September 3, 2013

Regulatory Challenges in the QbD Paradigm

The authors demonstrate how an integrated model is helping to achieve regulatory flexibility. This article is part of a special section on biopharmaceutical trends.

With the dawn of the 21st century came the realization that changes must be made by both the pharmaceutical industry and regulatory authorities across the globe. These changes are necessitated by a plethora of issues that are faced by companies and the regulatory agencies alike. The number of blockbuster drugs launched each year has remained relatively constant at 6.5 per year (1). The nearly threefold increase in R&D spending over the past decade has resulted in an increase in the number of drug candidates entering Phase I trials. However, this increase has been almost completely neutralized by an increase in attrition, with the probability that a candidate entering Phase I will become a successful product decreasing from 10% in 2002 to 5% towards the end of the decade (1). This decline in success rate, along with the increasing scrutiny of healthcare costs in developed economies, has resulted in unrelenting pressure on the pharmaceutical companies to control drug-development costs. 

On the other hand, regulatory authorities are also grappling with the increasing complexity of pharmaceutical manufacturing. Most pharmaceutical products sold in the US are manufactured outside the US. Even for those drugs that are manufactured in the US, a significant portion of the raw materials and process intermediates is imported from manufacturers outside the US. It's no wonder that "Supply Chain Management," "Accountability in a Global Environment," "Foreign Inspections," and "International Compliance" were some of the key sessions at the 2011 PDA/ FDA Joint Regulatory Conference. Implementation of quality by design (QbD) in this environment has further contributed to the need to clarify what information needs to be included in a regulatory filing and how it should be presented. FDA has addressed this gap to some extent through its ongoing QbD pilot program, but more guidance is needed from the regulatory authorities to ensure widespread successful implementation of QbD (2). 

Overall, the regulatory authorities must make changes to address the drug safety dangers that the global environment poses as well as make changes to the drug review and approval processes to encourage regulatory and pharmaceutical innovation and faster product availability to patients. Regulators also must offer more flexibility regarding manufacturing changes and application supplements based on science and risk assessment, so that limited resources on both the industry and regulatory sides will be available for drug development and innovation.

In this 28th article in the Elements of Biopharmaceutical Production series, the authors focus on the regulatory challenges that arise in the QbD paradigm, in particular on how review and inspection practices have been and are evolving.

In 2002, FDA launched Pharmaceutical CGMP for the 21st Century–A Risk-Based Approach , an initiative to encourage the adoption of modern and innovative manufacturing technologies (3). Another aspect of the initiative was to ensure that "the product review and the inspection program operate in a coordinated and synergistic manner." The desired state was defined as "a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight." FDA and the pharmaceutical industry are spending considerable efforts to understand how to achieve this incredible feat and to identify the necessary elements required. This section discusses some of these elements.


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The authors would like to thank Patricia Hughes and Kalavati Suvarna, both from FDA, for helpful discussions regarding this article. 

ANASTASIA G. LOLAS (not pictured) is president of Visionary Pharma Consulting, Olney, MD, and ANURAG S. RATHORE, PHD*, is a consultant at Biotech CMC Issues and a member of the faculty in the department of chemical engineering at the Indian Institute of Technology. Rathore is also a member of BioPharm International's Editorial Advisory Board.

*To whom correspondence should be addressed, [email protected]
1. J. Arrowsmith, Nature Biotechnol. 11, 17–18 (2012).
2. FDA, Notice of Pilot Program for Submission of Quality Information for Biotechnology Products in the Office of Biotechnology Products, Docket number FDA-2008-N-03551.
3. FDA, Pharmaceutical CGMPs for the 21st Century - A Risk-Based Approach, Final Report (Rockville, MD, Sept. 2004).
4. J.M. Juran, Juran on Quality by Design, (The Free Press, 1992).
5. ICH Q8(R1) Pharmaceutical Development (2008).
6. FDA, Guidance for Industry, PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance (Rockville, MD, Sept. 2004).
7. ICH, Q9 Quality Risk Management (2005).
8. ICH, Q10 Pharmaceutical Quality System (2008).
9. FDA, Guidance for Industry, Process Validation: General Principles and Practices (Rockville, MD, 2011).
10. A.S. Rathore and H. Winkle, Nature Biotechnol. 27, 26–34 (2009).
11. A.S. Rathore Trends in Biotechnol. 27, 546–553 (2009).
12. S. Kozlowski and P. Swann (2009) "Considerations for Biotechnology Product Quality by Design," In: A.S. Rathore and R. Mhatre (eds) Quality by Design for biopharmaceuticals: Perspectives and Case Studies, (Wiley Inter-science, New Jersey, 2009), pp. 9–30.
13. FDA, "Drug and Biological Product Consolidation," Fed. Regist. 68 (123), June 2003.
14. FDA, Center for Drug Evaluation and Research Manual of Policies and Procedures, MAPP 4730.3, Office of Biotechnology Products and Office of ComplianceDivision of Manufacturing & Product Quality Interactions on BLA Assessments,
15. FDA, Inspections of Licensed Biological Therapeutic Drug Products, Compliance Program Guidance Manual, Program 7356.002M, 2006,
16. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 601.12.
17. FDA, Guidance for Industry, Guidance for Industry: Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products (Rockville, MD, July 1997).
18. ICH, Q5E Comparability of Biotechnological/ Biological Products Subject to Changes in Their Manufacturing Process (2003).

Tags: QbD; Quality-by-Design; regulatory