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Pharmaceutical cGMPs for the 21st
Century: A Risk-Based Approach
Progress Report of
the Working Group on
Product Specialists on Inspection
Teams
Comments on this report or on the activities of this working group 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 Docket Number 03N-0059.
Electronic
Management Comment Form: Docket 03N-0059 - Pharmaceutical Current Good
Manufacturing Practices for the 21st Century: A Risk-Based Approach
I. INTRODUCTION
In August 2002, the FDA announced the Pharmaceutical cGMPs for the 21st
Century: A Risk-Based Approach initiative. At that time, a multidisciplinary
working group was formed to evaluate and make recommendations on the use of
Product Specialists on inspection teams to achieve the following goals:
- To ensure that submission reviews and current good manufacturing
practice (cGMP) inspections are coordinated and synergistic
- To strengthen consistency in regulatory decisions
- To incorporate the most up-to-date concepts of risk management and
scientific advances
- To more effectively use resources and improve communications within the
Agency, and between the Agency and industry
- To encourage innovation and continuous improvement
The working group met periodically and has developed this report that
discusses using Product Specialists on inspection teams to further enhance
application reviews and cGMP inspections. In this report, we present and assess
current experiences with, and current thinking on, the issues and concerns
associated with this concept. For simplicity, we use the term Specialist to
refer to a regulatory review or research scientist, or other technical expert,
in an FDA Center who participates in an inspection. We expect the definition and
scope of the term to evolve during this project to a more comprehensive term
that encompasses the breadth of knowledge and skills necessary to realize goals
and objectives of this initiative.
II. CURRENT USE OF A SPECIALIST
During inspections, a Specialist is generally responsible for evaluating test
methods and method validation, as well as reviewing and interpreting raw
analytical data that may be outside the Investigators’ expertise. For
biological products, a Specialist is instrumental in assessing purification
processes related to active pharmaceutical ingredients. These processes include
complex operations such as column chromatography, utrafiltration, diafiltration,
viral inactivation, and related specifications along with product purity and
impurity profiles. Specialists provide a balance to the inspection team by
making their knowledge and expertise available for assessing the physiochemical
and biochemical complexities of inspected products.
A. How Specialists Have Been Used
● Center for Biologics Evaluation and Research (CBER)
CBER Specialists participate in essentially all prelicense, preapproval, and
cGMP inspections for products other than blood. Some Specialists participate
on-site, while designated specialists are available for phone consultation for
other inspections. CBER cGMP experts lead preapproval inspections, with product
office specialists participating on-site. For biennial cGMP inspections of
approved products (both in the United States and abroad), inspections are led by
a specialized group of 12-14 investigators assigned to ORA headquarters. The
team receives a detailed, firm-specific assignment package for each inspection.
Due to the complexity of the products or the data submitted in investigational
new drug applications (INDs) or biologics license applications (BLAs), CBER
specialists may also participate in some bioresearch monitoring inspections to
assess issues such as manufacturing viral vectors for use in clinical studies.
● Center for Drug Evaluation and Research (CDER)
For many years, CDER reviewers in the Office of New Drug Chemistry (ONDC)
have occasionally participated in preapproval, biennial, and for-cause
inspections. Funds have been allocated to facilitate ONDC reviewers’
involvement in preapproval inspections (PAIs), and their participation has
contributed significantly to ONDC review functions.
The Office of Generic Drugs (CDER/OGD) has used application reviewers on a
limited basis for preapproval, biennial, or for-cause inspections. Several years
ago, OGD developed a pilot program to create opportunities for reviewers and
firms to interact, discuss, and potentially resolve application issues outside
the conventional (and lengthy) submission-review-response-submission cycle
timeline. The pilot program was discontinued several years ago principally due
to a lack of adequate resources.
The role and responsibility level of the CDER reviewer during an inspection
varied depending on several factors: inspection timing, lead investigator
preferences for assignments, pre-inspection planning, investigator-reviewer
synergy, and type of inspection.
CDER’s Office of Compliance, Division of Manufacturing and Product Quality
has always maintained a cadre of investigators who participate regularly in pre-
and post-approval inspections, particularly foreign inspections and as needed in
domestic inspections, as well.
● Center for Veterinary Medicine (CVM)
CVM does not have a formal program by which reviewers participate in
inspections. When funding is available, the chemistry, manufacturing and
controls (CMC) reviewers within the Division of Manufacturing Technologies have
participated in preapproval and for-cause inspections. Reviewers have assisted
and/or shared their expertise with investigators, including participating in
exit interviews and/or write-ups of FDA Form 483 and the Establishment
Inspection Report (EIR).
B. Observations
Based on the observations from the applicable Centers and ORA, the benefits
of using of Specialists on inspections (all types) include:
- Facilitating the application review process and shortening the review
cycle.
- Facilitating the decision-making process for applications and
contributing to the industry’s understanding of what changes are
essential to correct deficiencies prior to obtaining approval.
