Drug Mfg. Process Reviews Merge with Facility Evaluations
Drug manufacturing process reviews by CDER’s Office of Process & Facilities are being integrated with the facility evaluations, Division of Process Assessment branch chief Ubrani Venkataram told a 7/22 CDER Office of Pharmaceutical Quality Symposium webinar. The ongoing integration project is a top priority for the Office and it is expected to “add value to future reviews,” he said.
One of the current review expectations when reviewing drug sponsors’ manufacturing process development in Product Development Reports (Common Technical Document 3.2.P.2) is a demonstration of process and product understanding and using a risk-based approach to assess the risks to product quality, according to Venkataram. In discussing common deficiencies uncovered during reviews, he said the manufacturing process development sections often lack a “sufficient discussion of why a certain manufacturing process was selected. For example, he said some manufacturers may use a dry blending versus a dry granulation or wet granulation process, but product development reports may not discuss adequately why the specific process was chosen. Typically the review team will send an information request to the sponsor asking for more information to complete the review. He said such responses should “discuss with data why the proposed process was selected and what measures are in place to mitigate any potential risks.”
Another common deficiency involves the physical stability of the active pharmaceutical ingredient (API) not being adequately addressed in product development reports, Venkataram said. Responses to agency information requests should provide data (XRPD, IR) to show no change in API morphic form during processing and shelf-life, he said, adding that it should also discuss analytical method suitability. The response could also note that even if the API physical characteristics change there may be no particular effect on the in-vivo/in-vitro performance (dissolution not changed), he said.
Venkataram’s presentation also reviewed common deficiencies with master batch records, such as differences in executed batch vs. commercial batch (variation in equipment percentage utilization) or process differences due to sub-lots. Information request responses should explain/justify differences and list equipment percentage utilization, he said. Also, they should justify any process differences as they relate to proposed process parameters (for example, blend time vs. blender rotation). Other common master record deficiencies addressed were:
- Overage not justified
- Not all components specified quantitatively
- Low yields not explained/justified
- Proposed limits not justified with data
- Hold Times and Conditions Not identified and justified adequately for high risk intermediates
Overall, Venkataram recommended that applicants “verify that their commercial batch records include clear instructions for the operators, well justified and consistent process parameters (ranges) and in-process controls. Explain if the proposed commercial process deviates from the development or executed batches, explain or justify if the proposed commercial process parameters and controls deviate from those studied during product development studies or used in the exhibit batches.”
To view a recording of Venkataram’s presentation, click here.