Regulatory Beat: Biotech Firms Face New GMP Policies

Published on: 
BioPharm International, BioPharm International-11-01-2004, Volume 17, Issue 11

Even if FDA does not require pharma companies to co-market a diagnostic test, insurers and health plans

Over the past two years, FDA officials have issued numerous guidances and revised compliance programs as part of an initiative to revise current good manufacturing practices (cGMPs) to fit the 21st century. The agency aims to encourage manufacturers to adopt new production technologies and quality-based systems and promote risk-based management approaches for industry and within FDA itself.

A final report issued in September summarizes FDA's accomplishments during the initial assessment phase of this initiative. This 30-page white paper describes how quality systems and risk-based approaches can enhance FDA plant inspections, application reviews, post-approval changes, and electronic submissions. It also discusses how these initiatives should encourage manufacturers to implement process analytical technology (PAT) and continuous manufacturing improvement to reduce product variability. The report sets the stage for "shifting from assessment to implementation," explained David Horowitz, director of CDER's Office of Compliance, at the PDA/FDA conference in September.

Jill Wechsler

A new draft guidance on how drug and biotech manufacturers can establish comprehensive quality systems approaches to comply with GMP regulations and international standards is a cornerstone of the initiative. The proposal outlines the elements of a robust quality system, including management responsibilities and resources as well as manufacturing operations and evaluation activities. It links recommendations for building quality systems to specific GMP provisions, indicating where and how the regulations fit within the model and where they may diverge. For example, the guidance notes that GMP regulations require a higher standard for equipment calibration and maintenance than most quality system models and place more emphasis on process and testing equipment.



Industry comments on this draft proposal will help FDA decide whether and how it needs to revise basic GMP regulations, always a lengthy and arduous task. Last year, FDA officials agreed it was necessary to change the regulations governing electronic records and signatures (21 CFR Part 11), which have generated complaints and confusion among manufacturers for years. Now agency officials indicate that it may be necessary to modify certain GMP regulations (21 CFR, parts 210 and 211) to reflect a risk-based regulatory approach. FDA wants to harmonize differing manufacturing policies for drugs and biologics with those for medical devices to simplify oversight of the increasing number of combination products.

This decision to open the door to new rulemaking emerged from a year-long analytical exercise to determine what it would take to bring all FDA regulated medical products "under one umbrella cGMP regulation," explained Kimberly Trautman, medical officer in the Center for Devices and Radiological Health (CDRH), at the PDA/FDA conference. The GMP Harmonization Analysis Working Group was established in July 2003 to compare existing regulations and assess the value of making rule changes. After comparing GMP regulations for all FDA product areas and examining differences and similarities between US and EU standards, FDA officials decided to modify current rules.

The September report notes that the working group found more similarities than differences among various GMP regulations and that FDA will take "an incremental approach" to modifying the rules. If necessary, new rule-making will be launched to clarify regulations, further international and internal harmonization of manufacturing requirements, and improve FDA's ability to detect product defects and quality problems.

As a first step, FDA is withdrawing a 1996 proposed rule that sought to update GMP requirements for process and methods validation by clarifying quality control and documentation requirements. The proposal generated 1,500 comments and was put on hold. FDA says it will take a "fresh look" at those comments along with industry responses to the new quality systems draft guidance. Another indication of the need to revise regulations may come from comments to a new draft guidance on GMPs for combination products that aims to allow manufacturers of combination products to follow only one GMP policy.

Any revision in GMP regulations will seek to harmonize US rules with standards in Europe and other nations. FDA is pursuing collaborative efforts through the International Conference on Harmonization (ICH), which is working on proposals (Q8, Q9) to establish a common approach to pharmaceutical quality systems based on risk management. FDA also announced in September that it will join the Pharmaceutical Inspection Cooperation Scheme (PIC/S), a cooperative arrangement among international health authorities to harmonize cGMP standards and quality pharmaceutical inspection systems.


The next phase of the GMP initiative also will more explicitly encourage manufacturers of biotech products to adopt innovative approaches to quality assurance. FDA plans to add an observer from CBER and a member of Team Biologics to the PAT steering committee. In addition, a second PAT team is being formed with representatives from CDER's Office of Biotechnology Products and Team Biologics inspectors. The aim is to identify best practices and to encourage biotech firms to consider innovative manufacturing process design and control approaches.

Team Biologics also will formally adopt a quality systems management framework and further integrate product specialists into the program. The team will expand to cover biological therapeutic products transferred from CBER to CDER last year. The program is adopting risk-based principles for planning inspections and other assignments, and additional training is being provided. An overall aim is for the Team Biologics operations group to assist the new pharmaceutical inspectorate for drugs and the PAT team in implementing quality management systems.


The need for further regulatory change and policy development related to manufacturing will be evaluated by a new FDA Council on Pharmaceutical Quality. This high-level panel replaces the temporary GMP initiatives steering committee and will provide a central forum at the agency to address ongoing issues related to inspections and application review as well as policy development and change management.

The council, headed by Janet Woodcock, FDA acting deputy commissioner for operations, already has a substantial list of priorities:

  • Revise the 1987 industry guideline on process validation to include risk management and a life-cycle approach to regulation.

  • Oversee the refinement of cGMP regulations to meet both the internal and international harmonization goals.

  • Communicate FDA's thinking on quality issues in order to facilitate compliance.

  • Enhance FDA's own quality systems as applied to application review, compliance oversight, and other activities.

  • Oversee FDA's new dispute resolution program, designed to resolve technical or scientific issues raised during inspections of drugs and biologics.

  • Issue a final guidance on use of comparability protocols to reduce oversight of postapproval manufacturing changes.

New GMP Policies & Programs

FDA concluded phase one of its GMP initiative in September by issuing a number of guidances and documents, which are available at

. In addition to a white paper describing its risk-based approach and a draft guidance on quality systems, the new documents include:

  • PAT final guidance establishing a regulatory framework to facilitate adoption of process analytical technology instruments and tools

  • a white paper on innovation and continuous improvement in pharmaceutical manufacturing explaining how GMP initiatives may spur adoption of modern quality systems by eliminating wasted production efforts

  • aseptic processing final guidance (This much-debated document encourages manufacturers to prevent product contamination by ensuring adequate design and control of equipment, facilities, and raw materials. It encourages adoption of modern technology such as automated systems and isolation concepts.)

  • draft guidance on GMPs for combination products

  • additional documents that describe FDA's risk-ranking model for prioritizing GMP pharmaceutical site inspections, outline a new review approach for CMC data to be implemented by CDER's Office of New Drug Chemistry, and offer guidance for using computerized systems in clinical trials to reflect recent changes in 21 CFR Part 11.