Levels of Cleaning in cleaning Validation
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.
The level of cleaning required in order to ensure that the API is free from unacceptable levels of contamination by previous substances varies depending on the step being cleaned and the next substance being manufactured in the same piece of equipment (train).
API`s and related intermediates are often produced in multi-purpose equipment with frequent product changes which results in a high amount of cleaning. To minimize the cleaning effort the concept of using different levels of cleaning as a function of the level of risk related with the possible carryover may be applied without affecting the
safety of the API.
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.
The levels established as shown in figure 1 are based on the approach that in general the thoroughness of cleaning will increase and the acceptable carryover of the previous product will decrease from early steps in the route of synthesis to the final API due to the fact that early steps undergo further processing and/or purification and so the potential carry over will be reduced by further processing. Physical operations, which mean e.g. powder handling such as drying, sieving or milling obviously do not reduce the potential carry over. During the risk assessment it should be taken in consideration that the residues may contribute to a degradation of the next product’s quality or safety and ultimately have a detrimental effect on the final consumer.
Fig 1 shows examples of several possibilities of equipment usage patterns
1) The following product is the next step in the synthetic chain A typical manufacturing process applied to production of Active Pharmaceutical Ingredients consists of various chemical reaction and purification steps followed by physical changes, as can be generally illustrated by the sequence of the production line of a product A or B. In this case level 0 may be applied because the previous product is the starting material of the following manufacturing step and the analytical methods applied for the following product are usually suitable to detect the previous product which is covered and limited by the impurity profile.
2) Between different steps of the same synthetic chain
In general there is a higher potential for contamination of the API if the following product in a sequence is close to the final API – step. So progression of levels from early steps to later steps in the synthetic chain is expected as outlined in figure 1. In the example of product changeover “A – 2” to “Final API A” level 2 may be chosen if
“A – 2” is not specified in the specification of “API A” or “A – 2” is a toxic compound. If it is specified or is purged during the process or harmless, level 1 may be acceptable.
3) Between batches of different product lines The level of cleaning required depends on the stage of manufacture. If the following product is an early stage in the API chain, in general lower levels are required than if it is an intermediate or final stage.
The progression of levels is outlined in figure 1, however an individual risk assessment for each potential product changeover scenario has to be performed to decide which level is applicable. This risk assessment should address the following topics:
- Easiness of cleaning
- Toxicological / pharmacological activity of the previous product, its side products or degradants.
- Maximum daily dose of the following product
- Microbiological growth
- Batch size of the following product
- Solubility, experience, difficult to remove previous product
- Chemical interactions
- Campaign lengths should be evaluated and determined as part of the risk assessment.
Reference: GUIDANCE ON ASPECTS OF CLEANING VALIDATION IN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS