Pharmaceutical cGMPs for the 21^st Century: A Risk-Based Approach

Progress Report of the Working Group on

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 21^st 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.

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

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.

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.

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).

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.

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

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.

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.

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 21^st 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:

1. Coordinate the development of the Specialist program with actions planned by other Initiative Working Groups.
   
2. 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).
     

3. Define Specialist broadly and based on areas of expertise necessary; develop a database of resident expertise.
   
4. Outline when and how Specialists can be used, defining roles and responsibilities of the team members.
   
5. Perform resource assessment for the proposed program (additional staffing, training, travel, communication/information technology needs, etc.).
   
6. Seek FDA commitment and resource allocation for implementation of this program.

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Date created:  February 27, 2003

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