Docket Management
Docket: 03N-0059 - Pharmaceutical Current Good Manufacturing Practices for the 21st Century: A Risk-Based Approach
Comment Number: EC -17

Accepted - Volume 1

Comment Record
Commentor Dr. Christine-Lise Julou Date/Time 2003-03-21 12:45:04
Organization EFPIA
Category Association

Comments for FDA General
1. General Comments Thank you for offering the opportunity to provide comments. Detailed comments of the European Federation of Pharmaceutical Industries and Associations which represents the research and development based pharmaceutical industry operating in Europe are given in the concept copied below. EFPIA Concept Paper on Quality Systems and Regulatory Innovation for the 21st century Executive summary EFPIA welcomes the FDA’s initiative to develop regulations and guidelines that would result in advancing scientifically sound and integrated systems, applicable to ensuring pharmaceutical product quality. EFPIA also appreciates the chance to comment on the concept paper. EFPIA wishes to emphasize that the primary objective of this initiative should be to ensure that patient safety is paramount, that product quality is “fit for purpose” and that the regulations are designed to achieve a product which is “fit for purpose”. Science and patient safety should be the basis of any compliance requirements. EFPIA welcomes the FDA’s initiative to encourage technological innovation and to remove obstacles to its implementation. EFPIA would welcome and strongly wishes to support a harmonised approach, working with the regulators and industry from the different regions, via the ICH process, in order to achieve a global approach to regulation and risk management, which is appropriate for the globalised pharmaceutical industry. EFPIA proposes that a holistic approach should be taken related to: - The product life cycle from development through to end of product life, - The process chain from purchasing through to distribution, - The regulatory chain from submissions through to review and inspections. EFPIA proposes giving priority to the replacement of existing GMPs by the introduction of a Quality System approach to Good Manufacturing Practices consisting of: - Harmonised regulations and standards which define the objective to be achieved (the “WHAT’s”) Together with, for example, - Appropriate harmonised, science-based guidelines, which propose how the standards may be achieved, when necessary (the “HOW’s”). EFPIA proposes an inspection system schedule based on the risk assessment of the product, process and company and an inspection system that reviews both the Quality Standard achieved and scientific assessments on which procedures and processes are based. EFPIA suggests that regulatory submissions could contain a risk assessment of the product and of the processes used to control critical parameters that ensure that the product quality is fit for purpose. EFPIA is proposing a shift in emphasis towards more responsibility being taken by the pharmaceutical company to make correct judgements and decisions, based on good science and risk-based assessments EFPIA feels that the concepts outlined above would have considerable benefits: - For public health, by ensuring reliable medicines that are fit for purpose - Ensuring more efficient use of the Regulators’ resources, - Better understanding of the regulations and more flexibility for industry in how they are applied. - Removal of non-scientific Compliance requirements and arbitrary limits that do not add to the products fitness for purpose. - Technological innovation not being hampered by undue regulation. 1. Introduction FDA is undertaking an initiative to update its approach to the regulation of pharmaceutical manufacturing and product quality. This paper represents the views of EFPIA. Its purpose is to provide a framework for further discussion between regulators and industry. It outlines the principles on which regulators and industry should be working together to achieve common goals. 2. Goals The primary goals of this initiative should be to: - Ensure optimal patient safety, - Ensure that pharmaceutical products are fit for purpose and fit for use by the patient, - Create clear, concise and well understood requirements and regulations, - Implement quality systems within the pharmaceutical industry which: • Ensure that these requirements and regulations will be met, • Allow the industry the flexibility to implement GMPs, based on good science and risk- based principles, • Allow the industry the flexibility to make innovations and technological improvements. - Implement a risk-based approach to decision making: • for industry, during the development and the manufacturing process, • for the regulators, during review of submissions and during inspections. - Optimise the efficient use of resources. - Harmonise a global approach in ensuring that the above goals are reached. 3. Harmonisation The GMP regulations throughout the world have the same objectives and purposes. In many cases, they are very similar. However, differences often arise in their interpretation. The pharmaceutical industry is a global industry with materials and products being imported and exported to many countries, making compliance with different interpretations of GMP difficult and rendering a global approach a necessity in the 21st Century. Regulators and industry have already demonstrated that they can work well together in preparing a harmonised format for CTD submissions, in preparing harmonised cGMP guidelines, (e.g. ICH Q7A )and other ICH guidelines. EFPIA therefore makes a very strong appeal that key elements of this initiative should be moved forward as a harmonised approach between regulators and industry, via the ICH process, including both regulatory aspects and GMPs. EFPIA proposes that priority is given to developing and harmonising: - A quality systems-based set of GMPS - A risk-based integrated approach to CMC submission and review (including changes) - Risk-based Systems Inspections. 