Validation Protocol
Title: Name
Type: Validation No: Version No:
Page 1 of 22
Cleaning CVYY NNN 01
Product Code:
Product Name:
Cleaning Procedure:
Equipment:
Location:
Approval and Authorisation
The author is signing to confirm that this document has been prepared in accordance with
SOP283 – Equipment Cleaning Validation.
Authored by: Job Title: Signature: Date:
The XXX Manager is signing to confirm that …
Authored by: Job Title: Signature: Date:
The XXX Manager is signing to confirm that …
Authored by: Job Title: Signature: Date:
The contents of this document are confidential and proprietary to Sigma Pharmaceutical and
should be used for internal purposes only. This document shall not be disclosed or used by third
parties except with the prior approval of the Compliance Manager.
No. XXVYY-NNN vVV
NAME
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TABLE OF CONTENTS
1 INTRODUCTION..................................................................................................................... 3
1.1 Aim 3
1.2 Formulation for Product Code – Product Name.......................................................................3
1.3 Equipment Used..................................................................................................................... 4
1.4 Other equipment and products validated.................................................................................4
2 CLEANING METHODS........................................................................................................... 5
2.1 Cleaning procedure Ref No.....................................................................................................5
2.2 Cleaning agents used............................................................................................................. 5
3 SAMPLING & TESTING METHODS.......................................................................................6
3.1 Qualitative Evaluation - Visual inspection................................................................................6
3.2 Quantitative evaluation............................................................................................................ 6
3.2.1 Residual detergent....................................................................................................6
3.2.2 Residual Active.......................................................................................................... 7
3.2.3 Microbiological analysis.............................................................................................7
4 ACCEPTANCE CRITERIA......................................................................................................8
4.1 Qualitative evaluation - Visual inspection................................................................................8
4.2 Quantitative evaluation............................................................................................................ 8
4.2.1 Residual detergent....................................................................................................8
4.2.2 Chemical Residues of Active.....................................................................................8
4.2.3 Microbiological Analysis...........................................................................................10
5 DOCUMENTATION OF RESULTS & DISCUSSIONS..........................................................10
5.1 Results for Equipment (3 batches)........................................................................................10
6 FUTURE WORK................................................................................................................... 14
6.1 Revalidation.......................................................................................................................... 14
6.2 On-going monitoring.............................................................................................................. 14
APPENDIX 1: EQUIPMENT FLOW CHART..................................................................................15
APPENDIX 2: SAMPLING LOCATIONS........................................................................................16
APPENDIX 3: PRODUCTS SHARING VALIDATED EQUIPMENT................................................17
APPENDIX 4: MAXIMUM PERMISSIBLE CONTAMINATION OF ACTIVE....................................18
APPENDIX 5: VALIDATION OF RECOVERY OF ACTIVE BY SWABBING...................................21
APPENDIX 6: DETECTABLE CONTAMINATION BY HPLC..........................................................22
Form prepared by Date Approved by Date Form F283a.01
No. XXVYY-NNN vVV
NAME
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1 INTRODUCTION
All manufacturing equipment must be cleaned according to an approved departmental cleaning
procedure to prevent the contamination of product with residual cleaning agents, micro-organisms,
potent or active chemicals from previous batches or air-borne particles, dust and lubricants.
This validation protocol is prepared in accordance with SOP 283 - Equipment Cleaning Validation,
and is initiated for Product Name which has been identified from the Site Cleaning Matrix as the
exhibit (hardest to clean) product for the cleaning procedure Ref No.
1.1 Aim
The aim of this protocol is to determine and confirm the effectiveness of standard cleaning
materials and procedures in removing physical and chemical residues of Product Name from
Equipment via the Ref No. Cleaning procedure Ref No is described in Section 2.
Testing for the removal of residual detergents during rinsing will also be done to ensure that there
is no residual detergent left on the equipment. Microbiological swabbing will also be performed for
microbiological evaluation of the equipment after cleaning. The validation is to be performed on at
least three batches of the product in order to confirm the reproducibility of the process.
