How does the FDA deal with Processes that cannot be validated?

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4/5 October 2023

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In an interesting Warning Letter, the FDA replies to a letter from a pharmaceutical manufacturer that had received a 483 deficiency report in which the FDA criticized, among other things, deficiencies in process validation. Following you will find out more about the correspondence.

The FDA investigator specifically mentioned as inadequate that process validation consisted of tests on the first production batch and that R&D and Quality Assurance then jointly decided whether the batch could be released or not. 

Reply to the 483 Form

In its reply to the 483, the company mentioned, inter alia, that due to its variability, the production process can in general not be validated, but instead all relevant parameters are controlled by measurements.

For the FDA, this is not acceptable. With reference to the FDA Process Validation Guideline, the FDA requested a process validation that shows that the development of the process is science-based and that the process remains in a controlled state throughout its life cycle. For this purpose, each manufacturing step must be developed accordingly. The process qualification studies then demonstrate whether the initial control state is maintained. They are necessary before the product can be marketed.

For this reason, the FDA requires:

• An assessment of drug manufacturing processes to ensure that a data-driven, scientifically based programme is in place to identify and control the sources of variability. This is achieved by ensuring that the production process consistently meets predetermined specifications and manufacturing standards. This includes, among other things, an assessment of the suitability of the equipment, sufficient detectability through the monitoring and control system and quality aspects of the source material. 
• A summary of the validation programme that ensures the "state of control" over the life cycle.
• The programme for the Process Performance Qualification and the "Continued Process Verification" with regard to intra-batch and inter-batch variability.
• Furthermore, the qualification programme (equipment and facilities) and the corresponding work instructions shall be demonstrated.
• The documentation will be supplemented by validation protocols and the schedule for the implementation of PPQ for products going to the USA.  

For more detailed information please see the complete FDA Warning Letter to Dental-Kosmetik GmbH & Co. KG.