Quality by Design - a status report

Siegfried Schmitt explains why the time is right to raise awareness of QbD in the regulatory affairs community. The concept of Quality by Design (QbD) is mostly known to and discussed by pharmaceutical operations and quality personnel, and less so by regulatory affairs professionals. The main reason for this is likely to be the low number of QbD new drug applications or variations to existing marketing authorisations, both in the EU and the US. Though no official figures have been published, verbal feedback from various regulators indicates that there have been few successful submissions or variations to date. It is, however, the right time to raise awareness of QbD in the regulatory affairs community, as several leading pharmaceutical companies are poised to file significantly more QbD new drug applications or variations. This article provides an overview of the QbD concept, the historical background, the current regulatory status and expected developments. Most of the information provided is taken from a recent publication1 edited and co-authored by the author of this article, and intelligence gathered in recent months at conferences and meetings. Historical background At this stage, it is appropriate to go back to basics and provide a definition of QbD in the pharmaceutical context and to explain why it is so important to the industry. QbD is designed to help both industry and regulators move towards a more scientific, risk-based, holistic and proactive approach to pharmaceutical development. The concept promotes industry's understanding of the product and manufacturing process starting with product development – basically building quality in rather than testing it2. Under QbD, when designing and developing a product, a company must define desired product performance and identify critical quality attributes (CQAs). Using this information, the company then designs the product formulation and process to meet those product attributes. This enables understanding of the impact of raw material attributes and process parameters on the CQAs and identification and control of sources of variability. A company is then able to continually monitor and update its manufacturing process to assure consistent product quality. This systematic approach to product development and manufacturing varies a great deal from the traditional approach, which was more empirical. The traditional approach puts the emphasis for quality on meeting specifications, whereas the QbD approach puts equal emphasis on specifications and process controls. The US Food and Drug Administration published its vision for drug regulations (current Good Manufacturing Practices) for the 21st Century in 20033, 20044 and 20065. This initiative began in 2002 and pertains to veterinary and human drugs and select human biological products such as vaccines. The FDA's goal is to transform the chemistry, manufacturing and control (CMC) section review into a modern, science and risk-based pharmaceutical quality assessment, which is expected to result in an increased number of successful drug applications, consequently providing more and better treatment options for patients. In particular, the FDA's objectives are to: encourage the early adoption of new technological advances by the pharmaceutical industry; facilitate industry application of modern quality management techniques, including implementation of quality systems approaches, to all aspects of pharmaceutical production and quality assurance; encourage implementation of risk-based approaches that focus both industry and agency attention on critical areas; ensure that regulatory review and inspection policies are based on state-of-the-art pharmaceutical science; and enhance the consistency and co-ordination of the FDA's drug quality regulatory programmes, in part, by integrating enhanced quality systems approaches into the agency's business processes and regulatory policies concerning review and inspection activities. These objectives were subsequently reflected in a suite of guidance documents developed by the International Conference on Harmonisation, the founding member regions of which are the US, Japan and the EU. The FDA has made a conscientious effort to restructure as needed and to align its operations with the changing regulatory framework. The agency, like all other agencies, will have to change the way it address regulatory submissions/applications. Its assessment will focus on critical quality attributes (chemistry, pharmaceutical formulation, and manufacturing processes) as they relate to product performance. Three offices in the agency's Office of Pharmaceutical Science are focused on facilitating the implementation of QbD: Office of New Drug Quality Assessment; Office of Biotechnology Products; and Office of Generic Drugs. These offices are developing new paradigms for submission reviews and in some instances even a new set of skills6. The reviewers expect to see evidence that companies, as a result of implementing QbD, use high-quality pharmaceutical science and engineering along with a structured set of product and process development tools and an overarching governance and project management process. All three offices are developing processes that satisfy the needs of their particular regulations and products. However, all three processes have the same objectives, namely a better understanding of the product development and manufacturing processes. This goal was the basis for what developed into the suite of ICH guidance documents, which were published between 2005 and 2009: ICH Harmonised Tripartite Guideline Pharmaceutical Development Q8(R2) (August 2009)7; ICH Harmonised Tripartite Guideline Quality Risk Management Q9 (9 November 2005)8; and ICH Harmonised Tripartite Guideline Pharmaceutical Quality System Q10 (4 June 2008)9. These three guidance documents are interrelated and form the basis for national and international legislation. ICH Q8 (the revision numbers are generally omitted) describes the concept of QbD. ICH member states have incorporated the ICH Q8 guideline into their legislation; however, the application of QbD is entirely voluntary. The reasons for not mandating QbD are manifold10. Industry has thus been slow in adopting and implementing QbD, despite some very obvious benefits of the concept. The European perspective on QbD has been covered in several