The draft revision of the European Commission (EC) Guidelines on Good Manufacturing Practice for Medicinal Products, Annex 15 which addresses the qualification and validation of processes from a GMP vantage point, sparked significant interest among ISPE Members when it was released for public comment. 22 individual ISPE Members and groups submitted more than 200 detailed comments during the comment period, with the sections on Qualification, Process Validation and Cleaning Validation drawing the most scrutiny. The comments were vetted by members of the PQLI’s process validation team before being submitted to the EC on behalf of ISPE.

Section 3: Qualification Stages for Equipment, Facilities and Utilities

The Annex 15 draft includes User Requirement Specification (URS) as well as Factory Acceptance Testing (FAT) and Site Acceptance Testing (SAT) in this section. ISPE members made several recommendations regarding FAT/SAT, including the deletion of section 3.4 which states, “Equipment, especially if incorporating novel or complex technology, should be evaluated at the vendor prior to delivery.” ISPE Members recommended that FAT should not be based upon the equipment novelty or complexity but on a risk assessment. ISPE members also recommended the removal of section 3.5 which states, “Prior to installation, equipment should be confirmed to comply with the URS/ functional specification at the vendor site unless otherwise justified,” suggesting that the location of the acceptance testing performed is a business decision and that the requirement should be for the equipment to meet GMP and URS only.

Section 4: Process Validation

The section on Process Validation is divided into “Traditional” and “Continuous Process Verification,” with a hybrid of the two allowed. ISPE Members recommended changing section 4.27 to “Ongoing process verification should be conducted under an approved protocol or procedure. Data should be statistically analyzed and results obtained should be continually monitored to assess the state of control,” noting that having a separate protocol may not be sufficiently holistic at times. In situations where the same procedures and acceptance criteria may be used for multiple pieces of equipment, the verification may occur per procedure using controlled forms for documenting results as opposed to the use of a unique protocol and report.

Section 9: Cleaning Validation

In Section 9, the draft states that cleaning validation is required to be based on a toxicological evaluation to determine the product specific permitted daily exposure (PDE) value. ISPE Members recommended the addition of risk assessment to several items in this section. For example, Members proposed changing section 9.9 to “Cleaning validation protocols should detail the locations to be sampled, the rationale based on a risk assessment for the selection of these locations and define the acceptance criteria” to provide a sound basis for selection rationale. Member’s also proposed changing section 9.10 to read “Recovery studies from materials used in the equipment should be based on risk assessment for each sampling method used,” noting that recovery studies for all materials may not be necessary and that a risk-based approach to all activities should be undertaken.

A common theme throughout the comments was the desire for more clarity of terminology.  For example, in a new section named “General,” the draft states that “justified and documented” risk analysis should be the basis of decisions regarding the scope and depth of the qualification/validation. ISPE Members suggested that in the absence of a justification standard, the phrase “justified, approved and authorized by appropriate personnel” would clarify and align the statement with wording used elsewhere in the draft.

ISPE thanks all the Members who reviewed the Annex 15 draft and submitted comments, and expresses gratitude to the process validation review team, which was headed by Mike Westerman, for uniting the 200+ comments into useful input for the EC. See the complete set of ISPE comments on Annex 15 here.

How You Can Contribute to Future ISPE Comments

As a Member of ISPE, you have the opportunity to influence the development of new or revised regulations and guidance by contributing to the comments that ISPE submits to regulatory agencies.  When a regulatory draft is released for, which ISPE can provide technical and scientific input, the Regulatory and Compliance Committee (RCC) invites ISPE Members to submit comments. The invitation is posted on the ISPE website and disseminated to relevant CoPs and other ISPE groups. Prior to submission to the regulatory agency, the comments are vetted by ISPE Member SMEs and/or the RCC, and ISPE Regulatory Advisors.

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