Regulatory Beat: Quality Standards to Reshape Manufacturing

Manufacturers look to modern manufacturing systems and risk management to reduce costs and oversight
Feb 01, 2007
Volume 20, Issue 2

Jill Wechsler
A series of ICH guidances are encouraging industry to adopt quality-based approaches for achieving the "desired state" of drug and biotech manufacturing: more efficient and flexible operations that can reliably produce high quality therapies with less regulatory oversight.

Pharmaceutical manufacturing has not been "state-of-the-art," observed Janet Woodcock, deputy commissioner of the FDA at a December 2006 conference on implementing ICH Q8 and Q9, sponsored by the International Society for Pharmaceutical Engineering (ISPE) and the Parenteral Drug Association (PDA). Woodcock described why drug manufacturing costs are as high as R&D investments at many companies: factory utilization rates are as low as low 15% due to batch production processes; waste may top 50% for some products; scale-up is unpredictable; global operations are fragmented; and manufacturers often don't know the reasons for production failures.

Under the traditional manufacturing model, companies have submitted extensive chemistry, manufacturing and controls data (CMC) to FDA that set tight product specifications. The aim has been to develop production processes to meet those specifications and to avoid system changes later. The result is drug shortages, delays in new product development, and the need for more oversight than FDA can afford to provide.

The new approach calls for manufacturers to use modern statistical and analytical methods to define the critical sources of variability in a production system and to establish appropriate quality controls. Manufacturers that can demonstrate to regulatory authorities a sufficiently high level of understanding and control may benefit from a smoother application approval process and reduced oversight through the product life cycle. Risk management can help companies identify activities that require closer monitoring and also those that merit less attention.

Woodcock expressed optimism that the industry is beginning to move towards a more efficient and science-based process. She envisions biomedical manufacturing systems based on extensive company knowledge about critical production and process parameters that defines a "design space." In this vision, instead of reviewing massive amounts of data, checking batches and spending days inspecting facilities, FDA will provide initial verification of a quality production operation followed by periodic audits.

The bottom line for FDA: a big reduction in manufacturing supplements. Companies now have to inform the agency when they make relatively minor changes in production processes and suppliers. The goal is to limit such filings to major changes, such as new formulation development, and end filing supplements for the vast number of modifications and improvements.


The shift to such quality-by-design (QbD) approaches also provides an opportunity to move away from disparate regulatory requirements and put everyone "on the same page," Woodcock said. To this end, ICH participants from the US, Europe, and Japan have developed a series of guidances for establishing a more science-based approach to ensure the quality of products and processes.

The ICH Q8 guidance on product development explains how manufacturers should provide information on product development and quality manufacturing in the P.2. section of the Common Technical Document for new drugs and biologics. Through the ICH deliberations, though, Q8 expanded to discuss more fully how a manufacturer can establish effective quality control and design systems. The document describes the scope of QbD, from how starting materials and process parameters affect product quality, to how the process should be monitored, evaluated, and updated to ensure consistent quality over time. The positive response to the Q8 guidance is encouraging further development of Q8 annexes on oral dosage forms and moving on to parenterals in the future.

Full implementation of Q8 and QbD methods could lead to more formal regulatory agreements between manufacturers and regulators on postapproval regulatory flexibility. If a manufacturer provides specific information on how it controls its production process as part of its application, that could lead to some kind of "compliance commitment" from FDA, explains Moheb Nasr, director of the Office of New Drug Quality Assessment in the Center for Drug Evaluation and Research (CDER). So far, FDA has not negotiated any formal agreements, but has been discussing generally how it could implement the concept and how such information would be shared with the public. The agency is inviting manufacturers to propose such regulatory agreements, and FDA officials and lawyers are discussing internally how such agreements could fit within the existing compliance system.

lorem ipsum