presentations11, where the current and desired states are described as follows: current state – pharmaceutical products marketed in the EU are of good quality (quality itself is not an issue) but pharmaceutical development and manufacturing can be improved; and desired state – enhanced product and process understanding through enhanced, QbD approach to pharmaceutical development. It is important to understand the fundamental differences between the European authority – the European Medicines Agency – and the FDA as these have led to a different approach in addressing QbD. Unlike the FDA, the EMA co-exists with over 40 national competent authorities in the EU/European Economic Area, forming an integrated network of agencies. The centralised procedure for marketing authorisations (via the EMA) co-exists with marketing authorisation procedures at national level (national procedures, decentralised procedures, mutual recognition procedures) that are all specific to each member state. The EMA is co-ordinating the existing scientific resources in the member states, provides an interface between all parties and is working towards harmonisation of regulatory and technical requirements within the EU. The EMA has, therefore, put its focus first on Process Analytical Technology (PAT) and is addressing QbD through involvement in the ICH activities. The EMA describes PAT as an enabling tool to a more systematic approach to pharmaceutical development (QbD). PAT can be seen (together with statistical process control) as the control mechanism to maintain the validated state. The FDA was and is aware of industry's hesitance to submit dossiers based on unproven guidance and concepts, which is why the agency made it clear from the beginning that QbD-related issues would not hold up approvals for NDAs or supplements. This created a win-win situation. Pilot programmes were run by the FDA starting in July 2005. The pilot programmes provided an opportunity for firms to submit CMC information that demonstrates QbD. The FDA's Office of Biotechnology Products pilot programme was announced in July 2008. Results are not expected before 2015. A "pilot"' was run by the EMA following its publication of a document on a work sharing procedure for PAT variations to nationally authorised products in June 2006 (EMEA/120457/2006). In Japan, a total of three submissions on Real Time Release (RTR) have been received with regards to QbD. No further information on the matter could be obtained. Though there is no pilot for generic products, the FDA's Office of Generic Drugs has developed a question-based review (QbR) for quality evaluation of generic drug applications12. QbR is based on QbD concepts and principles and focuses on product and process design and understanding. All abbreviated new drug applications are now done in the QbR format. On 16 March this year, the EMA and the FDA announced a pilot programme that will allow parallel evaluation of relevant QbD components of selected applications that are submitted to both agencies at the same time13. The pilot started on 1 April and will conclude on 31 March 2014. Under this programme, both agencies will assess the parts of the applications relevant to QbD, such as development, Design Space (DS) and RTR testing. The evaluation will be performed separately by each agency, with regular communication and consultation throughout the review, with the aim of giving a common list of questions to the applicants and conducting a harmonised evaluation of their responses. Figure 1 depicts the historical developments related to QbD. Current legislative situation The FDA has updated its pre-approval inspection (PAI) compliance programme guidance (CPG 7346.832) to better reflect the agency's 21st century quality initiative and the new ICH Q8-10/QbD regulatory paradigm14. The new PAI CPG represents a significant overhaul of the programme guidance to reflect current agency risk-based thinking and objectives, and is the first major revision since its original release in 1994. The FDA worked on revising the programme for some time and has issued interim revisions with more minor changes in the past few years. The DS concept is now incorporated into EU legislation. However, it is not mandated. The EMA released a revised version of its document on "Compilation of community procedures in inspections and exchange of information" on the "Conduct of Inspections of Pharmaceutical Manufacturers or Importers" in March 201015 to align with recent revisions to its EU GMP guide reflective of ICH Q8-10 principles16. In this revised document, wording has been added to recommend the use of risk-based planning for inspections, which also brings the inspection process itself in line with the risk-based compliance approach stipulated by the regulations. Impact on the CTD/eCTD Before analysing the impact of QbD on regulatory filings, it is necessary to look briefly at the technical information required to gain market access and how this is evaluated and kept up to date. Before commercialisation, prospective marketing authorisation holders must file an application with a regulatory authority by submitting regulatory information in the form of a technical file. In the pharmaceutical industry, the format of the technical information has been harmonised across Europe, the US and Japan in the common technical document (CTD); the electronic form of this information is the electronic eCTD. Although the requirements have not been completely harmonised, the CTD has helped harmonise dossier requirements. Since 2003, the CTD format has been mandatory in the EU and Japan. It is not mandatory in the US, Canada or Australia, but is highly recommended. The ICH guidance, M4 Organisation of the Common Technical Document, outlines a common agreed-upon format for applications made to regulatory authorities. The CTD is organised into five modules as shown in Figure 2. The Module 3 quality section of the CTD covers information pertaining to CMCs as well as regional specific information and appendices of both the drug substance and drug product. Although the structure has been harmonised, ICH guidelines do not exist for all CMC topics (eg drug substance synthesis, drug product manufacture and container closure), hence the content is not totally harmonised. The current version of this module was adopted in the EU by the EMA's Committee for Proprietary Medicinal Products in March 2003 (CPMP/ICH/2887/99 rev.1 Quality) and by Japan's Ministry of Health, Labour and Welfare in July 2003 (PFSB/ELD Notification No. 0701004). ICH Q8 was developed specifically to describe the pharmaceutical development section (3.2.P.2) of a regulatory submission in the ICH M4 CTD format. Mock examples of this section have been developed and are freely available on the internet. However, QbD elements can also be considered to be part of the proposed manufacturing process, and can be described in section P.3.3 of the application that includes the description of the manufacturing process and process controls. Information on the control of critical steps and intermediates should be placed in section P.3.4. In addition, information related to product and process development studies can be placed in sections P.2.1, P.2.2, and P.2.3. The relationship of the design space(s) to the overall control strategy can be discussed in section P.5.6 of the application (justification of the drug product specification). DS is a specific new concept in ICH Q8. ICH Q8 defines the DS as the multidimensional combination and interaction of input variables (eg material attributes) and process parameters that have been demonstrated to provide assurance of quality. The DS describes the relationship between the process inputs (material attributes and process parameters) and the critical quality attributes. This should be described in a submission by the applicant and is subject to regulatory assessment and approval. Once a DS has been authorised, movements within the DS are not considered a change from a regulatory point of view (no variation to be submitted). It is expected that operation within the DS will result in a product meeting the defined quality. Movement out of the DS is considered to be a change and would normally initiate a regulatory post-approval change process based on national requirements. Benefits of QbD From a regulatory affairs perspective, it is important to realise that in the pharmaceutical industry, post-marketing activities are the most resource-intensive phase of the entire product lifecycle. This includes managing the lifecycle of a product from its conception, through design and manufacture, to service/use and disposal17. QbD has a direct impact on regulatory documentation by allowing movements within the DS, which are not considered a change from a regulatory point of view and do not require the submission of a variation to the regulatory authorities. This can have a positive impact on manufacturers by ensuring a better quality end product, less batch failure and better control while at the same time reducing the number of post-market variations. This improves the return on investment and reduces the burden on both manufacturers and authorities. In addition, QbD can reduce the time to market, thus allowing patients better access to higher quality medicines. Summary A harmonised global approach to QbD, from both an application assessment and an inspection perspective, is likely to be a long way away. As most agencies, especially those in Europe, are downsizing significantly, smaller agencies will find it even more challenging to cope with QbD applications. Apart from the differences within the various global regulatory systems and the nationally diverse interpretations of the regulations, there is also the matter of (lack of) training and education of agency staff, necessary for achieving harmonisation across the globe. On the other hand, the application of QbD enables a company to assure quality in a reliable manner, which demonstrates a true level of control. Applying QbD principles will drive and deliver compliance at optimised cost/benefit levels. Any changes to the design that may become necessary can then be easily assessed as to their potential impact on product quality, and consequently to their acceptability by the regulators. QbD is a concept that is here to stay and that is being fully embraced by early adopters in the industry. As was the case with the GMPs, such a paradigm change will take time to be fully understood and accepted by both industry and the regulatory agencies. AcknowledgementsWith special thanks to Salma Michor, Michor Consulting eU, for her contributions to the CTD section of this article.References 1. Quality by Design – Putting Theory into Practice, edited by Siegfried Schmitt, 2011, www.pda.org 2. Rathore AS, Winkle H, Quality by design for biopharmaceuticals, Nature Biotechnology, 2009, 27(1), 26-34 3. FDA, Pharmaceutical cGMPS for the 21st Century – A Risk-Based Approach: Second Progress Report and Implementation Plan, 2003, http://tinyurl.com/23mquup, last updated 17 Aug 2010 4. FDA, Critical Path Opportunities List, March 2006, http://tinyurl.com/28mpsjz 5. Winkle HN, director, Office of Pharmaceutical Science Center for Drug Evaluation and Research, Food and Drug Administration, FDA Modernization Implementation of Quality by Design Progress, Challenges, Next Steps, 46th DIA Annual Meeting, Washington, DC, 16 June 2010 6. FDA, Guidance for Industry PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, September 2004, http://tinyurl.com/2dnl5h9 7. ICH Q8, August 2009, www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf 8. ICH Q9, 9 November 2005, www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf 9. ICH Q10, 4 June 2008, www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf 10. See Reference 1 11. See, for example, Riccardo Luigetti, QbD: A Global Implementation Perspective, The EU Perspective, The Siena Conference on Product and Process Optimization, 6 October 2008, http://tinyurl.com/288v3uk 12. See Reference 6 13. EMA-FDA pilot program for parallel assessment of Quality by Design applications, 16 March 2011, http://tinyurl.com/3sv58g7 14. International Pharmaceutical Quality, Monthly Update July 2010, http://tinyurl.com/67slcza 15. EMA Conduct of Inspections of Pharmaceutical Manufacturers or Importers, 17 March 2010, http://tinyurl.com/3ae2385 16. See Reference 14 17. Fundamentals of International Regulatory Affairs, Regulatory Affairs Professionals Society, 2010, Chapter 5, Pharmaceutical Postmarketing and Compliance, page 44 Siegfried Schmitt, PhD, is a principal consultant at global bio/pharmaceutical services organisation PAREXEL Consulting, based in Uxbridge, UK. He is the practice lead for Quality by Design. Website: www.parexel.com. Email: siegfried.schmitt@parexel.com.