1.2 Formulation for Product Code – Product Name
Table 1: Formulation for Product Code – Product Name according to Formula Maintenance
Rev. X.XX
Batch
Code Ingredient %w/w
Quantity (kg)
Total:
Rationale on why product and equipment combination is chosen, refer to matrix, “Products for CV”
Page.
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1.3 Equipment Used
The equipment to be validated in this protocol is:
Equipment and Parts
Digitised images of the equipment and sampling locations are in Appendix 2.
The process flow chart in Appendix 1 shows the equipment train involved in the manufacturing of
Product Name. It can be observed that other equipment is involved in the manufacture of Product
Name and comes in contact with Active. However, only the equipment listed above is to be
validated as per this protocol as other equipment is cleaned using a different cleaning procedure.
Other Equipment
Cleaning validations for the other equipment listed above are documented in separate protocols.
The worst case product and equipment combination for each cleaning procedure is defined in the
Cleaning Matrix and subsequently validated to minimise the risk of contamination.
1.4 Other equipment and products validated
Cleaning procedure Ref No is shared in the cleaning of other pieces of equipment. Table 2 below
lists all the equipment that is covered by this protocol and its respective cleaning SOP.
Table 2: SOP and Equipment sharing the validated cleaning procedure
SOP/OM Equipment
A list of all products, used in the equipment listed above is contained in Appendix 3.
The validation of Product Name in equipment is assumed to cover these other equipment and
products that are cleaned via cleaning procedure Ref No as it is considered to be the worst case
cleaning episode presented to Ref No.
List Checked By:
Name: Job Title: Signature: Date:
Area Production Manager
Name: Job Title: Signature: Date:
Product Development Manager
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2 CLEANING METHODS
2.1 Cleaning procedure Ref No
The cleaning procedure Ref No for Equipment follows the procedure in SOPXXX – SOP Title. An
outline of the cleaning procedure is described below:
Insert brief procedure
2.2 Cleaning agents used
The following cleaning agents are used in the cleaning process. These cleaning agents are listed
in SOP810 – Approved cleaning reagents.
Table 3: Information on cleaning agents used in the cleaning procedure
Ingredient ACRXX
Name of Detergent
Supplier
pH
Surfactants
Sodium Hydroxide
Non hazardous ingredients
Sodium Hypochlorite
Corrosion inhibitor
Dye
Water
Location & method of use
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3 SAMPLING & TESTING METHODS
All equipment must be cleaned prior to cleaning validation sampling in accordance with the
currently approved equipment cleaning procedure in the SOP or OM. The person conducting the
study must examine the equipment for visible evidence of product, lubricant and detergent
residues and for any odour indicative of inadequate cleaning. In order to challenge the cleaning
process samples will be taken in hard to clean areas that are in contact with the product, such as
outlet valve, wall in the inside corner of the equipment. Sampling methods are described in
SOP283. The sample plan is to include all locations indicated in section 5. Additional samples
may be taken, if necessary, and the results must be included in the report.
The time elapsed between washing of equipment, sampling, and testing (for both direct surface
swabbing and rinse water sampling) is to be recorded.
3.1 Qualitative Evaluation - Visual inspection
Visual inspection must be conducted before collecting samples for cleaning validation.
All surfaces should be inspected for evidence of any residues, smells, oils, material or powder,
as per SOP283.
The inspection must cover all equipment; dismantled parts and seals, grooves of seals, and all
valves must be dismantled for inspection.
The inspection must also determine if there are any odours coming from any of the parts,
especially any plastic or synthetic rubber parts.
Any areas in doubt should also be wiped with a blue cloth to check for residues.
Areas appearing to have residues are to be re-washed, and these areas should be included in
the locations for swabbing. Rewashing due to odour detection is to be reported in the
validation report.
3.2 Quantitative evaluation
3.2.1 Residual detergent
Sampling method
The vessels used are to be final rinsed with purified water (or WFI), and 50 mL of this rinse water
should be collected in a sample container for pH & conductivity testing, as per SOP 283. Duplicate
40mL rinse samples are also collected for TOC testing in certified TOC vials.
Alternatively the washed parts can be placed in a stainless steel bucket containing approximately
10L of purified water and swirled around to rinse. Samples of this rinse water are taken for pH and
TOC testing. This applies to the sampling of dismantled outlet valves or filling lines in the wash
bay, before the equipment is re-assembled and sanitised.
