Summary Progress Report
Pharmaceutical cGMPs for the 21st Century:
A Risk-Based Approach
Comments on this report or on the activities of this initiative
should be submitted to the Dockets Management Branch (HFA-305), Food and
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
All comments should be identified with the Docket Number 03N-0059.
Electronic
Management Comment Form: Docket 03N-0059 - Pharmaceutical Current
Good Manufacturing Practices for the 21st Century: A Risk-Based Approach
A science and risk-based approach to product quality regulation,
incorporating an integrated quality systems approach
Introduction
On August 21, 2002, FDA announced a major new initiative on the
regulation of drug product quality. The two-year program, which applies
to human drugs and biologics and veterinary drugs, has several ambitious
objectives. One is to ensure that regulatory review and inspection
policies are based on state-of-the-art pharmaceutical science and to
encourage the adoption of new technological advances by the
pharmaceutical industry. FDA will determine the best pathway to better
integrate advances in quality management techniques, including quality
systems approaches, into the Agency's regulatory standards and systems
for the review and inspection processes. Additionally, risk-based
approaches, that focus both industry and agency attention on critical
areas, will be implemented. Finally, enhancements to the consistency and
coordination of Agency drug quality regulatory programs will be made.
Current Progress
The initiative is overseen by an Agency steering committee with
representatives from CBER, CDER, CVM, ORA and the Office of the
Commissioner. CFSAN and CDRH are also involved in the Part 11
implementation. Working groups dealing with specific issues have been
formed. The August 21 announcement included a number of "immediate
steps," with planned completion at 6-months. FDA is now reporting
on the overall progress of the initiative. In the six months since the
announcement, steps have been taken to achieve both short and
longer-term objectives.
The following planned six-month milestones have been completed:
21 CFR Part 11 implementation
FDA issued a Notice of Availability (NOA) of a
draft guidance on
Part 11 on February 20, 2003. The draft guidance clarifies the scope and
application of the regulation and provides for enforcement
discretion in certain areas that have been problematic. The Notice
explains FDA’s intent to reexamine Part 11, which may lead to
revisions to clarify its scope and requirements. FDA encourages
submission of comments on the draft guidance.
Encouraging innovation within the existing framework
Today FDA issued an NOA and draft guidance entitled
"Comparability Protocols-Chemistry, Manufacturing and Controls
Information." This guidance applies to nonprotein
pharmaceuticals and veterinary drugs. Under appropriate
circumstances, use of a comparability protocol can allow
manufacturers to implement changes to their processes without
submission of a prior approval supplement to the FDA. This
facilitates continuous improvement and innovation. Related guidances
are under development.
Center review of drug cGMP warning letters
Starting March 1, all drug cGMP warning letters will be reviewed
by the relevant Center prior to issuance. This will help identify
possible program inconsistencies and resolve them before warning
letters are issued.
Implementation of a technical dispute resolution process for cGMP
disputes
Today the Agency issued a progress report from the Dispute
Resolution working group. The Agency seeks comments on the issues
and processes discussed in the progress report.
FDA plans to consider and implement dispute resolution procedures
for cGMP’s that allow for discussion of scientific and technical
issues, that bring the best technical expertise to bear on the
particular issue, that allow for development of best practices and
policies across FDA, and that improve transparency of the regulatory
process.
Evaluating optimal mechanisms to effectively and efficiently
communicate deficiencies
FDA will clarify the status of the observations that are noted on
the FDA Form 483 form, and to highlight avenues for further
discussion with FDA on the inspectional observations.
Progress Report of
the 483 Communications Working Group
Holding scientific workshops with stakeholders
FDA will be holding the inaugural workshop on April 22-24 in
Washington D.C. [Draft Agenda
and Registration].
This workshop will provide an opportunity for
in-depth discussion on four topic areas, namely:
- Risk-Based cGMP
- Integrated systems approach to the CMC review and cGMP
inspections
- Post approval manufacturing changes
- Manufacturing science
Emphasizing a risk-based approach to the work planning process
In fiscal year (FY) 2003, FDA, using a basic risk management
approach, identified three categories of potentially higher-risk
pharmaceutical manufacturing sites for prioritizing inspections: sites
making sterile drugs; sites making prescription drugs, and sites of
new registrants not previously inspected by FDA.
By FY 04, FDA intends to have developed a more detailed risk model
to help predict where FDA’s inspections are most likely to achieve
the greatest public health impact.
Effective January 27, CDER reorganized its Office of Compliance,
creating a new Division of Compliance Risk Management and Surveillance
to enhance the Office’s capacity to implement risk management
approaches.
CDER
Office of Compliance Organizational Chart
Improving the operations of Team Biologics
CBER/ORA workgroups have been actively implementing improvements
to the Team Biologics program including:
- adopting an internal quality management system
- developing metrics to determine the impact of Team Biologics on
the industry
- standardizing training and qualifications of the Core Team
members
- risk-based work planning
- increasing communications between headquarters and the field.
