURES:
9.0 REFERENCES:
ANNEXURE-1
INSTRUMENT VALIDATION
1 2 3 4 5 6
INITIAL C C
TEMP
C C C C C C C C C
AFTER 15 C C
MIN
C C C C C C C C C
AFTER 30 C C
MIN
C C C C C C C C C
AFTER 45 C C
MIN
C C C C C C C C C
AFTER 60 C C
MIN
C C C C C C C C C
Specified limits.
DATE: DATE:
DUE ON DATE
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TABLE OF CONTENTS
-- Table of content 1
1.0 Objective 2
2.0 Scope 2
3.0 Responsibility 2
1.0 OBJECTIVE:
To perform long term stability study on production batches to evaluate and justify
the recommended shelf life. Storage conditions and desired packing.
2.0 SCOPE:
Long term stability studies: A minimum of one batch per year for long term
stability study and any batch where a process change is made which will affect the
stability and quality of the product.
3.0 RESPONSIBILITY:
The recommended shelf life, storage conditions, and desired packaging should be
accompanied by the results of the testing.
Batches details:
1 DESCRIPTION:
2 IDENTIFICATION (IR)
3 ASSAY
4 MELTING POINT
5 LOSS ON DRYING
6 CLARITY
7 RESIDUE ON IGNITION
All of the analytical methods used for carrying out the above mentioned tests are
the same as those described in European Pharmacopoeia – Annexure-I.
Temperature: 25°C 2° C
Relative 60% 5%
humidity:
3 Months
6 Months
9 Months
12 Months
18 Months
24 Months
36 Months
48 Months
60 Months
ANALYTICAL TEST PROCEDURES
The following Test methods were applied to verify product integrity during the
time period tested as per Specification.
DESCRIPTION
DENTIFICATION (IR)
LOSS ON DRYING
MELTING POINT :
CLARITY :
RESIDUE ON IGNITION:
ASSAY :
o Results of tests
o Conclusion:
Annexure-II
Product name :
Batch No :
Manufacturing date :
Batch size :
1 DESCRIPTION:
2 IDENTIFICATION (IR)
CHROMATOGRA-PHIC .
3
PURITY
4 MELTING POINT
5 LOSS ON DRYING
6 CLARITY
7 RESIDUE ON IGNITION
Sr. No. Test Limits Analysis (after months)
0 3 6 9 12
8. ASSAY
Results of Long term testing at Temperature 25°C 2° C & Relative
Humidity 60% 5%
Product name :
Batch No :
Manufacturing date :
Batch size :
1 DESCRIPTION:
2 IDENTIFICATION (IR)
CHROMATOGRA-PHIC
3
PURITY
4 MELTING POINT
5 LOSS ON DRYING
6 CLARITY
7 RESIDUE ON IGNITION
8. ASSAY
Conclusion:
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5.0 Procedure :
After sampling of raw materials / finished products, keep used tools in poly bag.
If required use suitable solvent for the cleaning of tools, then thoroughly wash with water.
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Purpose : To provide instructions for selection, standardization and storage of reference and working
standards.
Objective: To provide documented procedures for selection, standardization and storage of reference and
working standard
cope : This procedure is applicable for selection, standardization and storage of reference and working
standards in QC Department.
4.0 Responsibility :
Primary : QC Chemist
5.0 Procedure :
Store them in suitable container (e.g. desiccators) moisture free atmosphere under
temperature-controlled condition.
The selected raw material’s working standards having high purity or negligible impurities and
low moisture content.
For solvent working standard shall be used from any reputed external manufacturer, pure
grade materials with certificate of analysis.
Selected raw material working standard shall be re-tested and note down the observations in
respective worksheet.
Selected intermediate and finished product working standards can be prepared by repeated
crystallization in suitable solvents.
These working standard having high purity or negligible impurities and low moisture / loss on
drying content.
R&D and QA should authorize procedures for the preparation of intermediate and finished
products working standard.
Working standards should be standardized at regular intervals against the reference standards
or previous working standards.
Loss On Drying / Moisture content and Assay tests parameters taken for standardization.
Note down the observations in respective worksheet. And maintained relevant graphs in
respective working standard file.
Information on status label includes name of material, working standard batch number, purity,
LOD / moisture content, date of preparation, valid up to etc.
(Approx – 2 to 10 gm each) and filled appropriate vials / bottles (minimum 2 to 4). Vials should
be cleaned and dried.
Each vial/bottle is to be used for three months from the date of opening and then discarded.
Open on date shall be mentioned on the label.
The other information of the label includes name of material, open on date, purity, LOD/Water
value, and use before date and valid up to.
The bottles are then sealed and kept in desiccators at the prescribed storage condition for the
future use.
The last bottle is kept for use as a reference std. during next standardization. Reference
standard to be re-validated every year.
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Purpose : To provide instructions for the Preparation, Standardization and Shelf-life of Volumetric solutions,
Standard reagent solution and Indicators.
Objective : To provide documented procedures for Preparation, Standardization and Shelf life of Volumetric
solutions, Standard reagent solution and Indicators
cope : This procedure is applicable for preparation, standardization and shelf life of volumetric
solutions, standard reagent solution and indicators in QC Department.
4.0 Responsibility :
Primary : QC Chemist
5.0 Procedure :
Volumetric Solutions
Volumetric solutions shall be prepared by accurately weighing a specified quantity & dissolving
it to produce a specific volume.
Volumetric solutions shall be standardized before use; shelf life of this solution is one month
from the date of preparation. Discard the solution after one month or if observed hazy.
Note: Strength of the volumetric solutions should not deviate more than 10% of the prescribed
strength.
All volumetric solutions should be standardized in triplicate set & % RSD should not be more
than 0.20 %. Average value shall be reported.
All the bottles should be labeled indicating the name, strength of the solution, date of
preparation, signature of the person who prepared it, use before date, standardization due on,
date of standardization.
Records shall be maintained for each solution starting with the value determined when the
solution was prepared & continuing with the values determined throughout the shelf life of the
solutions in respective register.
This record shall be retained for at least 1 year after the solution has expired.
Solutions of limited stability should be prepared on the day of use & discarded on completion
of analysis.
Standard Reagent solutions shall be prepared by accurately weighing a specified quantity &
dissolving to produce a specific volume.
All the bottles should be labeled indicating the name, strength of the standard reagent solution,
date of preparation, signature of the person who prepared it, use before date.
Shelf life of these standard reagent solutions is Three months from the date of preparation.
Discard the solution after three months or if observed hazy.
This record shall be retained for at least 1 year after the solution has expired.
Indicators:
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1.0 Purpose : To provide instructions for sampling of Raw Material for Testing Purpose.
Objective: To provide a documented procedure for raw material sample quantity for testing.
3.0 Scope : This procedure for raw material sample method for testing in QC Department.
4.0 Responsibility :
Primary : QC Chemist
5.0 Procedure :
On receiving the requisition of the raw material from the store. The QC Chemist will draw the
sample from store with proper safety. If sample is in tanker from outside factory gate.
If the sample is in crystal form & powder form the sample will be taken by SS sample tube.
If the sample is in liquid form then sample will be taken by glass sample tube.
If the sample is in tanker the chemist will take the sample from the each compartment of the
tanker of the bottom. And top of the each compartment with the help of glass sample tube.
Sample to be taken from each batch or lot as per the package label. If the package are less
than 10. The sample should be drawn from each & every package is more than 10. Then
sample should be taken as per this rule √n + 1.
We after drawing the sample chemist will put the label of UNDER TESTING on the package or
drums from where sample has been taken.
Chemist will bring the sample to QC lab and test the sample as per SOP of testing method.
If the sample is approved as per SOP then sample will be approved QC Manager and test
report will be sent to store incharge and production incharge and chemist will put the approved
label on the package of the new material and remove the under test label.
If the sample is not passed as per SOP testing method. The QC Manager will reject the raw
material and sent the report to the store incharge and plant in- charge, after that QC Chemist
will put the REJECT label on the package or drum and remove the UNDERTESITNG label.
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Wednesday, December 29, 2010
Internal Audit Plan as per GMP
This document describes the conduct of the Management review of the quality system for GMP Conforma
Certification, including the conduct of an internal audit to assure the system meets the requirements of
Guidelines and is effectively implemented..
To Provide Documented Procedure for review of the quality system for GMP Conformance Certification, inclu
the conduct of an internal audit to assure the system meets the requirements.
4.0 Responsibility :
o Board of Internal Audit and Management Review Committee: Arranges for the internal audit and gather
information for the Management Review.
o QA Management Committee: Provides all information as required by the Board of Internal Audit
Management Review Committee and is responsible for follow-up corrective and preventive actions.
5.0 Procedure :
The QA Management Committee, by consensus, selects three qualified individuals for the Board of Inte
Audit and Management Review Committee. Members to the Committee serve until they are replaced.
The Board of Internal Audit and Management Review Committee arranges for the half yearly internal aud
be conducted.
