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Representatives of one pilot program participant, Wyeth, outline the experiences and lessons learned for implementing a science- and risk-based approach to drug-development and manufacturing.
The US Food and Drug Administration launched the Chemistry, Manufacturing, and Controls (CMC) Pilot Program in the Federal Register in 2005 (1), as part of its Pharmaceutical CGMPs for the 21st Century initiative (2). The purpose of the CMC Pilot Program was twofold: to provide pharmaceutical companies the opportunity to demonstrate enhanced process and product understanding by submitting critical CMC information in a new drug application (NDA), and to collect feedback from the industry that could enable the agency to develop a guideline on the new FDA quality-assessment system.
The quality-assessment system aims to promote innovation throughout the product life cycle and provide regulatory flexibility. The fundamental principles behind the development of a risk-based scientific approach to the development of quality systems are described in the International Conference on Harmonization (ICH) Q8(R2), Q9 , and Q10 guidelines (3–5) as well as in the FDA guidance for industry on process analytical technology (PAT) (6). These guidances are intended to provide regulatory pathways for the modernization of the pharmaceutical industry and to facilitate the incorporation of quality into the design of drug products (i.e., quality by design [QbD]).
Two small-molecule developmental compounds were submitted to FDA under the CMC Pilot Program. Wyeth (Madison, NJ) submitted marketing applications (MAs) for these compounds in other regions of the world during the same timeframe. Table I provides a summary of the unique aspects of the dossiers for the two compounds, labeled Product X and Product Y throughout this article.
Table I: Unique aspects of dossiers.
Product X was being developed for two separate indications and, therefore, had two associated NDAs, both of which were accepted into the CMC Pilot Program. FDA agreed to assign one team to review both NDA CMC sections for Product X.
Product X and Product Y were in Phase 3 development. A combination of retrospective and prospective approaches, therefore, were included in the application to the pilot program. Scientific interactions between CMC Pilot Program reviewers and Wyeth subject-matter experts facilitated NDA approval for both products.
This article summarizes Wyeth's experiences in the CMC Pilot Program as well as lessons learned for implementing QbD in drug development and manufacturing. In addition, this article highlights the review of global regulatory submissions for Products X and Y. Because the experiences of the two programs were similar, the authors emphasize Product X and point out how the interactions regarding Product Y differed.
Regulatory submission experiences
CMC Pilot Program: Wyeth had several interactions (either via teleconferences or face-to-face meetings) with FDA to discuss the scientific content of its NDA submissions. For Product X, Wyeth also interacted with the agency during a preapproval inspection (PAI) and a preoperational visit (POV) at the product manufacturing sites. Wyeth requested the POV to gain the agency's feedback and suggestions on the implementation of real-time release (RTR), or in-process tests, for the extended-release drug product through a comparability protocol (7). Before FDA accepted the company's applications into the pilot program, Wyeth discussed with the agency its development approach for both compounds during Type B and C meetings. These interactions gave Wyeth insight into the approach that would be used during the NDA review.
Early in the review process for the NDA for Product X, Wyeth and FDA agreed that certain changes needed to be submitted as amendments, and that similar changes needed to be made to the NDA for Product Y. This agreement was a key factor in simplifying the review process. During the review of the Product X NDA, most discussions focused on QbD concepts. Reviewers emphasized the demonstration of the mechanistic understanding and the process and product understanding. Topics discussed included:
The process and product understanding discussions established a platform for the review of the comparability protocol for RTR implementation. Topics addressed during these interactions included the rationale for the choice of the process analyzers; development, validation, and maintenance of chemometric models; and acceptance criteria for RTR tests and their correlation to the regulatory specifications and sampling plans.
FDA's guidance for industry, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, does not address PAT approaches (8). Therefore, Wyeth and FDA extensively discussed the approach for handling out-of-trend, OOS, reaction modes, management of PAT failures, and alternate approaches to release product when such events occur. The parties also discussed batch disposition in the PAT environment.
For Product Y, Wyeth concentrated the QbD work on the impurities and degradation of the drug substance and then linked this information to the degradation of the drug product. Wyeth conducted in-depth analyses of the synthetic steps and crystallization, evaluated the root causes of the formation of impurities and degradation products, and established controls of the CPPs to minimize those impurities and degradation products in the drug substance. Further controls beyond compendial testing were placed on an excipient to minimize the potential formation of degradation products in the drug product.
Preapproval inspection and preoperational visit. A field inspector and two reviewers from FDA's Office of New Drug Quality Assessmement participated in the PAI for Product X. The inspection was science- and risk-based with a strong focus on the quality systems for QbD implementation. Topics discussed during the PAI included systems for QRM implementation at the manufacturing site, change controls, corrective action/ preventive action (CAPA), product and process monitoring, and the implementation of design space.
