Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach
Final Report - Fall 2004
Table of Contents
PHARMACEUTICAL CGMPs FOR THE 21st CENTURY —
A RISK-BASED APPROACH - FINAL REPORT
In August 2002, the Food and Drug
Administration (FDA or the Agency) announced a significant new
initiative, Pharmaceutical Current Good Manufacturing Practices (CGMPs)
for the 21st Century, to enhance and modernize the
regulation of pharmaceutical manufacturing and product quality — to
bring a 21st century focus to this critical FDA
responsibility. The initiative, which this final report describes in
detail, was intended to modernize FDA’s regulation of pharmaceutical
quality for veterinary and human drugs and select human biological
products such as vaccines. As part of this initiative, both the
pharmaceutical, as well as the chemistry, manufacturing, and controls
(CMC) regulatory programs were evaluated with the following objectives
in mind.
- Encourage the early adoption of new technological
advances by the pharmaceutical industry
- Facilitate industry application of modern quality
management techniques, including implementation of quality systems
approaches, to all aspects of pharmaceutical production and quality
assurance
- Encourage implementation of risk-based approaches that
focus both industry and Agency attention on critical areas
- Ensure that regulatory review, compliance, and
inspection policies are based on state-of-the-art pharmaceutical
science
- Enhance the consistency and coordination of FDA's drug
quality regulatory programs, in part, by further integrating enhanced
quality systems approaches into the Agency’s business processes and
regulatory policies concerning review and inspection activities
Over the course of the 2 years, FDA
released reports documenting its progress and plans. The first,
issued on February 20, 2003, conveyed the initial accomplishments and
listed the first steps toward achieving FDA's goals for a 21st century regulatory framework for pharmaceutical manufacturing. In
September 2003, on the first anniversary of the initiative, FDA
released its second progress report and an outline of its
implementation plan for achieving the objectives announced the
previous year.
Early in the initiative, a number of
multidisciplinary working groups were formed, comprising FDA experts
from various areas of scientific and regulatory practice within FDA.
These working groups have shaped the initiative during the past 2
years under the oversight of the FDA's current good manufacturing practice (CGMP) Steering
Committee
As a result of the diligent work of
these groups, the FDA has completed its assessment of the existing
CGMP programs. We assessed current practices as well as available new
tools of enhancing manufacturing science. Our assessment helped us
create a new framework for the regulatory oversight of manufacturing
quality that is based on quality systems and risk management
approaches. Our findings have put the Agency on a path to restructure
its oversight of pharmaceutical quality regulation, thereby developing
the product quality regulatory system of the future. The following
remain our guiding principles:
- Risk-based orientation
- Science-based policies and standards
- Integrated quality systems orientation
- International cooperation
- Strong public health protection
Implementation of the envisioned new
framework, the elements of which are explained in detail in this
report, will require a highly educated and well-trained and integrated
team of individuals throughout the FDA who use risk-based and
science-based approaches for regulatory decision-making throughout the
entire life-cycle of a product. We believe we have created a
framework that will streamline the quality review of many products,
allowing us to use our valuable resources in a more efficient manner.
Our primary focus will remain the same: to minimize the risks to the
public health associated with pharmaceutical product manufacturing.
To help implement this new framework
in the coming years, the Agency has formed a Council on
Pharmaceutical Quality, which has been charged with policy
development, coordination, and continuing change management, including
the ongoing implementation of specific quality management systems
within the FDA. Charter
of the Council on Pharmaceutical Quality
The following report explains the
FDA's CGMPs for the 21st Century Initiative as well as the
individual charges and achievements of the various working groups that
have been involved in the initiative. The report also outlines our
path forward in implementing the pharmaceutical quality regulatory
system for the future. The report discusses in some detail various
other documents that have resulted from work group activity. For
example, a number of guidance documents have been developed that are
being made available with this report, or will be available soon. We
already have an extensive Web page on the CGMP
initiative, and all of these documents, including this report,
will be there, as they are made available.
Although a number of specific
accomplishments have resulted from the CGMP Initiative, several key
accomplishments are worth highlighting here.
At the outset of the initiative, FDA
conveyed its goal of bringing an integrated quality systems
orientation to all Agency activities and programs. A specific goal
was the development and implementation of 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. The Quality Systems Framework
Working Group, formed as a result of a restructuring of some the
working groups at the 1-year mark of the initiative, developed such a
model for the CGMP initiative, referencing key recognized external
quality and risk management standards. During this past year, the
Agency's Management Council — the highest management level group in
FDA — reviewed the model and found it so impressive that they
incorporated it into the FDA quality systems framework for application
across the entire Agency. FDA will now be using a quality systems
approach to improve the predictability, consistency, integration, and
overall effectiveness of our entire regulatory operation. This
quality systems model, now incorporated into the FDA Staff Manual Guide, Quality Systems Framework for Internal Activities, defines the essential quality elements to consider as part
of any system that controls an internal FDA regulatory activity.
The Quality Systems Guidance
Development working group considered what Agency guidance could be
developed to encourage industry to implement the use of quality
management systems and risk management principles. The Agency has
released the results of this working group’s efforts, the draft
guidance for industry on Quality Systems Approach to
Pharmaceutical Current Good Manufacturing Practice Regulations.
Once finalized, this guidance is intended to provide recommendations
to the regulated industry on meeting the requirements of the Agency's
CGMP regulations via a comprehensive quality systems approach, which
encourages continuous improvement and risk management in the
manufacturing of human and veterinary drugs, including human
biological products. This guidance, when implemented, and other
aspects of the initiative, (e.g., the pharmaceutical inspectorate),
will work in concert with the new risk based pharmaceutical quality
assessment system being developed by the Office of New Drug Chemistry
(ONDC) within the Center for Drug Evaluation and Research (CDER). (Final Guidance)
Implementation of Risk-Based Management Plan
FDA has identified a risk-based
orientation as one of the driving principles of the CGMP initiative.
The progress outlined below reflects FDA's commitment to the adoption
of risk management principles that will enhance the Agency's
inspection and enforcement program, which is focused on protecting the
public health.
- FDA's Strategic Action Plan
One year
after the start of the CGMP initiative, FDA released the Strategic
Action Plan for the Agency, Protecting
and Advancing America’s Health. The Agency's Strategic Plan
identified efficient risk management as a key element. Efficient risk
management requires using the best scientific data, developing quality
standards, and using efficient systems and practices that provide
clear and consistent decisions and communications for the American
public and regulated industry. FDA has identified efficient risk
management as the primary way to make the most effective use of
Agency resources and address these challenges. This approach
incorporates rigorous analysis to consistently identify the most
important risks, and the use of a quality systems approach to
designing, conducting, and evaluating FDA core business processes.
- Risk-based Model for Inspectional Oversight
The Agency
has developed and will be piloting a risk-based model for prioritizing
sites for manufacturing inspections. FDA publicly presented the
highlights of this model on July 21, 2004, to the Manufacturing
Subcommittee of the Pharmaceutical Science Advisory Committee. Subcommittee Transcript This model is explained later in this
report and, in more detail, in the attached white paper.
A
complementary and ongoing approach to efficient risk management is an
analysis underway by Professor Jeffrey Macher of Georgetown University
and Professor Jackson Nickerson of Washington University, St. Louis.
Using 13 years of data from more than 38,000 FDA inspections for more
than 3,700 manufacturing facilities, their statistical analysis seeks
to identify a wide variety of product-, process-, facility-,
manufacturer-, and FDA-related factors that correlate with
inspectional outcomes. Their analysis will be used to help refine the
risk-based management of Agency resources.
With the
issuance in 2003 of the guidance for industry Part 11, Electronic Records, Electronic Signatures — Scope and Application, many barriers to scientific and
technological advances were removed, and the use of risk-based
approaches to managing computer systems is encouraged.
