SOP FOR CLEANING VALIDATION
PURPOSE: To describe the procedure for Cleaning Validation studies to be followed for equipment/ accessories used in manufacturing.
SCOPE: This SOP is applicable for documented evidence and actual experimental data that the procedure being followed for cleaning of equipment and accessories is effective and removes all residues of previous product up to a predetermined acceptance level thereby avoiding the risk of cross contamination. This procedure is also applicable for deciding worst case products for performing cleaning validation at the manufacturing facility.
RESPONSIBILITY:
Preparation of SOPs: Officer QA Department
Checking and Review of the SOPs: Sr. Officer QA Department
Approval of the SOPs: Executive QA Department
Authorizing of SOP: Head QA/Designee
Provide Utility support in execution of cleaning validation – Officer/Executive Engineering.
ACCOUNTABILITY: Head Production and head QA
PROCEDURE:
Definitions: Cleaning Validation: Cleaning validation shall be performed to provide a documented evidence and actual experimental data that the procedure being followed for cleaning of equipment and accessories is effective and removes all residues of previous product up to a predetermined acceptance level thereby avoiding the risk of cross contamination. This procedure is also applicable for deciding worst case products for performing cleaning validation.
Worst case product: The product selected from group of products that represents a great risk carry over contamination to other products made in the same equipment by virtue of its solubility, toxicity, dose or a combination of these factors and clean ability aspects.
Cleaning Validation Approach:
Method of Calculating Acceptance criteria for residue of Active Ingredient:
Criteria No. 1 (Dose criteria): The principle for the requirement is that the standard Therapeutic Daily Dose (TDD) of the next product may be contaminated by no more than a certain proportion (1/1000 part i.e. NMT 0.001 dose) of the TDD of the product investigated in the cleaning validation (“worst product”). This method only applies when the therapeutic daily dose is known. Scientific rationale for above statement is that pharmaceuticals are often considered to be non-active at 0.1 of their normally prescribed dosage (1/10th) and the facility is solid dosage manufacturing.
Criteria 2 (ppm criteria): NMT 10 ppm of previous product shall appear in next product. 10 PPM criteria shall be followed until the identification of the worst case product. Scientific rationale of above statement is based on regulations for food industry which provides for maximum permissible limit of certain levels of hazardous substances.
Criteria No. 3 (Visually clean criteria): No quantity of residue should be visible on the equipment after cleaning procedure is performed. Scientific rationale of above statement is that the active ingredients in most of the product are visible at approximately 100 µg per 4sq. inch of surface area. Below that level, the residues are not visible human eye considered as acceptable in products that enter human food chain.
Criteria No. 4 (Based on Toxicological Data): In cases in which a therapeutic dose is not known (e.g. for detergents/cleaning agents) toxicity data shall be used for calculating MACO.
Criteria no. 5 (Health Based Data): In this case, the Maximum Allowable Carry MACO) should be based upon Permitted Daily Exposure (PDE). In the health-based data criteria, the principle of MACO calculation is based on acceptable carry-over of your previous product, based upon the PDE, into your next
10 PPM criteria shall be followed for cleaning validation until the finalization of product matrix and identification of worst-case molecule. If the same product is being manufactured in the respective area then the cleaning shall also be verified based on the 10 ppm criteria.
Cleaning validation shall be carried out on the three batches of the identified worst case to evaluate the effectiveness of cleaning
Bracketing Approach shall be followed identify the worst product from the product matrix and the equipment train.
Grouping of Product/Product Matrix: The product matrix shall be prepared to identify the worst molecule (marker) on which the cleaning validation shall be performed In cases where a highly toxic and less soluble compound is contained in a product, it shall be chosen as marker, although additional markers shall be chosen if they are less soluble than the marker selected based on toxicity.
The ‘Worst molecule’ shall be identified on the basis of following factors:
Physical Characteristics i.e. Toxicity, Therapeutic dose of product, Maximum daily dose of the product, Batch size of the product, Concentration of Active Ingredient, Cleanability aspects.
On the basis of product matrix Active pharmaceutical substance having low solubility in cleaning media and having more toxicity shall be considered for cleaning validation.
If the solubility and toxicity of two or more molecules are identical then the molecule having more difficulty in cleaning shall be considered for cleaning validation.
In case the multiple batch size of the worst product is being manufactured then the batch in which the API load is more shall be considered in cleaning validation.
In the setting of acceptance criteria for swab, based on the dose based criteria the minimum daily dose of the product, maximum daily dose of the product, minimum batch size of the product among all products mentioned in the product matrix shall be selected.
In the setting of acceptance criteria for swab based on the 10 PPM criteria the minimum batch Size of the product among all products mentioned in the product matrix shall be
In the equipment train/matrix the all the equipment’s shall be considered from which all the products mentioned in the product matrix shall be manufactured in evaluating the total equipment surface area.
Maximum surface area among all the identical equipment (working on same principal) shall be considered in evaluating the total equipment surface area.
The product matrix and equipment train/matrix shall be evaluated after the introduction of new molecule and equipment. If the introduction of new equipment and product shall affect the maximum allowable carry over limit/product then the cleaning validation shall be again performed to evaluate the suitability of existing cleaning procedure. If the cleaning agent is used in the cleaning process, then their absence shall be evaluated in the cleaning validation and to assure the effectiveness of cleaning.
Recovery of identified worst molecule shall be carried out on the different material of construction and the recovery results shall be included in the calculation of cleaning validation sample results, Authorized designee of Quality Control shall include the recovery factors during calculation of cleaning validation sample results.
In case the worst-case molecule has not going to manufacture for a period, and it is evaluated based on 10 ppm criteria then the second worst case shall be considered in the cleaning validation, and the cleaning data of the worst case shall be evaluated against the specified limit.
Authorized designee of quality assurance shall ensure that the prerequisites for cleaning validation as listed below are available (but not limited to) prior to initiate cleaning validation.
Approved cleaning validation protocol.
Validated analytical method for estimation of previous product in the rinse/swab.
Sampling plan and Sampling
Cleaning procedure of Equipment. If the Quantity has been quantified in the equipment cleaning SOP then the same shall be challenged in the validation study and deviation from the mentioned quantity shall be recorded if any and if required SOP of the respective equipment shall be revised to introduce the validated quantity. If the quantity has not been mentioned in the SOP, then the same shall be mentioned in the respective equipment cleaning SOP.
Swab (Micro and chemical) and rinse collection procedure
Swab and rinse collection location
Criteria and Procedure of Visual verification of Cleaning.
Availability of the analytical testing procedure of swab/rinse and microbiological testing of cleaning samples to quantify the amount of the residue present in each swab.
Acceptance Criteria:
Health based Criteria (PDE): Formula to calculate PDE:
PDE= NOAEL or NOEL or LOAEL or LOEL X Weight Adjustment / F1XF2XF3XF4XF5
The modifying factors are as follows:
F1 = A factor to account for extrapolation between species.
F1 = 5 for extrapolation from rats to humans.
F1 = 12 for extrapolation from mice to humans.
F1 = 2 for extrapolation from dogs to humans.
F1 = 2.5 for extrapolation from rabbits to humans.
F1 = 3 for extrapolation from monkeys to humans.
F1 = 10 for extrapolation from other animals to humans.
F2= A factor of 10 to account for variability between individuals.
F3=A variable factor to account for toxicity studies of short- term exposure.
F3= 1 for studies that last at least one-half lifetime (1 year for rodents or rabbits 7 years for cats, dogs and monkeys).
F3= 1 for reproductive studies in which the whole period of organogenesis is covered.
F3 = 2 for 6-month study in rodent, or a 3.5-year study in non-rodents.
F3 = 5 for 3-month study in rodent, or a 2-year study in non-rodents.
F3 = 10 for studies of a shorter duration.
F4 = A factor that may be applied in cases of severe toxicity.
E.g. Non-genotoxic carcinogenetic, neurotoxicity or teratogenicity, in studies of reproductive toxicity, the following factors are used.
F4 = 1 for fetal toxicity associated with maternal toxicity.
F4 = 5 for fetal toxicity without maternal toxicity.
F4 = 5 for a teratogenic effect with maternal toxicity.
F4 = 10 for a teratogenic effect without maternal toxicity.
F5 = A variable factor that may be applied, if the NOAEL was not established. When only a LOAEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.
Note: If values of individual factors are not available then considered highest value. As a worst-case highest value of F3 (i.e. 10) should be consider during calculation of PDE.
In case where no severe toxicity encounter, F4 should be considered as 1.
Acceptance Criteria using health-base data: The Maximum Allowable Carryover (MACO) should be based upon the Acceptable Daily Exposure (ADE) or Permitted Daily Exposure (PDE) when this data is available. The principle of MACO calculation is that you calculate your acceptable carry-over of your previous product, based upon the ADE / PDE, into your next product.
Procedure: Calculate the ADE (Acceptable Daily Exposure) or PDE (Permitted Daily Exposure) according to the following equations and use either result for the calculation of the MACO.
ADE =NOAEL x BW___/ UFc x MF x PK
PDE = _____ NOAEL x BW ______/ F1 x F2 x F3 x F4 x F5
From the ADE / PDE number, a MACO can be calculated according to:
MACO = ADE / PDE previous x MBSnext / TDDnext
MACO: Maximum Allowable Carryover: Acceptable transferred amount from the previous product into your next product (mg).
ADE: Acceptable Daily Exposure (mg/day)
PDE : Permitted Daily Exposure (mg/day)
NOAEL : No Observed Adverse Effect Level (mg/kg/day)
BW : Is the weight of an average adult (e.g. 50 kg)
UFc : Composite Uncertainty Factor: combination of factors which reflects the inter- individual variability, interspecies differences, sub-chronic-to-chronic extrapolation, LOEL-to-NOEL extrapolation, database completeness.
MF: Modifying Factor: a factor to address uncertainties not covered by the other factors
PK: Pharmacokinetic Adjustments
F1-F5: Adjustment factors to account for uncertainties.
TDDnext : Standard Therapeutic Daily Dose for the next product (mg/day)
MBSnext : Minimum batch size for the next product(s) (where MACO can end up) (mg) Instead of calculating each potential product change situation, the worst-case scenario can be chosen. Then a case with most active API (lowest ADE or PDE) is chosen to end up in the following API with the smallest ratio of batch size divided with TDD (MBS/TDD ratio).
If OEL data is available, the ADE or PDE can be derived from the OEL
Acceptance criteria based on Therapeutic Daily Dose: When limited toxicity data is available and the Therapeutic Daily Dose (TDD) is known, this calculation may be used. It is used for final product changeover API Process-A to API Process-B.
Procedure
Establish the limit for Maximum Allowable Carryover (MACO) according to the following equation.
MACO = TDDprevious x MBSnext / SF x TDDnext
MACO: Maximum Allowance Carryover: acceptable transferred amount from the previous product into your next product (mg).
TDD previous: Standard Therapeutic Daily Dose of the investigated product (in the same dosage from as TDDnext) (mg/day).
TDD next: Standard Therapeutic Daily Dose for the next product (mg/day)
MBS next : Minimum batch size for the next product(s) (where MACO can end up (mg)
SF: Safety factor (normally 1000 is used in calculations based on TDD).
Acceptance criteria based on LD50
In cases where no other data is available (e.g. ADE, OEL, TDD,…) and only LD50 data is available (e.g. chemicals, intermediates, detergents, …), the MACO can be based upon LD50 data.
Procedure: Calculate the so-called NOEL number (No Observable Effect Level) according to the following equation and use the result for the establishment of MACO.
NOEL = LD50 x BW/ 2000
From the NOEL number a MACO can be calculated according to:
MACO =NOEL previous x MBS next/ SFnext x TDDnext
MACO: Maximum Allowance Carryover: acceptable transferred amount from the previous product into your next product (mg).
NOEL previous: No Observed Effect Level (mg/day).
LD50: Lethal Dose 50 in mg/kg animal. The identification of the animal (mouse, rat etc.) and the way of entry (IV, oral etc.) is important (mg/kg)
BW: Is the weight of an average adult (e.g. 50 kg) (kg)
2000: 2000 is an empirical constant.
TDDnext :Standard Therapeutic Daily Dose for the next product (mg/day)
MBSnext: Minimum batch size for the next product (s) (where MACO can end up)
SFnext: Safety factor
The safety factor (SF) varies depending on the route of administration (see below). Generally a factor of 200 is employed when manufacturing APIs to be administered in oral dosage forms.
Safety factors:
Topicals: 10 – 100
Oral products: 100 – 1000
Parenteral :1000 – 10000
General Limit as acceptance criteria
If MACO calculations result in unacceptably high or irrelevant carryover figures, or toxicological data for intermediates are not known, the approach of a general limit may be suitable. Companies may choose to have such an upper limit as a policy. The general limit is often set as an upper limit for the maximum concentration (MAXCONC) of a contaminating substance in a subsequent batch.
Procedure: Establish MACO ppm, based on a general limit, using the following equations.
