DDoowwnnllooaaddeedd ffrroomm jjoouurrnnaall..ppddaa..oorrgg oonn AApprriill 44,, 22001199 Summary of the EMA Joint Regulators/Industry QbD workshop (London, UK; 28-29 January 2014) Graham Cook, Georges France, Øyvind Holte, et al. PDA Journal of Pharmaceutical Science and Technology 2016, Access the most recent version at doi:10.5731/pdajpst.2015.006171 Downloaded from journal.pda.org on April 4, 2019 Summary of the EMA Joint Regulators/Industry QbD workshop (London, UK; 28-29 January 2014) Cook, Graham1; France, Georges; Holte, Øyvind; Lorenti, Giampiero; and Tainsh, David. Authors: Graham Cook (Pfizer, UK); 12 Greenhill Way, Farnham, Surrey GU9 9SY. United Kingdom Georges France (Novartis, Switzerland); present address (GSK, Switzerland) GSK, Route de l´Etraz, CH-1260 Prangins (Nyon), Switzerland Øyvind Holte (NOMA, Norway); Norwegian Medicines Agency, PO box 63, Kalbakken,NO- 0901 Oslo, Norway Giampiero Lorenti (AIFA, Italy); Italian Medicines Agency, Via del Tritone, 181 - 00187 Roma, Italy David Tainsh (GSK, UK); GSK, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom 1Author for Correspondence: Dr Graham Cook 12 Greenhill Way Farnham Surrey GU9 8SY United Kingdom [email protected] +44-7717-878781 1 Downloaded from journal.pda.org on April 4, 2019 Abstract This paper summarises the discussions and insights gained from the key themes that emerged during the Quality by Design (QbD) Workshop held at the European Medicines Agency offices in London, UK, on 28-29 January 2014. Industry and regulators shared practical experiences from 6 case studies (5 approved small molecule products and one phase 3 biotechnological product) based on QbD submissions by 5 companies (AstraZeneca, GlaxoSmithKline, Novartis, NovoNordisk and Pfizer). The case studies covered a range of different development, regulatory submission and post- approval aspects of QbD, and were developed through confidential discussions between the company representatives and regulators. Key themes that emerged from the workshop discussions were: 1. Presentation of Information in Submissions (Development story and the presentation of information in Marketing Authorisation Applications; Risk assessment and criticality); 2. Development Aspects (Design space; Use of models; Control strategy); and 3. Post Approval Aspects (Lifecycle management; Dossier – Quality System interactions; Handling of Deviations). Many aspects of QbD for biotechnological products are similar to small molecules, but there are some important differences highlighted in this paper. The final section of the paper discusses some proposals for future developments to address the issues that were identified. Keywords Quality by Design (QbD); European Medicines Agency (EMA); Workshop London 2014; Presentation of Information; Submissions; Regulatory Dossier; Development; Risk 2 Downloaded from journal.pda.org on April 4, 2019 assessment; Criticality; Design space; Models; Control strategy; Post-Approval; Lifecycle management; Quality System; Deviations 3 Downloaded from journal.pda.org on April 4, 2019 Lay Abstract This paper summarises the discussions and insights gained from the key themes that emerged during the Quality by Design (QbD) Workshop held at the European Medicines Agency offices in London, UK, on 28-29 January 2014. Industry and regulators shared practical experiences from 6 case studies (5 approved small molecule products and one phase 3 biotechnological product) based on QbD submissions by 5 companies (AstraZeneca, GlaxoSmithKline, Novartis, NovoNordisk and Pfizer). The case studies covered a range of different development, regulatory submission and post- approval aspects of QbD, and were developed through confidential discussions between the company representatives and regulators. Key themes that emerged from the workshop discussions were: 1. Presentation of Information in Submissions (Development story and the presentation of information in Marketing Authorisation Applications; Risk assessment and criticality); 2. Development Aspects (Design space; Use of models; Control strategy); and 3. Post Approval Aspects (Lifecycle management; Dossier – Quality System interactions; Handling of Deviations). Many aspects of QbD for biotechnological products are similar to small molecules, but there are some important differences highlighted in this paper. The final section of the paper discusses some proposals for future developments to address the issues that were identified. 4 Downloaded from journal.pda.org on April 4, 2019 Introduction On 28-29 January 2014 the European Medicines Agency hosted a Quality by Design (QbD) Workshop, organized by European regulators, industry and the PDA, at its offices in London. During the workshop industry and regulators shared practical experiences from 6 case studies based on QbD submissions by 5 companies (AstraZeneca, GlaxoSmithKline, Novartis, NovoNordisk and Pfizer). Presentations from the workshop are available on the EMA website QbD page (Ref. 1) and this paper summarises the discussions and insights gained from the key themes that emerged during the workshop. The case studies (5 approved small molecule products and one phase 3 biotechnological product) were chosen to cover a range of different development, submission and post- approval aspects of QbD, and were developed through confidential discussions between the company representatives and regulators. Many aspects of QbD for biotechnological products are similar to small molecules and this was reflected in the issues and proposals discussed during the workshop. However, there are some important differences; and those are highlighted in the paper, albeit that to date there has been limited experience in Europe with ‘QbD’ biopharmaceutical submissions. The discussion points and recommendations from the workshop were collated into key themes and grouped into three areas, as follows: 1. Presentation of Information in Submissions 1.1 Development story and the presentation of information in Marketing Authorisation Applications 1.2 Risk assessment and criticality 2. Development Aspects 5 Downloaded from journal.pda.org on April 4, 2019 2.1 Design space 2.2 Use of models 2.3 Control strategy 3. Post Approval Aspects 3.1 Lifecycle management 3.2 Dossier – Quality System interactions 3.3 Handling of Deviations The final section of the paper discusses some proposals for future developments to address the issues that were identified. This paper was developed from summaries of the different themes prepared by teams of industry workshop participants with contributions from the regulatory agency participants listed in the Acknowledgements section. The success of the workshop was the result of hard work and enthusiastic contributions by Organisers, Case Study Developers, Presenters and Attendees. 