Industry insight: Process validation and monitoring

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:

  • Focus on failures in process validation, with an emphasis on failure to conduct ongoing process monitoring to ensure the process remains under control
  • Focus on supplier controls, including testing of incoming raw materials and components including APIs and
  • Increased, and seemingly disproportionate, focus on over-the-counter (OTC) drug product manufacturers, both foreign and domestic, including manufacturers of homeopathic products.

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:

  • “Understand the sources of variation
  • Detect the presence and degree of variation
  • Understand the impact of variation on the process and ultimately on product attributes
  • Control the variation in a manner commensurate with the risk it represents to the process and product.”

The following examples include highlights of some of the critical text that reflects the requirements in the FDA guidance.

  • Warning Letter 320-17-46 issued on Aug. 15, 2017 states: “Your firm does not have an adequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.” The deficiency identifies that “Your investigations into process deviations and out-of-specification (OOS) laboratory results are insufficient, and do not include scientifically-supported conclusions.” In response to the warning letter, the firm is to provide information to the FDA including “your detailed retrospective review of the manufacturing process validation for each product that can be exported to the US, including (b)(4), to ensure your manufacturing processes are capable of consistently yielding finished products that meet quality attributes and manufacturing requirements. For each process, identify sources of variability in your raw materials and manufacturing process, and indicate the steps you have implemented to reduce variability or mitigate its potential effects on the quality of your products.”
  • Warning Letter 320-18-06 issued Nov. 6, 2017 addresses, among other issues, lack of established adequate hold times for bulk product. The firm invalidated OOSs without adequate investigations or identification of root cause and remediation.
    • The FDA asked the firm to provide the following in response to the warning letter:
    • “Perform a retrospective review of all batches shipped to the U.S. Place batches with (b)(4) held more than (b)(4) on the stability program. Provide initial test results (dissolution, content uniformity, and assay) on each such batch within 45 days of receipt of this letter.
    • For each batch with an OOS result (whether or not it was later invalidated) since 2014, provide the associated holding times for each significant manufacturing step.
    • For each product, perform representative and robust studies to establish appropriate time limits for all significant manufacturing steps.
    • Create improved production procedures that prevent future occurrences of unnecessarily long hold times.
    • Provide interim procedures that establish in-process hold time restrictions.”
  • Warning Letter 320-18-12 issued Dec. 4, 2017 included inadequate management of OOS results. The FDA asks the firm to “For any OOS with an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of manufacturing steps, raw materials, process capability, deviation history, batch failure history). Provide a CAPA plan that identifies the potential manufacturing root causes for each such investigation and includes process improvements where appropriate.”

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.

Process under control

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.

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