This guidance document was published by the APIC Cleaning Validation Task Force on behalf of the Active Pharmaceutical Ingredient Committee (APIC) of CEFIC for cleaning validation in active pharmaceutical ingredient manufacturing plants. Six specific areas are addressed in this Guidance document:
- Acceptance Criteria
- Levels of Cleaning
- Control of the Cleaning Process
- Bracketing and Worst Case Rating
- Determination of the amount of residue
- Cleaning Validation Protocol
Acceptance Criteria
Companies must demonstrate during cleaning validation that the cleaning procedure routinely employed for a piece of equipment limits potential carryover to an acceptable level. The limits established must be calculated based on sound scientific rational.
The acceptance criteria preferably should be based on the Acceptable Daily Exposure (ADE) or Permitted Daily Exposure (PDE) calculations whenever this data is available. The APIC Guidance refers primarily to ADE in the examples of calculations included in this chapter, in line with the ISPE recommended calculations.
Calculations of ADE/ PDE of API’s and intermediates are usually done with involvement of industrial hygienists and toxicologists, who review all available toxicology and clinical data to set the limits. The justification of the calculation should be documented.
In certain cases where availability of pharmacological or toxicological data is limited, for example for chemicals, raw materials, Starting Materials, intermediates or API’s in early phase clinical trials, cleaning limits based on fraction of clinical doses, LD50 and / or general cleaning limits may be calculated. In these cases, carcinogenic, genotoxic and potency effect of these structures should be evaluated by toxicologists.
Read details: Methods of Calculating Cleaning Validation Acceptance Criteria
Levels of Cleaning
The manufacturing process of an Active Pharmaceutical Ingredient (API) typically consists of various chemical reaction and purification steps followed by physical changes. In general, early steps undergo further processing and purification and so potential carryover of the previous product would be removed.
It is recommended that at least three levels of cleaning in the production of a commercial product may be implemented. This approach is outlined in the table below, however it should be mentioned that additional levels might be necessary depending on the nature of the process and requirements of individual companies but should always be based on risk assessment where the characteristics of the previous and subsequent products such as solubility, recovery studies, nature of residues, process step, etc. should be considered.
Control of the Cleaning Process
In order to validate a cleaning process, the cleaning process needs to be repeatable and sufficiently robust for the to-be-cleaned load. It should be clear which steps are considered part of the production process/ unit operation and which are part of the cleaning process, for example if the pre-rinse or wash-out which may be routinely applied to bring the equipment in a good starting position is part of the overall cleaning process or not.
For manual cleaning, this is typically accomplished by sufficiently detailed cleaning instructions, including an unambiguous description of the attributes to be used and how to handle these, together with adequate training. The detailed description should consider:
- the system boundaries
- cleaning agents/solvents to be used
- volumes and or concentrations
- reflux or rinse times, and temperatures
- the sequence of cleaning steps or pre-defined repeats
- in process analyses
- description of pumps used (if needed)
- sample instructions (if needed)
Bracketing and Worst Case Rating
The cleaning processes of multiple product use equipment in API facilities are subject to requirements for cleaning validation. The validation effort could be huge. In order to minimize the amount of validation required, a worst case approach for the validation can be used.
- By means of a bracketing procedure the substances are grouped.
- A worst case rating procedure is used to select the worst case in each group.
Validation of the worst case situation takes place. However, it is of utmost importance that a documented scientific rational for the chosen worst cases exists.
Read details: Bracketing and Worst Case Rating in Cleaning Validation
Determination of the Amount of Residue
The carryover acceptance limit (Mper) is a calculated figure that represents the specification limit for the equipment cleanliness, however, the determination of the actual amount of residue (M) remaining in the equipment following cleaning must be achieved using appropriate methods i.e. for both the sampling method and the quantitation of the contaminant in the sample.
Cleaning Validation Protocol
Cleaning validation protocol should include but not limited to the following sections:
- Background
- Purpose
- Scope
- Responsibility
- Sampling procedure
- Testing procedure
- Acceptance criteria
- Deviations
- Revalidation