A concurrent sample of purified water should be also collected in a separate container. One
control sample each for pH & conductivity, and duplicate control samples are taken for TOC
testing.
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Testing method
The pH of the rinse samples can then be determined as per OM0003.34.
The conductivity can be determined using conductivity probe in chemistry laboratory.
The TOC samples are sent to the QC laboratory in Merrindale Drive for TOC testing.
The makes and models of the instruments used to test the TOC samples, pH, and conductivity,
as well as the last calibration, date and time of testing, and the person doing the testing should
be recorded in the cleaning validation report.
3.2.2 Residual Active
Sampling method
Chemical swabs are taken where a potent active is present in the product that comes in contact
with the cleaned equipment (prior to be cleaned). Any locations that appeared to have residues
during the initial visual inspection are also to be swabbed after additional cleaning. Swabbing
should follow the procedure set out in SOP283. The swabs are prepared as per G0041 and
moistened with swab solvent. All samples must be numbered and referenced to either an
equipment diagram or swab list indicating their location.
Testing method
The Active content of each swab will then be determined using HPLC (OM003.23) test method,
incorporating the recovery factor determined in analytical method validation MVXXX.XXX
Each area swabbed for Active residues must be wiped subsequently with 70% alcohol or rinsed
with purified water (or WFI) before the equipment is assembled for use. The time elapsed between
washing of equipment and swabbing will also be recorded. Any locations that appeared to have
residues during the initial visual inspection are also to be swabbed after additional cleaning.
The model and make of the equipment used for HPLC analysis should be recorded, including last
calibration date, and person responsible for the testing.
3.2.3 Microbiological analysis
Surface swabs should also be taken for microbiological testing. Micro swabs should be carried out
according to G00118 and SOP283. The microbiological and chemical samples must not be
collected from the same place, and should be taken in adjacent areas, or in identical pieces of
equipment (where more than one set of the equipment is used, eg: filling nozzles or pumps).
Each area swabbed must be wiped subsequently with 70% alcohol before it is assembled for use.
The time elapsed between washing of equipment and swabbing will also be recorded. All samples
must be numbered and referenced to either an equipment diagram or swab list indicating their
location. Where possible, the swabs should be agar-plated within a day of taking the sample.
A record stating the person responsible for microbiological analysis should be included in the
report.
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4 ACCEPTANCE CRITERIA
4.1 Qualitative evaluation - Visual inspection
The cleaning procedure must produce equipment that is visibly clean with no evidence of detergent
or lubricant or residues or powder accumulation on any surfaces, no discolouration of wetted cloths
and no odour detected.
4.2 Quantitative evaluation
4.2.1 Residual detergent
The pH of the final rinse water must not differ from the pH of the water used for cleaning by more
than 0.3 units, either higher or lower, depending on whether the detergent under investigation is
acidic or alkaline.
The conductivity of the final rinse water should be less than 4.3µS/cm at 20ºC for purified water
samples, and less than 1.1µS/cm at 20ºC for WFI (water for injection) samples. This is the
maximum conductivity of purified water or WFI (according to BP), which is used to final rinse the
equipment.
The TOC result should be no more than 500ppb per 40mL sample. This is the maximum TOC
count as specified in BP for purified water or WFI. It translates to 500ppb of carbon residues in the
sample.
The Pharmacopoeia standard is assumed to be sufficient in setting the cleanliness of the
equipment from detergent.
4.2.2 Chemical Residues of Active
The cleaning procedure must leave less than 0.1% of the stated content of active carried over
either into the next dosage unit produced or into the next batch produced, depending on the swab
position. For active materials of high physiological potency and/or known adverse effect at low
dose, the maximum no-effect threshold dose in humans may be considered a more appropriate
measure. The method for calculating the limits is outlined in SOP 283.
Reasoning for Permissible Contamination
The approved safety factor in the pharmaceutical industry is usually 0.1%. For products which do
not have a defined daily dose (eg: creams, eye drops etc), a unit such as the smallest container fill
size is used in place of doses sizes.
