OR WAIT null SECS
ICH Q8, Q9, and Q10 support and implications for the future.
The mission of the International Conference on Harmonization (ICH) is to make recommendations towards achieving greater harmonization in the interpretation and application of technical guidelines and requirements for pharmaceutical product registration. The organization, launched in 1990, brings together the drug regulatory authorities and the pharmaceutical industry associations of Europe, Japan, and the United States.
Regulatory harmonization offers many direct benefits to both regulatory authorities and the pharmaceutical industry with beneficial impact for the protection of public health. Key benefits include: streamlining the regulatory assessment process for new drug applications, and reducing the development times and resources for drug development.
Harmonization is achieved through the development of ICH Tripartite Guidelines, which are developed through a process of scientific consensus among regulators and industry. Key to the success of this process, however, is the commitment of the ICH regulators, including FDA, EMA, and Japan's Ministry of Health, Labor & Welfare, to implement the final guidelines.
The new ICH paradigm
In 2003, the quality experts in ICH developed a new vision: "Develop a harmonized pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to quality risk management and science" (1). This goal led to the creation of the following Quality guidelines: ICH Q8 Pharmaceutical Development; ICH Q9 Quality Risk Management; ICH Q10 Pharmaceutical Quality System, and the pending ICH Q11 Development and Manufacturing of Drug Substance (see cover story in this issue for details).
These guidelines represented methodologies addressing the challenges of the pharmaceutical industry with regard to emerging techniques based on the rapid growth of technology and new opportunities in drug development and manufacturing. These guidelines introduced in detail a new quality vision for industry, one focused on science- and risk-based concepts and approaches, and one that emphasized an adequate quality system. In addition, ICH Q9 was the first harmonized document applicable to processes performed by both industry and regulators.
Following these developments, the ICH Quality Implementation Working group (Q–IWG) worked out a way to facilitate harmonized implementation of this new paradigm. The Q8, Q9, and Q10 guidelines, although independent, are interlinked. As a consequence, implementation support was needed and provided.
The ICH Steering Committee endorsed the establishment of the Q–IWG to ensure the globally consistent implementation of ICH Q8, Q9, and Q10, and to make sure that maximum benefit is achieved from the interaction between these guidelines (1). In parallel, Q–IWG supported the development of ICH Q11 to guarantee a harmonized approach. As its first deliverable, Q–IWG developed a Question-and-Answer document (Q&A) about the guidelines as well as enhanced training (2).
Q&As. The Q&A document answers key questions raised at several conferences and workshops. For example, clarification of process validation and continuous process verification are included, as are answers related to questions about quality by design (QbD), including design space, real-time release testing (RTRT), and control strategy. The series of answers about the pharmaceutical quality system focus on inspection practices, knowledge management, and software solutions (2).
Training program. Defining how the ICH Quality guidelines work together throughout the product lifecycle was a key goal of the Q–IWG training and workshop series, held from 2009 to 2011, in Tallinn; Washington, DC; Ottawa; and Seoul, with participation from the ICH Global Cooperation Group and the Asia–Pacific Economic Community. A case study was developed for the training workshops to explain how a product developed using a science- and risk-based approach might be challenged during regulatory assessment. Postapproval manufacturing implementation, quality system considerations, and potential thoughts during inspections were included in the case-study discussion.
In addition, key messages on design space, control strategy, pharmaceutical quality systems, and quality risk management were discussed through interactive sessions among participants and Q–IWG members. Slides of the presentations are available in English and Japanese (3). During these training workshops, participants brought up many additional questions not addressed in the Q&A document, which triggered the need for further clarifications.
"Points to Consider" documents. Q–IWG therefore developed several "Points-to-Consider" to further clarify concepts and practices. The single document, covering additional Q8, Q9, and Q10 implementation issues, is meant to supplement the existing Q&A document and the workshop materials (2, 3). The industry and regulators are encouraged, however, to use all of these documents together.
The Points-to-Consider document covers the following key areas.
Criticality of quality attributes and process parameters. The information developed to determine critical quality attributes (CQAs) and critical process parameters (CPPs) will help to develop the control strategy, ensure the quality of the product throughout the product lifecycle, and increase product and process knowledge as well as the transparency and understanding for regulators and industry evaluating any changes.