MACO ppm = MAXCONC x MBS.
MACOppm : Maximum Allowable Carryover: acceptable transferred amount from the investigated product (“previous”). Calculated from general ppm limit.
MAXCONC : General limit for maximum allowed concentration (kg/kg or ppm) of “previous” substance in the next batch.
MBS : Minimum batch size for the next product(s) (where MACO can end up)
E.g. for a general limit of 100 ppm: MACO = 0.01% of the minimum batch size (MBS), and for a general limit of 10 ppm: MACO = 0.001% of the minimum batch size (MBS).
A general upper limit for the maximum concentration of a contaminating substance in a subsequent batch (MAXCONC) is often set to 5-500 ppm (100 ppm in APIs is very frequent) of the previous product into the next product depending on the nature of products produced from the individual company (e.g. toxicity, pharmacological activity etc.).
The Threshold of Toxicological Concern (TTC) concept could be applied to intermediates or API’s with no clinical (e.g. early development) or toxicological data. This concept includes three categories of products with limited or no data:
Products that are likely to be carcinogenic
Products that are likely to be potent or highly toxic.
Products that are not likely to be carcinogenic, potent or highly toxic
The corresponding ADE’s recommended for these three categories are 1, 10, 100 µg/day, respectively.
Note – If you decide to employ the concept of levels of cleaning (ref. section 5), then different safety factors (ppm limits) may be used for different levels. Especially if the product cleaned out is within the same synthetic chain and covered by the specification of the API, much higher (qualified) levels are acceptable
Setting Swab Limit: The swab limits shall be established for dose based, 10 ppm, Ld50 and PDE criteria. In calculating the swab limits MACO obtained based on each criterion shall be used for calculation of swab limits for each criterion (dose based, 10 ppm, Ld50 and PDE criteria). The Swab limit shall be calculated based on the below mentioned criteria
Swab Limit (drug in mg per swabbed area) = MACO X SWAB AREA (cm 2)/TS (cm2)
Where, TS: Total product contact surface area.
Swab Limit: The swab limits shall be established for dose based, 10 ppm, Ld50 and PDE criteria. In calculating the swab limits MACO obtained based on each criterion shall be used for calculation of swab limits for each criterion (dose based, 10 ppm, Ld50 and PDE criteria). The Swab limit shall be calculated based on the below mentioned criteria
Swab Limit (drug in mg per swabbed area) = MACO X SWAB AREA (cm 2)/TS (cm2) Where, TS: Total product contact surface area.
Rinse Limit: The rinse limits shall be established for dose based, 10 ppm, Ld50 and PDE criteria. In calculating the rinse limits MACO obtained based on each criterion shall be used for calculation of rinse limits for each criterion (dose based, 10 ppm, Ld50 and PDE criteria). The rinse limit shall be calculated based on the below mentioned criteria Rinse Limit (Drug in mg per liter) = MACO (mg)/ Total Volume of Rinse (liter)
The least MACO/Swab and MACO/Rinse obtained from the calculations in each criterion shall be considered as acceptance criteria in cleaning validation studies.
Acceptance criteria for Microbial contamination: If the estimated value of probable contamination in the next product is within limits of acceptance criteria, then the procedure being followed for cleaning of the equipment shall consider validated otherwise investigation shall be carried out based on the Failure Investigation SOP.
Swabs of equipment/ accessories/ items/area:
| Total microbial count | |||
| Grade A | Grade B | Grade C | Grade D |
| < 1CFU/Swab | NMT 05 CFU/Swab | NMT 25 CFU/Swab | NMT 50 CFU/Swab |
For rinse of equipment/ Accessories/ Item:
Total microbial count – NMT 10 CFU/ 100ml
Hold time of equipment:
The cleaned equipment/Dirty Equipment/Campaign product hold time study shall be carried out based on the criteria specified in the respective study protocol and the hold time period shall be evaluated and specified.
Revalidation:
Revalidation shall be carried out in following situation. Equipment changes/modifications which affects the MACO value.
Changes in cleaning procedure.
On appearance of new findings based on current knowledge.
Revalidation of cleaning procedure shall be carried out a frequency of 5 years, if worst case molecule remains same during defined period.
REFERENCE:
PDA technical report No.29 (Revised 2012 points to be considered for cleaning validation.)
FDA Guide to inspection validation of cleaning processes.
APIC- active pharmaceutical ingredients committee (Sep-2016)