1. Presentation of Information in Submissions 1.1 The Development Story and Presentation of Information in Marketing Authorisation Applications One of the major issues with science-rich CMC submissions has been the effective communication of the important aspects of a development program in a way that appropriately differentiates the critical aspects from the mass of supporting data. Industry and regulators share a common interest in concise, focussed submissions that facilitate efficient 6 Downloaded from journal.pda.org on April 4, 2019 assessment and support optimised lifecycle management after approval. Particular aspects of the presentation of information explored during the workshop included: • How can the development story in QbD submissions be presented to facilitate assessment? • What details are necessary for review of risk assessments, design of experiments (DoEs), Process Analytical Technology (PAT) tools, etc. and how would this vary depending on the use of the information in the finished product design, manufacturing process and control strategy? • Is the Common Technical Document (CTD) format adequate to support presentation and review of ‘enhanced development’ submissions? Is separation of ‘registered detail’ from supportive information in the CTD format clear? • How and where should the control strategy (including any proposed Design Space) and its development be described in the submission? • When assessors are considering requests for operational flexibility would it be helpful to describe elements of the Quality System in the Application file to aid understanding of how changes are foreseen to be managed during the lifecycle? Recommendations Information presented in a dossier will vary according to the product type and complexity, the nature of the challenges overcome during development and the knowledge gained - it is not ‘one-size-fits-all’. ICH terminology should be used and non-ICH terminology such as “key”, “major” or “minor” should be avoided as the lack of agreed definition can create confusion. 7 Downloaded from journal.pda.org on April 4, 2019 Assessment is facilitated by summarising the control strategy that assures delivery of the critical quality attributes (CQAs) and explicitly stating the extent of flexibility proposed by the applicant. The CTD structure is not optimal for provision of this overall perspective to the assessor, but experience of the workshop participants suggests that the limitations can be overcome. Sections S.2.6 and P.2 have been used successfully for providing summary information. This control strategy summary would also be useful for the inspector. Tabular formats are recommended to present important elements of the Control Strategy, linking the quality target product profile (QTPP), to CQAs of drug product and drug substance and to critical process parameters (CPPs) (and material inputs) of the process. The presentation of ‘enhanced’ or QbD aspects should include sufficient detail or rationale to explain the derivation of CQAs and CPPs, and the tabular format can link/reference detailed sections of the CTD where further detail can be found. The depth and/or extent of information presented on risk assessments, DoEs, mathematical models etc. should depend upon their purpose or use in assuring the quality of the product and associated disposition decisions. For example, if a DoE was used for screening purposes, summary information could be sufficient. By contrast, a DoE used to establish a design space employed as part of the control strategy would need considerably more detail. This might include the rationale for the DoE approach, tables of inputs (including batch size, ranges studied, factors kept constant during the DoE) and results, data interpretation, statistical significance of parameters studied, scale-dependence, and so on. It may be helpful to consider the degree to which commitments in the manufacturing process and control strategy could be thought of as ‘non-traditional’ because it is likely that more understanding (science and risk / criticality based) would be expected in such cases e.g. if a flexible manufacturing process 8 Downloaded from journal.pda.org on April 4, 2019 and/or a “RTRt-like” control strategy is applied, more understanding is expected to be presented under development. It was agreed that Pareto plots and Ishikawa / fishbone diagrams are useful tools for communicating some risk assessments. If a design space is proposed, its development should be clearly described in the relevant development sections (e.g. S.2.6 / P.2.3), and it should be explicitly defined (e.g. by equation, tables and/or visual representations) in the manufacturing process description sections of the dossier (e.g. S.2.2 / P.3.3). 1.2 Risk Assessment and Criticality Communication of risk assessment/management in regulatory submissions presents a number of challenges, including: • Translation of the raw Quality Risk Assessment outcomes into an appropriate summary. • The difficulty in defining the threshold for ‘critical’ given that it is perceived as a continuum in ICH guidance (e.g. ICH Q11 Section 10.2 example 2). • The provision of linkages between risk assessment and the development of the control strategy. • The difficulties managing post-approval changes given the differences in the post- approval frameworks between markets (and potentially the approval of what is a CPP and non-CPP). Furthermore, for biotechnological products additional key differences add to the challenges: • Immunogenicity is a significant concern for biologics – and only limited knowledge exists on the relationship between quality attributes and immunogenicity. 9