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.
THE DESIRED STATE FOR REGULATORY AND PHARMACEUTICAL INNOVATION
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.