GMP consultant Barbara Unger comments on the trend seen in warning letters issued by the FDA to drug product manufacturers citing process validation and monitoring programmes in 2017
Shortcomings in data governance and data integrity are a prominent feature in drug GMP warning letters over the past three years. FDA inspections also focused on contracted services including manufacture and laboratories. Additional areas were the subject of FDA investigator attention in 2017 but have been overshadowed by these two. These include:
Each represents the FDA’s enforcement of fundamental GMP requirements rather than a novel interpretation or implementation of a new requirement.
The FDA continues to cite producers of sterile drug products for failing to validate aseptic processes and sterilisation processes as required by 21 CFR 211.113(b). Now, however, we see an increasing group of firms manufacturing non-sterile products that appear to skip the process validation concept entirely. Moreover, those firms do not have an ongoing program to ensure that the process remained in a state of control.
The latter appears to be the point of emphasis in recent warning letters. Common boilerplate text found in these warning letters includes: “You have not validated the processes used to manufacture your drug products. You did not perform process performance qualification studies, and lacked an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.”
The FDA also appears to link manufacturing failures and repeated out-of-specification (OOS) events to a failure to understand and design an adequate manufacturing process and controls. Note that what the FDA expects is consistent with its 2011 Guidance for Industry, Process Validation: General Principles and Practices, which states: “Focusing exclusively on qualification efforts without also understanding the manufacturing process and associated variations may not lead to adequate assurance of quality.”
Rather, firms should:
The following examples include highlights of some of the critical text that reflects the requirements in the FDA guidance.
Thus, the FDA potentially associates OOS events without an assignable cause to manufacturing processes that may not be adequately controlled or understood. The two activities should feed into an adequate validation protocol and ongoing process controls.
The FDA places significant emphasis on understanding the manufacturing process and factors that contribute to variability to ensure a robust process validation exercise. Failures in these areas are suggested by an unexpected number of OOS events for which root cause cannot be determined, as well as an unexpected number of lot rejections.
Lack of process validation, and particularly the failure to have an ongoing monitoring programme to ensure the process remains in a state of control, is also notable.
The expectation for an ongoing process control programme reflects the requirements in the 2011 Guidance for Industry, Process Validation: General Principles and Practices. The FDA is enforcing the expectation that manufacturers understand the sources of variability in their processes, including that contributed by raw materials, and the expectation for ongoing process monitoring raised in the 2011 guidance.
The continued focus on fundamental deficiencies in supply chain controls is significant. The FDA several times identified firms that falsely misrepresent the origin of materials in the certificate of analysis provided to customers. Also, firms were not testing raw materials and components upon receipt but instead were relying on the COA values without verifying their trustworthiness.
All of the shortcomings in these areas do not represent new requirements or new interpretations of existing requirements. Instead, they demonstrate a lack of understanding and application of essential GMP requirements.
The focus on OTC manufacturers is likely the most significant and is continuing at an increased rate in 2018. The FDA is likely focused on this product category based on the number of individuals who use these products on a daily basis. This may be approaching or replacing compounding pharmacies and outsourcing facilities as a product category that is subject to increased and highly visible enforcement.
I predict that the FDA will continue to identify and focus on deficiencies in process validation and supply chain controls, particularly within the OTC market segment.
Data integrity and CMOs will also continue to be areas of challenge for pharmaceutical and API firms. We will evaluate all of this in the FY 2018 warning letter report that we intend to publish at the end of this calendar year.
Editor's note: Barbara Unger granted permission to publish this excerpt from her article originally published in Pharma Online.