- Aseptic Processing Guidance
The final
guidance for industry on Sterile Drug Products Produced by Aseptic
Processing — Current Good Manufacturing Process, issued today,
advocates a risk-based framework, underscoring the value of proactive
approaches to ensure sterility. Among the sections of the guidance
that address risk-based approaches are those relating to key roles
played by personnel, design, environmental control, and media fills in
an aseptic processing operation.
- ONDC Pharmaceutical Quality Assessment System
The Office
of New Drug Chemistry (ONDC) within CDER has developed and is
implementing a new risk-based pharmaceutical quality assessment system
to replace its current CMC review process. This new system should
reduce the need to submit manufacturing supplements and increase
first-cycle approval of new drug applications, thereby making drug
products available to patients in a timelier manner. The system should
also encourage manufacturers to implement new technologies, such as
process analytical technology, and facilitate continuous manufacturing
improvements. ONDC Reorganization
As pharmaceutical manufacturing
evolves from an art to a science and engineering based activity,
application of this enhanced science and engineering knowledge in
regulatory decision-making, establishment of specifications, and
evaluation of manufacturing processes should improve the efficiency
and effectiveness of both manufacturing and regulatory
decision-making. As a pillar of the initiative (and guiding
principle), the Agency must ensure that science-based policies and
standards form the foundation upon which product quality regulation is
based. Because the American public is the ultimate customer of
pharmaceutical manufacturing and because the public is often unable to
judge the quality of a product, the goal of our regulatory system is
to make sure that patients do not have to worry about the quality of
their medicines.
We believe that using a scientific
framework to find ways of mitigating risk while facilitating
continuous improvement and innovation in pharmaceutical manufacturing
is a key public health objective. Our shift from the current CMC
review system to a new risk-based pharmaceutical quality assessment
system within CDER’s ONDC, explained in the section above, is one such
example. This new system will encourage the implementation of new
technologies, such as process analytical technology (PAT), and
facilitate continuous manufacturing improvements via implementation of
an effective quality system.
Quality and productivity
improvement share a common element — reduction in variability through
process understanding (e.g., application of knowledge throughout the
product life-cycle). Reducing variability provides a win-win opportunity from both public health and industry perspectives. And,
since manufacturing technologies and practices are generally similar
between both innovator and generic companies, facilitating efficiency
improvements provide opportunities for both sectors of the
pharmaceutical industry. An efficient and secure U.S. pharmaceutical
manufacturing sector will be essential in the 21st century. The progress in the area of PAT and manufacturing science
should prepare us well to meet the 21st century challenges.
The PAT
Team and the Manufacturing Science Working Group have continued their
collaboration and significant progress has been made in building
consensus on the principles of manufacturing science and process
understanding. The final PAT guidance will issue soon, and the PAT
team has completed its training. A significant support structure for
the PAT guidance is evolving in the pharmaceutical community including
the American Society of Testing Materials (ASTM)
E55 committee on Pharmaceutical Applications of Process
Analytical technology. Progress and next steps are described later in
this report.
- International Collaborations
The FDA has
increased its collaboration with international health and regulatory
partners and will continue to actively collaborate with other
regulatory authorities, in multilateral and international forums, to
harmonize pharmaceutical quality standards or requirements to the
fullest extent possible. Our active collaboration with other
regulatory authorities as part of the International Conference on
Harmonisation of the Technical Requirements for Registration of
Pharmaceuticals (ICH) and the International Cooperation on
Harmonization of Technical Requirements for Registration of Veterinary
Medicinal Products (VICH)[1] will continue. Agreement was reached last year by ICH to work on an
internationally harmonized plan for developing a pharmaceutical
quality system based on an integrated approach to risk management and
science. FDA is developing bilateral and multilateral confidentiality
agreements and specific information exchange agreements to facilitate
these activities. Finally, the FDA is seeking membership in the
Pharmaceutical Inspection Cooperation Scheme (PIC/S), a cooperative
arrangement among health authorities whose purpose includes leading
the international development, implementation, and maintenance of
harmonized CGMP standards and quality systems of world-wide
pharmaceutical inspectorates.
Accomplishments and specific achievements since 2003 related to the
key accomplishments outlined in the above sections are discussed in
detail in the following sections.
[1] The VICH is an international forum patterned after ICH that takes note
of ICH experience in developing guidance related to veterinary
medicinal products, including pharmaceuticals, biological products,
and medicated premixes.
FDA regulates pharmaceutical
manufacturing to ensure that the drug supply in the United States is
of consistently high quality. In the past, as a result of the many
uncertainties in drug manufacturing, the FDA exercised extensive
control over virtually every aspect of the manufacturing process.
Consequently, pharmaceutical companies have often been reluctant to
change their manufacturing processes and equipment because of
perceived, and sometimes real, regulatory hurdles. In recent years,
significant advances in manufacturing science, quality management
systems, and risk management have taken place, yielding modern
manufacturing tools that can be used to help ensure manufacturing
quality. Such new tools enable manufacturers to detect, analyze,
correct, and prevent problems and continuously improve their
manufacturing processes. It has been the goal of the CGMP initiative
to create a regulatory framework that will encourage pharmaceutical
manufacturers to also make use of these modern tools, to facilitate
the implementation of robust manufacturing processes that reliably
produce pharmaceuticals of high quality and that accommodate process
change to support continuous process improvement.
The quality management framework we
have created has a number of elements. They are summarized in the
following paragraphs.
To keep pace with the many advances
in manufacturing quality management and to enable the Agency to more
effectively allocate its limited regulatory resources, the FDA is
implementing a risk-based approach to regulating pharmaceutical
manufacturing. The approach will be applied to the review,
compliance, and inspectional components of FDA regulation.
The intensity of FDA oversight
needed will be related to several factors, including the degree of a
manufacturer's product and process understanding and the robustness of
the quality system controlling their process. For example, changes to
complex products (e.g., proteins, naturally derived products) made
with complex manufacturing processes (or products that are less well
understood from a manufacturing or quality attribute perspective) may
need more regulatory oversight. Process changes with critical
variables that have not been sufficiently defined (e.g., processes for
many older products) may require the submission of additional data or
comparability protocols. In other cases, changes in well understood
processes could be managed under a firm’s change control procedures.
Additional factors in performing risk-based quality assessments
include instances when manufacturing processes are crucial to the
safety of the product (e.g., adventitious agent clearance,
inactivation of live product) or when products serve a critical
medical need or have a critical public health impact (e.g., products
for the prevention of communicable diseases).
Other considerations, such as public
health impact and the compliance status or compliance history of the
manufacturer, will continue to influence the intensity of FDA
oversight.
Beginning in the fall of 2004, FDA
will begin using a risk-based approach for prioritizing domestic
manufacturing site inspections for certain human pharmaceuticals.
This approach will help the Agency predict where its inspections are
likely to achieve the greatest public health impact. The frequency
and/or scope of inspections will be reduced for firms that FDA
determines have acquired sufficient process understanding and have
succeeded in implementing effective quality systems approaches. We
hope that this approach will create positive incentives for other
firms to implement effective quality systems at their manufacturing
sites.
At the same time, the Agency will
continue to apply risk-based principles to the product quality review
process (i.e., the product quality aspects of the investigational new
drug (IND); preapproval chemistry, manufacturing, and controls (CMC);
and postapproval supplement processes). FDA is expecting that these
risk-based changes will facilitate continuous improvement in
pharmaceutical manufacturing and improve availability of new drugs
while increasing product quality and process efficiency.
