Introduction
This document describes the rationale and recommended microbiological methodology for consideration during cleaning validation of product contact surfaces for Active Pharmaceutical Ingredients (APIs) and drug products.
The guidance on Clean Equipment Hold Time may be used to determine if micro testing is required during cleaning validation.
Microbial control should be taken into consideration for cleaning procedures that provide conditions favourable to the growth of microorganisms. If the risk of the growth of microorganisms is high, microbiological sampling of product contact surfaces is one activity that can demonstrate that the cleaning process does not contribute to the increase of the microbial load above previously defined acceptable levels.
Recommendations & Rationale for Recommendations
Microbiological cleaning validation for product contact surfaces for drug products and the final stage of drug substances is advisable when the surfaces are not sterilized and water is used as a final rinse. Water used to clean and rinse equipment is capable of supporting growth and can potentially add bioburden. When it is determined that there is a microbial risk due to the cleaning procedure, it is important to demonstrate that the cleaning process does not create an adverse effect on the drug substance and product.
When cleaning validation microbiological sampling is required, a final purified water (PW) or water-for-injection (WFI) rinse sample of product contact surfaces following the cleaning procedure is the preferred sample collection method. Alternatively, if a water rinse sample is not practical, then direct sampling (e.g. contact plates or swabbing) of the product contact surfaces may be used.
Regulatory Requirements
The FDA states in 21 CFR 211.113 that “Appropriate written procedures designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed”. In addition, the FDA Guide to Inspection of Validation of Cleaning Processes (1993) states, “Microbiological aspects of equipment cleaning should be considered. There should be some evidence that routine cleaning and storage does not allow microbial proliferation”.
The PhRMA report on microbiological monitoring in nonsterile pharmaceutical manufacturing areas (1997) recommended that depending on the product type, cleaning validation should include microbial sampling to ensure microbiological quality.
The ICH Q7A Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients states “Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).
The Canadian Health Products and Food Branch Inspectorate on Cleaning Validation Guidelines further states “There should be some documented evidence that routine cleaning and storage of equipment does not allow microbial proliferation. These studies are designed to demonstrate and document that cleaning procedures are effective and do not contribute to conditions favorable for the proliferation of microorganisms.”
Risk assessment has become an acceptable approach in cleaning validation. A documented and approved risk assessment is recommended for microbial testing of non-sterile equipment and for affirming the proposed acceptability limits. One of the considerations of a risk assessment is whether the final rinse of the clean equipment is performed using an organic solvent or water.
Recommended Methodology
If it is determined that microbiological testing is needed, where possible, it is recommended that bioburden samples be collected via rinse sampling. A known quantity of Purified Water or Water for Injection (dependent on the final rinsing type prescribed by the cleaning procedure) sufficient to completely rinse the product contact surfaces of the equipment is used. A sample of the effluent rinse is collected in a sterile container and microbiologically evaluated.
Sampling should be conducted according to a sampling plan which does not either contribute to the potential contamination of the samples or impacts the integrity of subsequent samples. If surface sampling is needed, sterile swabs saturated with a sterile diluent such as Sterile Water for Injection or Sterile Saline Solution are used. Alternatively, RODAC® plates may be employed for sample sites in which the entire surface of the RODAC® plate is able to be in contact with the equipment surface. If RODAC® plates are used; the sampled surface should be cleaned by a qualified cleaning procedure prior to use of the equipment for production (e.g. wiped with a sterile saturated 70% isopropyl alcohol wipe).
The following sampling guidelines and associated limits are recommended. They should be applied at the completion of the cleaning cycle.
For manufacturing equipment for sterile drug products and the final stage of sterile drug substances where applicable (except where cleaning is followed by a validated overkill sterilization cycle):
- Final Water for Injection (WFI) rinse samples – Recommended alert limits are based on preliminary or historical studies and action limits should take into consideration the microbiological limit of the rinse water used, for example, not to exceed 10 cfu/100 ml (USP <1231> and EP “Water for Injections”).
- Swabs-Recommended alert limits are based on data from preliminary or historical studies and action limits should not exceed those reported for non-product contact surface areas.
- Contact Plates (e.g. RODAC®) – Recommended alert limits are based on data from preliminary or historical studies and action limits should not exceed those reported for non-product contact surface areas.
For manufacturing equipment for non-sterile drug product and the final stage of drug substance where applicable:
- Final Purified Water rinse samples – Recommended limits should be based on preliminary or historical studies and action limits should take into consideration the microbiological limit of the rinse water, for example, not to exceed 100 cfu/ml (USP <1231> and EP “Water, Purified”). Drug substances using other than USP Purified Water must comply with site standards for water used as the final rinse.
- Swabs-Recommended alert limits are based on data from preliminary or historical studies and action limits should not exceed those reported for non-product contact surface areas.
- Contact Plates (e.g. RODAC®) – Recommended alert limits are based on data from preliminary or historical studies and action limits should not exceed those reported for non-product contact surface areas.