The date for the audit is established by mutual agreement between the Board of Internal Audit
Management Review Committee and the General Manager Production and Asst. Manager Production (AMP
The audit is conducted by any member of the board or Internal auditor qualified to participate on
Certification Board so long as the auditor is not a member of the QA Management Committee, is qualified
knowledgeable in certification, auditing.
During an audit, it is possible that a difference of opinion can arise as to the severity of an observation.
important not to spend too much time debating the merits of the observation. If it does not appear that
difference of opinion can be resolved, then the auditee should be informed that the audit report is subjec
review by the Board of Internal Audit and Management Review Committee and the QA Management
The draft report is issued to the Board of Internal Audit and Management Review Committee within
calendar days. The Committee members review and comment on the report and a final report is issued.
The QA Management committee drafts a response to the audit report that is finalized after review:
Findings, nonconformities, trends, and other opportunities for improvement are identified; investigate
determine the causes; and corrective/preventive actions are developed. These actions are implemented
soon as possible and recorded.
The response to the internal audit report is submitted to the Board of Internal Audit and Management Rev
Committee for their concurrence.
Upon agreement on the response to the internal audit, the Board of Internal Audit and Management Rev
Committee prepares a complete Certification Program Management Review Report that includes,
appropriate,:
Feedback from clients and interested parties related to the fulfillment of the Certification Process
The Board of Internal Audit and Management Review Committee submit their Certification Prog
Management Review Report to the QA Management Committee.
The Certification Program Management Review Report with the response to the internal audit is discusse
the next meeting of the full Board. The expected outputs of the review includes decisions and actions rela
to:
Resource needs.
Decisions and actions of the Board are documented in the Board Minutes and all open Corrective/Preven
Actions are reviewed and their status documented at all subsequent quarterly Board Meetings.
6.0 Abbreviations :
QA : Quality Assurance
Quality control should be carried out during all stages of manufacturing operation which is the primary
requirement of good manufacturing practices.
Emptyhard capsules
According to Japanese Pharmacopoeia, the test called ‘purity’ uses five capsules which are tested
individually. Each is placed in a 100 ml conical flask and shaken vigorously after adding 50 ml of water
37C throughout the test. The capsule passes the test if it completely dissolves within 10 mins giving
odorless, neutral (or slightly acidic).
Weight variation
For hard capsules: Accurately weigh 10 capsules. By suitable means the contents of each capsule should
be removed. The weights of emptied shells should be recorded individually. The difference of both the
weights will yield the net weight of the contents. Then calculate acceptance value.
For soft capsules: pre weigh 10 capsules. Cut the capsules by suitable means (either scissors or any
open blade) remove the contents by washing with a suitable solvent and let the solvent evaporate by
placing them at room temperature for about 30 mins. Weigh the individual shells. Calculate the
acceptance value.
Content uniformity
Hard capsules containing 25 mg or more of the drug contents should meet content uniformity
requirements.
Assay 10 capsules individually and calculate the acceptance value.
The requirement is met if the acceptance value of 10 capsules is less than or equal to 15%. If acceptance
value is greater than 15% or is about 25 % then, test the next 20 units and calculate the acceptance
value. The 30 capsules if less than or equal to 15% and no individual unit is 1-25*0.01 nor more than
1+25*0.01.
Disintegration:
The disintegration of capsules is different from those of tablets because the determination of end point is
difficult owing to the adhesive nature of shell. The shell pieces after disintegration may agglomerate
forming large mass of gelatin taking more time to dissolve and may adhere to the mesh thus, blocking the
holes.
According to USP, place one dosage unit in each of the tubes of the basket with water or any other
specified medium (depends on individual monograph) maintained at 37 + 2C. Attach a removable wire
cloth with a plain square weave of 1.8-2.2 mm of mesh aperture and a wire diameter of 0.60-0.655 mm to
the surface of upper rack of the basket assembly. Observe the capsules for a time limit (specified in
individual monograph), at the end of prescribed time, all of the capsules must have been disintegrated
excluding the fragments from the capsule shell. If 1 or 2 capsules fail, the test should be repeated on
additional of 12 capsules. Then, not fewer than 16 of the total 18 capsules tested should disintegrate
completely.
Dissolution
Place each of the capsules in the apparatus 1, excluding air bubbles from the surface of the capsule.
Operate immediately at specified rate within specified dissolution medium at 37 + 0.5C. Aliquots should
be withdrawn at specified time points mentioned in individual monograph.
The requirements are met if the quantity of active ingredients dissolved conforms the following:
1) At stage 1 (S1): When 6 capsules are tested, amount of each of the dissolved content should not be
less than +/- 5% of the mentioned in monograph.
2) At stage 2 (S2): when 6 capsules are tested, the average of 12 (both from step 1and 2) should be
equal to or greater than 15% and no capsule should be than 15%.
3) At stage 3 (S3): when 12 capsules are tested, the average of 24 capsules (all 1,2 and 3 steps) should
be equal to or greater than the amount mentioned in the monograph, not more than two units are less
than 15% and no unit s less than 25%.
NOTE: 15%, 25% represent Q1 and Q2 unless and otherwise mentioned in the monograph.
“Quality is not the step that can be incorporated at last, it is mandatory and should be inbuilt into the
products” to, make this happen, apart from all these mandatory tests certain other tests can be performed
like
Raw materials1
The gelatin of the capsule shells should be assayed for various physical properties like bloom strength 3,
viscosity and its loss (by atomic force microscopy).4 Chemical tests like purity, microbial properties, and
limits for heavy metals like arsenic, ash content should be determined.
The colorants should also be checked for purity, limits for heavy metals, color properties, dye content,
subsidiary dye content and color value.5
Machine output
The manufacturing machine’s output should be monitored continuously via the dimensional correctness
during each lot production.
The color of the capsules should be checked against a standard strip; in case of any changes the gelatin
solution should be adjusted by adding standardized dye solutions which can be ensured via thin layer
chromatography.
Moisture content
Moisture content can be monitored with the aid of data the drying kilns can be adjusted.
Loss on drying
Determination of loss on drying via the oven method consumes more time. To prevent this advanced
methods like infrared balances, humidity meter etc.
Sorting of defects
After electronic or manual inspection, they are sampled by quality control inspectors. The results should
meet the inspection plan, if not the capsules should be resorted or rejected depending upon frequency of
faults.
Printing inspection
Quality inspectors sample the lot and are inspected for quality of print. The results will again be compared
with the inspection plan and in case if it does not match then, either capsules should be resorted or
rejected depending upon number of faults present.
Final inspection
After the capsules are placed in final containers, samples are checked for various parameters like
dimensions, physical defects and color. These samples are also subjected to various microbial tests also.
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1.0 OBJECTIVE : To lay down the procedure for operation and calibration of Disintegration test
apparatus
2.0 RESPONSIBILITY
3.0 ACCOUNTABILITY
4.0 PROCEDURE
4.1.1 Ensure that the power supply to the apparatus is switched OFF before cleaning.
Clean the equipment with a clean dry cloth per day. Occasionally wet cloth dipped in dilute
soap solution may be used. Precaution has to be taken to clean the equipment immediately
with dry cloth to remove the moisture.
4.1.2 Clean the beaker and basket at the end of every operation.
4.2.2 When the power is switched ON the TIMER and TEMP. shows digital value.
4.2.3 Set the temperature 37°C by using SET, TEMP. , D , Ñ, DISP.SEL and ENTER
keys.
4.2.4 Set the timer 15.00 by using SET, TIME. , D , Ñ, DISP.SEL and ENTER keys.
4.2.6 Fill the beaker of DT apparatus with Purified water and adjust the temperature
between 37 ± 1 OC
4.2.7 Fix the beaker in its position and adjust the level of water so that when the basket
is in upper most position, wire mesh of the basket is 25 mm below the water level, and when it is
at lower most position the wire mesh is at least 25 mm above the bottom of the beaker.
4.2.10 Place on tablet / capsule in each of the tube and insert a disc in each of the tube.
4.2.11 Start the apparatus and Note the time taken by the last tablet / capsule for
complete disintegration.
4.2.12 Switch OFF the apparatus and power supply after the test is over, clean the
basket, discs and beaker.
4.3.3 Place the standardized calibrated thermometer to record the actual temperature against the
temperature displayed.
4.3.4 Note the temperature of water in the beaker and Oscillation per minute of the basket-rack
assembly.
4.3.5 Switch OFF the apparatus and record the observations in the calibration record as per
annexure –1.
4.3.6 Report and discrepancy observed during calibration or operation of the instrument to Quality
Assurance Manager and notify the defect to Service Engineer to rectify the defect. Affix ‘Under
Maintenance’ label on the instrument.
4.6 ABBREVIATIONS :
QA = Quality Assurance
DT = Disintegration test
Harmonization of format.
6.0 TRAINING:
7.0 DISTRIBUTION:
ANNEXURE –I
INSTRUMENT CALIBRATION RECORD
Revision No.: 00
REF. SOP NO.: Page No. : 1 of 1
Effective from:
Instrument Ser. :
No.