The Office of New Drug Chemistry (ONDC),
within CDER, is taking the first step toward establishing a new
risk-based pharmaceutical quality assessment system to replace its
current CMC review system. This new assessment system will focus on
critical pharmaceutical quality attributes (chemistry, pharmaceutical
formulation, and manufacturing processes as they relate to product
performance) and their relevance to safety and efficacy. The new
assessment system has the potential to reduce the regulatory burden in
proportion to the manufacturer’s efforts to achieve continuous
improvement and manufacturing process optimization. FDA's regulatory
strategies will be based on the degree to which an application
reflects a manufacturer's understanding of manufacturing process,
process control, and quality systems. ONDC
Reorganization
Best practices in quality management
methods, particularly in other high-tech industries, have undergone
significant progress since 1978 when the CGMP regulations were last
updated. The FDA wants to ensure that its regulatory practices
encourage similar progress in the pharmaceutical industry. The draft
guidance for industry Quality
Systems Approach to Pharmaceutical Current Good Manufacturing Practice,
issued today, describes a comprehensive quality systems model that
manufacturers could use and highlights the model's consistency with
the CGMP regulations for manufacturing human and veterinary drugs,
including biological products. The guidance explains how
manufacturers implementing such a comprehensive quality system can
ensure that they comply fully with the CGMP regulations (21 CFR parts
210 and 211). This guidance is intended to serve as a
bridge between the 1978 regulations and our current understanding of
quality systems.
As
mentioned during earlier updates, the FDA's product quality regulatory
approach of the future will include a staff of highly trained
individuals, known as the Pharmaceutical Inspectorate (PI), within the
Office of Regulatory Affairs (ORA). These individuals will devote
most of their time to conducting drug quality inspections of
prescription drug manufacturers and other complex or high-risk
pharmaceutical operations. The PI will also conduct preapproval
inspections and will continue to be trained on the latest science and
manufacturing technology. Joint technical training sessions and
creation of new mechanisms for collaboration among review, compliance,
and inspectional personnel will allow FDA to enhance the consistency
and sound scientific basis of its regulatory decisions. The PI will
enhance the Agency's overall inspection program, which includes
preapproval inspections conducted by CDER and CBER personnel for
licensed biologics and Team Biologics, a program that includes a core
team of highly trained individuals for biological product inspections.
It is crucial that pharmaceutical
quality standards or requirements be harmonized internationally to the
fullest extent possible. The development of a global economy during
the last few decades has had a profound effect on product
development. To achieve its public health goals and leverage its
resources, the FDA has increased its collaboration with international
health and regulatory partners. Working together, international
regulatory authorities have continued to harmonize their activities,
especially in quality-related areas, and increased the sharing of
regulatory information. Harmonizing scientific standards and
assessments of drug product quality will promote technological
innovation and, ultimately, enhance public health promotion and
protection. The FDA will continue to actively collaborate with other
regulatory authorities, in multilateral, international forums, such as
the International Conference on Harmonization of the Technical
Requirements for Registration of Pharmaceuticals (ICH) and the
International Cooperation on Harmonization of Technical Requirements
for Registration of Veterinary Medicinal Products (VICH). In November
2003, an agreement was reached by ICH to work on an internationally
harmonized plan for developing a pharmaceutical quality system based
on an integrated approach to risk management and science. FDA is
developing bilateral and multilateral confidentiality agreements and
specific information exchange agreements to facilitate these
activities.
It is important to note that FDA
will seek membership in the Pharmaceutical Inspection Cooperation
Scheme (PIC/S), a cooperative arrangement between health authorities
whose purpose includes leading the international development,
implementation, and maintenance of harmonized CGMP standards and
quality systems of world-wide pharmaceutical inspectorates.
Membership in the PIC/S provides networking opportunities among
participating authorities, the development of mutual confidence among
authorities, and mutual training of inspectors, as well as the
exchange of information and experience in the field of CGMP and
related areas. FDA expects that its involvement with PIC/S will
further increase opportunities for information sharing and facilitate
steps toward harmonizing the interpretation and application of CGMP
requirements.
As
reported in the September 2003 announcement, FDA created a CGMP
Harmonization Analysis working group to analyze internal and external
CGMP requirements, including those related to quality systems. This
working group performed a formal analysis of 21 CFR parts 210 and 211
against the GMPs of the European Union (EU), PIC/S, as well as other
Agency CGMP regulations to identify the differences and consider the
value of adding or changing the current regulations. Upon completion
of their analysis, the working group concluded that there are many
more similarities than differences among the various regulations.
Where differences exist, the working group found that they can often
be explained by unique aspects of the specific product subject to the
regulation. For example, the device quality system regulation (21 CFR
820.200) requires that procedures for performing servicing be
established and maintained by the manufacturer, where appropriate,
which is an activity unique to devices. The EU GMPs have explicit
requirements for separate areas for maintenance workshops and weighing
of materials, whereas 21 CFR 211.42(c) requires that operations be
performed within specifically defined areas of adequate size.
Based on the working group's
analysis, the Agency decided to take an incremental approach to
modifying parts 210 and 211 while pursuing international harmonization
through ICH and PIC/S. The ultimate goals of the modifications will
be to encourage timely detection and response to emerging defects or
indications that product quality has been compromised; to provide
further clarity and modernize the regulations; and to harmonize
various aspects of parts 210 and 211 both internationally and with
other Agency regulations.
Keeping the key concepts in mind,
the Agency intends to withdraw its 1996 Proposed Rule: Current Good
Manufacturing Practice: Amendment of Certain Requirements for Finished
Pharmaceuticals and take a new look at the comments received on
that proposal in the context of more recent scientific and technical
advances and quality systems and risk management concepts.
FDA has also taken steps to clarify
our approach to process validation, which was a subject of the 1996
proposal. Earlier this year, FDA published a revised compliance
policy guide (CPG) entitled Process Validation Requirements for
Drug Products and Active Pharmaceutical Ingredients Subject to
Pre-Market Approval (CPG 7132c.08, Sec.490.100). FDA intends to
further address the validation aspects of the CGMPs by updating the
1987 Guideline on Process Validation, as announced on March 12,
2004. A draft revision for public comment will address the
relationship between modern quality systems and manufacturing science
advances to the conduct of process validation. We hope to issue this
draft guidance in 2005.
Specific activities and achievements
related to implementing the future of pharmaceutical manufacturing
regulation are outlined in more detail in the
following pages.
In September 2003, the CGMP Steering
Committee issued its second progress report. The following paragraphs
outline achievements since 2003 as well as future plans, as
appropriate, for the various working groups.
Consistent with the objectives of
our CGMPs for the 21st Century Initiative, FDA has created
a risk-based approach that manufacturers can use to comply with Part
11 electronic records requirements.
As a first step, FDA issued a draft
guidance in September 2003, to clarify the scope and application of
part 11 and describe several aspects of the regulation for which
enforcement discretion can be exercised. Following the evaluation of
public comments, the guidance for industry Part 11, Electronic Records, Electronic Signatures — Scope and Application, was finalized FDA’s next
step was to publish a notice in the Federal Register on April
8, 2004, announcing its intention to amend part 11 and seeking the
input from the public. The comment period for this notice closed on
July 9, 2004. Although FDA had originally intended to have a public
meeting on the subject, we have determined that the extensive written
comments submitted to the docket provide an adequate basis for
beginning the rulemaking process. All interested parties will have
ample time to comment when the proposed amendment for part 11 is
issued. It is expected that this proposed amendment will issue for
public comment during 2005.
Next, we have issued a draft
guidance for industry titled Computerized Systems Used in Clinical Trials.
Once finalized, the guidance will replace the guidance of the same
name issued in April 1999. This guidance is being revised to make it
consistent with Agency policy as reflected in the part 11 final
guidance. The draft revision reflects policy that also is consistent
with the Agency’s international harmonization efforts. The guidance
provides recommendations about computerized systems that are used to
create, modify, maintain, archive, retrieve, or transmit clinical data
intended for submission to FDA. These data form the basis for the
Agency’s decisions regarding the safety and effectiveness of new human
and animal drugs, biological products, medical devices, and certain
food and color additives. Because the data have broad public health
significance, they are expected to be of high quality and integrity.
The
Dispute Resolution Working Group began developing dispute resolution
procedures for CGMPs by holding a meeting with the related trade
associations to solicit their concerns and suggestions regarding the
current processes for raising and resolving disputes related to CGMP
inspectional findings. This information supported the development of
a draft guidance Formal Dispute Resolution: Scientific and
Technical Issues Related to Pharmaceutical CGMP, which issued in
August 2003. Once finalized, the document will provide guidance to
manufacturers of veterinary and human drugs, including human
biological drug products, on how to resolve disputes of scientific and
technical issues relating to CGMP requirements.