Development and operational personnel from Wyeth were involved in the PAI. The development personnel led discussions related to the pharmaceutical development (process and product understanding), while the site's operational personnel led discussions about the quality systems and implementation of QbD within the site. The POV was made by three employees from the Center for Drug Evaluation and Research (one from the review division, one from the Office of Regulatory Policy, and one from the Office of Compliance) and three from the field (two from the district and one from the PAT team). The discussions were science- and risk-based with an emphasis on the quality systems for the implementation of PAT and RTR at the site. Specific talks focused on:
The PAIs for Product Y were conducted at the drug-substance and drug-product manufacturing sites. Two reviewers participated in the inspection at the drug substance site because the QbD work was focused there. The inspection assisted in clarifying the definition of the starting materials and the synthetic process flow.
Overall regulatory assessment. Wyeth's experience during the CMC Pilot Program review was positive. The open communication with FDA resulted in several scientific discussions that led to a common understanding of various topics. The agency's centralized coordination of the two NDAs for Product X under one CMC review team enhanced overall efficiency and avoided duplication of efforts for FDA and the sponsor. The POV served as an opportunity to obtain feedback on the modifications to the quality systems that were based on science-and risk-based approaches.
Wyeth submitted MAs for Products X and Y to the regulatory authorities of the European Union, Australia, South Africa, Canada, and several other markets outside the United States. The company requested a meeting with the European Medicines Agency (EMEA) PAT working group to discuss its planned QbD approach before submitting the MA for Product X. Members of the EMEA PAT working group and rapporteurs were present at the meeting, which led to a common understanding of the developmental approach using QbD principles. Besides these discussions, there were no formal opportunities for scientific interchange during the review process. A similar approach was taken with the Canadian submission. Wyeth's QbD strategy was discussed at a pre-new drug submission meeting.
In a majority of the other markets, formal processes for scientific interactions before the submission or during review may not exist. Therefore, clarifications of the QbD strategy were provided in writing upon receipt of Board of Health queries. Global understanding of applications of QbD by all reviewers is, at times, variable.
The MAs submitted to regions outside the US required a traditional Quality Overall Summary (QOS), as opposed to the comprehensive QOS that was required by the FDA CMC Pilot Program. In addition, because a framework for the comparability protocol does not exist in other regions, Wyeth did not include its RTR proposal in international MAs.
The review of the MAs and the interactions with regulators were beneficial to Wyeth despite the traditional approach. A majority of the agencies posed primarily science-based questions. In a few cases, however, the review was very traditional and the expectations of the agencies were sometimes inconsistent with ICH Q8, Q9, and Q10. In such cases, the application had to be modified to incorporate traditional control strategies.
Wyeth learned several lessons during the submission and review process for its Products X and Y applications for the CMC Pilot Program and for international MAs, as outlined below.
Comprehensive QOS. The feedback received during the NDA review indicated that the contents of the comprehensive QOS were important. The QOS ultimately served as the roadmap and launching point for the review of the dossier. Clear presentations, including tables and pictures that showed results, allowed the reviewer to reach the fostered conclusions. Wyeth found that the QOS document should be concise, emphasizing the data and providing conclusions based on data analysis. The document also should highlight the process used for the identification of CPPs, CMAs, and so forth.
Wyeth's experiences with the CMC Pilot Program and the submission and review of MAs in other regions of the world indicate that a traditional QOS as described in ICH M4Q (R1) on the common technical document (9) may be needed for some markets, while others may accept the comprehensive QOS, the contents of which may exceed the requirements specified in the harmonized guideline.
Development report. The primary goal of QbD is to adopt a structured approach to yield a deeper product and process understanding. Regulatory flexibility may be an outcome. Wyeth found that this goal of understanding needs to be driven home in development reports. To increase the reviewer's confidence in the application and facilitate a smoother review, the expanded Pharmaceutical Development Report (3.2.P.2) section for the drug product and an expanded drug-substance manufacturing process module (3.2.S.2.6) should demonstrate the enhanced product and process understanding by including the following information for various experiments: rationale, data summaries, analysis of data, and conclusions drawn from all experiments. Expanded development reports increase the reviewer's confidence in the applicant's ability to reliably and consistently manufacture quality drug substances and drug products.
Raw-material characterization. The characterization of raw materials and their functionality affects product performance, manufacturability, and quality; this information is critical for complete process and product understanding. Although there has been a considerable effort to further understand excipient functionality, sponsors still tend to rely on compendial specifications for raw-material testing and release. Further emphasis on the functionality testing, raw materials with greater variability in design of experiments, and an understanding of the limitations of the process and product development studies is also needed. When appropriate, enhanced controls beyond the compendial specifications should be applied to the excipient to ensure the product's performance. In the absence of the necessary understanding, further downstream controls may be needed to ensure product quality.
