Protocol Validation Residual of Betalactam
Protocol Validation Residual of Betalactam
Protocol Validation Residual of Betalactam
1.0 PURPOSE
1.1 To define the minimum basic technical and regulatory requirements for penicillin or
cephalosporin decontamination to render a facility suitable for use for non-lactam production.
This document is to be used for one-time decontamination of facilities. There may be
additional requirements or more appropriate methods based on local regulations. This
document does not preclude, but rather supports, the need for site specific change control
documentation.
1.2 The analytical standard for demonstrating adequate Penicillin (beta-lactam antibiotic)
decontamination of facilities, separation within the same building, or measurement of
cross-contamination of facilities is codified at CFR 211.176.
2.0 SCOPE
2.1 Any manufacturing facilities undergoing decontamination for penicillin or
cephalosporin.
3.0 RESPONSIBILITIES
3.1 Quality & Compliance - Quality Operations
3.1.1 Reviewing decontamination plans and protocols.
3.1.2 Reviewing decontamination data submitted by the local facility.
3.1.3 Providing technical assistance with the decontamination upon request.
3.2 Engineering/Production Operations
3.2.1 Generate SOPs for the decontamination and sampling process.
3.2.2 Obtain the resources for performing the actual decontamination and
sampling, and assure that the SOPs for these activities are followed and that all
activities are documented.
3.2.3 Carry out the routine (3-lactam monitoring program (Section 13.0)
3.3 Validation Group
3.3.1 To ensure overall adherence to this guideline during the decontamination program.
Specific responsibilities include:
3.3.1.1 Preparation of the decontamination and sampling protocol.
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Subject/Title:
PINICILLIN/ CEPHALOSPORIN DECONTAMINATION OF FACILITIES
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Subject/Title:
PINICILLIN/ CEPHALOSPORIN DECONTAMINATION OF FACILITIES
4.2.1.5Rooms shared by employees e.g. offices, cafeterias, wash
areas, laboratories, etc.
4.2.1.6 Personal equipment (typewriters, calculators), file cabinets, etc.
4.3 Items to be Discarded
4.3.1 Depending on the scope of the decontamination, ceilings and even walls and
floors may be marked for removal. Certain items cannot be subjected to
complete decontamination and would have to be discarded. This would include
the following:
4.3.1.1 Air handling ducts.
4.3.1.2Filter media for HVAC systems including pre-filters,
dust-collecting filters, and HEPA filters.
4.3.1.3Porous materials such as insulation, ceiling tiles, fiber drums,
wooden pallets, and wooden boxes.
4.3.1.4Paper work which must be retained should be placed in plastic
bags, sealed and moved to a storage site or archive. All other paper
work should be discarded.
4.3.1.5All clothing, including shoes, previously worn or stored in the
penicillin or cephalosporin area.
4.3.1.6Some structural material, e.g. cinder block or porous concrete
surfaces are not suitable for decontamination but may not be
replaceable either. This type of item must be cleaned as thoroughly
as possible, sealed by painting with an epoxy paint and then
decontaminated.
Note: Quality & Compliance Quality Operations must be notified and give approval for any exceptions prior
to initiation of the decontamination program.
Note: All replacement parts, equipment, etc. must be kept off site until the decontamination is
completed and approved.
5.0 PRE-DECONTAMINATION PROCEDURE
5.1 Remove all items which have been identified as Items to be Discarded (Section 4.3), to
an appropriate disposal site.
5.2 The area should be disassembled to its most basic form.
5.3 The preparation, cleaning and decontamination procedures should be performed
working from the upper areas to the lower areas, e.g. start from the roof area to the
mezzanine; proceed to the upper most and then to the lower floors. Within a room or
area, begin with stationary equipment followed by the ceiling, walls and finally the floor.
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Subject/Title:
PINICILLIN/ CEPHALOSPORIN DECONTAMINATION OF FACILITIES
8.2.2 8.2.1.2
Wiping: Electrical components. Wipes must be disposable, non-linting if in a
sterile area, and changed with each major item change.