This draft became the foundation for
the launch of a 12-month Dispute Resolution Pilot Program that began on January 1, 2004, and is still ongoing. The Working
Group has reviewed all of the comments submitted in response to the
draft guidance and is closely monitoring the operation of the pilot
program to help determine the value of the dispute resolution process
and learn what changes might improve the guidance and its
implementation.
Most recently, on September 8, 2004,
the Working Group held a second meeting with interested trade
associations to hear their thoughts on the pilot program and any final
comments on the draft guidance. The Working Group will make
appropriate modifications as it finalizes the final guidance on this
subject, targeted for early 2005. Internally, the Working Group is
completing the formation of the Tier II Panel, as outlined in the
draft guidance, and establishing procedures for public disclosure of
the substance of issues that are raised through the dispute resolution
process.
FDA has revised its regulatory procedures for determining when to
issue warning letters in response to noncompliance with CGMP
requirements. Beginning in March 2003, all proposals to issue warning
letters to human and animal drug and medicated feed manufacturers are
reviewed by the centers with product jurisdiction and by the Office of
the Chief Counsel. The final letter is issued by the recommending
field office.
The centers' continued role in the process will ensure that adverse
findings will be based on the best science available. We are
enhancing communication and coordination between the field and centers
with the goal of identifying possible program inconsistencies that can
be resolved before a warning letter is issued.
In March 2004, the Agency completed an internal assessment of the
content, consistency, and outcome of the Warning Letter recommendation
process related to CGMP deficiencies for human and animal drug and
medicated feeds. Overall, the assessment showed that the rescission
of direct reference authority (i.e., ability of district offices to
issue CGMP warning letters prior to center concurrence) added value to
the CGMP warning letter process. Steps have been initiated to address
the concerns noted in the assessment.
Finally, the ORA Office of Enforcement is leading an Agency-wide
initiative to implement a quality system for overseeing the warning
letter process. Executive Summary on Warning
Letter Assessment
As
international cooperation has been one of the guiding principles of
this initiative, FDA’s international strategy to improve the quality
of pharmaceutical products includes enhancement of relevant
international harmonization activities and increased sharing of
regulatory information with counterpart authorities in other
countries.
FDA believes that the harmonization
of international scientific standards on drug product quality will
promote technological innovation for enhanced public health promotion
and protection. To facilitate this, CDER and CBER actively
collaborate with other regulatory authorities via the International
Conference on Harmonisation of the Technical Requirements for
Registration of Pharmaceuticals (ICH). The Center for Veterinary
Medicine (CVM) is a participant in a separate International
Cooperation on Harmonisation of Technical Requirements for
Registration of Veterinary Medicinal Products (VICH), an international
harmonization process for animal drug products. CVM also attends ICH
meetings to facilitate FDA harmonization for human and animal
pharmaceutical drug products and gain knowledge for development of
comparable guidelines in the VICH international harmonization process
for animal drug products.
In November 2003, ICH agreed to work
on a harmonized plan to develop a pharmaceutical quality system based
on an integrated approach to risk management and science.
To implement its vision, ICH
established two Expert Working Groups (EWGs) on pharmaceutical
development. The first (ICH Q8 EWG) seeks to incorporate elements of
risk and quality by design throughout the life-cycle of the
product. The ICH Q8 EWG articulated the “desired state” for
pharmaceutical manufacturing in the 21st century as:
- Product quality and performance achieved and assured by
design of effective and efficient manufacturing processes.
The second working group (ICH Q9 EWG)
is trying to better define the principles by which risk management
will be integrated into decisions by regulators and industry regarding
quality, including CGMP compliance. The outcome should be a risk
management framework intended to lead to more consistent science-based
decision-making across the life-cycle of a product. These two expert
working groups work in parallel and exchange information on a regular
basis.
Currently, ICH Q8 EWG is developing
a guidance describing the
suggested contents for the 3.2.P.2 Pharmaceutical Development section
of a regulatory submission in the ICH M4 Common Technical Document (CTD)
format. The Pharmaceutical Development section will provide the
Agency the opportunity to use the knowledge gained through both the
application of scientific approaches and various risk management
strategies to the development and review of a product and its
manufacturing process. Pharmaceutical
development information will help to reduce uncertainty with respect
to critical variables, sources of variability, and their clinical
relevance while improving FDA's ability to make risk-based decisions.
In the current state, uncertainty during the review process delays
approval of certain complex drug delivery systems (e.g., inhalation
products). With increasing complexity in drugs and drug delivery
systems, this challenge is anticipated to increase and is likely to
result in multiple review cycles for new drug applications and/or an
inability to approve generic drug products in a timely manner.
Furthermore, significant industry and FDA resources are being spent
debating issues related to acceptable variability, need for additional
testing controls, and how specification acceptance limits should be
established. Often these debates are focused on acceptance limits or
the statistical aspects. In these debates a proportionate focus on
the underlying manufacturing science is often missing.
The emerging ICH
Q8 creates an opportunity for an applicant to demonstrate an enhanced
knowledge of product performance over a wider range of material
attributes (e.g. particle size distribution, moisture content, and
flow properties), processing options and process parameters. This
knowledge can be gained in a structured manner by, for example,
applications of formal experimental designs, PAT concepts, or risk
management tools (e.g. failure mode effect analysis or FMEA) and can allow regulatory agencies to develop more flexible
regulatory approaches, for example, to:
- Facilitate risk based regulatory
decisions (reviews and inspections)
- Implement manufacturing process
improvements, within the boundaries of the knowledge described in
the dossier, without the need for regulatory review
- Implement real time quality
control, leading to a reduction of end-product release testing
It is hoped that this document will reach ICH step 2 in November,
2004. ICH Q8 EWG is working closely with the ICH Q9 EWG to
incorporate certain risk management principles in pharmaceutical
development.
At the same time, FDA continues its
active participation in the development of an internationally
harmonized guidance on quality risk management by the ICH Q9 EWG.
Since adoption of this topic by the ICH Steering Committee in November
of 2003, EWG meetings were held in March and June of 2004. The next EWG meetings are scheduled
for September 29, 2004, (via telephone) and November 2004. FDA
believes that Q9 will encourage industry and regulators to increase
the use of risk management tools to ensure drug quality. In addition,
the development of harmonized guidance on this topic will improve the
level of discourse, both within and among regulators and industry,
concerning risk management tools and terminology.
While Q8 and Q9 continue to
progress, ICH will begin to pursue Q10, a document that will cover
life-cycle management for process and system control. Q10 is intended
to promote postapproval improvements to manufacturing processes. This
document will address current pressures felt by both regulatory
authorities and industry with respect to postapproval changes. For
the regulatory authority, there is a need to reduce the burden of
supplement review and provide review oversight to only certain changes
using a risk basis. For manufacturers, the regulatory process should
not delay implementation of improvements in manufacturing processes
once a product has been approved for marketing. In addition, it is
hoped that manufacturers will also be more willing to use innovative
solutions to resolve quality problems.
As already mentioned, to further
advance its collaboration with international partners and strengthen
its oversight of non-U.S. drug manufacturing sites that produce
FDA-approved pharmaceuticals for Americans, FDA will be seeking
membership in the Pharmaceutical Inspection Cooperation Scheme (PIC/S).
Today, the FDA has issued the final guidance for industry Sterile Drug Products Produced by
Aseptic Processing-Current Good Manufacturing Practice. This
guidance replaces the 1987 Guideline on Sterile Drug Products
Produced by Aseptic Processing. The guidance recommends "building
quality into products" through science-based facility, equipment,
process, and system design for sterile drug manufacture. This
guidance includes two central themes:
-
Ensure robust product protection through adequate
design and control of equipment and facilities
-
Ensure that the operational and raw material inputs
are predictable through adequate quality control and quality
assurance
Sterile drug products are a major component in
FDA’s risk-based inspectional program. Through this guidance, FDA
hopes to facilitate the application of good science and modern
technology, and thus lessen or eliminate avoidable risks from aseptic
operations. The adoption of better contamination prevention practices
and a higher assurance of process consistency is expected to reduce
the incidence of sterile drug manufacturing problems, thus
facilitating the ongoing availability of these often therapeutically
significant pharmaceuticals.