Calibration date :
Calibration due on :
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1.0 OBJECTIVE : To lay down the procedure for operation and calibration of friability test
apparatus
2.0 RESPONSIBILITY
3.0 ACCOUNTABILITY
4.0 PROCEDURE
4.1.1 Clean the apparatus free of dust with dry cloth from out side every day.
4.1.2 Clean the rotating disc and unloading pan from inside with dry cloth at the start and end of every
operation. Wet cloth may be used occasionally if cleaning is not proper with dry cloth but this
should follow drying of the inner surface by first wiping with dry cloth and exposure to
atmosphere air.
4.2.5 Press SET button and set the RPM to 25 with the help of numerical key’s (0 to 9) & press
ENTER
4.2.7 Load the weighed tablets in the drum, close the lid and secure it by tightening he screw and
press ENTER and then press START to run test.
4.2.8 After the completion of set rotations, the apparatus will automatically unload the tablets into the
tray. Observe the tablets.
4.2.9 Dedust the tablets, weigh and record the weight {W2}.
Initial Wt. of Tablets (W1) – Wt. of tablets After 100 rotation (W2) X 100
Initial Wt. of Tablets (W1)
4.3.2 Set the RPM to 25 and start the machine simultaneously with the stop watch. Count the actual
rotations and not the time required for the same.
4.3.3 Similarly set the RPM to 100 and note the time required and actual rotations.
4.3.7 In case of any discrepancy, report the observations to QC manager / QA Manager and notify
the defect to Engg. Department. Affix an ‘UNDER MAINTENANCE” label on the instrument.
4.4. FREQUENCY
Harmonization of format.
6.0 TRAINING:
7.0 DISTRIBUTION:
Certified Copy No. 3 : For Display Near The Friability Test Apparatus
ANNEXURE – 1
Revision No.: 00
REF. SOP NO.: Page No. : 1 of 1
Effective from:
Name of Instrument Friability Test Apparatus
Calibration date :
Calibration due on :
SET ROTATION
ROTATION ROTATIONS OBSERVED
ACCEPTANCE
Sr. DISPLAYED TIM
MA CRITERIA
No. E
NUALLY
25 1 min ± 05
sec
1.
100 4 min ±
2 20 sec
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BJECTIVE: To lay down the procedure for operation and calibration of serological water bath.
2.0 RESPONSIBILITY:
Q.C. Chemist
3.0 ACCOUNTABILITY:
Head - Q.C.
4.0 PROCEDURE:
4.1. PRECAUTIONS
4.1.2 Ensure that water bath is never operated without DM water, otherwise heater will
be damaged.
4.1.3 Check that water does not fall on the thermostat knob ( bellow the tray ).
4.1.4 Ensure that the mercury bulb of the thermometer is always dipped in water.
4.2.1 Maintain the DM water level in the water bath & switch 'ON' the main switch of the
Water Bath.
4.2.2 Set the thermostat knob to the desired temperature setting on the knob ( 0 – 100
settings ).
4.2.3 If desired temperature is not achieved, then fine tune the thermostat knob as per
requirement.
4.3.3. Wash with soap solution and rinse thoroughly it with DM water.
4.4.1 Set the temperature of serological water bath at 45C and switch on the
instrument.
4.4.8 Affix calibration tag , if calibration is satisfactory & under maintenance if found
unsatisfactory.
4.5 ABBREVIATION
C - Degree centigrade
Harmonization of format.
6.0 TRAINING:
7.0 DISTRIBUTION:
ANNEXURE I
Revision No.: 00
REF. SOP NO.: Page No. : 1 of 1
Effective from:
Identification No. :
Date Of Calibration :
100 98 – 102 °C
Boxes as per n +1 and take out sampling quantity for visual inspection as per sampling
plan MIL – STD 105D Acceptable Quality Level (AQL) (Refer Annexure – 5).
4.18 Note down the sampled quantity in Sampler’s checklist based on the number of
packages to be sampled.
4.19 Examine the sampled material as per AQL against the approved standard for
general appearance, deviation from normal visual quality, colour, text etc. wherever
applicable.
4.20 Record the results in approved Visual Inspection Report for Aluminium foil and
PVC Foil.
4.21 After completion of sampling the material pack shall be resealed with BOPP
Tape or tied with the help of cable – tie.
4.22 Affix the “UNDER TEST” refer Annexure – 4. to all the rolls of sticker labels,
foils and every container of rubber plugs. For all other packaging materials at least one
“UNDER TEST” Label shall be affixed on bottom container/ pack of each pallet.
4.23 Affix the SAMPLED BY QC (Refer Annexure – 4) sticker label duly signed and
mentioning the container number according to sampling plan, on outer container of the
material from which sample is taken.
4.24 Check that the number of packs is correct as mentioned in under test label.
4.25 Take out composite sample for analysis as per respective Packing Material
Specifications. Put the sampled quantity in self-sealing polybag bearing the label of
“SAMPLE FOR ANALYSIS” Refer annexure – 4.
4.26 Carry out testing of the packaging material as per the laid down specifications of
respective material.
4.27 The sampling procedure described above will not be applicable for Tertiary
Packaging material like Shipper, pad, partition and corrugated trays. For these materials
only one unit shall be collected and carry out the analysis as per laid down specification.
5.0 REASON FOR REVISION
Harmonization of format
6.0 TRAINING:
Trainer -- Manager – QC
Trainee -- Chemist / Associate – QC Packaging
Period -- One day
7.0 DISTRIBUTION:
Certified Copy No. 1 : Head of Department – Quality Control
Certified Copy No. 2 : File Copy for Packaging Department
Certified Copy No. 3 : Head – PLANT OPERATIONS
Certified Copy No. 4 : For Display in Packaging Laboratory
Original Copy : Head – QUALITY ASSURANCE
8.0 ANNEXURES:
Annexure - 1 : Format for Packaging Material Register
Annexure - 2 : Format for Sampler’s Remarks
Annexure - 3 : Format for Cleaning Record of LAF.
Annexure – 4 : Format for labels of UNDER TEST, SAMPLE FOR ANALYSIS and
SAMPLED
Annexure – 5 : 105 D Military Standard Acceptable Quality Level Chart
9.0 REFERENCE:
APPROVAL AND REJECTION OF PACKAGING MATERIALS
1.0. OBJECTIVE:
The objective of this SOP is to describe the procedure for Approval and
Rejection of Packaging
Material.
2.0. RESPONSIBILITY:
2.1.1. Responsible for ensuring proper documentation of sampling and adequate number
of quantity sampled.
2.1.2. Responsible for carrying out analysis of packing material (s) accurately & precisely
by following specification and standard testing procedure.
2.1.4. Responsible for preserving the reserve sample along with Analytical Test Report.
2.1.5. Responsible for recording the correct results in the Analytical Test Report for every
PM in a stipulated time.
2.2 The Executive – Quality Assurance shall be:
2.1.1 Responsible for verify and review of the recorded results and of the
ensuring the results are within the
standard limits.
2.1.3 Responsible for ensuring all laboratory instruments are calibrated and
working satisfactorily.
3.0. ACCOUNTABILITY:
4.1. The sampling of the packaging material shall be carried out as per the SOP
4.2. Before starting the analysis take out Standards and Results Sheet from
Respective Product File and take out photocopy and get it issued from Sectional
Head by signing the space provided.
4.3. The sampled items shall be analysed as per respective laid down specifications
and general test procedure. The results shall be recorded in the Analytical Test
Report and compare for its limits.
4.4. Prepare Certificate Of Analysis in case the material is being used, to the
Regulated Market. (Refer Annexure – 1).
4.5. Then compile the results along with Sampler’s Remark and keep one Reserve
Sample for printed packaging material by affixing Reserve Sample Label on non-
printed part (Refer Annexure – 2 for Reserve Sample Label).
4.6. The Goods Receipt Note (GRN) along with complete analytical report shall be
checked thoroughly by another person.
4.7. Then this complete report shall be forwarded to the Head – QC or Executive – QC
for further disposition (Approval / Rejection).
4.8. The results are not within the specified limits and standards, the material shall be
rejected
4.9. If the material is rejected, the Material Rejection Note (Refer Annexure – 3) shall
be prepared and get it approved from Head – Plant Operation, Head – QA / QC.
4.10. If all parameters found within the prescribed range Executive or Head – QA shall
approve the Analytical Test Reports and GRN.
4.11. The report with regards to the disposition of the said consignment is then made &
the status label as whether it is APPROVED or REJECTED (Refer Annexure – 2) shall
be generated by using the computer System.
4.12. Affix the duly signed APPROVED / REJECTED label to the consignment.
4.13. Each approved pack of packing material shall be identified by affixing the small
green label (Refer Annexure – 2) having the A.R. No. for identity of the Consignment.
4.14. Forward the approved / rejected copies of GRN to Warehouse for further actions.
4.15. File the entire report along with Quality Control GRN Copy.
4.16. Then Warehouse personnel shall shift the Approved / Rejected material in the
designated areas.
Key.
4.18. The approved material is then used for Production as per requirement.
4.19. The shelf life of each individual packaging material is being work out, on the basis
of stability study of these materials. Till that time the shelf life of packing materials
is three years from the date of release of material.
