Interpretation of 21 CFR 211.67 Cleaning of Equipment

The US-American GMP regulations for medicinal products are laid down in 21 CFR 211. Section 21 CFR 211.67 requires the establishment of and adherence to written instructions regarding the cleaning and maintenance of equipment. What is exactly meant by this?

In a Warning Letter, the FDA has given an interpretation on the cleaning of equipment. It criticises the fact that the company concerned manufactures both pharmaceuticals and cosmetics on multi-purpose equipment without the cleaning process for this equipment being validated. Moreover, the microbiological monitoring was not validated.

The company assured the FDA that it would prepare a validation plan and also perform the validation. The company also intends to validate the microbiological monitoring. 

This answer was far from sufficient for the FDA. It demands an evaluation of the cleaning processes as well as the validation plan and report. It also demands interim measures to show that the multi-purpose facilities are being cleaned adequately until the cleaning validation is completed.  

The FDA has also specified worst-case scenarios that should be considered:

• Medicinal products with higher toxicities
• Medicinal products with higher API contents
• Medicinal products with low solubility in the cleaning solvent
• Medicinal products with properties that make them difficult to clean up
• Swab sampling sites at places that are most difficult to clean up
• Standing time before cleaning
• Overview of updated SOPs to ensure that an adequate cleaning process verification and validation programme is in place for products, processes and equipment.

In addition, the FDA also requires the necessary steps to be taken in the Change Control System before a new manufacturing device or a new product can be introduced. A CAPA plan is also requested, based on the retrospective observation of the cleaning processes with suggestions for improvement including timelines for implementation. A detailed summary of the weak points in the lifecycle management of cleaning is also to be provided, as well as improvements to the ongoing cleaning verification.

As several GMP deficiencies were identified at this company, some of which were the same as during a 2018 inspection, the FDA strongly recommends that the company engage a consultant. When selecting the consultant, attention should also be paid to the requirements under 21 CFR 211.34 regarding consultants, according to the FDA.

Further information can also be found in the respective Warning Letter published on the FDA website.