Consistent with the objectives of the initiative,
the guidance encourages the adoption of new technological advances by
the pharmaceutical industry. In particular, the guidance underscores
the advantages that automation and isolation concepts offer in
protecting the exposed sterile drug product during its aseptic
manufacture. The guidance also encourages use of modern
microbiological testing methods that are more accurate and precise.
It also advocates a risk-based and quality system framework that
stresses contamination prevention. In particular, risk-based
approaches are covered in sections describing the roles played by
personnel, design, environmental control, and media fills in an
aseptic processing operation. Through this guidance, FDA hopes to
facilitate the application of good science and modern technology, and
thus lessen, or eliminate, avoidable risks from aseptic operations.
The adoption of better contamination prevention practices and a higher
assurance of process consistency is expected to reduce the incidence
of sterile drug manufacturing problems, thus facilitating the ongoing
availability of these often therapeutically significant
pharmaceuticals. Sterile Drug
Products Produced by Aseptic Processing-Current Good Manufacturing
Practice
This guidance, made available today, describes a regulatory framework
that will encourage the voluntary development and implementation of
innovative approaches in pharmaceutical development, manufacturing,
and quality assurance. Guidance for Industry PAT — A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance. Many new technologies are currently available that provide information on
physical, chemical, (micro)biological characteristics of materials to
improve process understanding and to measure, control, and/or predict
quality and performance. The guidance facilitates the introduction of
such new technologies to improve efficiency and effectiveness of
manufacturing process design and control (e.g., feedforward and
feedback controls) and quality assurance. Gains in quality and
efficiency will vary depending on a process and a product, and are
likely to come from:
- Reducing production cycle times by using on-, in-, and/or at-line measurements and
controls
- Preventing rejects, scrap, and re-processing
- Real time release
- Increasing automation to improve operator safety and reduce human errors
- Improving energy and material use and increasing capacity
- Facilitating continuous processing to improve efficiency and manage variability
By definition PAT brings a systems
perspective to the design and control of manufacturing processes.
Therefore, a systems approach was absolutely necessary for regulatory
assessment of PAT applications. To achieve this objective, the PAT
team for CMC review and CGMP inspection was created. It includes
reviewers, investigators and compliance officers. A comprehensive
scientific training program was developed with guidance from the
Advisory Committee for Pharmaceutical Science's PAT Subcommittee.
The entire team trained together. As a part of their certification
process they were asked to work as a team to address comments received
on the draft guidance. Two assignments, a PAT inspection and
preoperational site visit, have been successfully completed by this
team. Several team members have participated in a number of
scientific conferences. The feedback received from their instructors,
conference participants and companies has been very positive. The
many organizational and communication barriers that existed at the
beginning of the initiative have been removed, and the members are
functioning as a team committed to a common purpose.
The integrated quality system
orientation afforded a flexible regulatory approach for implementation
of PAT. For example, regulatory implementation plans can include the
following.
- PAT can be implemented under the facility's own quality
system. CGMP inspections by the PAT Team or PAT certified
investigator can precede or follow PAT implementation.
- A supplement (CBE, CBE-30 or PAS) can be submitted to
the Agency prior to implementation, and, if necessary, an inspection
can be performed by the PAT team or PAT certified Investigator before
implementation.
- A comparability protocolcan be
submitted to the Agency outlining PAT research, validation and
implementation strategies, and time lines. Following approval of this
comparability protocol by the Agency, one or a combination of the
above regulatory pathways can be adopted for implementation.
The PAT process has been successful in bringing a
systems perspective and a team approach to facilitate innovation. The
PAT team has approved one application that included a joint team
inspection and has recently completed a preoperational visit for a
major PAT application. Several PAT proposals have been received, and
it is expected that many of these will be received as applications in
the near future. The PAT Framework is supported by the ASTM
International Technical Committee E55: Pharmaceutical Applications of
Process Analytical Technology
The pharmaceutical community was asked to take on responsibility for
developing standards to support the introduction of innovative tools
and technologies under the PAT framework. In this regard, ASTM
International provided an excellent process to identify and develop
standards in a timely manner using technical expertise in all relevant
disciplines from the pharmaceutical community and other industrial
sectors. The
FDA’s PAT team worked with ASTM International to establish the Technical Committee E55 on Pharmaceutical
Application of Process Analytical Technology. Focusing on process
monitoring and control, instead of testing, requires process control
standards consistent with guiding principles of the control theory. ASTM International provides an opportunity to bring a
strong engineering process control perspective and to learn from other
industrial sectors that have used process analyzers and controls for
many years. The E55 committee is tasked with developing standards
related to process analytical technology with the primary focus on
process understanding and control. Three
subcommittees of E55 include PAT system management, PAT
system implementation & practice, and PAT terminology. The standard E2363-04: Standard Terminology related to
PAT was recently published. The PAT Team is represented on E55 committees with a goal to ensure
that standards developed are aligned with the PAT guidance and
acceptable to FDA.
The definition of PAT in the FDA
guidance and ASTM E55 as well as other concepts are being incorporated
into the ICH Q8 guidance. The ASTM International provides another
venue for international cooperation, and the current E55 membership
reflects broad international interest in these standards. The next
steps in the PAT process include:
- Following the issuance of the PAT guidance, workshops are planned in
the three ICH regions.
- The PAT process will be incorporated into the FDA's quality system.
- FDA will continue to participate in the ASTM E55 Committee to support development of standards consistent with
the PAT framework.
- We will help to strengthen the emerging support structure in
scientific societies and association (e.g., AAPS, ISPE, IFPATMA, PDA,
and others).
- CBER (as observer) and a Pharmaceutical Inspectorate member from
Team-Biologics will join the PAT Steering Committee.
- The second PAT team will be selected (to include Office of
Biotechnology, Compliance and ORA Team-Biologics CGMP Inspection
staff).
- Teambuilding, training, and certification of the second team will
begin.
- Invitations will be extended to Health Canada, Japan’s Ministry of
Health, Labour and Welfare (MHLW) and EMEA to participate in
the second training program.
- We will share lessons learned and training materials with Health
Canada, MHLW, and EMEA.
- The PAT team will continue its education and training.
- PAT Team and Team-Biologics will collaborate to identify best
practices and lessons learned; recommendations will be sought on how
to develop a team approach between Product Specialists and
Pharmaceutical Inspectorate.
- We will seek out critical path research and research collaborations
(academia and industry).
- Following the second PAT team training, we will expand the PAT program
to include all Product Specialist and Pharmaceutical Inspectorate.
To provide the most effective
public health protection, FDA must determine how best to perform
regulatory review based on its understanding of product risk and how
best to mitigate such risk. In the past, FDA has depended on
notification of postmarket manufacturing changes on all products
without considering the extensiveness of change and risks associated.
These notifications — supplements to approved NDAs, BLAs and ANDAs —
are reviewed by CMC reviewers who in turn communicate with
manufacturers on the suitability of the changes. Decisions on
postmarket changes need to be made based on an understanding of the
process and risks associated with the changes on the quality of the
manufactured product. Knowing that a company has a scientific and
technical understanding of its manufacturing processes and
relationship to the specific manufactured product at the development
stage enables the Agency to access risks and make decisions as to when
and if additional information is needed before a postapproval
manufacturing change is implemented.
The Changes Without Prior Review
Working Group was established to look at various options for a
systematic risk-based approach to the review process for post-approval
manufacturing changes.