Harmonization of format.
6.0 TRAINING:
7.0 DISTRIBUTION:
9.0 REFERENCES:
In house
ANNEXURE – 1
CERTIFICATE OF ANALYSIS
ALKEM
LABORATORIES LIMITED PACKAGING MATERIAL
(NAME)
DAMAN
Material name:
TESTS
RESULTS SPECIFICATIONS
APPROVED / REJECTED
Remarks: Sample COMPLIES / DOES NOT COMPLIES as per above Specification
ANNEXURE – 2
NAME
ITEM CODE
G.R. No QTY.
RETEST DATE
SIGN. Date
ALKEM LABORATORIES LTD.. 333/1 KACHIGAM, DAMAN- 396210 ( U.T )
APPROVED
DOC/QC/001
A.R.NO B. NO.
POTENCY NO. OF
CONTAINERS
SIGN. Date
REJECTED
DOC/QC/002
RESERVE SAMPLE
Analytical Reference No.
A.R. No. : Sticker Label
G.R.N. No. :
Signature :
(149P – 2A/01)
Date :
ANNEXURE – 3
Head – Warehouse
Name Of Item:
Name Of Manufacturer/Supplier:
Date Of Analysis:
Remarks:
Head – QA / QC
(Executive – QA)
K/QC/002/F-2/00
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0 Purpose: To provide instructions for numbering system for Standard Operating Procedures and
Index of Standard Operating Procedure. (SOPs).
0 Objective: To provide a documented procedure of numbering system for Standard Operating
Procedures and Index of Standard Operating Procedure. (SOPs)
3.0 Scope : This procedure is applicable for numbering system for Standard Operating Procedures
and Index of Standard Operating Procedure. (SOPs).
4.0 Responsibility:
Primary: Officer–QA
Secondary: Manager-QA
5.0 Procedure:
SOP is prepared after studying total activities and interacting with all the concerned
Departments.
SOP is classified into following six main groups.
Sr. No. Name of the Department. Department SOP No.
Code
1 Personnel and Administration PA ABC/XX/SOP/YYY
2 Production Department PR ABC/XX/SOP/YYY
3 Engineering Services MT ABC/XX/SOP/YYY
4 Quality Control Department QC ABC/XX/SOP/YYY
5 Quality Assurance QA ABC/XX/SOP/YYY
6 Store Department ST ABC/XX/SOP/YYY
1.0 Purpose : To provide an instruction for analytical report numbering procedure (AR No.)
3.0 Scope : This procedure is applicable for analytical report numbering in QC department .
4.0 Responsibility :
5.0 Procedure:
YY =month.
ZZ = year (e.g. 2009 as 09)
YY = month. (e.g.01,02.. )
I-WWW/XXX/YY/ZZ.
Where, I = Intermediate
YY = month. (e.g.01,02.. )
Numbering of analytical report of finished product shall be in the form of XXX or WWW or
WW//XXX/YY/ZZ
YY = month (e.g.01,02.. )
I- WWW/XXX /ZZ/I1
Where, I = intermediate
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Purpose : To provide the procedure for receiving liquid raw materials in road
tankers.
bjective : To provide documented procedure for receiving liquid raw materials in road tankers.
Scope : This procedure defines instructions for receiving liquid raw materials in road tankers in
the stores department.
4.0 Responsibility :
Primary : Officer – Stores
Secondary: Stores In charge/ Manager Store.
5.0 Procedure :
Receive and verify the delivery documents (DC, Performa Invoice, Central Excise
Invoice, COA) and check for the Purchase Order copy for the material. The documents
shall essentially consist of the following information.
Name of the material
Name of the supplier
Batch No. / Identification No.
Manufacturing date
Quantity of material including the units of measurement
Number & date of Purchase order
Contact the Purchase department, if PO copy for the material received is not available.
Check for the security inward stamp on the delivery documents and the signature of the
security personnel along with the Security inward number.
Inform QC Dept in writing about the arrival of tanker for tanking sample giving the
following details:
Date
Time of Reporting
Name of the Product
Name of the Supplier
Name of the manufacturer
Quantity
DC / Invoice No. & Date
If the sample from the tanker does not conform to the specification, inform the purchase
department regarding the “REJECTION”. Return back the tanker.
On receipt of approval of the tanker from the QC, assign a Stores Asst. to the tanker
and send it to approved public weighing bridge for taking the gross weight.
Instruct the tanker driver to position his vehicle near to the unloading point.
Inform the engineering personnel to make arrangements for connecting the delivery
lines to the tanker, connect the earthing cable from the tanker outlet to the earthing point
to ensure the discharge of static electricity.
Ensure all the safety precautions for unloading the material from the road tanker have
been taken.
After the unloading is completed verify the compartments of the tanker by checking the
individual compartments and opening the outlet valves completely.
Assign a store asst. and send the tanker for weighing to the weight bridge.
On receipt of the weight of the empty tanker compute the net weight of the material
transferred. Check against the delivery documents and compute the difference if any.
Enter in the raw material inward register including the actual content of the material
transferred.
Sign for received on the delivery documents and retain the original copy.
Return the duplicate copy to the driver and mention deviations observed for suppliers’
reference.
Prepare the GRN and forward the same to the QC Dept for analysis of composite from
the storage tank.
On receipt of report from QC, forward copy of the GRN to Accounts and Purchase
department.
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Dispensing of raw materials
Raw material Weighing
Purpose : To provide store management instructions for Engineering department as per safety and
cGMP requirements.
Objective : To provide documented procedure of store management instructions for engineering
department as per safety and cGMP requirements.
Scope : This procedure defines instructions for Engineering store management system. The SOP
specifies the responsibilities of staff for the various functions outlined here.
4.0 Responsibility :
Primary : Officer – Stores
Secondary: Stores In charge/ Manager Store.
5.0 Procedure :
Before raising the indents for material:
Prepare the Bill of Quantity (BOQ) for the each job. Discuss with the contractor /
superiors and finalize it.
Consider the physical stock of the quantities already exists / ordered.
Procedure for indenting the material:
If required, float the inquiry and invite the three quotations.
Prepare cost comparative statements.
Finalize the purchase order after negotiations.
Prepare purchase order and hand over to the party.
Procedure for Receiving the material:
After getting the intimation, receive the material at the gate house.
Check the material at gate house, as per delivery challan and quality of material i.e.
damage, scratches, finishing etc.
Take the required quantity and use for it was indented.
Procedure for releasing the intermediate payment of ordered material:
After getting the Receiving Report (RR) from store department, check with the original
purchase order (PO).
If okay, release the intermediate payment as per terms and condition mentioned in the
PO.
Procedure for releasing the final payment of ordered material:
If party has already completed all the terms and condition under his scope and supply,
then fill the certificate for “Final Payment”.
Release the final payment as per PO.
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Guidelines for production activities as per safety & cGMP requirement
Guidelines for Engineering & Maintenance
Cleaning of Sampling Area
Floor
Clean the floor using detergent solution after using disinfectant solution use. And
Using lint free cloth.
If the sampling area is not in use then clean the floor once in a day using
detergent after using with lint free cloth.
Walls -If the dispensing area is not in use then clean the walls once in a day
using Detergent after using disinfectant solutions and with lint free cloth.
Door
Clean the door using detergent after using disinfectant solution and mop with
Using lint free cloth. If the Sampling area is not in use then clean the door once
In a day using same procedure.
Weighing balance
Clean the surface of balance with slightly wet lint free cloth.
Labeling
After completion of cleaning, affix the “cleaned “label on equipment / area.
Frequency: Once in a day and whenever before starting the Batch.
urpose : To provide a documented procedure for preventing accident & Recording accident.
2.0 Objective : To maintain safety aspects
3.0 Scope : Preventing accident & Recording accident
4.0 Responsibility :
Follow up : Concern department head
Over all responsibility: Personnel & Administration Manager.
5.0 Procedure :
Accident Prevention
Workman shall engage themselves in the duties which have been assigned to them.
The execution of their duties must be in the safe manner laid down in S.O.P. for the
operation, of the machine or duty concerned.
Removal of guards or safety devices, cleaning of machines which they are
Running, etc., are expressly forbidden.
Workmen working beyond the height of 10 feet shall wear the safety belt.
If any employee / work man working beyond the height of 10 feet on ladder shall work
with one additional work man / employee to hold ladder.
Safety instructions given or posted on Notice Boards are to be followed.
Workman shall not keep sharp edge tools into their pocket.
Any employee / workman working with electricity shall wear safety shoes &
Sock proof gloves.
Any workman working with hazardous chemicals / acid shall wear the safety
Wears like goggles, gloves etc.
Speed of vehicle inside the factory premises shall not exceed 20 km / hr.
When welding work is to be carried out in closed area, extra fire extinguisher
Shall be provided.
After working with oil, floor shall be cleaned thoroughly to wipe out the oil.
Solvents shall be stored in tight closed container.
Used drums of solvent / chemicals shall be discarded by skilled workman.
Sufficient emergency light shall be provided.
