Cleaning validation has been the most debated compliance topic of the year 2018. Cleaning validation is a critical aspect of GMP and quality control and is under constant scrutiny by the FDA and other regulatory authorities. cGMPs include the prevention of possible contamination and cross-contamination of APIs and Finished products.
An example from 1988 of major cross contamination was traceable back to inadequate cleaning and cleaning validation.
Europe wide recall of HIV Drugs due to Cleaning Related contamination. Reports indicate an MSA storage tank cleaned with ethanol was not free of ethanol prior to charging with MSA. API produced soon after had elevated levels of potential GTI (10 Times more than TTC)
In a more recent example,
An API supplier of Cholestyramine Resin recalled the product due to contamination with low levels of intermediates and degragants from the production of agricultural pesticides. This cross-contamination attributed to drums used to recover solvent from agricultural pesticides manufactured at another location. The drums were not properly cleaned leading to agricultural pesticides entering the API manufacturing process.
Cleaning is defined as the removal of residues and contaminants from process equipment to a scientifically acceptable level, such that the same equipment can be safely used for subsequent product manufacture. The residues and contaminants can be from
- Cross-contamination from previously manufactured products in the equipment
- The cleaning procedure (detergents/sanitisers) or degradation products resulting from the cleaning process
- Microbiological sources
- Precursors of the drug substance. By-products and/or degradation products of the drug substance
Pharmaceutical manufacturers must validate their cleaning process to ensure compliance with cGMP regulations. Formally, “Cleaning validation is documented evidence that an approved cleaning procedure will reproducibly remove the previous product or cleaning agents used in the equipment below the scientifically set maximum allowable carryover level”. It is thus, a quality control process for determining the effectiveness of a cleaning process for a specific cleaning event. (Source: PIC/S Guide to GMP for Medicinal Products; Annex 15 Qualification & Validation
The industry is slowly adopting HBELs (Health-Based Exposure Limits) ever since EMA (European Medicines Agency) published its Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities
Regulatory Requirements for Cleaning Validation
The FDA’s guide to cleaning inspections includes the following guidelines:
- FDA expects firms to have written standard operating procedures (SOP) detailing the cleaning process used for various pieces of equipment.
- FDA expects firms to have written procedures [Standard Operating Procedures (SOPs)] detailing the cleaning processes.
- FDA expects firms to have written general procedures on how cleaning processes will be validated.
- These procedures will “address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required.
- FDA expects firms to conduct the validation studies in accordance with the protocols and to document the results of studies.
- Besides ensuring chemical cleanliness, “the microbiological aspects of equipment cleaning should be considered. This consists largely of preventive measures…
- Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants.
- The firm should challenge the analytical method in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface and at what level.
- Direct sampling (e.g., with swabs) is ‘most desirable,’ although rinse sampling may be satisfactory.