Department | Validation/Technical Services | Document no | VAL-195 | ||
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A. PURPOSE
The purpose of this document is to instruct the user on the operations required in order to conduct a Maximum Safe Carry-Over Determination (MSCO) for a piece of equipment or product equipment grouping.
B. SCOPE
The scope of this SOP is limited to instructing the user on how to conduct a MSCO determination, following documented risk assessment of the materials and products to be processed on a piece of equipment or product equipment train.
C. RESPONSIBILITITY
i. The Validation Engineer and/or Supervisor is responsible for obtaining true, compliant data for conducting a Maximum Allowable Carry Over (MACO). They are responsible for following the calculation process as defined in this SOP and for review of the MACO calculations generated by peers.
ii. The Quality Assurance Manager(s) and/or Quality Manager are responsible for review of the MACO calculations and formal acceptance of the indicated results for reference in future studies.
D. PROCESS SPECIFIC INFORMATION
1. Regulations
Regulatory References which govern the actions outlined in this SOP are contained below.
1.1 PIC/S Guide to Good Manufacturing Practice (GMP) – 15 January 2009, PE 009-8.
1.1.1 Guide to Good Manufacturing Practice for Medicinal Products – Part II, Chapter 12: Section 12.7
1.1.2 Guide to Good Manufacturing Practice for Medicinal Products Annexes, Annex 15: Qualification and Validation, Clauses 36 – 42
2. Guidelines
The guidelines utilized for reference for this SOP are included below
2.1 Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (EMA, 2014)
2.2 ICH Topic Q3C (R4) Impurities: Guideline for Residual Solvents (EMA, 2009)
E. BACKGROUND AND CALCULATION INFORMATION
1. Guideline for MSCO Calculation
1.1 The MSCO calculation is derived from the European Medicines Agency (EMA) guidelines for compliance with European Union (EU) GMP regulations regarding cleaning validation. This is required for product which is exported to regions governed by EU GMP regulations. The previous term utilized for calculating residue limits “Maximum Allowable Carry-Over” (MACO) has been replaced with Maximum Safe Carry-Over, owing to the derivation of the value from the Permitted Daily Exposure calculations.
1.2 The EU guideline to GMP Annex 15, section 10.6 states that “Limits for the carryover of product residues should be based on a toxicological evaluation. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references. Limits should be established for the removal of any cleaning agents used. Acceptance criteria should consider the potential cumulative effect of multiple items of equipment in the process equipment train.”
1.3 The EU GMP regulations is legislated to audit standards stipulated in PIC/S Guide to Good Manufacturing Practice (GMP) – 15 January 2009, PE 009-8.
1.4 The procedure proposed for determination of health-based exposure limits for residual active substance is based on the method for establishing the so-called “Permitted (or acceptable) Daily Exposure (PDE)”.
1.5 The PDE represents an estimate of a daily exposure (dose/application) that is likely to be without an appreciable risk of deleterious effects to the potential patient population during an average lifetime (i.e. a substance specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime)
1.6 The equation for the derivation of the PDE is as follows:
PPDE = (NOAEL x Weight Adjustment) / (F1 X F2 X F3 X F4 X F5)
1.6.1 Where NOAEL is the determination of the No-Observed-Adverse-Effect Level (also referred to No –Observed Effect level (NOEL)), that is the highest dose in a study at which no adverse effects of treatment are observed
The NOAEL is the highest tested dosage at which no “critical” effect is observed.
1.6.2 Where the “weight adjustment” factor compensates for the NO(A)EL value to calculate the PDE on a mg/kg bodyweight (bw) basis.
