Legacy Products and Process Monitoring Raise Concern in Revised Process Validation Guidance

In the Food and Drug Administration’s draft revision of the 1987 Process Validation Guidance, the lack of clarity about how the revised guideline applies to legacy products and the potential burden of new requirements for ongoing process monitoring are common concerns raised in many of the comments submitted by industry to the agency. To date, more than 45 companies or organizations have submitted comments on the draft revision, issued in November 2008.

Legacy Products

Generally, the companies and organizations who submitted comments said they welcomed the revised guidance and its overall alignment with current approaches to process validation and the concepts outlined in the International Conference on Harmonization (ICH) Q8, Q9, and Q10 documents.

Several companies asked for clarification, however, about how the new guidance will apply to products that have been in commercial production for some time. In particular, some asked whether such products will require revalidation or increased process verification during routine production. “It may be burdensome and unwarranted to apply some of the new expectations to legacy products with a successful history of commercial production,” Baxter noted in its submitted comments.

Wyeth made a similar point, and stressed the need to ensure that all FDA staff take the same approach. “Wyeth believes that Industry and FDA (reviewers and inspectors) would benefit from a consistent understanding in the expectations, interpretation, and application of the guidance to legacy products,” the company said.

Alignment of FDA Reviewers and Inspectorate

The Biotechnology Industry Organization (BIO), in turn, made a more general request for alignment among FDA staff, saying, “We ask FDA to ensure alignment within the inspectorate and review groups and between the review and inspectorate groups.” The lack of such alignment has often been a point of concern in the industry with new approaches and guidance documents issued by the agency.

Burden of Ongoing Monitoring

A number of organizations also expressed concern that the wording regarding process monitoring was too restrictive, and could be too burdensome. In particular, several companies expressed concern that the recommended sampling for Stage 3, Continued Process Verification, is at the same level as conducted during Stage 2, Process Verification, saying this requirement would place and unnecessary burden on industry. “As more confidence is obtained in the robustness and capability of the process, reduced testing should be allowed, if justified by the ever increasing process knowledge obtained for the product,” the Pfizer comments say.

Application of GMPs to Viral Clearance Studies

Several companies also said that the guidance’s requirement that viral and impurity clearance studies be conducted under current good manufacturing practices should be modified. “We believe that using a risk based approach, and CGMP appropriate for the stage of development with oversight by the quality unit would be consistent with existing ICH Q9 Quality Risk Management guidance and FDA guidance on CGMP for Phase 1 Investigational Drugs,” Genentech said in its comments.

Many of the comments also recommended that the guidance include a glossary, and that the agency align the terminology used in the guidance with that used in the ICH Q8, Q9, and Q10 documents.

In addition, several companies also responded to the document’s emphasis on the importance of relying on statisticians. Several companies and organizations suggested this language focus instead on the proper use of statistics, whether or not that be done by a statistician.

The comment period closes on March 16. Comments may be submitted at www.regulations.gov.The warning letter is available as a PDF on the FDA's web site.