Bacpac & Supac
Bacpac & Supac
&
BACPAC
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SCALE UP
&
POST APPROVAL
CHANGES
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SCALE UP & POST APPROVAL CHANGES
WHAT IS SUPAC?
TYPES OF SUPAC
LEVEL OF CHANGES
1. In component or composition
2. The site of manufacture
3. The scale up of manufacture, and
4. The manufacturing(process and equipment)
PRESENTATION
OUTLINE BULK ACTIVE POST APPROVAL CHANGES
INTRODUCTION
BACKGROUND
ASSESMENT OF CHANGES
TYPES OF CHANGES
1. Site, Scale, And Equipment Changes
2. Specification Changes
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1. In the process of developing the new product, the batch size
used in earliest human studies are small.
2. The sizes of the batch is gradually increased
WHAT IS (scale up).
SUPAC ? 3. The scale up and the changes made after approval in the
composition manufacturing process , manufacturing
equipment and change of site have become / known as scale
up and post approval changes (supac)
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o Supac- IR (immediate release solid oral dosage
form .
o Supac- MR (for modified release solid oral dosage
TYPES o
form)
Supac- SS (for non sterile semisolid dosage form
including creams, ointments, gels and lotions)
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SUPAC GUIDELINES - DEFINE
• Minor changes
• Moderate changes
LEVEL OF • Major changes
CHANGES
• Annual report
• Changes being affected supplement
FILING • Prior approval supplement
• Application/compendial tests
• In-vitro dissolution/release
TESTS • In-vivo
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Likelihood of impact on formulation qualityand performance
LEVEL LEVEL 1:
Those changes that are unlikely to haveany detectable impact on formulation quality and performance.
OF
Example --Changes in the color,flavors, Changes In the excipient express as the percentage (w/w) of total formulation, less than or equal to the following range
CHANGES
LEVEL 2:
1) Changes are those that could havesignificant impact on the formulation quality and performance
3) Example –1) Changes in the technical grade of excipient (Avicel PH102 vs. Avicel PH200); 2) Changes expressed as percent (w/w of total formulation)
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LEVEL 3:
Changes are those that are likely to have significant impact on formulation
quality and performance. Example --Any qualitative or quantitative
excipient changes to a narrow therapeutic drug beyond the range for level 1 All
other drug not meeting the dissolution criteria as level 2.
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COMPONENT 1)Focus on the changes in amount of
AND excipients in the drug product
COMPOSITION 2)Not focus on change in the amount of
the drug substance .
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LEVEL 1 CHANGES
TEST DOCUMENTATION
1. CHEMISTRY DOCUMENTATION
Application/ compendial release requirements stability testing (One batch long term)
2. DISSOLUTION DOCUMENTATION
None beyond the compendial requirements
3. IN VIVO BIOEQUIVALENCE DOCUMENTATION:- None
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LEVEL 2 CHANGES
TEST DOCUMENTATION
1. CHEMISTRY DOCUMENTATION
Level 1 + 1 batch with 3 month accelerated stability study
2. DISSOLUTION DOCUMENTATION
Case A – High permeability, High solubility
Case B – low permeability, High Solubility
Case C – High permeability, Low Solubility Drugs In vivo
FILING DOCUMENTATION
– prior approval supplement , annual report
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It consist of changes in location of the site of
manufacture, packaging operations, and/or analytical
testing laboratory for both company owned and contract
manufacturing facilities.
TEST DOCUMENTATION
1. CHEMISTRY DOCUMENTATION
Location of new site and updated batch records. Application/compendial release requirements
2. DISSOLUTION TESTING – Case B
3. NO BE REQUIRED
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LEVEL 1 CHANGES
o Changes in the batch size up to and including factor of 10 times the size of the pilot /
biobatch where
o The equipment is of same design and principle
o Batches are manufactured According to the CGMP compliance.
o Same SOP’s followed
o Test and filing documents are same as of the level 2 of the site changes requirement.
LEVEL 2 CHANGES
o Changes in the batch size beyond the factor of 10
TEST DOCUMENTATION
1. STABILITY TESTING
As per level 1 + one batch with three months accelerated stability + Case B dissolution
testing. (Other documents are same as above).