4. Quality system principles and a risk-based approach 4.1. Two - tier approach As already announced, the FDA wishes to introduce up-to-date concepts of risk management and a quality systems approach, while continuing to ensure product quality. This approach could be designed as a two tier system which: 1. Provides clear regulations and standards with which the industry should comply. These regulations and standards should define “WHAT” has to be done and “WHAT” has to be achieved. 2. Provides additional guidance for industry, where required and when necessary, in the form of guidelines, on “HOW” the required standard may be achieved. The relationship between the regulations/standards and the guidances should be clear to regulators, inspectors and to industry. Regulations and standards should be mandatory. Guidances should give proposals and advice on how the standards may be achieved, while still leaving industry the flexibility to achieve the same required standards by alternative, equivalent or better means, providing they are based on good science and achieve the same required end result, with at least the same level of quality. This two-tier approach would allow industry to make innovative and technological advances if it wished, while not making the introduction of new technologies, such as process analytical technology, mandatory 4.2. Responsibility of the manufacturer The quality system approach would require each manufacturer to: - Establish and maintain a quality system that is appropriate to the type of product(s) he is developing and/or producing. - Maintain a quality system that is appropriately applied: • throughout the product life cycle i.e. starting in development through to the end of product life, • throughout the manufacturing process chain i.e. from purchasing through to distribution of the product. - Ensure that quality is designed into the product and the process during the development phase. - Demonstrate that the specific processes and procedures are appropriate and fit for purpose. - Perform appropriate risk analyses to determine the criticality of processes and procedures and to adequately manage the risks to ensure that the required product quality is achieved. 4.3. Re-writing harmonised Quality System Regulations This approach would involve a re-writing of the current regulations based on a quality systems structure. The re-write should include: - Management responsibilities, - Risk- and science-based concepts, - Continuous improvement concepts, - Designing quality into the process and the product, - Designing “fit for purpose” concepts into the process and the product, - Deletion of non-scientific / low patient risk GMP requirements, - Elimination of non-scientific controls and unnecessary requirements that have no added value for the product. 5. Inspections based on quality systems, good science and risk assessment during review Based on the above approach of a two-tier quality system, inspections would have two purposes: 1. To ensure that the quality systems established conform to the regulations and the standards i.e. to ensure that the “WHAT” is achieved. 2. To evaluate, based on good scientific judgement, knowledge and expertise that the processes and procedures established are appropriate and fit for purpose and result in the required product quality, which is fit for use by the patient. This will include the review of risk analyses and correct implementation of risk management activities. This approach could alleviate the need for routine Pre-Approval Inspections based on the knowledge that the developer and manufacturer have adequate quality systems in place which ensure that: - critical process parameters have been identified, assessed and are controlled, - correct procedures are in place, e.g. for establishing specifications and for technology transfer, - adequate procedures are established for ensuring product consistency and quality. Furthermore, as already outlined by FDA, an evaluation system, based on a risk assessment should be established which classifies both the product, based on product and process type, and the company, based on the findings during previous system based inspections. Inspections should be scheduled on the basis of high risk. This approach may also be a suitable topic for the harmonisation of inspections. It could lead to more efficient use of inspectorate resources around the globe while maximizing public health protection by focusing on high-risk products and accepting the findings of “foreign” inspectorates for products and companies classified as low risk. This two-tier approach would give clarity to the industry and to the inspectors and could greatly reduce the inconsistencies with respect to GMP deficiencies found during inspections, because deficiencies would be based on non-conformance to the regulations and standards (the “WHAT”) and not on their interpretation (the “HOW”). Inspectors would be required to be well trained in order to be able to evaluate, using good scientific judgement, knowledge and expertise, whether appropriate risk assessments have been carried out by the manufacturer that have resulted in correct decisions being made. Inspector training and scientific expertise is essential for constructive scientific discussion and dialogue to take place during an inspection. EFPIA supports the FDA’s proposals for a dedicated, expert Pharmaceutical inspectorate. This approach could alleviate some of the concerns raised by the FDA’s working group on dispute resolution and the proposals made by this working group for dispute resolution would fit well into this concept. It would also stimulate an atmosphere of openness and trust between industry and inspectors, instead of one of mistrust. This would greatly enhance the quality and the usefulness of inspections for both industry and regulators. The proposal already made by FDA for a “Specialist” to participate in inspections is also appreciated by EFPIA. 6. Submission and review issues The regulatory submissions and their review should be based on: - Good science - Risk assessment approach - The two-tier quality system approach. 