1.6.3 Also where F1 – F5 are critical various adjustment factors (also referred to as safety-, uncertainty-, assessment- or modifying factors) to account for various uncertainties and to allow extrapolation to a reliable and robust no-effect level in the human or target animal population. F1 to F5 are addressing the following sources of uncertainty:
– F1: A factor (values between 2 and 12) to account for extrapolation between species
– F2: A factor of 10 to account for variability between individuals
– F3: A factor 10 to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks
– F4: A factor (1-10) that may be applied in cases of severe toxicity, e.g. non genotoxic carcinogenicity, neurotoxicity or teratogenicity
– F5: A variable factor that may be applied if the no-effect level was not established. When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.
1.7 The PDE can then be utilized to determine the MSCO quantity which can then be utilized to set detergent and/or API residue limits. The PDE is derived from toxicological data on the active pharmaceutical ingredient which is the focus of the study. If no toxicological data is available it may also be derived from the “No-Observed Effect Level” (NOEL) quantity defined by animal study or calculations based on the LD50 of the substance.
1.8 The MSCO is determined by the following equation:
MSCO = [PDE (mg/day) x Batch Size (mg)] / [Maximum daily dose (subsequent batch in mg)]
1.9 The surface residue then can be determined with the following equation:
Surface Residue (µg/cm²) = MSCO (µg) / Equipment Surface Area (cm²)
1.10 With regard to direct surface sample collection (via swabbing), it can then be determined from the surface residue limit:
Residue on swab (µg) = Surface Residue (µg/cm²) x Area Swabbed (cm²)
1.11 With the final reported swab residue when reconstituted in solvent solution being able to be calculated by:
Residue on swab (µg) / Swab dilution volume (mL) = Residue level in swab sample (ppm)
It should be noted that swab residues are subject to analytical recovery factors as determined in method validation studies.
2. Risk Assessment
2.1 Cross reference the risk assessment conducted for the target product(s) and equipment(s) to be covered within the scope of the MSCO. The risk assessment should have identified the “worst-case” product(s) and equipment combination for which a MSCO determination is to be made.
2.2 If the equipment to be utilized will be dedicated for a single product (family) then the MSCO assessment is not required.
2.3 If no risk assessment has been conducted for the equipment and product combinations then perform a separate risk assessment on the equipment and processes to isolate the target substances and equipment (equipment train(s)) to be evaluated in the calculation.
3. Equipment / Equipment Train
3.1 Clearly identify the target product contact equipment (or target product equipment train) that is to be subject to the cleaning evaluation. Calculate the product contact surface area of the target equipment. Where appropriate, form Appendix A may be utilized to assist in the assessment of the target equipment identification.
F. PROCEDURE
The procedure for conducting the MSCO calculations is described in the following steps. For any MSCO calculation, include all reference information and justification on choice of F-values. Simple MSCO calculations can be included in appendices as part of validation protocol documentation or where the processes or matrices are complex; the MSCO determination may be made as a standalone report or integrated with the Risk Assessment.
1. NOAEL Source Information
1.1 Obtain a NOAEL value from toxicological data for the target species. Toxicological data of APIs may be found from references below or from toxicological study reports.
1.1.1 European Medicines Agency: European Public Assessment Reports – Summary of Submission and Evaluation
1.1.2 US FDA: Drugs@FDA
1.1.3 National Institute of Health: TOXNET database, DailyMed index
1.1.4 For vitamins and minerals, use the Nutrient Reference Valuses (Upper Levels): US IOM
1.1.5 EPA Department of Pesticide Regulation Medical Toxicology Branch
1.2 Alternatively, obtain a NOAEL estimated from the LD50 – median lethal dose. The NOAEL can be obtained from the following calculation:
NOAEL from LD50 = [LD50 (mg/kg per day) x Target animal weight (e.g. 50 kg for sheep)] / 2000
1.2.1 It should be noted that this formula (adapted from the “guidance on aspects of cleaning validation inactive pharmaceutical ingredient plants” (APIC, 2000)) should only be utilized where toxicological data has not been found available.
1.3 The use of this equation in place of toxicological assessment data should be considered based on the risk of the target species.
