Maximum Safe Carry-Over (MSCO) Determination

Sample Content

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. RESPONSIBILITY

• 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.
• 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.
• Process Specific Information
  

1. Regulations

Regulatory References which govern the actions outlined in this SOP are contained below.

• PIC/S Guide to Good Manufacturing Practice (GMP) – 15 January 2009, PE 009-8.
• Guide to Good Manufacturing Practice for Medicinal Products – Part II, Chapter 12: Section 12.7
• 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:

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

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 utilised to determine the MSCO quantity which can then be utilised 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:

1.9     The surface residue then can be determined with the following equation

1.10   With regard to direct surface sample collection (via swabbing), it can then be determined from the surface residue limit:

1.11   With the final reported swab residue when reconstituted in solvent solution being able to be calculated by:

It should be noted that swab residues are subject to analytical recovery factors as determined in method validation studies.