Process Validation: The Impact of Equipment Change

In a previous news youi could already read about the cleaning issues at a US-American pharmaceutical company. Now, the Warning Letter issued provides much more information - also with regard to process validation.

Referring to 21 CFR 211.100 (b), the FDA criticised a poor change management system regarding changes in blend size, formulation and manufacture itself. Batches manufactured with the modified processes haven't been included in a stability programme.

With reference to the avoidance of contamination, the company just replaced the equipment. This change has been done without evaluating the validated process. The FDA names the example of a batch which has been manufactured after the change and didn't meet the dissolution specifications. Further equipment changes which haven't been evaluated even led to a recall. Furthermore, the FDA criticised the lack of a programme for monitoring process control to ensure stable manufacturing and the respective production of drug quality. Continued/Ongoing Process Verification is to be understood here. It is interesting to note that the FDA considers it being the duty of executive management to look after the source of variations and stop them if significant process variabilities occur. 

In the company's response to the FDA, Mylan stated that equipment and in-process controls as well as verification of physical attributes would provide a high degree of assurance of process control for compression operations. The FDA didn't accept this answer.

What does the FDA require?

Referring to a poor "Quality Oversight", the FDA expects:

• A comprehensive and independent evaluation of the change management system. The review should include the complete change management process. The change management programme should particularly take into consideration changes to be included in the stability programme. Besides, arrangements for qualification and validation activities should be considered and the effectivity of changes should be determined.
• A retrospective review of all changes that may have an impact on increased variations in the manufacturing procedures.
• An assessment of the reliability of the manufacturing operations
• A plan describing the improvements with regard to the facility and equipment design and to mitigate/eliminate human errors.
• Details of the validation plan to ensure "state of control" over the complete product life cycle.The FDA explicitly mentions intra-batch and inter-batch variation.

In a kind of conclusion, the FDA criticises the insufficient functionality of the "Quality Unit".

Conclusion: For the FDA, taking into consideration further measures such as stability programmes and process safety (process validation, continued/ongoing process verification) plays an important role in change management. With regard to process safety, it is the "Executive Management" who is explicitly responsible.

Please also see the complete FDA Warning Letter for Mylan Pharmaceuticals.