8.2.1.3 Soaking: Utensils, tools, etc.
Contact Time
8.2.2.1 The exposure time before rinsing is at least 2 hours and must be supported by agent
effectiveness studies.
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Subject/Title:
PINICILLIN/ CEPHALOSPORIN DECONTAMINATION OF FACILITIES
8.3 A rinsing procedure adequate to remove all the decontaminating agent should be
performed.
9.0 SAMPLING (SWABBING) PLAN FOR TRACE PENICILLIN/CEPHALOSPORIN
9.1 A Swabbing Procedure for Sampling Surfaces for Trace Residues is provided as
Appendix II and describes the swabbing method which should be used (other methods
may be used when validated).
9.2 Swab recovery studies must be done to determine levels of contamination that can be
recovered from the various surfaces within the facility. The minimum recovery efficiency
will be specified as part of method validation.
9.3 Critical versus non-critical areas/items must be recognized when designing the sample
plan. The most difficult to clean areas should be swabbed; this should include horizontal
surfaces, hard to clean areas on motors and at surface intersections. The exact location
of each swab must be documented. A swab may be used to sample related items
(minimum sample area 5 cm x 5 cm, or as per other validated method) as long it is
understood that a positive test result will require re-decontamination of all items swabbed
with that individual swab. It must be kept in mind that a swab will represent a predefined
area or item.
9.3.1 Critical Areas/Items
9.3.1.1 All areas/items designated critical must be swabbed.
Areas/items may require multiple swabs based on size.
9.3.1.1.1 Walls 1 swab per 100 square feet. Minimum of 1
swab/each wall (include an upper corner of the room).
9.3.1.1.2 Floors 1 swab per 100 square feet. Minimum of 2
swabs/room.
9.3.1.1.3 Ceilings 1 swab per 100 square feet.
Minimum of 2 swabs/room.
9.3.2 Non-Critical Areas/Items
9.3.2.1 The number of points sampled should be determined after the
area/item list is reviewed.
9.3.2.1.1 Walls 1 swab per 400 square feet. Minimum of 1
swab/room.
9.3.2.1.2 Floors 1 swab per 400 square feet. Minimum of 1
swab/room.
9.3.2.1.3 Ceilings 1 swab per 400 square feet.
Minimum of 1 swab/room.
9.3.2.1.4 All Other A minimum of 10% of the total
number of items listed as the most difficult to clean
non-critical equipment must be swabbed.
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Subject/Title:
PINICILLIN/ CEPHALOSPORIN DECONTAMINATION OF FACILITIES
10.0 TEST METHOD
FDA-By-Lines N:3
11.0 LIMITS
The Limits which apply for the testing must be designated in the protocol and SOP.
11.1 Critical Items Negative to test.
11.2 Non-Critical Items Negative to test.
12.0 ACTION PLAN FOR AREAS OR ITEMS WHICH EXCEED THE LIMITS
For both critical and non-critical items, the unit to be re-decontaminated is defined based
on how the swab areas were defined (Attachment I). Even if there is more than one swab
for a particular surface, each swab sample is representative of an entire surface area of a
wall, floor, ceiling, or other item. Therefore, when a swab sample exceeds the limits, the
decontamination process for the entire surface area must be repeated followed by swab
sampling.
12.1 For example, if a floor sample is out of specification, the entire floor area and any
other affected floor areas must be re-decontaminated; if a table has an area out of
specification, the entire table must be re-decontaminated.
12.2 The first pass minimum decontamination effectiveness must be indicated as part
the facility cleaning protocol. The decontamination procedure used may require
revision if deemed inadequate for the decontamination of the facility.
13.0 ROUTINE MONITORING
13.1 Following satisfactory decontamination of a facility, a program of routine swab
monitoring must be established. This program must provide an assessment of the
facility and equipment on an ongoing basis.
13.2 Following introduction of non-beta-lactam products, testing of these products for
the presence of beta-lactam residue must be conducted on a batch-by-batch basis.
13.3 A program to control and monitor for future demolition and construction activities
for the decontaminated facility must be in place to ensure these interventions do not
create contamination potential by disturbing previously undisturbed structures and
fixtures.
