Regulatory Beat: Quality Standards to Reshape Manufacturing

Published on: 
BioPharm International, BioPharm International-02-01-2007, Volume 20, Issue 2
Pages: 40–45

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.

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.

Jill Wechsler

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.


An important component of QbD is a risk management system that can identify and evaluate potential problems. The ICH Q9 standard, which has been adopted by Japan and the US (where the guidance was issued in June 2006), but still awaits final implementation in Europe, describes a range of methods that manufacturers and regulators can use to establish Quality Risk Management (QRM) systems, which can determine the appropriate level of control for a manufacturing process.

QRM involves identifying risks, analyzing the risks, evaluating the consequences of a high-risk event occurring, and establishing policies for risk reduction. The aim is to determine the most essential areas to monitor, and to evaluate where such efforts may be unnecessary or redundant. An annex to the guidance describes more specifically how to apply risk management to documentation, product defects, inspections, change management, maintaining facilities and equipment, material management, and validation.

For FDA, a risk-based approach is being applied to standards development, regulatory decisions, inspection choices, and setting enforcement priorities. Joe Famulare, deputy director of CDER's Office of Compliance, explained that FDA is using risk management in selecting sites for good manufacturing practices (GMP) inspections as well as to audit adverse event reporting and sampling programs. FDA asks "so what" and "what if" questions in evaluating a system's state of control, Famulare added.


A third ICH document (Q10), which is still under development, will link product development and risk management to assist manufacturers in establishing pharmaceutical quality systems. These will include process and product monitoring, corrective actions, and managing change in the postmarket environment. The ultimate quality system begins with the development of active ingredients and excipients and moves through product formulation, manufacturing process development, design of container closure and packaging, product release, and distribution, explained Jean-Louis Robert, representing EU authorities at the ISPE–PDA workshop.

To implement quality manufacturing and risk-based approaches, industry needs to invest in new technology, including statistical process controls and continuous processing methods, said Woodcock. There is a growing confidence that "we have the science and technology to get there," and now "we need to change the system."

Regulatory authorities insist that the ICH documents do not impose new requirements on industry. But they do "strongly encourage" companies to adopt more advanced quality control approaches, and will increasingly look for such programs in weighing a company's ability to meet regulatory requirements.

Many of the elements in this science-based, QbD approach are similar to policies and guidances developed under FDA's GMP modernization program, pointed out Karen Main of AstraZeneca. FDA will examine the status of "GMPs for the 21st Century" further at a workshop in late February 2007. The aim is to review what this initiative has accomplished so far, what new challenges have emerged in achieving initial goals, and what remaining issues need to be addressed to continue moving forward.

Jill Wechsler is BioPharm International's Washington editor, 301.656.4634,