FDA Draft Guidance for Industry on Process Validation: General Principles and Practices; Availability

Re: Docket No. FDA-2008-D-0559, Draft Guidance for Industry on Process Validation:

General Principles and Practices; Availability

Dear Sir/Madam:

The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the Draft Guidance for Industry on Process Validation: General Principles and Practices. BIO welcomes this guidance from the Agency and agrees with most of the high level concepts put forth in the document. BIO member companies concur that validation is a lifetime cycle activity, and that the general approach of 3- lot validation does not truly ensure that a process operates under a state of control. This guideline will facilitate the full realization and benefits from the International Conference on Harmonisation’s (ICH) Q8, Q9, and Q10 guidances, describing process validation for products wherein a Quality by Design approach has been applied, especially over the early part of the life cycle of the product.

BIO represents more than 1,200 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment. BIO is pleased to offer the following comments in support of the guidance.

I. TERMINOLOGY AND NOMENCLATURE SHOULD BE APPLIED CONSISTENTLY AND ALIGNED WITH ICH DOCUMENTS:

BIO believes that the guidance would be enhanced through more consistent application of nomenclature and alignment with previously defined terminology. We strongly recommend that FDA use terms as defined in previously published ICH documents. BIO requests that where new terms are introduced (such as validation stages 1, 2, and 3), that the guidance please provide clear definitions.

For example, the document uses “Qualification” and “Validation” interchangeably (example: line 132). BIO recommends using the following terminology consistent with the definitions in

ICHQ7.

• Qualification: Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation.

• Validation: A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting predetermined acceptance criteria.

In addition, it would be helpful to provide definition and/or clarification on the following:

• Process Design (what is included, early phases, experiments)

• Product Development Activities

• Impurity

• Relationship between Process Characterization and Process Monitoring when making major process changes

• Applicability of Retrospective Validation (especially with regard to statement on Line 85 and in relationship to legacy products).

• Design Space and relationship to Process Validation principles and practice BIO also believes that the guidance document could be improved and potential confusion avoided through better incorporation of the principles of critical quality attributes and critical process parameters. In many places throughout the document, better alignment of terminology with terminology in ICH Q 8, 9 and 10 would greatly improve and better harmonize this guidance with existing ICH quality guidance. A few examples are listed below:

• Line 91: change “design characteristics” which is not defined in ICH to “Each step of a manufacturing process is controlled to assure that the finished product meets its critical quality attributes and performance characteristics as defined in the target product profile.”

• Line 114: change “those attributes relating to identity, strength, quality, purity and

potency” to “its critical quality attributes”

• Line 267: change “multifactorial interactions” to “multivariate interactions”

• Line 289: change “strategy for control” to “product control strategy”

• Line 291: change “Establishing a Strategy for Process Control” to Establishing a

Product Control Strategy”

• Line 510-511: change “verify the critical quality attributes are being controlled throughout the process” to “the product control strategy consistently ensures that critical quality attributes and product performance characteristics are achieved.”

II. CLARIFICATION IS NEEDED REGARDING STATISTICAL METHODS

BIO also requests additional clarity regarding references to statistical sampling in the draft guidance (e.g., lines 427- 432). We note that not all samples taken can be statistically justified, such as ID testing. BIO recommends adding “where appropriate”, and suggests the manufacturer should justify the sampling plan. For example, “The number of samples should be adequate to provide sufficient statistical confidence, where appropriate, of quality both within a batch and between batches.” Indeed, it would be unusual to have sufficient data to apply meaningful statistical evaluation of data during drug development, prior to manufacture of approximately 30 lots at commercial scale. BIO also requests that FDA allow for flexibility in the use of statistical methodology consistent with process and product knowledge, stage of development and type of product. For example, orphan drugs will generally have few lots available at all stages of development and commercialization and thus the data available for rigorous statistical analysis will be limited.

III. CGMPS FOR SMALL SCALE STUDIES:

BIO believes that small scale impurity removal studies in support of the commercial scale manufacture should be conducted consistent with appropriate application of Current Good Manufacturing Practice (CGMP) concepts. These CGMP concepts include good documentation practices and should be supported by sound science to ensure validity and traceability of the data. We agree that viral removal and inactivation studies should be conducted under appropriate phase specific CGMPs due to the potential impact to patient safety. Laboratory evaluation of these samples should be conducted under CGMP conditions when they are used to support a license application.

IV. EXPECTATIONS SHOULD BE ALIGNED BOTH AMONG AND BETWEEN REVIEW AND INSPECTORATE STAFF:

We agree that determining minimal requirements for commercialization is best done on a case-by-case basis taking into account the process, product type, patient population and knowledge base. We are concerned, however, about consistency of application of this approach both within and between the review and inspectorate staff. We ask FDA to ensure alignment within the inspectorate and review groups and between the review and inspectorate groups.

V. CLARIFACTION IS REQUESTED FOR LEGACY PRODUCTS AND PRODUCTS NOT DEVELOPED UNDER FULL QBD:

As noted previously, this guidance will be beneficial in describing process validation for products wherein a Quality by Design approach has been applied, especially over the early part of the life cycle of the product. However, for existing legacy products and/or products currently developed with less than full QbD approaches, the guideline, as written, may be difficult to apply. In order to bridge the different expectations between this new guidance and existing practice for products that are not developed under full QbD, a risk-based approach may need to be applied when changes that generally require validation are made to legacy product processes. Also, we request that FDA confirm that a non-QbD approach to product development remains an alternative, and thus validation for these non-QbD products should employ a risk-based approach relative to the concepts in the new guidance.

VI. TOPICS FOR FUTURE ICH DISCUSSIONS:

To maximize the impact of this effort to update the approach to validation on a global scale, it might be reasonable to consider this as a topic for future ICH efforts. In lieu of an ICH document on this topic, FDA might maximize the impact of this effort to update the approach to validation on a global scale, by including reference to other consensus guidance documents. This includes:

• General – ASTM E2537-08, Continuous Quality Verification Standard

• Line 315 – ASTM E2474-06, Standard Practice for Pharmaceutical Process

Design Utilizing Process Analytical Technology

• General or Line 336 – ASTM 2500

SPECIFIC COMMENTS

BIO is please to offer the following specific comments in support of the guidance. The cells highlighted in gray indicate the areas of primary concern for BIO member companies.

SECTION ISSUE PROPOSED CHANGE

I. BACKGROUND

*Table Extracted

II. STATUATORY AND REGULATORY REQUIREMENTS FOR PROCESS VALIDATION

*Table Extracted

IV. RECOMMENDATIONS – B. Specific Stages and Activities of Process Validation

*Table Extracted

CONCLUSION:

BIO appreciates this opportunity to comment on the Draft Guidance for Industry on Process Validation: General Principles and Practices. We would be pleased to provide further input or clarification of our

comments, as needed.

Sincerely,

Andrew J. Emmett
Director for Science and Regulatory Affairs
Biotechnology Industry Organization (BIO)