1.3. Quality by Design – the authorities’ initiative to improve the science in NDAs and the quality of drug products

These figures have also alarmed the health authorities and they therefore started several initiatives over the last couple of years to improve the quality of drug products consistently starting at the root cause of the problem. While the focus formerly had been to improve quality during manufacturing (CGMP guidelines, QA systems and quality guidelines for testing, specifications, impurities, etc.) the new paradigm was now to improve the quality by the excellence in the design of new drug products and manufacturing processes. Combining a customer driven development focus, risk based decision making and science based development approaches into a new philosophy aiming to improve the quality of drug development itself is the still fairly new approach of Quality by Design.

Furthermore, the authorities also hoped to relieve themselves of some of the burden in reviewing NDAs, when they often were missing the relevant science in the provided dossiers to make informed decisions during the approval process. This also prolonged the review times for NDAs, which they had set themselves as a target to shorten considerably in the future.

Therefore, the FDA started its PAT initiative in 2004 with the publication of the Guidance for Industry: “PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance”. This guidance wants to achieve a shift of paradigms in the development of new drug products and promotes to “design and develop well understood processes that will consistently ensure a predefined quality at the end of the manufacturing process”. The guidance also outlines in much detail different tools to achieve this objective, focusing on online and inline analytical measurement methods during manufacturing as process analyzers. As an incentive to adopt the new paradigm, the authority offeres close collaboration with the applicant and support in problem solving during development and submission of new drug products under the PAT approach.¹⁶

Unfortunately, the concept was misinterpreted by most of the innovators and early adopters of this new concept - companies that started early to embrace PAT technologies. Generating continuously analytical data already during manufacturing, they hoped to relieve themselves of the burden of tedious end control testing of batches as traditionally required in the pharmaceutical industry. As most of the PAT analyzers are rather expensive to implement and validate. Mostly the big pharmaceutical companies started adopting the new tools first. Smaller companies realised that they had neither the financial means nor the resources of people and skills to implement these tools. Additionally the perceived benefits and regulatory incentives were too small to achieve wide spread acceptance of the new concept and its associated costs during development and manufacturing. Therefore, the adoption level remained quite low throughout the industry and even the early adopters failed to perceive the full intention of the concept, i.e. to implement a different approach to the development of new drug products.

In order to specify the intention of the new paradigm more clearly the FDA then published a draft annex (R1) to the ICH Q8 guideline (Pharmaceutical Development) in 2008 to provide further clarifications on the requirements as to the pharmaceutical development part of a submission. “In addition, this annex describes the principles of quality by design (QbD). The annex is not intended to establish new standards; however, it shows how concepts and tools (e.g., design space) outlined in the parent Q8 document could be put into practice by the applicant for all dosage forms. Where a company chooses to apply quality by design and quality risk management (ICH Q9, Quality Risk Management), linked to an appropriate pharmaceutical quality system, then opportunities arise to enhance science- and risk-based regulatory approaches (see ICH Q10, Pharmaceutical Quality Systems).”¹⁷

In August 2009 the second revision of this annex, ICH Q8(R2),¹⁸ which had been prepared by the ICH Working Group, was recommended for adoption to the regulatory bodies of the European Union, Japan and USA. This guideline describes the contents of the pharmaceutical development report for a NDA in part I and in its part II how the key elements of QbD should be applied during such development and then be described in the module 3 of the dossier (CMC part of the CTD for a NDA). The key elements of a QbD driven development are the Quality Target Product Profile, Critical Quality Attributes, the risk assessment linking material attributes and Critical Process Parameters to drug product Critical Quality Attributes, the Design Space, the Control Strategy, Product Life Cycle Management and Continual Improvement.

It also emphasises that a QbD driven development is a holistic approach, which always needs to be undertaken in combination with the principles of Quality Risk Management as described in ICH Q9 and Pharmaceutical Quality Management as described in ICH Q10. Therefore, QbD can also be described as a new paradigm for a systematic, risk based and science driven development approach for drug products, supported by the triangle of ICH Q8(R2), ICH Q9 and ICH Q10.

In May 2011 the draft of ICH Q11 also extended this approach to the development of the drug compound (for both, small chemical molecules and biopharmaceutical molecules) itself thereby transferring the new principles to all CMC activities and not just the drug product.

¹⁶ FDA; Guidance for Industry: PAT; 2004
¹⁷ ICH Q8(R1); 2008
¹⁸ ICH Q8(R2); 2009