6.1. Development report EFPIA suggests the submission of a development report in which the company could define, based on appropriate risk analyses: - The critical elements in the design of the product and the process and the controls that have been put in place to minimize the risk to product quality and patient safety. - Technological innovations, such as process analytical technology approaches that enhance the control of product quality and increase patient safety. - Controls at the most appropriate place in the process to guarantee the product quality, which may eliminate the necessity for controls at the end of the process (QC). - Quality criteria and specifications related to materials, process and products that have a well-defined scientific basis. (What is required, instead of what can be achieved). - How procedures and controls are implemented that are appropriate to the product and the process and achieve the objectives required by regulations and standards. - Fitness for use based on the type of product and its indication (i.e. life saving drug or a palliative) 6.2. Submission details This approach could also eliminate or reduce the amount of detail required in submissions by concentrating on critical attributes such as therapeutic window, adsorption characteristics, impurity profiles, fitness for purpose and eliminating non-critical process details (i.e. submission of flow charts + critical parameters and controls instead of batch records and full process descriptions) 6.3. Coordination of review and inspection Based on the risk assessment presented in the development report, the reviewer can evaluate the risk category of the product and the process and can determine the necessity for an inspection. This will result in a more efficient use of resources and provide a mechanism for more effective and efficient reviews. If an inspection is planned, the reviewer and the “scientific-specialist” inspector should coordinate the inspection, so that the inspector can make the most efficient use of his/her time by concentrating on those areas deemed the highest risk or least well controlled. 6.4. Change Management A similar approach should also be taken towards Change Management. The criteria should be a good change control system within the company and systems for investigation of deviations and discrepancies and adequate corrective and preventive actions. Change management should be based on risk assessment, science and systems. A scientific approach should result in the ability to make changes without the need to always seek (prior) regulatory approval, based on the impact assessment of the change on the product quality. The approach recently announced by FDA for “Comparability Protocols” based on science and risk assessment should be supported by industry, as a step in the right direction. Systems inspections covering the change management system could also potentially reduce the level of information that is required to be submitted. 6.5. Existing products Although the primary focus of this concept of risk assessment is for new products and new submissions, this new approach should not prejudice existing products with a history of being fit for purpose. It is proposed that a review could be carried out of existing products based on a retrospective evaluation of fitness for purpose and level of risk. Such an evaluation could be submitted to regulators as a review report. 7. Management issues in the Pharmaceutical Industry In the above approach, the onus is put firmly on management accountability to ensure that: - Policy and objectives for and commitment to quality are established, - The right systems are in place which ensure product quality, which is fit for purpose, - Training is given in and expertise is available in risk assessment techniques, - Scientifically based judgements can be made, - Systems are in place for review of performance by management. The Company should have the scientific competence and expertise to make risk-based assessments, scientifically based decisions and reasoned judgements. Knowledge of the process, of the product and of its use is a prerequisite in making these decisions. The Quality Function should be independent and have the responsibility and authority to make decisions based on good science and risk assessments. The Company and the Quality Function should be held accountable for the decisions taken. All decisions should be appropriate and scientifically motivated with appropriate supporting documentation that is also fit for its purpose. 8. Benefits and efficient use of resources Industry has already worked closely with regulators to harmonise the content and format of the CMC submission and also on the GMP guidelines for Active Pharmaceutical Ingredients. EFPIA would welcome and support the opportunity to participate in moving this process forward to: - Harmonise an approach to Quality Systems, - Improve submissions based on a risk assessment approach and - Improve the coordination between the reviewer and inspector in identifying areas of concern. This could have the following benefits for Regulators: - Better use of regulator’s resources to focus on the critical elements through a scientific risk- based approach. - Mutual recognition of inspection reports, particularly for low-risk products and low-risk companies, resulting in a more efficient use of inspectorate resources, both locally and globally. - Mutual recognition of dossiers, particularly for low-risk products, resulting in more efficient use of reviewer time, both locally and globally, to concentrate on high-risk products depending on the potential risk for patient and to reduce review time particularly of life saving drugs. The benefits for industry are perceived to be: - Better clarity and understanding of the regulations and standards, allowing greater focus on areas that really matter with the elimination of non-added value activities.. - More flexibility for the manufacturer to determine suitable methods to achieve the quality objectives. - Scientifically based inspections, allowing scientific discussion of the issues in an atmosphere of openness and mutual trust. - Scheduling of inspections based on risk assessments of the product, process and company. - Quicker review of submissions and lower burden of submissions for changes. The benefits for public health are perceived to be: - Better quality medicines that are fit for purpose. - Improved safety for the patient, based on risk assessment and scientific judgements.

EC -17