The working group focused mainly
on establishing a mechanism for regulatory relief through the use of
comparability protocol. A draft guidance Comparability
Protocols Protein Drug Products and Biological Products - Chemistry,
Manufacturing, and Controls Information was issued in September
2003, which describes recommendations for preparing and using
predefined change evaluation plans, generally referred to as
comparability protocols. A comparability protocol is a comprehensive, detailed, written plan that describes the specific
tests and studies, analytical procedures, and acceptance criteria to
be achieved to demonstrate the lack of adverse effect for a specified
type of CMC change that may relate to the safety or effectiveness of
the drug product. A reduced reporting category can be justified when
a comparability protocol provides evidence that an applicant has a
scientific and technological understanding of the drug, manufacturing
process, controls, proposed change and potential effect of that change
on the product quality. The use of a comparability protocol could
allow an applicant to implement a CMC change without waiting for prior
approval from FDA and therefore place a product in distribution sooner
than without the use of a protocol. A comparability protocol may also
provide a means to facilitate process improvement and/or process
optimization. In some cases, a comparability protocol may provide a
means to prevent or mitigate drug supply disruptions or shortages.
This
guidance is currently being finalized to incorporate the tenets of the
risk-based approach to ensuring reductions in postapproval
manufacturing changes and to ensure that appropriate manufacturing
science is incorporated in the decision-making processes.
The Agency will continue to
incorporate up-to-date concepts of risk management and quality systems
approaches. The Agency will also continue to identify opportunities
for improving coordination between review and inspection activities to
identify and implement opportunities for managing manufacturing
changes without the need for prior FDA review or approval. The
following opportunities are being considered.
-
ICH Q8 will describe the
suggested contents for the 3.2.P.2 Pharmaceutical Development
section of a regulatory submission in the ICH M4 Common Technical
Document (CTD) format. It is not intended to be a how to guidance. It will provide sponsors of drug applications an
opportunity to present knowledge gained during development of a
product and its manufacturing process and relevant prior knowledge.
It will indicate areas where the provision of greater understanding
of pharmaceutical and manufacturing sciences can create a basis for
flexible regulatory approaches to support continuous improvement.
-
Under the Manufacturing
Subcommittee of the Advisory Committee for Pharmaceutical Science (ACPS),
a working group will be formed to identify specific steps needed to
move towards the desired state. The group will be asked to develop
case examples to support the ICH Q8 document and CPG 7132c.08
and to illustrate the relationship between an adequate level of
process understanding and regulatory flexibility to make changes
without prior review.
-
ACPS recommendations on
regulatory flexibility for postapproval changes (e.g., reduce the
need for prior review) will be considered for modifying the draft
Comparability Protocol Guidance (for small molecules only).
Continuous improvement is an
essential element in a modern quality system. Its aim is to improve
efficiency by optimizing a process and eliminating wasted efforts in
production. Improvement efforts are carried out in a structured manner
with appropriate predefined protocol and oversight. These efforts are
primarily directed towards reducing variability in a process and
product quality characteristics and are not for changing the
fundamental design of a manufacturing process.
Generally the
term continuous improvement is broadly used for all improvement
efforts including those that result from corrective actions.
In the regulatory setting a distinction between corrective action and
continuous improvement is essential. Need for corrective actions
occur when product quality characteristics are in question (e.g., out
of specification). Such a situation can require urgent risk
assessment and sound quality decisions to prevent any adverse impact
on patients.
In the current
state corrective actions are the dominant mode for improvement and
continuous improvement is difficult. The attached white paper entitled Pharmaceutical
CGMPs for the 21st Century: Innovation and Continuous
Improvement in Pharmaceutical Manufacturing examines the challenges for continuous improvement in the
manufacturing process for pharmaceutical dosage forms. It is a
combined report of the PAT team and the Manufacturing Science Working
Group and provides a summary of their learning, contributions
and proposed next steps for moving towards the desired state of
pharmaceutical manufacturing in the 21st century.
It provides a systems view of the
current system and describes the desired state and explains how the combined work products of the CGMP initiative are
positioned to provide a comprehensive set of regulatory tools to
facilitate the journey to the desired state. However, the
challenge ahead is significant. At the end of the CGMP Initiative the
pharmaceutical community has arrived at a cross-road; one path goes
towards the desired state and the other maintains the current state.
The path towards the desired state is unfamiliar to many while the
current state provides the comfort of predictability. The Agency
hopes the pharmaceutical community will choose to move towards the
desired state. Innovation and Continuous
Improvement in Pharmaceutical Manufacturing
The value and
advantages of a team approach to CMC review and CGMP inspections has
been recognized and practiced for many years (e.g., Team Biologics).
This principle was used to develop the PAT team. To accommodate
specific objectives of the initiative and the need for a systems
approach in the PAT team, team building and joint training and a
certification process were developed. The entire team of CMC
reviewers, CGMP investigators and compliance officers trained together
on all aspects of PAT.
The PAT team building and training program identified several
challenges. Of these the most critical challenge was that of
organizational barrier (review/compliance/inspections). Team building
exercises and a joint training program were critical for overcoming
the organizational barriers and communication challenges.
Lessons learned from the PAT team and Team-Biologics will be used for
the Product Specialists on Inspection program. Team building and
joint training opportunities will be created for CMC reviewers,
compliance officers and investigators, including the Pharmaceutical
Inspectorate on the work products of CGMP Initiative prior to
initiation the Product Specialists on Inspection program.
To improve the integration of the
preapproval and CGMP inspection programs, a memorandum of
understanding (MOU) between CDER and ORA, signed on August 22, 2003,
establishing the Pharmaceutical Inspectorate (PI) and defining the
roles and relationships of CDER and ORA. The PI will be a staff of
highly trained individuals within ORA who will devote most of their
time to conducting drug quality inspections of identified
pharmaceutical operations. The PI will also conduct preapproval
inspections and participate in various other investigations that
require their technical expertise.
The
previously established Level III Drug Investigator Certification Board
reviewed submission packets and selected 26 candidates for membership
into the PI. The curriculum was established, and a course advisory
group developed the first of several PI training modules, which were
presented in August 2004. Pharmaceutical
Inspectorate Curriculum. The next set of training modules will be
delivered in January 2005, and a third set of training modules will be
presented in mid-2005. In keeping with the effort to foster a close
working relationship between the individuals in the field and
individuals in CDER, CVM, and CBER; the staff of Center Compliance
Offices and the review divisions participated in the initial training
modules along with the ORA staff. The PI candidates will also go on
temporary details to offices in relevant centers to gain a better
understanding of the work of the different centers. These temporary
details will allow for team building among the field PI candidates and
center staff. The experience of ORA and CBER in the development and
implementation of the Team Biologics Program has served to inform the
development of the PI program.
To serve as a member of the PI, an
investigator will have to obtain and maintain a Level III Drug
Investigator Certification. The Level III Drug Investigator
Certification signifies that an investigator is primarily working on
highly complex drug inspectional work, has been endorsed by his or her
district, and has been selected by the Level III Drug Investigator
Certification Board. The investigator will receive extensive training
on advanced technology in pharmaceutical manufacturing and complete a
detail in the center.
Next steps for the PI are to define,
under the risk-based quality management system, the process and procedures for interactions among the involved centers and the field
offices and the role of the PI members in those interactions. This
segment of the quality systems framework will be implemented in the
involved centers and the field to ensure quality and consistency and
regulatory effectiveness of inspections.
FDA has also taken steps to improve
its preapproval inspection (PAI) program. In the September 2003
update, it was announced that an interim change had been made to
Compliance Program 7346.832, Preapproval Inspections. That change
eliminated mandatory categories for performing inspections and listed
a smaller number of categories that should trigger inspections based
on the risk and complexity of the product subject to the pending
application. The plan for the next year is to revamp this entire
program to further reflect the thinking that has been derived from the
CGMP for the 21st Century Initiative, including means for
better Agency communication from review to inspection on product
design, identifying process issues that are most relevant to product
design, and the use of center specialists on inspections.
During the past 2 years, FDA has
made significant strides in designing and implementing programs to
encourage and manage the quality of pharmaceuticals with a more
systematic approach. The value of systematic approaches has been
embraced both within the Agency as well as by the industry at large.