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A. EQUIPMENT
LEVEL 1 CHANGE
o This consist of
MANUFACTURING 1) Change from non-automated to automated or vice versa to
CHANGES move ingredients
2) Change to alternative equipment of same design and the
operating principle of the same or different capacity
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LEVEL 2 CHANGES
o Change in equipment to a different design
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B. PROCESS CHANGES
LEVEL 1 CHANGES
o This changes includes process changes like mixing times and operating speed
within application/validation range
o TEST AND FILING DOCUMENT as per level 1 of site change
LEVEL 2 CHANGES
o This changes includes process changes like mixing times and operating speed
outside the application/validation range
o TEST AND FILING DOCUMENTATION – as per the level 2 changes in
site changes
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LEVEL 3 CHANGES
o Change in the type of the process used in the manufacture of the product,
such as a change in from the wet granulation to the direct compression of
dry powder.
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o COMPONENTS AND
COMPOSITION-
NONRELEASE CONTROLLING
EXCIPIENT
SUPAC - MR
Focuses on changes to nonrelease controlling
excipients.
TEST DOCUMENTATION
1. CHEMISTRY DOCUMENTATION
Application/compendial product release requirement
2. STABILITY: First production batch-Long term stability data
3. DISSOLUTION DOCUMENTATION: None
4. BIOEQUIVALENCE DOCUMENTATION: None
o FILING DOCUMENTATION
Annual report- all information including long term stability data
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LEVEL 2 CHANGES
o TEST DOCUMENTATION
1. CHEMISTRY DOCUMENTATION
Application/compendial product release requirements and updated executed batch
records.
2. STABILITY: One batch with three month accelerated stability data reported in prior
approval supplement and long term stability data of first production batch reported in
annual report.
3. DISSOLUTION DOCUMENTATION
Extended release
Multipoint dissolution profile in 0.1N HCl and USP buffer media at pH 4.5 and 6.8
for the changed drug product and the bio batch or marketed batch (unchanged
drug product).
Delayed release
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BIOEQUIVALENCE DOCUMENTATION: None
FILING DOCUMENTATION
Prior approval supplement (accelerated stability data) annual report (long term stability
LEVEL 3 CHANGES
TEST DOCUMENTATION:
1. CHEMISTRY DOCUMENTATION:
Application/ compendial product release requirements and updated executed batch records.
2. STABILITY:
Significant body of information available:
One batch with three months accelerated stability data reported in prior approval supplement
and long term stability data of first three production batches reported in annual report.
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o BIOEQUIVALENCE DOCUMENTATION:
A single dose bioequivalence study. The bioequivalence study may be waived in presence of
an established in vitro/in vivo correlation.
FILING DOCUMENTATION:
Same as level 2 changes.
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COMPONENTS AND COMPOSITION —
RELEASE CONTROLLING EXCIPIENT
• Focuses on changes in release controlling excipients in the drug product.
• For modified release solid oral dosage forms, consideration should be given as to whether
or not the excipient is critical to drug release.
• The sponsor should provide appropriate justifications for claiming any excipient(s) as a
release controlling excipient in the formulation of the modified release solid oral dosage
form. The functionality of each excipient should be identified.
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LEVEL 1 CHANGES
TEST DOCUMENTATION
B. STABILITY: First production batch on long-term stability data reported in annual report.
D. BIOEQUIVALENCE DOCUMENTATION-None.
FILING DOCUMENTATION
Annual report (all information including long-term stability data)
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LEVEL 2 CHANGES
Are those that could have a significant impact on formulation quality and performance..
TEST DOCUMENTATION
a. CHEMISTRY DOCUMENTATION Application/compendial product release requirements
and updated executed batch records.
STABILITY: !
a. NON NARROW THERAPEUTIC RANGE DRUGS: One batch with three months'
accelerated stability data reported in prior approval supplement and long-term stability data
of first production batch reported in annual report. !
b. NARROW THERAPEUTIC RANGE DRUGS: Three batches with three months'
accelerated stability data reported in prior approval supplement and long-term stability data
of first three production batches reported in annual report
FILING DOCUMENTATION
Prior approval supplement (all information including accelerated stability data);
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annual report (long-term stability data).