Entry into transformer yard / explosive storage yard shall be restricted to selected
Personnel.
Machine which is under maintenance shall be labeled as “Under Maintenance”.
Workman shall enter into water tank, drainage, septic tank only after permission Of
Personal & Administration department.
Workman shall carry out repairing work of high pressure line / high temperature Line /
or any explosive line only after permission of Engineering In charge.
Wear earplugs near high noise area.
ecording of Accident
Accident shall be recorded into Accident Register.
The accidents are categorized as critical major and minor depending on the
Seriousness of the incident.
The First aid, if required, after the accident shall be provided at the earlier marked
Locations and trained persons are available.
The telephone no. of fire station, doctor, ambulance shall be displayed in all the
Departments to call upon in an emergency.
The affected employee shall be immediately rushed to the hospital, if needed and is
provided the required medical help.
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Appraisal of Employee
Appraisal of Employee
1.0 OBJECTIVE
To lay down a procedure for Handling of Samples for Analysis of Raw Materials./ Formulations.
2.0 RESPONSIBILITY
3.0 ACCOUNTABILITY
Quality Control Manager.
4.0 PROCEDURE
4.1.1 The Quality Control Officer shall receive the samples along with the GRN and
‘sampler’s
check list.
4.1.2 The samples shall be kept in the tray labeled ‘Under Test Raw Material, till those are
allocated for analysis.
4.1.4 The samples shall be allocated for analysis by Quality Control Manager and relevant
details
shall be mentioned in the register.
4.1.6 The samples for destruction shall be kept in a container labeled as “samples for
destruction”
and shall be destroyed as mentioned below,
4.19. The container shall be destroyed by breaking (in case of glass), by cutting (in case of
plastic).
4.1.10 Collected material shall be destroyed by putting the material in water , but the cephalosporin
materials shall be destroyed by putting the material in 2% w/v solution of sodium
hydroxide.
Then all the collected material closed properly and send to the burning pit.
4.2 FORMULATIONS
4.2.1 The Quality Control Officer shall receive the samples along with the sample request
form and he
shall ensure intactness of the samples by visual checking.
4.2.2 The entries of the samples shall be made in the respective register by the Quality Control Officer.
4.2.3 Sample shall be kept in the tray labeled as ‘Under Test formulation till those are allocated for analysis.
4.2.7 The samples for destruction shall be kept in a container labeled as ‘Samples for destruction and shall be
destroyed as mentioned below.
4.2.8 Tablets, capsules, dry syrups and powder of vials shall be removed from their respective pack.
4.2.8 Packaging material shall be destroyed by burning at burning pit and product shall be
destroyed by burning at burning pit after breaking.
4.3 All Formulations / Raw Material Samples of Cephalosporin group of products shall be disposed off after
treating with 2% w/v Sodium Hydroxide solution.
4.4 No samples shall Under Test for more than 60 days. Any sample found pending for analysis
for more than 60 days shall be investigated for delay in analysis & documented.
4.5 ABBREVIATIONS
6.0 TRAINING:
Trainer -- Head – Quality Control
Trainees-- Quality Control Chemists & Assistants
Period -- One day
7.0 DISTRIBUTION:
8.0 ANNEXURES:
Nil
9.0 REFERENCES:
In house.
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CONTROL OF ISSUANCE OF RECORD OF ANALYSIS
Sending sample to contract lab
Sampling of Raw Material
PROCEDURE FOR OPERATING OF SONICATOR
1.0. OBJECTIVE
2.0. RESPONSIBILITY
Micobiologist .
3.0. ACCOUNTABILITY
4.1 Generate Sampler’s checklist-RM as per the Batch Number mentioned in the
Under Test list and decide the number of containers to be sampled as per sampling
plan (Annexure – I).
4.2 Check and reconcile number of containers and the total quantity as
shown in Under Test.
4.3 Check the packing condition of the containers for any damages.
Physically damaged
containers shall not be considered for sampling and the same shall
be Rejected..
below,
4.5.1. Select the containers to be sampled and inform Ware-House Officer to
transfer these containers to the raw material storage area of production block.
4.5.2 Sterilize and dehydrogenate all sampling accessories as mentioned in point no.
5.0.
4.5.3 Prepare label for individual container sample, with details of name of the
material, Batch no., and container number.
4.5.4. Total number of labels to be prepared shall be equal to the number of containers
to be sampled.
4.5.5. Prepare labels (annexure-II ) for Sample for Analysis, microbiology test and
control sample.
4.5.6. Transfer the containers to the buffer zone. Follow the SOP on ‘Raw material
receipt, storage, and transfer to sterile area’.
4.5.7. Enter into the sterile area following gowning and degowning procedure for sterile
area.
4.5.8. Transfer the container to be sampled to the Quality Control Microbiology Lab
( Sterile Area.)
4.5.9. Ensure that temperature inside the room is less than 25 deg.C. & RH is less than
40% or as specified on Manufacturer’s label.
4.5.10. Place one container under LAF. Peel off the outer tape/seal from the mouth of the
container and open the lid of the container aseptically.
4.5.13. If any abnormalities are observed, collect the sample in two separate vial, for
separate evaluation.
4.5.15. Close the lid of the container tightly, wrap the mouth with adhesive tape and
remove the container from LAF booth.
4.5.16. Mark the sample containers using glass marker with batch number and container
number in case of individual sample and only batch number in case of pool, control
sample & micro sample.
4.5.17. Mark containers / packs which are selected for sampling with marker as N/1/n,
N/2/n….N/S/n (‘N’ stands for total number of packs / containers, ‘S’ for serial number
of container selected for sampling and ‘n’ for total number of containers taken for
sampling).
4.5.18. Similarly sample the rest of the containers aseptically. Refer annexure-II for total
quantity to be sampled.
4.5.19. Seal all the vials with aluminium tear off seals.
4.5.21. Transfer all the samples & sampling aids in the Air lock-1.
4.5.22. Clean the LAF bench and room and leave the sterile area alongwith the samples.
4.5.23. Label all the collected sample vials.
4.5.24. Affix ‘SAMPLED’ labels (Annexure – III) duly signed with date of sampling on the
container.
4.5.26. Give the samples along with the Sampler’s checklist-RM, Supplier’s COA (if
available) to Quality Control Laboratory for Chemical Analysis.
4.5.27. Inform the Ware-House Officer to shift all the containers back to Stores ‘UNDER
TEST STORAGE’ area after performing decontamination of external surfaces.
4.6.2. Rubber Stopper : Follow washing steam sterilization and drying procedure as
followed in normal production run.
4.6.3. Spoons : Wash the spoon dry and wrap in 3 layers of aluminium foil,
depyrogenate in Dry Heat Sterilizer at 250 degree Celsius for one hour.
Remove outer layer of wrap here, from this hatch transfer the
accessories to aseptic area
hatch. Remove the second layer of the wrap and transfer them to
buffer zone LAF.
4.7 ABBREVIATIONS :
Harmonization of format
6.0 TRAINING:
7.0 DISTRIBUTION
9.0 ANNEXURES:
Annexurer-1 Attached
ANNEXURE – I
SAMPLING PLAN
ANNEXURE – II
QUANTITY TO BE SAMPLED
Tests Sample Quantity (Approx.)
ANNEXURE- III
SAMPLED
SING. /DATE
1.0 OBJECTIVE
2.0 RESPONSIBILITY
4.0 PROCEDURE
4.2.3 Glass ware used for Sterility / Endotoxin purposes must be sterilized /
depyroginated for 30 minutes at 250º C .
4.2.4Glass ware used for microbiological analysis etc. must be sterilized by heating
for 30 minutes at 120º C .
4.5 CAUTION
4.5.1 While preparation of chromic acid solution ensure that must wear
gloves and goggles.
4.7CAUTION
4.7.1 These materials are extremely corrosive. Wear gloves and goggles
when using.
4.8 ABBREVIATIONS
Harmonization of format
6.0 TRAINING:
7.0 DISTRIBUTION:
8.0. ANNEXURES:
Nil
9.0. REFERENCES:
IP/BP/USP
CLEANING OF QUALITY CONTROL LABORATORY
1.0 OBJECTIVE
2.0 RESPONSIBILITY
Hygiene supervisor
3.0 ACCOUNTABILITY
4.0 PROCEDURE
4.1 Broom the floor of all the sections including the staircase, daily and then
mope with wet mope.
4.2 Clean all the tables and reagent racks with dry mopping.
4.3 Empty the dust bins, clean them and keep them at place.
4.5 Once in a week clean all the fixtures with dry mopping.
4.6 Clean all the racks in chemical stores once every week .
4.7 Clean all the walls and ceiling once every week .
4.8 After cleaning the area by workmen, check the cleanliness of the area and
put the Yes in
4.1. Frequency :
Harmonization of format
6.0 TRAINING:
7.0 DISTRIBUTION:
8.0 ANNEXURES:
9.0 REFERENCES:
In house
ANNEXURE I
CLEANING RECORD
QC Lab : Wet chemistry lab / Instrument rooms / chemical stores / Control sample room.