The acceptance criteria assume that the carryover detected is evenly distributed over all surfaces,
which is generally not the case. However, this assumption still represents the worst case in the
sense that if the swabbings are done on the hardest to clean locations, it will be harder to meet the
residue limits of even distribution. In addition, it is expected that for some equipment, the residues
will only affect the first lot of product transferred. By combining the surface area of the entire piece
of equipment, one uniform acceptance limit will be obtained, and this limit will be lower than limits
for individual equipment parts (since larger surface area result in lower limit).
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The acceptance limits for the marker (most toxic) product for equipment is calculated in appendix
4. The marker product is the product containing the most toxic active ingredient used in the
equipment, and generally has the lowest therapeutic dose amongst all other active. The limits
calculated for the marker product are used as the maximum permissible contamination for the
exhibit (hardest to clean) product to be validated.
Most Toxic Active has been identified from Appendix 3 as the most toxic active in Equipment. The
acceptance limit of Most Toxic Active will therefore be used in as the acceptance limit of the Active
(Exhibit product) residue. It is assumed that if the test for Active residue can pass Most Toxic
Active acceptance limit, it will pass its own acceptance limits too. The calculations for the limits are
covered in Appendix 4. Reword sentence if the active being tested is also the most toxic
Recovery of Active
The recovery study of Active from swabs is required to show that the sampling procedure is able to
recover sufficient amount of active and that the analytical method used, which in this case is
HPLC, is capable to detect active and is accurate and reliable.
The recovery of active from stainless steel surfaces has been validated as Recovery% (Appendix
5), and the recovery of active from other surfaces has been validated as Recovery% (Appendix 5).
The limit of detection of active using HPLC assay was found to be LOD μg/mL (Appendix 6).
Therefore, the minimum level of active detectable by swabbing and HPLC analysis is
LOD*4/Recovery μg/swab (Appendix 6).
Acceptance Limits
The acceptance limits of Active are summarised in the Table 4 below:
Table 4: Acceptance limits of active residues for equipment validated
Total acceptable residue Maximum residue per swab
Equipment
(Appendix 4) (Appendix 4)
mg µg
The total acceptable residue of active for equipment is X mg. The maximum residue per 100 cm²
(typical swab area) is X µg. Assuming that the residue is evenly distributed, this limit is acceptable
for all of the equipment parts involved in the manufacturing of this product in Equipment.
As the detectable contamination by HPLC is LOD*4/Recovery μg per 100cm² swab area, these
maximum residue limits are within the detection limits of the analytical procedure.
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4.2.3 Microbiological Analysis
Acceptance criteria for microbiological loading are determined as per G00118.
The microbiological loading on the cleaned equipment in non-sterile area must be less than:
Alarm Limit: 50 cfu/100cm2
Action Limit: 100 cfu/100cm2
5 DOCUMENTATION OF RESULTS & DISCUSSIONS
The results and discussions for the cleaning validation are to be separately documented in
cleaning validation reports. The reports will also be required to include digitised images of sampling
locations not covered in Appendix 2 of this protocol.
Results for each batch monitored will be written up and revised separately to avoid undue delay in
reporting results, while awaiting schedules of future batches. The final report will review the
previous reports and draw a conclusion.
5.1 Results for Equipment (3 batches)
The following table format will be used to record the results for each validation batch. There will be
3 validation batches performed on the equipment.