BULK ACTIVE
POST APPROVAL
CHANGES
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This guidence provide recommendation to holders of
NADAs (New animal drug application), ANADAs
(Abbreviated new animal drug application),
VMFs(Veterinary master files)
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The reporting category for a change is based on the potential for the change to
have an adverse effect on the identity, strength, quality, purity, or potency of
the drug product as these factors may relate to the safety or effectiveness of the
drug product.
The guidance applies to synthetic drug substances and the synthetic steps involved
in the preparation of semisynthetic drug substances.
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THE GUIDANCE COVERS – TYPES OF CHANGES
2. SPECIFICATION CHANGES
For raw materials, starting materials, and intermediates, except the final intermediate,
and
4. MULTIPLE CHANGES
Combination of all above changes
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THE FOLLOWING CHANGES ARE EXCLUDED FROM THE BACPAC 1
Any specification change for a raw material, starting material, or intermediate derived
from a biotechnology process .
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Changes in virus or adventitious agent removal or inactivation methods
Changes in source material (e.g., Plant species, geographic location of plant harvesting,
microorganism) or supplier ofsubstances derived from natural sources that are the
intermediates that begin the synthetic part of a semi synthetic process.
The final intermediate was chosen as the break point in this attempt to categorize risk
because
(1) it is typically the most well characterized material in the synthetic scheme, except for
the drug substance itself, and
(2) physical properties of the drug substance usually will not be affected by changes
made up to that point.
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ASESSMENT OF CHANGES
A HOLDER OF AN APPROVED APPLICATION must assess the effects of the changes
before distributing a drug product made with the manufacturing change (according to
section 506a of the act).
A central tenet is that a given change in drug manufacturing process can be adequately assessed
by comparing pre and post change materials(i.e. Of same or better quality).
Two major factors for determining equivalence in drug substance are the:-
Impurity profile
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Physical property
A. EQUIVALENCE OF IMPURITY PROFILES
The analytical procedures used to evaluate the change should be adequate for
quantitating both existing and new impurities at the recommended levels. Development
of new analytical procedures may be called for.
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When new analytical procedures are developed for this purpose, a summary of validation
data should be provided. The same analytical procedure should be used when comparing
impurity levels in Pre- And Post Modification Batches.
The impurity profile will be considered equivalent after a given change if three consecutive
post modification batches of either an isolated intermediate or the drug substance are
evaluated and the test data for each batch demonstrate that
Each existing impurity is within its stated limit or, if not stated, is at or below the upper
statistical limit of historical data.
Total impurities are within the stated limit or, if not stated, are at or below the upper
statistical limit of historical data.
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Each existing Residual solvent is within its stated limit or, if not stated, is at or
below the upper statistical limit of historicaldata.
The batches of the intermediate or drug substance used for testing should be
synthesized using exclusively the material that has been subjected to the
change(s)(i.e., without blending with pre-change material)
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When a manufacturing change is made to an outsourced
intermediate, either the vendor or the customer can establish
equivalence. However, in addition to assessing equivalence of the
impurity profile, release testing by the vendor or acceptance testing
by the customer, as appropriate, should be conducted.
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EQUIVALENCE OF PHYSICAL PROPERTIES
Two physical properties of the drugsubstance,
1. Morphic Form
2. Particle Size,
The physical properties of the drug substance will be considered equivalent after a given
change if three consecutive post-modification batches of thefinished drug substance are
compared to three or more consecutive representative pre-modification batches and the test
data for each batch demonstrate
Conformance to established acceptancecriteria for Morphic form or, where acceptance criteria
do not exist, the isolation of the same form or mixture of forms within the range of historical
data
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Conformance to historical particle sizedistribution profile 43
A. SITE, SCALE, AND EQUIPMENT CHANGES
The manufacturing site, scale of manufacture, and
manufacturing equipment changes discussed inthis
section do not include any modifications to the
TYPES synthetic pathway (i.e., the samestarting
materials, intermediates, solvents, and reagentsare
involved).
OF
CHANGE
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1. SITE CHANGES
REPORTING CATEGORY:
Annual Report if the site change does not involve the final intermediate
Supplement :Changes Being Effected if the site change involves the final
intermediate
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2. SCALE CHANGES
Scale changes include increases and decreases in the batch size of
intermediates,including the final intermediate, beyond those approved in the
original application
3. EQUIPMENT CHANGES
A change to new equipment need not be submitted to the Agency, even where
equipment is specified in the approved application.