Some of the pivotal components of FDA’s own achievements have been
highlighted previously. Although all of the working groups that are a
part of this initiative have some aspect of quality management or
assurance in their plans, this has been the sole focus for several of
the working groups.
The Quality Systems Working Group,
formed at the launch of the initiative, was dedicated to enhancing the
consistency and predictability of FDA's approach to production quality
and safety assurance among our centers and field components. The
Quality Systems Working Group completed its initial charge in the
summer of 2003 and was then reformed into three new working groups (WGs):
the Quality Systems Framework WG, the Quality Systems Guidance
Development WG, and the CGMP Harmonization Analysis WG. In addition,
two other related workgroups were formed: one for quality
communications and another for quality systems implementation. The
communications group was charged with developing a mechanism similar
to CDER's CGMP Notes that, consistent with good guidance
practices, can quickly communicate FDA decisions and interpretations
related to CGMPs and FDA inspectional findings to FDA staff and the
public to improve the quality of both pharmaceutical products and
regulatory activities. The focus of the second group is coordination
with the implementation of a quality program for FDA’s Team Biologics,
which is being implemented by the Team Biologics Operations Group.
The achievements of these groups are discussed here.
The Quality Systems Framework WG has
developed a standard quality systems framework that integrates and
enhances the Agency's existing and planned internal quality programs.
This quality systems framework was created to ensure quality and
consistency of reviews, inspections, and other regulatory activities.
The framework provides common vocabulary and required system
elements. Elements include typical quality systems requirements, such
as ensuring that there are process plans with written procedures;
well-trained staff; record keeping and review; knowledge sharing and
coordination; and continuous process and product evaluation and
improvement.
The Quality Systems Framework for
Internal Activities was approved by the FDA Management Council and
incorporated into the FDA Staff Manual Guides to demonstrate executive
commitment and to ensure Agency-wide implementation of quality systems
approaches. To provide Agency-wide advice regarding the
implementation of quality systems, the Management Council chartered a
new subcommittee on July 1, 2004, the Quality Resource and Guidance
Team (QRGT). The QRGT has developed a White Paper, Defining the Customer in a Regulatory
Agency to assist FDA components in implementing internal
quality systems. The Quality Systems Framework emphasizes customer
identification as a critical step in developing quality awareness and
quality system effectiveness.
In addition to the FDA quality
systems work that is already underway discussed earlier, other
important projects are being undertaken using the new FDA Quality
Systems Framework:
-
Warning Letters for CGMP-related issues
-
Recalls
-
Pharmaceutical Inspectorate
-
PAT initiative
The draft guidance Quality
Systems Approach to Pharmaceutical Current Good Manufacturing Practice
Regulations is intended to provide recommendations on how to meet
the requirements of the CGMP regulations while using a comprehensive
quality systems approach to the manufacturing of human and veterinary
drugs, including biological drug products.
This draft guidance provides a
contemporary framework for implementing quality by design, continuous
improvement and risk management in the drug manufacturing process.
The guidance, along with the flexibility of the CGMP regulations,
allows manufacturers to implement modern quality systems in their
manufacturing operations in a manner that is tailored to their
specific manufacturing environment. The resulting robust quality
system may serve to lower the need for regulatory oversight, allowing
for more efficient, focused inspections and less review oversight.
Quality principles are inherent in
the CGMP regulations. However, the regulations do not fully delineate
the means by which quality is achieved during the manufacture of
pharmaceuticals. The Quality Systems guidance, once finalized,
will describe a comprehensive quality systems approach to drug
manufacturing that correlates closely with the regulatory
requirements. The elements that make up this approach intertwine with
the basic principles of CGMP and are instrumental to successful
pharmaceutical development and manufacture. The draft guidance is
consistent with Agency efforts to harmonize with international
regulatory standards as well as to implement a modern quality systems
approach for all medical products under FDA regulation.
A more uniform approach to quality
systems will, in turn, facilitate our handling of issues raised when
combining products (e.g., a drug with a device). Because we will be
receiving applications on increasing numbers of combinations products,
we have developed a draft
guidance for industry on Current Good Manufacturing Practice for
Combination Products, a first step in standardizing and
harmonizing quality requirements.
As part of the initial announcement
in 2002, FDA indicated that the CGMP regulations for pharmaceutical
products (21 CFR parts 210, 211) “appear to provide a degree of
flexibility to allow the Agency to shift the emphasis to a
science-based, risk management approach.” However, the evaluation of
comments from the May 1996 proposed drug CGMP amendments will
continue, and consideration will be given to revising these
regulations and others (e.g., 21 CFR 11) in the future.
The GMP Harmonization Analysis
Working Group was charged with the challenging task to, “Perform a
formal analysis of 21 CFR 210 and 211 against: EU GMPs, PIC/S and
other CGMP regulations across the Agency,” the goal being “to call out
the differences and benchmark against those to determine the value of
adding to or changing the current 210 and 211 regulations.”
The working group, comprising
members from CBER, CDER, CDRH, CFSAN, CVM, ORA and the Office of
Combination Products, assigned the comparisons accordingly:
- CBER, CDRH, and ORA members compared 210/211 with
820
- CDER members compared 210/211 with the EU GMPs
- CVM members compared 210/211 with 226 and compared
it looking the opposite way, from 226 to 210/211
- CFSAN members compared 210/211 with Juice HACCP
while an ORA member compared Juice HACCP with 210/211.
- A CFSAN member also compared 210/211 with 110/111.
The working group determined that
the EU GMPs and the PIC/S GMPs were virtually identical, in base
requirements, although the EU GMPs are more comprehensive. Therefore,
the working group decided to focus on the EU GMP comparison.
Upon completion of its assessment,
the group concluded that there are many more similarities than
differences among the various regulations, and, where differences do
exist, they are often related to the commodity in question. Although
a number of differences were identified between Parts 210/211 and the
main EU GMPs, most were not considered substantive.
To reinforce the Agency’s decision
stated earlier in this report, based on the analysis of this working
group, FDA will take an incremental approach to modifying parts
210/211, while pursuing international harmonization through ICH and
PIC/S. The ultimate goals of the modifications will be to encourage
timely detection and response to emerging defects or indications that
product quality has been compromised; to provide further clarity and
modernize the regulations; and to harmonize various aspects of parts
210/211 with other Agency regulations, and regulations of our
international counterparts.
This working group will carefully
consider comments on the draft Quality Systems guidance as well. The
Agency believes those comments will provide an opportunity to better
understand current industry practice in the area of quality systems.
Although the Agency intends to withdraw the 1996 Proposed Rule:
Current Good Manufacturing Practice: Amendment of Certain Requirements
for Finished Pharmaceuticals, it will not abandon the important
concepts presented in that proposal. The Agency will review those
concepts in light of the many comments submitted to the proposed rule,
more recent scientific and technical advances, and quality systems
principles in going forward with rulemaking to incrementally modify
parts 210/211.
We have begun updating our current thinking on validation under a
Cross-Agency Process Validation workgroup led by CDER's Office of
Compliance Coordinating Committee with participation from CDER, CBER,
ORA and CVM. In March of this year, FDA began this process issuing a
compliance policy guide (CPG) entitled Process Validation
Requirements for Drug Products and Active Pharmaceutical Ingredients
Subject to Pre-Market Approval (CPG 7132c.08, Sec 490.100). The
CPG stresses the importance of rational experimental design and
ongoing evaluation of data. The document also notes that achieving
and maintaining a state of control for a process begins at the process
development phase and continues throughout the commercial phase of a
product's life-cycle. The CPG incorporates risk-based approaches with
respect to inspectional scrutiny; use of advanced technologies, and by
articulating more clearly the role of conformance batches in the
product life-cycle. The document clearly signals that a focus on
three full-scale production batches would fail to recognize the
complete story on validation.