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Product prior to cleaning: «Product - Code»
Batch number:
Manufacturing Complete: Date: Time:
Cleaning Complete: Date: Time:
TOC Sampling Date: Time:
Swab Sampling: Date: Time:
Sampled by:
Cleaning procedure: Cleaning Ref. No: Cleaning SOP:
Cleaned by:
Notes: «Any deviations from SOP»
Cleaning agents:
Solvent used for swabs:
pH & conductivity testing: Tested by: Date/Time:
Active residues testing: Tested by: Date/Time:
TOC testing: Tested by: Date/Time:
Micro analysis: Tested by: Date/Time:
pH meter k meter TOC HPLC
Siever TOC Model
Make & Model
820 Analyzer
Last Calibration
Date
Area Swab Active Micro
Swabbing
Appearance Swabbed Register No. Residues Analysis
locations
(μg/swab) (cfu/swab)
Blank swab
Rinse water sampling location pH k (µS/cm) TOC Register No. Results
Control purified water
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Product prior to cleaning: «Product - Code»
Batch number:
Manufacturing Complete: Date: Time:
Cleaning Complete: Date: Time:
TOC Sampling Date: Time:
Swab Sampling: Date: Time:
Sampled by:
Cleaning procedure: Cleaning Ref. No: Cleaning SOP:
Cleaned by:
Notes: «Any deviations from SOP»
Cleaning agents:
Solvent used for swabs:
pH & conductivity testing: Tested by: Date/Time:
Active residues testing: Tested by: Date/Time:
TOC testing: Tested by: Date/Time:
Micro analysis: Tested by: Date/Time:
pH meter k meter TOC HPLC
Siever TOC Model
Make & Model
820 Analyzer
Last Calibration
Date
Area Swab Active Micro
Swabbing
Appearance Swabbed Register No. Residues Analysis
locations
(μg/swab) (cfu/swab)
Blank swab
Rinse water sampling location pH k (µS/cm) TOC Register No. Results
Control purified water
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Product prior to cleaning: «Product - Code»
Batch number:
Manufacturing Complete: Date: Time:
Cleaning Complete: Date: Time:
TOC Sampling Date: Time:
Swab Sampling: Date: Time:
Sampled by:
Cleaning procedure: Cleaning Ref. No: Cleaning SOP:
Cleaned by:
Notes: «Any deviations from SOP»
Cleaning agents:
Solvent used for swabs:
pH & conductivity testing: Tested by: Date/Time:
Active residues testing: Tested by: Date/Time:
TOC testing: Tested by: Date/Time:
Micro analysis: Tested by: Date/Time:
pH meter k meter TOC HPLC
Siever TOC Model
Make & Model
820 Analyzer
Last Calibration
Date
Area Swab Active Micro
Swabbing
Appearance Swabbed Register No. Residues Analysis
locations
(μg/swab) (cfu/swab)
Blank swab
Rinse water sampling location pH k (µS/cm) TOC Register No. Results
Control purified water
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6 FUTURE WORK
6.1 Revalidation
A revalidation is not required unless the following circumstances occur:
Change in formulation of product that will result in a worse case, e.g. higher concentration
Change in cleaning method, e.g. change in detergent
Change in production environment, e.g. different site
A new product containing a worse case ingredient is introduced to the equipment
More than 3 years has passed since the last cleaning validation
6.2 On-going monitoring
On-going monitoring should be instituted to ensure the consistency of the cleaning results. This is
a less strenuous exercise than the actual validation, and only one batch is required for each
monitoring exercise.
Periodic ongoing monitoring of cleaning procedures and cleaning operators will take place via TOC
analysis. As part of the analytical validation the LOD determined via HPLC analysis is equated to
a TOC value. This value is then use to represent an investigation limit during ongoing monitoring.
If this limit is breached an investigation into the root cause of the incident should follow.
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APPENDIX 1: EQUIPMENT FLOW CHART
The equipment covered by this protocol is highlighted in grey.
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APPENDIX 2: SAMPLING LOCATIONS
Solid arrows indicate recommended swabbing locations.
Dotted arrows indicate locations where rinse sample should be taken.
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APPENDIX 3: PRODUCTS SHARING VALIDATED EQUIPMENT
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APPENDIX 4: MAXIMUM PERMISSIBLE CONTAMINATION OF ACTIVE
The acceptance limits for the Marker (most toxic) product are used as the maximum permissible
contamination for the Exhibit (hardest to clean) product.
A. Equipment Surface Area
Equipment parts: Approximate Surface Area:
cm²
cm²
cm²
Total Surface Area: cm2
B. Method for calculating limits
The acceptance limits for the marker (most toxic) product for Equipment are calculated using the
0.1% safety factor, as follows:
Limit (mg) = 0.1% × Minimum therapeutic dose (mg) × Smallest No. doses in a batch
EQUATION 1
Where, the therapeutic dose is the minimum daily active dose in the marker (most toxic) product,
and can be calculated as follows:
Minimum Therapeutic dose (mg) = % (w/w) of active in product × Minimum daily dose (mg)
EQUATION 2
The number of doses in a batch for each product can be calculated as follows:
No. of doses in a batch = Batch size (kg) / maximum daily dose (mg)
EQUATION 3
The number of theoretical doses for each product is calculated as per equation 3, and the smallest
number of doses in a batch for any product in the equipment being validated is used to calculate
the Limit in Equation 1.