1.4 As an additional alternative, the Low Observed Adverse Effect Level (LOAEL) may be utilized to calculate the NOAEL. The LOAEL can be obtained from the Minimum Therapeutic Dose value (reported in appropriate scientific literature). If the LOAEL is utilized in the PDE calculation, then an F5 factor of 10 must be used (refer to section 2 for greater detail).
2. F – Value Assumptions for PDE
The assumptions for the F-values chosen for calculations are indicated in the sections below. Select the appropriate F – values corresponding to the toxicological data/NOAEL/LOAEL source as described in section F1.
Each F-value selection should be justified as per the guidance below or based on the risk of the target species.
2.1 The F1 Factor is for extrapolation of data between (animal) 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
2.2 The F2 factor is nominally a factor of 10 to account for variability between individuals
A factor of 10 is generally given for all organic solvents, and 10 is typically used consistently in guidelines.
2.3 The F3 factor is 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 a 6-month study in rodents, or a 3.5-year study in non-rodents.
F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents.
F3 = 10 for studies of a shorter duration. In all cases, the higher factor has been used for study durations between the time points, e.g., a factor of 2 for a 9-month rodent study.
2.4 F4 is a factor that may be applied in cases of severe toxicity, e.g., non-genotoxic carcinogenicity, 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
2.5 The F5 factor is one that may be applied if the no-effect level 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.
Use F5 = 6 for a target substance that is classed as an “irritant” in GHS “Health Hazard statements” for substance administered in the same manner as the medicine (e.g. topical = skin)
Use F5 = 8 for a substance classified as “Harmful”
Use F5 =10 for a substance classified as “Toxic” or “Fatal” when for the hazard statement same route of administration.
Otherwise for use of LOAEL use an F5 value of 4.
F5 = 1 when NOAEL or equivalent is used in the PDE calculation.
3. Weight Adjustment Factor in the PDE
3.1 In the PDE, the weight adjustment assumes an arbitrary adult human body weight for either sex of 50 kg. This relatively low weight provides an additional safety factor against the standard weights of 60 kg or 70 kg that are often used in this type of calculation. It is recognized that some adult patients weigh less than 50 kg are considered to be accommodated by the built-in safety factors used to determine a PDE. From the VICH guidelines, it is considered acceptable to apply the human assessment standard to animals for the purposes of these studies.
4. Calculations and Sample Type Selection
4.1 Conduct the PDE calculation as stipulated in step E – 1.6
4.2 From the risk assessment, the worst case (smallest batch size of follow on product to be manufactured in the same equipment) follow on products’ maximum daily dose should have been identified. Use this value for the MSCO calculation.
4.3 Conduct the MSCO calculation as stipulated in step E – 1.8
4.4 Dependent on the sampling type, the calculation can end here. For a rinse sample, it is generally assumed that a rinse sample will have contacted the entire product surface area so the expected concentration in a final rinse sample will be a factor of the rinse sample volume and the recovery factor.
Final rinse sample concentration limit = [(MSCO quantity / Rinse volume)] x Recovery Factor
The recovery factor source should be referenced here (e.g. recovery study)
4.5 For a swab sample (surface residue deposit sample) conduct the calculation in section E-1.9 from the calculated MSCO and Equipment Surface Area
4.6 For a swab sample (swabs typically being polyester type e.g. Puriwipe SWBX-8805P or Texwipe TX714A) the surface area required to be swabbed will be 100cm2. Conduct the “Residue on swab” calculation as per E-1.10
4.7 It is typical to report residue limits as a mass value, however if it is necessary or requested to report a residue limit in terms of analytical solution concentration, then utilize the formula contained in section E-1.11
4.8 As a set of GMP calculations, include a section at the conclusion of the calculation to sign that they were conducted by you in the Appendix or risk assessment project and another sign-off section for a trained colleague to verify the value transcription and calculations for accuracy.
Appendix A: Biological Area Cleaning Validation New or Changed Product, Process and Equipment Assessment