- Shortening the time needed to resolve CMC issues.
- Improving communication, as well as enhanced harmonization of scientific
issues between reviewers and investigators by having a Specialist
available to review and evaluate product and process-related changes.
- Improving understanding of the manufacturing processes and equipment has
facilitated reviewers’ assessments.
- Enhancing knowledge through sharing with the field investigator
information gleaned from the application review of the drug substance and
drug product (e.g., drug development, ID of critical manufacturing steps,
stability issues, physicochemical properties of the drug substance).
- Providing the investigators with an increased understanding of the
application assessment process and the reviewers an increased
understanding of the GMP requirements and the compliance process.
- Applicants have indicated that they found the joint inspection process
beneficial.
The working group noted the following hurdles and complicating factors:
- Scheduling problems:
- Time constraints make it difficult for a Specialist to travel for more
than 2 or 3 days, potentially disrupting the longer inspection process.
- Coordinating review completion dates and PDUFA deadlines with ORA’s
inspection schedule has been problematic.
- There may be conflicts between review milestones and necessary
rescheduling of inspections.
- Roles and responsibilities of the Specialist during the preapproval
inspections for CDER have not been well defined.
- Training is needed for the Specialist on the inspection process
and procedures.
- Significant funding and resources are needed to use Specialists.
- The Office of Regulatory Affairs (ORA) needs access to a directory that
identifies the Center review divisions, including products and personnel.
- ORA Investigators need instruction on when and how to use this
scientific resource.
III. THE NEED FOR A SPECIALIST
Rapid advancements in science and technology present many opportunities and
challenges for FDA’s review and inspection teams. FDA needs to acquire and
assimilate the latest scientific knowledge on a timely basis to (1) ensure
efficient and effective regulatory decisions and (2) facilitate timely
introduction of novel, often complex, drug products and manufacturing and
analytical technologies. Should FDA policies and systems lag behind in science
and technology, or be perceived to lag behind, there may be a negative impact
not only on the timely approval of safe and effective products, but also on the
introduction of modern manufacturing technologies. For example, discussions at
the FDA Science Board (11/01 and 4/02) and Advisory Committee meetings (6/02 and
10/02) on the Agency’s Process Analytical Technology (PAT) initiative revealed
that industry may have adopted a "don’t use" or "don’t
tell" approach to new manufacturing technologies. This approach may be due
to perceptions of delayed approval or concerns about misinterpretation of data
generated using new technologies. Thus it is essential that FDA enhance the
complementary scientific and technological knowledge of its headquarters and
field staff to positively impact the supply of safe and effective drug products.
Using Specialists on inspection teams is clearly one way to obtain the
benefits of the FDA’s scientific and technological expertise. Agency staffs in
the Centers and ORA have complementary responsibilities and different scientific
and regulatory backgrounds. All of FDA’s scientific research, review, and
investigation talents have to work together to realize the Agency’s public
health objectives and goals. Experience gained from current programs indicates
that collaboration improves regulatory effectiveness and consistency. Center
review staff, through their assessment of information in applications, establish
standards for product and process quality that relate to safety and efficacy of
a product. Bringing this knowledge to PAI inspections affords an excellent
opportunity to ensure a science and risk-based evaluation of manufacturing
facilities and also improves the efficiency of the review and inspection
processes. Additionally, this knowledge is essential to ensure scientific
risk-based regulatory decisions on other inspections and to minimize technical
disputes. A cohesive Specialist program will strengthen the desired consistent
approach to regulatory decisions.
By participating in inspections, Specialists may contribute the following
additional benefits:
- Create a more scientific, risk-based approach to the inspection process
- Provide a technical balance between product and process related issues
- Facilitate the inspection process — more scientific input to discuss
and resolve issues and prevent future issues
- Ensure the process has a state-of-the-art, "hands on"
approach; each component learns from direct interaction with the other
- Reduce the use of the prior approval supplement process to manage
postapproval changes (e.g., through use of Comparability Protocols)
- Improve communications within the Agency, and between the Agency and
industry
- Ensure timely interaction between team members and industry on science
issues;
- Reduce uncertainty and facilitate the introduction of new technologies
into manufacturing processes
- Provide an opportunity for cross training and team building
Issues and Concerns
A review of the historical/current observations on the use of Specialists
revealed the following issues and concerns relative to expanding the concept:
- Logistical impact on current work assignments — impact on PDUFA
timelines
- When to use Specialists (types of inspection and determining the
necessity for), whether to use on-site or otherwise
- Interaction of Specialist and investigators — clearly defining roles
to make it work, eliminating perceived barriers
- Training issues — enhanced GMP and inspectional process training
needed to make the Specialist even more useful to the process
- Coordination of schedules — pre-inspection contact between Specialist
and other inspection team members to discuss inspection issues,
plan/strategy development
- Increase in the overall inspection time
- Complicated logistics of inspection report preparation
- Outline of specific goals before the trip
- If a PAI, careful coordination of the inspection scheduling and
completion of the review of the pending application in relation to review
cycle to ensure maximum value
- Need for additional resources (travel, training, time away from review,
etc.)