The calculations for equations 2 and 3 are performed in the product matrix for each site, which is
located at S:\Everyone\Validation\Cleaning Validation\Cleaning Matrix for each site.
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C. Calculations
The most toxic active identified from the Site Product Matrix for Equipment is Active2 in Product
Name2
The therapeutic dose is calculated for the Marker (most toxic) product as follows:
Minimum Therapeutic dose (mg) = % (w/w) of active in product × Minimum daily dose (mg)
EQUATION 2
Product Name contains A %w/w of Active and the minimum daily dose of Product Name is B mg.
Therefore, the minimum therapeutic dose of Active is:
Minimum Therapeutic dose (mg) = A %w/w × B mg
= C mg
The number of doses in a batch for each product is calculated as follows:
No. of doses in a batch = Batch size (kg) / maximum daily dose (mg)
EQUATION 3
The product matrix shows that Product Name3 has the smallest number of doses per batch, with a
batch size of D kg, and a maximum daily (NOT active) dose of E mg. For liquids, the dose size
(mg) can be calculated by multiplying the dose size in mL by the specific gravity of the product
(from the product specifications).
Therefore, the number of doses for Product Name is:
No. of doses in a batch = D kg / E mg
= F units
This figure is used as the “Smallest No. of doses in a batch’ in Equation 1.
The limit in EQUATION 1 refers to the permissible contamination of the active for the whole
Equipment and is calculated as follows:
Limit (mg) = 0.1% × Minimum therapeutic dose (mg) × Smallest No. doses in a batch
EQUATION 1
Therefore,
Limit (mg) = 0.1% × C mg (From Equation 2) × F units (From Equation 3)
= I mg total permissable contamination for Equipment
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The limit per swab (assuming a typical swab area of 100cm²) can be calculated by:
Limit per swab (mg/swab) = Limit (mg) × 100cm²/ Surface area (cm²)
EQUATION 4
Appendix 3 shows that the total surface area that may come into contact with the product for
Equipment is H cm². Therefore:
Limit per swab (mg/swab) = I mg total permissable contamination × 100cm²/ H cm².
= J µg/swab
«Alter paragraphs below accordingly if active tested is also most toxic»
Total permissible contamination for the Marker product – Product Name2 is I mg, which is equal to
J µg/swab. This will be used as the maximum permissible contamination of active in the exhibit
(hardest to clean) product.
The Active in the Exhibit (hardest to clean) product has a maximum permissible contamination of K
mg, and therefore the limit for the Active2 in the marker (most toxic) product is approximately K/I
times lower.
Therefore, if the active residues from the Exhibit (hardest to clean) product detected from sampling
are lower than the limit from the Marker (most toxic) product, J µg/swab, the cleaning process is
almost guaranteed to have removed any more soluble active ingredients to an acceptable level.
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APPENDIX 5: VALIDATION OF RECOVERY OF ACTIVE BY SWABBING
The recovery of Active from swabbing different surfaces has been performed as per GM0041, and
analytical method validation MVXX.XXX is attached.
Attach Recovery Study from the lab or reference
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APPENDIX 6: DETECTABLE CONTAMINATION BY HPLC
The LOD for Active assay is found to be LOD μg/mL (as per Reference on the validation results
document).
The recovery of active from swabs of stainless steel surfaces has been validated as Recovery %,
and the recovery of active from other surfaces has been validated as Recovery % (Appendix 5).
The contamination on swab is rinsed into 4mL of diluent and injected directly for HPLC assay.
Therefore, the swab carries:
Minimum level of active detectable by swabbing and HPLC (µg)
= LOD (μg/mL) × 4mL / (Recovery %)
Minimum level of Active detectable by swabbing and HPLC analysis
= LOD μg/mL × 4mL / Recovery %
= XX μg per swab
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