1.0. OBJECTIVE:
The objective of this SOP is to ensure that the instrument performs satisfactorily
and gives accurate and reproducible data.
2.0. RESPONSIBILITY:
2.1.2. Responsible for timely calibration of HPLC System as per the SOP.
3.0. ACCOUNTABILITY:
4.0. PROCEDURE:
4.1.1 Ensure that the power supply to the instrument is switched off and main cord is
removed from supply.
4.1.2 Clean the instrument with a clean dry cloth everyday. A wet cloth dipped in dilute
soap solution may be used occasionally.
4.1.3 Precaution must be taken to clean the instrument immediately with dry cloth.
4.2.1 Ensure that the instrument is properly connected to the power supply.
4.3.1 Use HPLC grade solvent / water & AR/Excel/ HPLC grade reagent only.
4.3.2 Filter the mobile phase through 0.45 membrane filter after mixing it in required
proportion and de-gas on ultrasonic bath for about 5 minutes.
4.4.1 Switch on pump, auto injector, detector and then system controller.
4.4.2 Turn the drain valve knob to 180 in anti- clockwise to open the drain valve to run
the purge system.
4.4.5 Press pump key. The pump will run and indicator will glow.
4.4.6 Purge the auto injector by pressing purge key on auto sampler display.
4.5.3 It will show Confrigration, Real Time, and Sample Shedule & Post Run Analysis.
4.5.5 From the “file menu” create a new method or load the existing method.
4.5.6 Create a new sample shedule and feel sample name, batch number,,sample
volume , method name and file name ,after then save the shedule .
4.5.9 After every ten injection of sample (5 samples in duplicate), the standard solution
shall be injected 3 times and the RSD shall be calculated and ensure that it is within
the limit.
4.6.1 Close Sample Shedule, Real Time and then CLASS LC 10 to Software.
4.6.2 From Start button select “Shut down” and click yes.
4.6.6 Stop pump by pressing, “Pump” key and switch off the pump module.
4.7.1.1 Disconnect the column and connect the inlet and outlet tubing’s with a union.
4.7.1.2 Prime all the lines at 5 ml/min flow rate with water and ensure that flow line is
free from air bubbles.
4.7.1.3 Set the flow rate at 1ml / min and collect the mobile phase (water) in a dry
preweighed beaker and collect the mobile phase for 10 min. weigh the beaker to get
the weight of mobile phase.
4.7.1.4 Calculate the flow rate by dividing the weight obtained with weight per ml and 10
(run time).
4.7.1.5 Calculate the corresponding flow rate. Carry out the experiment in duplicate.
4.7.1.8 Acceptance criteria: Flow rate should be in between 0.99 to 1.01 ml / min..
4.7.2.1 Install union in place of column & flush solvent lines (A&B) at flow rate of 2ml/min
with water.
4.7.2.4 Fill reservoir A with 100% HPLC grade water & reservoir B with 0.3% acetone in
HPLC grade water as mobile phase.
0.01 B CONC 10
10.00 B CONC 10
10.01 B CONC 50
20.00 B CONC 50
20.01 B CONC 90
30.00 B CONC 90
40.01 B CONC 0
50.00 B CONC 0
CHECK FOR PRECISION: Purge the injector system with 100% water to ensure the
complete washing of injector.
Detector : 254 nm
4.7.5.5 Inject the standard preparation six times in the system. The peak areas observed
shall be consistent.
4.7.5.6 The relative standard deviation for area counts calculated shall not be more than
1.0%.
4.7.6.1 Inject 10, 20, 30, 40 & 50m litre of standard preparation in duplicate. Calculate
the average area counts corresponding to each set of injection.
4.7.6.2 Tabulate the average area against each injection. Plot a graph for area counts vs
mlitre the resulting graph shall be linear.
4.7.6.3 The correlation co- efficient calculated shall be not less than 0.99.
4.7.7.4 Record the results in the detection calibration record as per the Annexure - 4.
4.7.7.5 Affix a calibration status label on the instrument containing “Calibrated On”,
“Due On” and “Signature”.
4.7.7.6 Report to Head – QC, if any discrepancy observed during calibration or operating
the instrument and affix ‘Under Maintenance’ label on the instrument.
UNDER MAINTENANCE
EQUIPMENT :
SINCE :
SIGNATURE:
4.7.8.1 Detector : Once in three months and after each maintenance job.
4.7.8.2 Pump : Once in three months and after each maintenance job.
4.7.8.3 Injector : Once in six months and after each maintenance job.
4.7.8.4 Gradient : Once in six months and after each maintenance job in the pump.
6.0 TRAINING:
7.0 DISTRIBUTION:
8.0 ANNEXURES:
9.0 REFERENCES:
In house.
ANNEXURE – 1
Instrument No. :
Calibration Date :
Calibration Due On :
Pump-A
(W2 – W1) / 10
Pump-B
(W2 – W1) / 10
Weight per ml of water = ________ gm.
Date Date :
ANNEXURE – 2
Instrument No. :
Calibration Date :
Calibration Due On :
--------------------------------------
Date Date :
ANNEXURE – 3
Instrument No. :
Calibration Date :
Calibration Due On :
Standard Preparation:
Take ______ mg of Uracil (about 50 mg) 250 ml. 5ml 50ml with Methanol.
Parameters:
Mobile Phase : Methanol HPLC grade. Column : ODS (150 mm x 4.6 mm. 5
micron)
Inject six replicate injection of standard solution and calculate RSD for area of main
peak.
3
Not More Than 1.0 %
4
Correlation coefficient
Sr. Injection
Area Mean Observed
No. volume Limit
results
i)
3 30 l.
ii)
i)
4 40 l.
ii)
i)
5 50 l.
ii)
Date Date :
ANNEXURE – 4
Calibration Date :
Calibration Due On :
Calibration Of Detector
Standard Preparation:
Take _____ mg of Uracil ( about 50 mg.) 250 ml. 5ml 50ml with Methanol.
Parameters:
Mobile Phase: Methanol HPLC grade Column: ODS (150 mm x 4.6 mm. 5
micron)
1)
1 252
2)
1)
2 254
2)
1)
3 256
2)
1)
4 258
2)
1)
5 260
2)
1)
6 262
2)
1)
7 264
2)
Date Date :
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DESTRUCTION OF ANALYTICAL SAMPLES AFTER TESTING
1.0. OBJECTIVE:
The objective of this SOP is to describe a procedure for the destruction of balance
analytical samples after analysis and control samples.
2.0. RESPONSIBILITY:
2.1 Chemist Quality Control shall be responsible for Destruction of the remaining
unwanted Analytical samples after analysis.
2.2 Head - Quality Assurance shall be responsible for ensuring the destruction of
samples as per the procedure.
3.0. ACCOUNTABILITY:
4.0. PROCEDURE:
Blend Analysis
After analysis, discard the balance sample of the tablets and capsules into a wet bin
containing 2 % w/v solution of sodium hydroxide. Deface the label of poly bag and
discard the bag into waste bin after treating it with 2 % w/v solution of sodium
hydroxide
After analysis, discard each and every capsule or tablet into the wet bin containing
2 % w/v solution of sodium hydroxide. Deface the label of poly bag and discard the
bag into waste bin.after treating it with 2 % w/v solution of sodium hydroxide.
Cut the blisters / strip packs and take out the tablets / capsules and discard them
into the wet bin containing 2 % w/v solution of sodium hydroxide. Discard the empty
blisters / strip packs into waste bin. after treating it with 2 % w/v solution of sodium
hydroxide.
Discard the powders / liquids in wet bin containing 2% w/v solution of sodium
hydroxide. Deface the label on the bottle. Glass bottle shall be treated with 2 % w/v
solution of sodium hydroxide before disposal to the vial / bottle crusher.
4.5 Raw Materials
After analysis, discard balanced sample of raw material into the wet bin containing
2 % solution of sodium hydroxide. Deface the label of polybag and discard into the
waste bin.
4.6.1 After analysis, cut the material into pieces and it to scrap yard.
4.6.2 At the end of the day remove the wet bin from the laboratory premises and send
it to the ETP to discard the waste.
5.0. TRAINING:
6.0. DISTRIBUTION:
7.0. ANNEXURE:
Nil.
8.0. REFERENCE:
In-House
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1.0 OBJECTIVE
2.0 RESPONSIBILTY
3.0 ACCOUNTABILITY
4.0 PROCEDURE
4.1 For 0-200l micropipetter. (carry out all the activities at Temperature 25°C )
4.1.3 Pipette out in previously tared beaker on weighing balance and note the reading.
4.1.4 Carry out the procedure twice and note the weight displayed on the balance,
calculate the mean and standard deviation of three readings and record it in the
format as given in annexure-I.
4.1.5 The weight per ml of water at 25°C when weight in air is 0.99602 g .Divide the
mean with weight per ml to get the volume dispensed.
4.1.6 Carry out similar procedure by setting micropipetter to 100l and 200l .
4.2.1 Repeat the same procedure as above by setting 200, 500 & 1000l
quantity.
4.3.1 Standard deviation between three readings should not be more than
1%.