The following points could be taken into consideration for establishing CQAs and CPPs: the relationship between risk and criticality, various considerations for identifying and documenting CQAs, possible evolution of the CQAs and CPPs throughout the product lifecycle, and the relationship of criticality to control strategy. The critical aspect is the high risk of significant impact to product quality, safety, or efficacy, which requires a degree of control.
Control strategy. The main elements needed to develop and maintain the control strategy over the product lifecycle include continual improvement and change management. Different control strategies can be applied for the same product. As stated in ICH Q10, knowledge management is a key enabler. Further details are provided in the Point-to-Consider document on the suitability of control strategy at different scales, specifications and Certificate of Analysis for RTRT, and on the process for a deciding when to release a batch (4).
Level of documentation in enhanced regulatory submissions. It is helpful for regulators to have a statement describing the proposed regulatory outcome and expectations of a QbD or enhanced approach, as described in the submission. It is important to note that every study performed and/or data generated during product development does not need to be submitted to the appropriate regulatory authority. The document provides details on which studies and data to consider with regard to risk-management methodologies, design of experiments, and the manufacturing process description (4).
Design space. The Q–IWG training workshops demonstrated that clarification on how to develop a design space was also desired by the industry and regulators. The Points-to-Consider document therefore addresses the verification and scale-up of a design space, documentation of the space, and its life-cycle management (4).
Role of modeling in QbD. The categorization of models is a key part. After developing and implementing models, considerations on model validation and model verification during the lifecycle conclude with the documentation of model-related information in a regulatory submission.
Process validation/process verification. This section of the Points-to-Consider document provides general considerations on the continuous process verification (4). Please note that the the term continued process verification is used in the FDA process validation guidance to describe stage 3 of the life-cycle approach to process validation (5).
Since the approval of its Quality vision in 2003, ICH has made available appropriate guidance and training material for the industry and regulators to use in the implementation of science- and risk-based approaches to drug development and manufacturing at the global level. It is important to read, understand, and think about the concepts presented in the Quality guidelines before implementing them. ICH's goal is therefore to provide the key information and considerations needed to achieve a harmonized approach. The ultimate benefit is for patients in that quality is built into their products, thereby reducing the number of complaints, deviations, issues, recalls, and inspection observations.
The topics described in this article have been developed and discussed by members of the ICH Quality Implementation Working Group, namely: Jean-Louis Robert (rapporteur), Diana Amador-Toro, Robert G. Baum, Nicholas Cappuccino, David Cockburn, Georges France, Richard L. Friedman, Nigel Hamilton, Sabine Kopp, Hirotada Nagai, Yukio Hiyama, Takao Kyohara, Fusashi Ishikawa, Sabine Kopp, Urs Kopp, Akira Kusai, Yoshihiro Matsuda, Motoaki Mitsuki, Elaine Morefield, Jacques Morénas, Masatoshi Morisue, Markus-Peter Müller, Tamiji Nakanishi, Moheb Nasr, Kazuhiro Okochi, Anthony Ridgway, Rachael Roehrig, Stephan Rönninger, Swroop Sahota, Hideki Sasaki, Tetsuhito Takarada, Shigheki Tamura, Krishnan Tirunellai, Mats Welin, and Jean M. Wyvratt.
Stephan Rönninger is deputy topic leader for EFPIA in the ICH Q–IWG and head of External Collaboration Europe/Japan/CEMA at F. Hoffmann-La Roche. Sabine Scheitlin is operational support manager at F. Hoffmann-La Roche, both based in Basel, Switzerland, tel. +41 61 688 69 74.
1. ICH Steering committee (Brussels, Belgium, 2003).
2. ICH, Q8, Q9, Q10 Implementation, Question and Answers (Q&A), November 2010 (www.ich.org)
3. ICH, Q8, Q9, Q10 Implementation, Training material, November 2010 (www.ich.org).
4. ICH, Q8, Q9, Q10 Implementation, Points to Consider, December 2011 (www.ich.org)
5. FDA, Guidance for Industry: Process Validation: General Principles and Practices (Rockville, MD, 2011).