Including product specialists on inspection teams
FDA is issuing a progress report describing possible approaches
on including product and technical specialists, with relevant
expertise, to join inspection teams that do not yet include such
specialists. This should assist the Agency in enhancing the
technical quality and consistency of FDA inspection and further
facilitate the adoption of innovative manufacturing technologies.
Progress Report of the Working Group on Product Specialists on Inspection Teams
Enhancing expertise in pharmaceutical technologies
The Agency has hired a number of experts, and is collaborating
actively with academic and industry groups to harness available
expertise
In addition to achieving the short-term milestones, the Agency has
taken steps in the following areas:
International collaboration
- Senior FDA officials have discussed the initiative with drug
regulatory authorities in other regions.
- In Sept 2002 the initiative was presented to the ICH steering
committee, and the ICH plans to discuss possible topics for harmonization in July
2003 in Brussels.
Pharmaceutical Inspectorate
- ORA, CVM and CDER have agreed to the implementation of a "Pharmaceutical
Inspectorate"
- The inspectorate will consist of specially-trained individuals
who will spend a majority of their time in the drugs cGMP area
- Members will co-train with Center staff
- The first members are anticipated to be on board by the end of
FY 2003
Progress Report
of the Pharmaceutical Inspectorate Working Group
Process Analytical Technologies (PAT) Initiative
This collaborative initiative between CDER, ORA and CVM is designed
to address many of the objectives of the cGMP for the 21st
Century Initiative. It identified, through public meetings and
workshops, the benefits of PAT, and perceived/real hurdles to its
introduction in manufacturing. This initiative is exploring how FDA
can facilitate introduction of new process monitoring and process
control technologies to improve manufacturing efficiencies. Draft
guidance for industry on a regulatory process for applying PAT is
currently under development and a review-inspection team has been
assembled and is currently in a training and certification program.
Additional information on this initiative is available at http://www.fda.gov/cder/OPS/PAT.htm
Contract
As part of the initiative to ensure that the Agency uses current
business practices for risk and quality management, FDA will
commission a study of 'effective' business practices and policies
which could be applicable to FDA’s business model. Such a study will
assist the Agency in developing approaches that improve Agency
effectiveness and efficiency, and that will positively impact on
industry innovation and use of the latest advances in manufacturing
science and technology to improve the overall public health.
Progress Report on Effective Business Practices and Policies in Other Organizations
Quality management system
FDA is planning to develop a quality management system for the
regulatory processes associated with product quality regulation. The
scope of this effort is still under consideration.
Further Steps
The steering committee expects to finish an overall plan for the
initiative within the next four months. Work groups will continue to
develop their projects. Topics that require further work by the steering
committee include the definition of "quality" for
pharmaceutical products, risk assessment, the role of the CMC review
function, and the current regulatory structure for quality management
systems. As was stated in the August announcement, the existing
regulations appear to provide the flexibility to accommodate this
initiative, but, FDA will consider various options for enhancing the use
of quality systems approaches in FDA regulation of drug quality.
Criteria for evaluating the success of each working group, and for
the initiative as a whole, are being developed.
The Future
Pharmaceuticals will have an increasingly prominent role in the
health care of the future. The health of our citizens depends on the
availability of safe, effective and affordable medicines. In the future,
pharmaceutical manufacturing will need to employ innovation, cutting
edge scientific and engineering knowledge, and the best principles of
quality management to respond to the challenges of new discoveries and
ways of doing business such as individualized therapies or genetically
tailored treatments. Regulation of the future will also need to meet
these challenges, by incorporating new scientific information into
regulatory standards and policies. Both industry and regulatory
practices will need to be informed by the best techniques of risk
assessment and management. "Pharmaceutical cGMPs for the 21st
Century" is intended to jump-start progress into this future.
Pharmaceutical manufacturing is evolving from an art form to one that
is now science and engineering based. Effectively using this knowledge
in regulatory decisions in establishing specifications and evaluating
manufacturing processes can substantially improve the efficiency of both
manufacturing and regulatory processes. This initiative is designed to
do just that through an integrated systems approach to product quality
regulation founded on sound science and engineering principles for
assessing and mitigating risks of poor product and process quality in
the context of the intended use of pharmaceutical products. In this
regard, the desired future state of pharmaceutical manufacturing may be
characterized as:
- Product quality and performance achieved and assured by design
of effective and efficient manufacturing processes
- Product specifications based on mechanistic understanding of how
formulation and process factors impact product performance
- Continuous "real time" assurance of quality
- Regulatory policies and procedures tailored to recognize the
level of scientific knowledge supporting product applications,
process validation, and process capability
- Risk based regulatory scrutiny that relates to the level of
scientific understanding of how formulation and manufacturing
process factors affect product quality and performance and the
capability of process control strategies to prevent or mitigate
risk of producing a poor quality product
Dockets
Comments in the initiative may be submitted to Docket number
03N-0059. However, comments on either of the two draft guidances should
be submitted to the respective dockets.
Electronic
Management Comment Form: Docket 03N-0059 - Pharmaceutical Current
Good Manufacturing Practices for the 21st Century: A Risk-Based Approach
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Date created: February 27, 2003 |