4.3.2 The volume dispensed should not vary by more than 1% of the set
volume.
Quarterly
Harmonization of format.
6.0 TRAINING:
7.0 DISTRIBUTION:
Certified Copy No. 1 : Head of Department – Quality Control
8.0 ANNEXURES:
9.0 REFERENCES:
In house.
ANNEXURE –I
CALIBRATION DATE:-
MAKE / MODEL:-
CALIBRATION DUE:-
I II III
0 – 200 l
50 49.5-
50.5
100 99.0-101
200 198-202
200 – 1000 l
200 198-202
500 495-505
1000 990-1010
Done by:
Checked
by:
Sign.& Date
Sign.& DatE
1.0 OBJECTIVE
2.0 RESPONSIBILTY
Microbiologist./ Q.C Executive.
3.0 ACCOUNTABILITY
4.0 PROCEDURE
4.1 INTRODUCTION
4.1.1 Before employing any dehydrated media for analysis ensure that the growth
promotion test has been performed for that particular batch or lot or any new media
procured.
4.1.3 For preparing any culture media (Solid or Liquid) take properly cleaned glass
container of different volumes as per requirement.
4.1.5 Select the glass container such that the medium volume be prepared, is half of its
capacity.
4.1.6 Follow the instructions given by the manufacturer for preparing the culture media
(Name of the Mfr.).
4.1.7 Weigh the media powder as mentioned on the label of the container and Annexure
II . Reconstitute with distilled water and mix the powder stirring with glass rod.
4.1.8 Warm the powder mixed distilled water, if required, to dissolve the
powder
4.1.9 Plug the mouth of the container by non-absorbent cotton and wrap butter paper
/Alue. Foil to prevent any Contamination and label.
4.1.10 Boil or sterilize the media at 121°C for 20 min, as per manufacturer
instruction and
4.1.11 After completion of all the above procedures label each media containers with
media name, media lot no. date of preparation, and Use before date on the
container . Pre-incubation must be done at 30-35C
for at least 48 hrs before taken for use. In case if the medium is
required to be use
as mentioned in Annexure I.
4.1.13 Prepared media can be used within 1month period if properly sealed and stored at
temperature < 25°C.
4.1.14 Whenever new bottle is opened write the date of opening , Date of growth
promotion test and signature on the bottle.
Harmonization of format.
6.0 TRAINING:
7.0 DISTRIBUTION:
Certified Copy No. 1 : Head of Department – Quality Control
8.0 ANNEXURES:
Annexure –I
9.0 REFERENCES:
Himedia Manual
ANNEXURE –I
LIST OF MEDIA
Revision No. : 00
REF. SOP NO.: Page No.: 1 of 1
Effective Date :
1.0 OBJECTIVE
2.0 RESPONSIBILITY
3.0 ACCOUNTABILITY
Manager Q.C.
4.0 PROCEDURE
4.1. OPERATION
4.1.1. The apparatus consist of following switches.
4.1.8. The apparatus starts working and stroke rate displayed on the
screen.
4.1.9. After the completion of the specified stroke .The apparatus will go OFF
automatically with a buzzer.
Wt. of sample
Volume
4.2.2. Set the apparatus for 50 strokes by adjusting the push button.
50 : 49-51
75 : 73-77
100 : 98-102
4.3. FREQUENCY
Monthly.
Harmonization of format.
6.0 TRAINING:
7.0 DISTRIBUTION:
Certified Copy No. 2. : For Display near the Bulk Density Test Apparatus
8.0 ANNEXURES:
In house.
ANNEXURE – I
Make Model
75 75 ± 2
100 100 ± 2
CALIBRATED BY CHECKED BY
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1.0 OBJECTIVE
2.0 RESPONSIBILITY
3.0 ACCOUNTABILITY
Manager Q.C.
4.0 PROCEDURE
4.1 OPERATION
4.1.2. Switch on the instrument power supply, and wait for few minutes.
4.1.3. As soon as the power is switched on ,the monitor shows the company’s name and go on
initializing For 5.13 minutes.
4.1.4 After that the Instrument is in the "READY" mode for automatic operation indicated by
READY. Display :
4.1.5. Lift the door of the sample compartment and place the sample cell filled with media in which
sample is prepared (ensure that no air bubbles are there ). Push ZERO keys for zero clearing.
4.1.6. Push EDIT key and enter identification and concentration of sample .
4.1.7. Place the sample cell filled with sample solution ( ensure that no air bubbles are there ) and
press START key. Take the reading displayed on the digital screen .
4.2. CALIBRATION :
4.2.1. Prepare the standard solutions of sucrose in distilled water of different concentrations
from 10 %
To 50 % and sonicate if necessary . Use distilled water as a blank and operate the
instrument as
Per SOP.
4.2.2. Clean the sample cell with distilled water and check the reading . Press ZERO to get
the zero of the distilled water blank. Place the sucrose solution one after
another from 10 % to 50 % and measure the optical rotation for each solution which should be
comparable with values given below:-
10 % 13.33
20 % 26.61
30 % 39.86
40 % 53.06
50 % 66.23
4.4. If the Calibration is not proper then report the results to the Department Head for an
appropriate
Action.
STERILITY TESTING
1.0 OBJECTIVE
2.0 RESPONSIBILTY
3.0 ACCOUNTABILITY
4.0 PROCEDURE
4.1.3 Follow S.O.P for transferring materials inside the sterile area.
4.1.4 Disinfect LAF station wth 70% filtered IPA solution & check the
manometer reading (i.e
between 10-
powder of the vial to be tested under RLAF & suck out the sample.
For liquid injections-Suck out the sample with a sterile syringe after opening the
flip-off seal of the vials to be tested under LAF.
4.4 Place the sterilized filtration units on the filtration assembly under the RLAF which
is connected to a a collecting flask and with a vacuum pump by a tubing tightly
fitted with it.
4.5 Open the filtration units (A suitable unit consist of closed reservoir and receptacle
between which a properly supported membrane of Pore size of 0.22 and a
diameter of approx. 47 mm. At flow rate of 55 to 75ml of water per minute at a
pressure of 70 cm of mercury) carefully and pour the collected sample in the sterile
filtration assembly and filter the sample.
the outer portion of 20 nos. of ampoules/ vials and suck out water with the
help of sterile syringe.
4.12 Collect the sample in a sterile conical flask and filter it through 0..45
membrane filter and rinse the
membrane filter with 100ml of 0.1%sterile peptone water and in case of
liquid injections ,rinse the
4.13 After completion of filtration ,cut the membrane filter into two with the help
of sterile scissor and
forceps and inoculate each half portion of it into sterile 100ml SCDM and
FTGM
4.14 After inoculation, close the mouth of the container tightly and incubate
SCDM tubes at 20-25C and
FTGM at 30-35C.
4.15 Hold the incubated tubes at the above mentioned temperature in incubator
for duration as mentioned in
pharmacopoeia .
4.16 Note the observations in the format as in annexure-I. For any adverse
result inform Manager QC &
5.0 ABBREVIATIONS :
6.0 REFERENCES
ANNEXURE- I
QUANTITIES OF THE PRODUCT TO BE EXAMINED IN THE TEST OF STERILITY (AS PER
E.P)
Type of Quantity per Minimum qty to be used for each
preparation container medium ,unless otherwise justified &
authorized
Parenteral
Liquids
preparations
Less than 1 ml The whole content of each container
Solids
300 mg or 150 mg
more
ANNEXURE -II
SAMPLE
MEDIA PREPARATIONS
TEST RESULT
GROWTH
OBSERVED
NO. OF DAYS 1 2 3 4 5 6 7 8 9 10 11 12 13 14
GROWTH
OBSERVED
NEGATIVE CONTROLS
NO. OF DAYS 1 2 3 4 5 6 7 8 9 10 11 12 13 14
GROWTH
OBSERVED
NO. OF DAYS 1 2 3 4 5 6 7 8 9 10 11 12 13 14
GROWTH
OBSERVED
POSITIVE CONTROLS
MEDIA SOYABEAN CASEIN DIGEST FLUID THIOGLYCOLLATE
MEDIUM MEDIUM
DAYS 1 2 3 4 5 6 7 1 2 3 4 5 6 7
S. aureus NA - +v +v +v +v +v +v
ve e e e e e e
C albicans/A - - +v +v +v +v +v NA
niger ve ve e e e e e
C. sporogenes NA - +v +v +v +v +v +v
ve e e e e e e
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1.0 OBJECTIVE
To lay down the procedure for checking correctness of the computerized formulation order issue
system.
2.0 RESPONSIBILITY
3.0 ACCOUNTABILITY
4.0 PROCEDURE
For example:-
The formulation order printed in the month of Jun’2005 shall have the manufacturing
date
as “Jun 2005”.
4.3.2. Expiry Date
Check the expiry date of active Ingredient(s), against Analytical Report Number (AR. No.)
Mentioned in the formulation order. Check the correctness by comparing with expiry date
mentioned in COA. Following guideline shall be followed while assigning Expiry for the
product.