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B) SPECIFICATION CHANGES
Specification changes for the final intermediate are not included in this guidance, nor are
certain specification changes for raw materials, starting materials, and intermediates
derived from natural sources or biotechnology.
Test documentation
1. Rationale for the proposed change and a brief description of any newanalytical
procedures, including a discussion of improvements over existing procedures.
2. Updated specifications.
Reporting Category:
• Annual Report.
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3. OTHER SPECIFICATION CHANGES EXAMPLES:
Deleting a test
Replacing an existing analytical procedure with a new procedure that does not qualify
as an improvement
Revised specifications associated with changes in supplier/grade of starting
materials, reagents, or solvents
Elimination of a redundant test (e.g., deletion of a boiling point test for a solvent
where a chromatographic assay test is routinely performed)
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Elimination of a test that is no longer necessary (e.g., testing for an impurity that is no
longer present due to a change in the supplier of a starting material)
REPORTING CATEGORY:
1. Annual Report.
2. Supplement C
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C) MANUFACTURING PROCESS CHANGES
This category encompasses a wide range of process- related changes. New specifications may be
called for when different solvents, reagents, starting materials, or intermediates are involved
REPORTING CATEGORY:
1. Annual Report if equivalence is demonstrated priorto the final intermediate.
2. Supplement: Changes Being Effected if equivalence is demonstrated at the final
intermediate or drug substance.
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2. CHANGES IN THE ROUTE OF SYNTHESIS IN ONE OR MORE
STEPS INVOLVING DIFFERENT STARTING MATERIALSAND/OR
INTERMEDIATES (EXCEPT THE FINAL INTERMEDIATE)
TEST DOCUMENTATION
1. Description of the change with details of the new synthetic procedure, the operating
conditions,and controls of critical steps andintermediates
2. Appropriate structural characterization data for new intermediate
3. Specifications for any new starting materials and/or intermediates
4. Evaluation of the Impurity profile and physical properties.
REPORTING CATEGORY:
1. Supplement: Changes Being Effected in 30 Days if equivalence is demonstrated prior to the
final intermediate.
2. Prior approval supplement if equivalence is demonstrated at the final intermediate or drug
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substance.
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3.CHANGES IN WHICH AN INTERMEDIATE IS REDEFINED AS
A STARTING MATERIAL
This change is often in response to an increase in commercial availability of the proposed
starting material. In general, the specification for the proposed starting material should be
more comprehensive than the intermidiates.
TEST DOCUMENTATION
1. Rationale for the proposed change and overview of current synthetic procedure
2. Evidence that the intermediate complies with the current definition and/or expected
characteristics of a starting material.
• A description of how the suitability of a new supplier or revised process from an existing
supplier will be assessed.
REPORTING CATEGORY:
• Supplement: Changes Being Effected in 30 Days
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D) MULTIPLE CHANGES
Multiple changes are those that involve various combinations of the changes described insections
V.A, B, and C.
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BACPAC
CDER: http://www.fda.gov/cder/guidance/index.htm
CVM: http://www.fda.gov/cvm/fda/TOCs/guideline.html
FDA Guidance Documents Specifically Referenced In BACPAC I:
1) Submitting Supporting Documentation in Drug Applications for
the Manufacture of Drug Substances, CDER, February 1987.
2) Changes to an Approved NDA or ANDA, CDER, November 1999.
REFERENCES 3) Changes to an Approved Application for Specified Biotechnology
and Specified Synthetic Biological Products, Center for Biologics
Evaluation and Research (CBER) and CDER, July 1997.
ICH GUIDELINS
1. ICH Q3A Impurities in New Drug Substances, January 1996.
2. ICH Q3C Impurities: Residual Solvents, Federal Register,
December 1997.
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3. VICH GL10 Impurities in New Veterinary Drug Substances, May 58
2000
SUPAC
1. ICH HARMONISED TRIPARTITIE GUIDELINES www.ich.org
2. USP 2000
3. Encyclopedia of Pharmaceutical technology, Vol-19, pg. 227-235.
4. Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C.
T. Rhodes
5. www.who.int/medicines
6. Expert Consultation for 2nd Addendum to the 3rd Edition of the Guidelines for Drinking-
water Quality, Geneva, 15–19 May 2006
7. Pharmainfo.net
8. www.fda.gov
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