Implementation of QbD. A multidisciplinary and cross-functional team is an important element of incorporating QbD. The team should comprise individuals from quality, regulatory affairs, manufacturing, and development departments so that multiple viewpoints can be considered in the decision-making process. Although the level of involvement may vary during the stages of development, a team approach facilitates a transfer of knowledge and ensures that the team considers the development of the supportive systems needed to implement QbD. Wyeth recognized that the skill sets of individuals required to develop and implement QbD may be slightly different. More control engineers and chemometricians, for example, may be needed to support the concept. In addition, quality and CMC personnel may need to be more familiar with the intricacies of design space and its application. Such training will enable them to understand the uncertainties involved in design space and thereby facilitate a science- and risk-based approach for evaluating changes.
The change of mindset from a reactive approach to a proactive approach is one of the challenges of implementing QbD. The development of a science- and risk-based approach to quality necessitates this change and it is important to incorporate this mindset throughout the organization to make QbD implementation successul.
Quality risk assessment. Quality risk assessments submitted in a sponsor's application should be clear and concise. The basis for the identification of process parameters as either critical or noncritical should be provided. Terminology used by the manufacturing firm should be clarified and facilitate review. Quality risk-assessments should be part of the firm's quality systems, and a process to review and maintain risk assessments based on current knowledge should exist within the manufacturing site.
Process scale-up. During the review and implementation of the design space for Product X, scale-up equations based on engineering principles were used to develop the commercial-scale design space. Although this approach was successful and accurate, development of design space based on scale-independent CQAs such as ribbon porosity for roller compaction has the potential to enable even greater regulatory flexibility.
The global regulatory submission and review process for Products X and Y provided Wyeth with enhanced understanding of the current regulatory landscape in various markets. The process helped crystallize the strategy for the development and submission of future QbD-based applications.
FDA's CMC Pilot Program provided a framework for pharmaceutical companies to gain experience in the submission, review, and inspectional aspects of a pharmaceutical quality- assessment system. This experience was positive and educational, and provided opportunities for scientific interactions and discussions. Similar experiences were gained from submissions to the international markets.
To ensure the success of the QbD initiative, Wyeth suggests that harmonized QbD concepts be applied globally. Consistent inspection practices among the regions of the world, common understanding of risk-management concepts and terminology throughout the industry and respective Boards of Health, and finalization of the FDA postapproval management plan (10) will further accelerate the QbD implementation.
The authors would like to acknowledge the assistance of the following scientists within Wyeth for their contributions: Dominic Ventura, PhD, Parimal Desai, PhD, Richard Saunders, PhD, Subodh Deshmukh, PhD, Michael O'Brien, PhD, Shailesh Singh, PhD, Arwinder Nagi, PhD, Carl Longfellow, PhD, and Loren Wrisley.
Thirunellai G. Venkateshwaran, PhD*, is senior director of new product quality and process knowledge (NPQPK), Stephen P. Simmons, PhD, is vice-president of NPQPK, Nirdosh Jagota, PhD, is vice-president of global regulatory affairs (GRA)–CMC, Donald G. Esherick is director of GRA–CMC, and Patricia Foti Mann is senior director of GRA for Asia Pacific and Latin America, all at Wyeth, firstname.lastname@example.org
*To whom all correspondence should be addressed.
1. FDA, "Submission of Chemistry, Manufacturing and Controls Information in a New Drug Application Under the New Pharmaceutical Quality Assessment System; Notice of Pilot Program," Fed. Regist. 70 (134), 40719–40720, (July 14, 2005).
2. FDA, "Pharmaceutical cGMP's for the 21st Century–A Risk-Based Approach, Final Report," (Rockville, MD, September 2004), www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm, accessed Sept. 8, 2009.
3. ICH, Q8(R2) Pharmaceutical Development, Step 4 version (Geneva, August 2009).
4. ICH, Q9 Quality Risk Management (Geneva, Nov. 2005).
5. ICH, Q10 Pharmaceutical Quality System (Portland, OR, June 2008).
6. FDA, Gudiance for Industry: PAT–A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (Rockville, MD, September 2004) www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070305.pdf, accessed Sept. 8, 2009.
7. FDA, Draft Guidance for Industry: Comparability Protocols—Chemistry, Manufacturing and Controls Information (Rockville, MD, February 2003) www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070545.pdf, accessed Sept. 9, 2009.
8. FDA, Guidance for Industry: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production (Rockville, MD, 2006), www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070287.pdf, accessed Sept. 9, 2009.
9. ICH, M4Q (R1) The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality—M4Q (R1), Quality Overall Summary of Module 2, Module 3: Quality (Geneva, Sept. 2002).
10. P.S. Hudson and D.D. Baker, "The Postapproval Management Plan—A Tool to Apply Science and Risk-Based Approaches," Pharm. Technol., 33 (1), 82–86 (2009).