The expiry date of the Finished Product shall be as per the expiry date of the product or expiry
date of its active Ingredient (s), whichever is earlier. Products having multiple active
ingredient(s) shall have expiry of Raw Material having the least expiry.
The expiry date of the Finished Product shall be as per the Shelf life assigned in Master
Formula.
4.6.1. Check the Formulation Order against the master formula issued by Product Development
Laboratory for following.
4.6.2.1. Collect potency and moisture data of the active ingredients issued in the formulation order by
referring to the Certificate of Analysis from Quality Control and check the same with the
formulation order.
4.6.2.2. Calculate the actual quantity of active ingredients to be issued by referring to the
formula
specified in the Master Formula given by Product Development Laboratory and
the quantity of
the Filler.
4.6.2.3. Check the correctness of the quantity by comparing with quantity mentioned in Formulation
order.
4.7.1. Check the “ First in – First out” System for any two ingredients issued in Formulation
order.
4.7.2. In case of active ingredients, Check for the material in stock having less expiry
than that of the issued material. If there is no stock of material having less
expiry, the “ First out” system shall be followed.
4.7.3. After taking out the Formulation Order, check Analytical Report Number wise stock on
computer screen. In case of other ingredients, If there is no stock of previous Analytical Report
Number in the system, the “First in-First out” principle shall be considered to be followed.
Shall investigate the matter and take corrective action. The investigation report shall be
documented.
Details of the investigation shall be documented as per Annexure-1.
Five Formulation Orders of different products shall be checked during each Calendar Month
4.10. ABBREVIATIONS:
Harmonization of format
6.0. TRAINING:
8.0. ANNEXURES :
9.0. REFERANCE
In-house
ANNEXURE-1
Investigation report
Revision No.: 00
REF. SOP NO.: Page No. : 1 of 1
Effective from:
Date
Product Batch Number
Market Batch Size
F.O. Serial No. Date
ANNEXURE - II
2. GENERAL CHECKLIST
Revision No.: 00
REF. SOP NO.: Page No. : 1 of 1
Effective from:
A. Manufacturing Date
B. Expiry Date
C. Master Formula
DONE BY CHECKED BY
1.0 OBJECTIVE :
2.0 RESPONSIBILITY
Chemist / Executive.
3.0 ACCOUNTABILITY
Manager Q.C
4.0 PROCEDURE
4.1. OPERATION
4.1.2. Clean the electrodes with purified water and wipe with tissue paper.
4.1.3. Switch ON the main power.
4.1.4. To check the pH of the sample by dipp electrode in the sample solution taken in a suitable
container.
4.1.5. .Push “READ” bottom ,it beep .When reading be stable by showing [A]
record the results.
4.1.6. Remove the electrode from the sample solution, wash with purified water and place in a
beaker of fresh purified water.
WITHIN 23°C - 27 °
4.2.1. In three, dry separate beakers take 1 buffer tablet of pH 4.0, 7.0 and 9.2
respectively.
4.2.3. Transfer the preparation from beakers to clean 100 ml volumetric flasks
separately.
4.2.3. Rinse the beakers with distilled water and transfer to the volumetric
flasks.
4.2.4. Make the volume accurately to 100 ml with Distilled Water in each case.
4.2.5. Transfer the prepared buffer solutions of pH 4.0, pH 7.0, pH 9.2, in three
different
bottles, appropriately labeled.
4.2.6. Affix the labels on the bottles indicating the USE BEFORE---- Date of solution.
4.2.7. Prepared buffer solution is valid up to 7 days from the date of preparation.
4.3.1. Clean the electrode with purified water and wipe excess water with tissue
paper.
4.3.2. Deep electrode in pH 4.0 buffer and push “CAL” bottom, after stabule ,record the result
.Repeat the process with pH 7.0 and pH 9.2 buffers .
4.3.3. While checking the pH of buffer 4.0, 7.0 and 9.2 clean the electrode with purified water
every time.
4.4.4. After use keep the electrode dipped in the purified water .
4.5. FREQUENCY
Daily
± 0.05 pH
6.0 TRAINING:
Trainer Head – Quality Control
Trainees-- Quality Control Chemists & Assistants
Period -- One day
7.0 DISTRIBUTION:
8.0 ANNEXURES:
9.0 REFERENCES:
Revision No. : 00
REF. SOP NO.: Page No.: 1 of 1
Effective Date:
MAKE : SERIAL No :
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OPERATION AND CALIBRATION OF ANALYTICAL BALANCE
1.0 OBJECTIVE
2.0 RESPONSIBILITY
3.0 ACCOUNTABILITY
4.0 PROCEDURE
4.2.1 Ensure that the balance pan is not loaded & the doors of the weighing chamber is
closed properly.
4.2.2 Press the ” Set up ” button ,the balance will display ‘ CAL ‘
4.2.3 Press ‘ Enter ‘ button the balance will displays ‘ CAL TYPE '
4.2.4 Then press ‘ Enter ‘ button the balance will display ‘ CAL TYPE ' ‘InCAL ‘
4.2.5 Then again press ‘ Enter ‘ button the balance will display ‘INCAL
After a few seconds the balance will display ‘ CAL SET ‘ & then return to WEIGH
mode & displays as WEIGH 00000.
4.3.1 After internal calibration is completed verify the performance of the balance by
weighing 50 mg,
4.4.3 Remove the weight & again place the weight on the pan & record the
display once again.
4.4.4 Repeat the above operation to get ten readings Calculate the standard
deviation of ten readings.
4.4.7 Report any discrepancy noted at the time of calibration to Q.C Manager &
notify the defect to rectify the instrument. & affix an ‘ UNDER MAINTENANCE ‘ label
on the instrument.
Harmonization of format
6.0 TRAINING:
7.0 DISTRIBUTION:
9.0 ANNEXURES:
ANNEXURE -I Attached.
In house/Manufacturer Manual
ANNEXURE -I
Revision No. : 00
REF. SOP NO.: Page No.: 1 of 1
Effective Date:
MAKE :
MODEL :
SERIAL No :
50 mg 100 mg 1 gm 10 gm 50 gm
Limits 50mg 100mg 1g ± 10g ± 50g ±
± 0.1 ± 0.1 1mg 10 mg 50 mg
ANNEXURE -II
Revision No. : 00
REF. SOP NO.: Page No.: 1 of 1
Effective Date:
Calibration date :
Calibration due on :
3
4
10
Standard deviation ( ) =
3 x
Wt measured
CALIBRATED BY APPROVED BY
Analytical balance-Libror
OPERATION AND CALIBRATION OF REFRACTOMETR
OPERATION AND CALIBRATION OF POLARIMETER
Analytical balance- Mettler Toledo
LinkWithin
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OPERATION AND CALIBRATION OF BURSTING STRENGTH TESTER
1.0. OBJECTIVE:
2.0. RESPONSIBILITY:
2.1.1. Responsible for carrying out the analysis as per the procedure.
3.0. ACCOUNTABILITY:
4.0. PROCEDURE:
4.1.2. If necessary wet cloth shall be used for effective cleaning it shall be dried
immediately using a dry cloth.
4.2.1. Switch On the mains. This will bring the plunger to its starting positions. If the
plunger is already at its starting position, motor will not start on switching ON main.
4.2.2. A representative sample of the material to be tested shall be placed over the
diaphragm. The sample size shall be cut to 10 X10 cm.
4.2.4. The tripod plate shall tightened to apply sufficient clamping pressure in such a
way that sample does not slip.
4.2.5. Select the gauge [II] for 3 ply shippers and partitions and gauge [I] for 5 ply and
7 ply shippers.
4.2.6. Set the maximum hand of the gauge at zero or a point on the scale below the
point at which bursting will occur.
4.2.7. Push the RED push button and keep it pressed so that plunger will start rotating
in clockwise direction till sample bursts. The push button is released as soon as the
sample bursts. Note down the gauge reading in Analytical Test Reports.
4.2.8. Release the pressure on the test piece by rotating the clamp wheel in anti-cock
wise direction and remove the sample specimen.
4.3.2. Check the glycerin level [this bursting strength tester is a hydraulic unit and its
accuracy depends on a completely filled hydraulic system. Inadequate glycerin
quantity affects the accuracy of the gauge readings]
4.3.3. Take the standard Aluminium foil of 5.4 Kg / cm 2 for Gauge II and 9.5 kg / cm 2
for Gauge I provided by the manufacturer.
4.3.5. Record the observations in the calibration record as per the Annexure - 1, in
case of any discrepancy observed, affix an “Under Maintenance” label on the
instrument and report to Executive - Quality Assurance to take necessary corrective
actions.
4.4.1. Quarterly.
Harmonization of format.
6.0. TRAINING:
7.0.DISTRIBUTION:
Certified Copy No. 3 : For Display near the Bursting Strength Tester.
8.0.ANNEXURE:
9.0.REFERENCE:
Manufacturer’s Manual.
ANNEXURE – 1
FORMAT FOR CALIBRATION RECORD OF BURSTING STRENGTH TESTER
Instrument no. :
Name of instrument : Bursting Strength Tester
Frequency : Quarterly
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