Of these concerns, the resource issues and the impact on current work
assignments (PDUFA timelines) present formidable barriers to overcome. Current
experience suggests that, on average, the use of a Specialist could potentially
entail between 2 and 3 weeks of Specialist time per inspection (for
pre-inspection contact/planning, actual inspections, participation in the EIR/483
write-up, and follow-up assessments). This estimate, which does not include the
travel time for each inspection, is based on a traditional approach to using
Specialists on inspections.
A more effective and efficient mechanism can be developed, and the working
group plans to do so in Phase II of the project. An essential aspect of the
envisioned approach is communicating and sharing information and knowledge to
ensure that regulatory decisions are based on the most up-to-date scientific
knowledge and risk management principles. Use of modern communication,
information, and knowledge management tools by the team can make it possible to
realize these goals without the physical presence of a Specialist during
inspections.
IV. DEFINITION OF A SPECIALIST
The definition and scope of a Specialist is currently being discussed
within the working group. Traditionally, this term has been used for a
regulatory CMC review scientist. However, the term does not bring into
consideration other available scientific expertise, such as Center research
scientists, non-review experts (e.g., compliance experts), or other technical
expertise within the Centers and ORA (e.g., National Drug Experts). A broader
definition of a Specialist is necessary to encompass all available scientific
expertise within FDA and to ensure that this program is not merely adding more
work for the staff. For example:
- CDER's research program has several non-reviewer scientists working on
lab-based research projects evaluating application of new technologies.
These individuals may be ideal to serve as a Specialist for certain
situations that involve the assessment of new technologies.
- CBER’s regulatory research program includes specialists in promising
new areas (e.g., cellular and gene therapy) who possess expertise unique
within FDA.
Identifying areas in pharmaceutical manufacturing and technologies where FDA
is seeking enhanced expertise, coupled with clearly defining the knowledge and
skills needed, will not only provide professional growth opportunities for
current staff, but also help FDA to effectively recruit such experts. In this
regard, the current approaches for hiring, training and certification,
evaluation, and peer-review practices in the various organizations may need to
be examined and systematized as the Agency moves forward with this initiative.
Why Use a Specialist?
Using Specialists on inspection teams can help further the stated objectives
of this initiative by:
- Ensuring that submission reviews and cGMP inspections are coordinated
and synergistic
- Strengthening consistency and quality in regulatory decisions
- Incorporating the most up-to-date concepts of risk management and
scientific advances
- Using Agency resources more effectively and improving communications
within the Agency and between the Agency and industry
- Encouraging innovation and continuous improvement
Even the traditional use of Specialists in inspections can help realize these
objectives. However, experience suggests that to accomplish these goals, it will
be necessary to clearly define the Specialist program as part of the Agency’s
regulatory policies and procedures and program evaluation systems. To this end,
the working group will coordinate closely with the other working groups in the
cGMP initiative (Pharmaceutical Inspectorate, Dispute Resolution, Scientific
Review of Warning Letters by Center, 483 Communications, Evaluation of Team
Biologics, Changes Without Prior Review, Risk-based Work Planning, and
Manufacturing Science). In addition, key scientific review and inspection
questions, issues, and information requirements need to be delineated and
synchronized to ensure efficient and effective focus on the public health
objectives of the FDA.
Many of the activities under this initiative are proposed to encourage
innovation and continuous improvement. The Process Analytical Technology
initiative developed by CDER, ORA, and CVM was designed to accomplish these
goals. The PAT initiative — review-inspection team, training and certification
program, policy development, and supporting research program — can serve as a
model for this initiative.
V. RECOMMENDATIONS
The working group has reviewed the Agency’s experience with using
Specialists on inspection teams. This Phase I assessment clearly indicates (1)
that using Specialists has added value to the regulatory processes and (2) that
a more formalized program will have significant positive impact on the cGMPs
for the 21st Century initiative. This concept should be developed
and implemented to ensure a consistent risk-based approach for all drug Centers
through the following Phase II activities:
- Coordinate the development of the Specialist program with actions planned
by other Initiative Working Groups.
- Delineate and synchronize the key scientific review and inspection
questions, issues, and information necessary to achieve the stated goals
through better use of current resources:
- Solicit grass roots input into the program from across the Agency,
including reviewers, Center Compliance offices, investigators, and their
supervisory personnel.
- Use the planned workshop to seek industry perspective(s).
- Define Specialist broadly and based on areas of expertise necessary;
develop a database of resident expertise.
- Outline when and how Specialists can be used, defining roles and
responsibilities of the team members.
- Perform resource assessment for the proposed program (additional staffing,
training, travel, communication/information technology needs, etc.).
- Seek FDA commitment and resource allocation for implementation of this
program.
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Date created: February 27, 2003 |
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