On
August 4, 2004, FDA implemented a new approach to providing timely
guidance on CGMP-related questions on human, animal, and biological
drug products. This approach will enable more widespread
dissemination of CGMP information and provide more transparency of FDA
policy concerning CGMPs. Guidance will be provided in a question and
answer format. The first set of questions and answers can be found at http://www.fda.gov/cder/guidance/cGMPs/default.htm. Questions
and answers will be provided as they arise. This resource is being
co-sponsored by CDER, CVM, CBER, and ORA.
Agency guidance represents the FDA’s
current thinking on a specific topic (21
CFR 10.115). It does not create or confer any rights for or on
any person and does not operate to bind FDA or the public. An
alternative approach can be used if the approach satisfies the
requirements of the applicable statutes and regulations. Inquiries
for information concerning a specific guidance document, should be
directed to the originating office.
In conjunction with all of the CGMP activities,
FDA hosted an internal seminar series for all FDA units involved in
the regulation of pharmaceuticals. This series was entitled Quality
Systems and Risk-Based Approaches and their Application to FDA
Pharmaceutical Product Quality Regulation. Over a 4-month period, six
seminars were presented that addressed quality systems and risk
management approaches. Speakers at the seminars were leaders from
industry, academia, and other government agencies who have had
extensive experience in the quality and risk arenas. The seminars
were designed to be informative and to stimulate thoughts about
implementing quality systems within the Agency and how the Agency
might add risk-based components to their regulatory structure.
Approximately 130 FDA staff and managers attended the presentations in
person at an FDA location while several hundred more viewed the
presentations from remote sites served by satellite video.
The presentations described the process of
implementing quality systems to build a quality organization, the
inclusion of risk-management approaches, and variation risk management
(VRM), an approach aimed at allocating organizational resources to
achieve maximum impact on manufacturing quality. The presentations
focused on the key elements needed to implement quality systems
successfully and to maximize the benefits. A follow-up survey of
participants resulted in the series receiving very high ratings and
requests for and suggestions for additional speakers on related topics
in the future.
This
working group’s development of the previously discussed risk-based
model will assist the Agency in further prioritizing domestic
manufacturing sites for human drug CGMP inspections. The model is
intended to help the Agency predict where its inspections are likely
to achieve the greatest public health impact. In addition, the model
should assist the Agency in creating positive incentives that reduce
the frequency or scope of inspectional oversight for firms that FDA
determines have acquired sufficient process understanding and
implemented effective quality systems. FDA intends to begin pilot
implementation of the model for certain pharmaceuticals regulated by
CDER beginning next month. The risk-based model will serve to
supplement, where appropriate, other risk-based inspection programs
used within the Agency. Risk
Management — Risk-Based Inspection Site Selection
In the September 3, 2003, second
CGMP initiative progress report, FDA listed several initiatives
underway by the Team Biologics Operations Group as a result of its
in-depth evaluation of the Team Biologics Program, which was designed
to review, assess, and improve the program. At the time the CGMP
initiative was initiated in August 2002, the Team Biologics Operation
Group had completed its evaluation of the Team Biologics Program and
had begun to implement several initiatives. The Team Biologics
initiatives fully complement the CGMP Initiative’s goals and efforts.
Since the second progress report,
much has been accomplished to enhance and improve the Team Biologics
Program. For example, Team Biologics has implemented a revised
charter that formally adopts a quality systems management framework,
improves processes for communication and coordination between
headquarters and the district offices, and further integrates product
specialists into the program. In addition, on an interim basis, the
Team Biologics program has expanded to include the CDER for those
biological therapeutic products that were transferred in October
2003. Other significant developments resulting from the evaluation
include:
- A quality policy has been developed and adopted.
- Enhanced risk based work planning principles are
being implemented.
- The standardized training and qualifications of Core
Team members is being strengthened to, among other things, help
ensure consistency in regulatory application, with additional
training programs of Core Team investigators and Center Product
Specialists scheduled for October 2004.
- Metrics are being developed to further assess the
impact of the Team Biologics Program on industry and to measure
success.
The Team Biologics Operations Group
also will be assisting the CDER/ORA Pharmaceutical Inspectorate and
PAT Team in developing and implementing quality management systems to
provide consistency throughout the program areas.
[2] Although Team Biologics is not a working group under the Initiative,
its activities and accomplishments are included in this section as
they fully complement the CGMP Initiative.
Under the cGMP Initiative, we have
spent the past two years assessing what is needed to enhance and
modernize the regulation of pharmaceutical manufacturing and product
quality. As we now begin the implementation phase of the initiative,
we are also putting in place a plan for evaluating the impact on
manufacturing and drug quality.
Business school professors Dr. Jackson Nickerson of Washington
University in St. Louis, and Dr. Jeffrey Macher of Georgetown University are conducting
research that will be helpful to our evaluation of this initiative. A
large part of their work involves identifying factors that predict
manufacturing performance in pharmaceuticals. This will complement
FDA’s work on improving the inspection process, including its
risk-based site selection model and training an inspectorate on how to
best identify risks to pharmaceutical quality.
FDA will also conduct its own
evaluation studies. The Agency will explore and identify
relationships between FDA actions and accomplishments under the CGMP
Initiative, and subsequent improvements in public health. Examples of
such actions and accomplishments are: the adoption of quality systems
by industry; the use of risk factors to select inspection sites; and
the review of the warning letter process. The studies will attempt to
link such activities to their impact on regulated industry and on
public health-related outcomes (e.g., improvement in drug quality).
FDA also plans to validate the CGMP Initiative’s contributions to the
Agency’s long-term goals and mission.
Conceptual Framework of Evaluations
The
study will be done in two phases—planning and implementation. The
Planning phase will involve deciding which components of the cGMP
Initiative to evaluate by: 1) identifying the actions and
accomplishments of each cGMP working group to date; 2) determining the
feasibility of evaluating their impact on public health issues; and 3)
prioritizing them, based on feasibility and resources, and selecting
which to evaluate. The Planning phase will be completed in the fall
of 2004.
In
the second phase, implementation, we will conduct some or all of the
evaluations selected and prioritized in Phase I, to determine possible
impacts on regulated industry, product quality, and public health.
In
addition, as FDA implements quality systems programs, an ongoing
evaluation will be incorporated into those programs.
To continue the important work
already underway, as well as to achieve the new goals that have
evolved from the CGMP Initiative, FDA is restructuring its oversight
of pharmaceutical quality regulation. To this end, the Agency is
instituting an Agency-wide Council on Pharmaceutical Quality that will be charged with policy development and implementation,
leadership, and oversight, including the ongoing implementation of
internal qualitymanagement
systems relating to drug quality regulation. The Council will oversee
and assist with the shift from the assessment and evaluation phase,
which has occurred over the past two years, to the implementation
phase. Although the initiative began two years ago as the
Pharmaceutical CGMPs for the 21st Century, the Agency
believes that this title does not accurately reflect all that has been
accomplished, nor the goals and objectives as we move forward, as all
aspects of pharmaceutical quality are involved.
The following are among the steps to
be included in the next phase of the initiative under the leadership
of the Council on Pharmaceutical Quality:
- Develop additional guidance on quality systems for
pharmaceutical manufacturing so that the Agency’s goal to enhance and
modernize the regulation of pharmaceutical manufacturing and product
quality is met.
- Continue development of the risk-based pharmaceutical
quality assessment system that will replace the current CMC review
system to remove hurdles to continuous improvement following drug
approval.
- Revise the 1987 industry guideline on Process Validation
to include 21st century concepts, including risk management
and a life-cycle approach.
- Continue to explore and formalize risk-based tools to
enhance FDA's regulatory oversight.
- Refine the CGMPs and meet our harmonization (internal
and international) goals.
- Continue timely communication of our current thinking on
various quality issues to the public to facilitate compliance with FDA
requirements.
- Further enhance FDA’s own quality systems (including
more mechanisms to facilitate communication within the Agency).
- Continue and expand on opportunities to integrate
science-based policy and standards into our product quality regulatory
approach.
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Date created: September 29, 2004, updated October 11, 2006 |