DRW Monthly
September 2008
Issue No. 22

FDA's Pharmaceutical CGMP Initiative to be Implemented in CDER's Office of Biotechnology Products

The Food and Drug Administration (FDA) has made considerable progress in implementing the pharmaceutical manufacturing and product quality objectives originally unveiled in its August 2002 initiative, Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century. The agency's 2004 final report, Pharmaceutical CGMPs for the 21st Century--A Risk-Based Approach, recaps accomplishments achieved during the first few years through its assessment of existing CGMP programs.(1) This evaluation enabled the agency to create a newly integrated framework in which it could establish regulatory oversight of pharmaceutical manufacturing based on quality systems and risk management approaches. A Quality Systems Framework Working Group was subsequently formed to develop a CGMP model that provides a "more systematic approach to regulating pharmaceutical quality, as well as more integration and collaboration among the different components of the agency that are involved in pharmaceutical quality."(2) This model has now been incorporated into FDA's quality systems framework and is being applied across the entire agency. This comprehensive quality systems approach underlies both the FDA Staff Manual Guide, Quality Systems Framework for Internal Activities and the Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations issued in 2006.

The agency's transition from its original chemistry, manufacturing, and controls (CMC) review system to the new risk-based pharmaceutical quality assessment system was initially implemented in the Office of New Drug Quality Assessment followed by the Office of Generic Drugs, both within the Center for Drug Evaluation and Research's (CDER's) Office of Pharmaceutical Science (OPS) branch. The new quality assessment system, also referred to as Quality by Design (QbD), was implemented in successive phases due to the distinctions in products, manufacturing complexity and focus within each CMC review office.(3) The Office of Biotechnology Products (OBP), which oversees the most complex products, is the third CMC review office based in OPS to embrace the QbD process. The FDA has begun seeking pharmaceutical company volunteers to submit CMC biotechnology product data for the OBP's QbD pilot program. Although the OBP has already begun using some aspects of the QbD approach, it now requires a formal collection of submission data, including Biologic License Applications (BLAs), BLA supplements or New Drug Applications that "should demonstrate an applicant's increased knowledge of product attributes, linking the attributes to process parameters in an expanded change protocol."(4) The agency will use this data to develop guidance to describe the tests, studies and acceptance criteria specific to biotechnology product development in order to demonstrate that certain manufacturing changes will not have adverse effects.

The QbD methodology, as applied in each of these CMC review offices, is a scientific, risk-based, holistic and proactive approach that employs a deliberate design effort from product conception through commercialization, and requires a full understanding of how a product's attributes and process relate to its performance.(5) The new system encourages manufacturers to implement modern technologies, such as process analytical technology, that are tailored to the unique design aspects of their product and processes. Because this approach aims to maximize a product's efficacy and safety while simultaneously improving product manufacturability, the agency is hopeful that the need for regulatory oversight will be reduced.(6) This is supported by the FDA's comments in its most recent Federal Register OBD pilot program notice, in which it states that its goal is to enable manufacturers to make manufacturing process changes without having to submit postapproval manufacturing supplements. Janet Woodcock, Director, CDER, also corroborates this viewpoint when she expresses her desire for the pharmaceutical industry to become "[a] maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight."(7)

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