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Subject/Title:
PINICILLIN/ CEPHALOSPORIN DECONTAMINATION OF FACILITIES
APPENDIX I
The following documentation must be prepared and maintained for the decontamination
program:
1. A statement indicating that all areas and items were prepared and cleaned as per SOP.
The SOP number and title should be listed.
2. A list of areas/items which were decontaminated. This list should indicate the specific
area or item, whether the item is critical or non-critical as defined in 4.1 and 4.2, the
decontamination date, the swab sampling date and result (if applicable), and any re-
decontamination/ resample/ retest and the dates performed if applicable (See
Attachment I).
3. A schematic diagram of the area including dimensions, room numbers, functions of the
rooms, and air system. The air system should indicate everything from intake to room
feeds. If the system is shared, the shared area should be included.
4. A list of items which were discarded as in 4.3.
5. Sampling protocols must clearly define exact sampling locations so that they can be
identified at a later date.
6. Swab method and analytical procedures and analysis and validation reports.
7. Swab recovery studies for each material to be cleaned.
8. Decontamination effectiveness study indicating agent, concentration and the minimum
effective hold times.
9. Any deviation investigations that were relevant to the decontamination process should
indicate root cause and corrective actions.
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Subject/Title:
PINICILLIN/ CEPHALOSPORIN DECONTAMINATION OF FACILITIES
APPENDIX II
PURPOSE:
To present a swabbing procedure that may be used to monitor decontamination activities.
RESPONSIBILITY
Personnel taking swab samples must adhere to this procedure when decontamination procedures are
being performed.
PROCEDURE:
1. Each sample requires application to each sample area of 2 sterile swabs (e.g. sterile, cotton
tipped applicator Pur-Wraps). The first swab applied to the sample area is pre-moistened with 1%
Potassium Phosphate buffer solution pH 6.0. The second swab applied to the sample area is
applied dry.
2. Carefully and permanently mark a tube containing 4 ml sterile 1% Potassium Phosphate buffer
solution pH 6.0 with an identifying number. A numbered worksheet should be prepared ahead
of time so the sample locations can be recorded.
3. Using the pre-moistened swab, swab the chosen location firmly over a 5 cm X 5 cm (2" x 2") area
(25 sq. cm. or 4 sq. inches). By rolling the swab as you contact the surface, the contact surface of
the swab will be maximized. Following contact immerse this swab in the pre-numbered tube.
Using the dry swab, swab the same area until visible residual moisture on the sample surface is
absent. Immerse this swab in the same tube as the first swab. Assay both swabs simultaneously
as one sample.
4. A minimum of one unexposed swab should be included for each 50 samples taken as a
control.
5. The swabs in the pre-numbered tubes are held (refrigerated at 2-8C) until tested as per the
applicable test, but for no longer than 24 hours.
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COMPLIANCE REPORT
PENICILLIN/CEPHALOSPORIN DECONTAMINATION
OF FACILITIES
ATTACHMENT I
REFERENCE # 1 2 3 4 5
ROOM #
ITEM
SWAB LOCATION
CRIT./NONCRITICAL
DECON. DATE
SWAB DATE
TEST DATE
SWAB DATE
TEST DATE
REFER 6 7 8 9 0
ENCE #
ROOM #
ITEM
SWAB LOCATION
CRIT./NONCRITICAL
DECON. DATE
SWAB DATE
TEST DATE
RESULT (per swab)
RE-DECON. DATE
SWAB DATE
TEST DATE
RESULT (per swab)
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COMPLIANCE REPORT
PENICILLIN/CEPHALOSPORIN DECONTAMINATION
OF FACILITIES
SWAB LOCATION at diffuser bottom right top left middle left middl
CRIT./NONCRITICAL C C C C C
DECON. DATE 1/Jul/90 1/Jul/90 1/Jul/90 1/Jul/90 1/Jul
SWAB LOCATION ft. top shield side south wall, middle drawer, rt. m
center side
CRIT./NONCRITICAL C C C NC NC
ATTACHMENT II
DECONTAMINATION APPROVAL