Pharmaceutical
cGMPs for the 21st
Century: A Risk-Based Approach
Questions and Answers
General
1. How does this initiative affect the Systems-Based Inspections
Pilot Program? Is the systems-based approach expressed in the compliance
program reinforced by the systems-based emphasis in the GMP initiative?
2. What advice do you have to new companies regarding good
manufacturing practices?
Encouraging innovation within the existing framework
3. Is the work of the Changes Without Prior Review Working Group
replacing other initiatives on postapproval changes including (1)
updating of the CDER and CVM regulations (21 CFR 314.70 and 514.8) as
required by Section 116 of the FDA Modernization Act of 1997 (FDAMA) and
(2) CDER's Scale-up and Postapproval Change (SUPAC) guidance documents?
4. How can the public be assured that changes in the manufacturing
process won't adversely affect the quality of the drugs they take if FDA
hasn't approved them before they are implemented?
Center review of drug cGMP warning letters
5. What is Direct Reference Authority? What
does the "rescission" of "direct reference"
authority for GMP warning letters mean?
6. When does the rescission of Direct Reference Authority begin?
7. Why are all drug cGMP Warning Letters now going to be reviewed by
the Centers?
8. Will the Centers/FDA be doing any kind of evaluation of the
inspectional information supporting proposed Warning Letters?
9. What are some of the inconsistencies that FDA is trying to
eliminate and why?
Dispute Resolution Process
10. What are the specific details for the dispute resolution process
being contemplated, such as the timelines and mechanics for submitting
and resolving disputes?
11. How will the dispute resolution panel operate and what kinds of
disputes would be considered by the panel?
12. How would improving the transparency help the regulatory process
for resolving disputes?
Effective Communications (FDA Form 483)
13. What reaction does FDA anticipate in response to the added
language clarifying the status of observations on the FDA Form 483?
14. Is this effort in response to industry complaints about how the
press and public perceive the FDA Form 483 they obtain through the FOIA
process?
Risk Management Workplanning
15. What are the factors for high risk?
16. Why doesn't FDA inspect all pharmaceutical
manufacturers at least every two years?
17. What about bringing risk-based approaches to other areas of the
cGMP and pre-approval programs?
18. Does this mean that FDA will stop inspecting "low risk"
products and manufacturing?
19. Will FDA suspend enforcement of all cGMP requirements until it
completes its effort to bring risk management concepts to cGMP
requirements?
20. What does the reorganization of CDER's Office of Compliance have
to do with risk management?
Product Specialists
21. Will the increased use of 'Specialists' on pre-approval
inspections affect PDUFA deadlines/timelines for application review
processes?
22. How will it be determined when to utilize a
'Specialist' on
inspections (pre-approval, biennial, for cause)?
23. Does this mean that current FDA inspectors have no specialized knowledge of what they are inspecting?
Enhancing Expertise
24. Does this support external criticism
that the review burden
doesn't allow for FDA employees to keep up-to-date with science and
technology involved in the products that they're reviewing?
International
25. How is this drug product quality initiative
being coordinated with our international colleagues and major trading
partners so that public health advances have global benefits?
21 CFR Part 11
26. Why did FDA withdraw the draft guidance titled "Guidance for
industry, 21 CFR Part 11 Electronic Records; Electronic Signatures,
Electronic Copies of Electronic Records"?
27. Why is a new draft guidance being published?
28. Are firms still required to have secure and reliable records?
29. What does the agency mean when saying "...it intends to
interpret the scope of Part 11 narrowly."?
30. The agency is announcing in the draft guidance on Part 11 the use of
"enforcement discretion." How will that be implemented and
clarified in the future?
General
1. How does this initiative affect the Systems-Based Inspections
Pilot Program? Is the systems-based approach expressed in the compliance
program reinforced by the systems-based emphasis in the GMP initiative?
Yes, and the cGMP initiative is even broader, reaching into the
chemistry and manufacturing controls review program as well. The
program, which began as a pilot, is now final and was implemented
nationwide as of February 1, 2002.
2. What advice do you have to new companies regarding good
manufacturing practices?
To manufacture drugs, a company must register with FDA and comply
with current good manufacturing practice regulations. We recommend that
they consult with experts in pharmaceutical manufacturing regarding the
latest innovations in complying with these requirements.
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Encouraging innovation within the existing framework
3. Is the work of the Changes Without Prior Review Working Group
replacing other initiatives on postapproval changes including 1)
updating of the CDER and CVM regulations (21 CFR 314.70 and 514.8) as
required by Section 116 of the FDA Modernization Act of 1997 (FDAMA) and
2) CDER's Scale-up and Postapproval Change (SUPAC) guidance documents?
No. The Working Group's efforts are complementary to these ongoing
initiatives and are just one part of FDA's overall strategy of examining
the postapproval change process.
4. How can the public be assured that changes in the manufacturing
process won't adversely affect the quality of the drugs they take if FDA
hasn't approved them before they are implemented?
Under the existing framework, FDA will review a protocol, or detailed
plan, for the proposed change. Any deficiencies in this protocol must be
addressed by the manufacturer prior to its approval. Once approved, the
manufacturer may execute the agreed upon protocol and, if successful,
may submit the data using a reduced reporting category. Using this
mechanism, FDA can ensure the quality of the product while enabling
distribution prior to supplement approval.
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Center review of drug cGMP warning letters
5. What is Direct Reference Authority? What does the "rescission" of "direct reference" authority for GMP warning letters mean?
FDA district offices have had the authority to issue Warning Letters
to firms after inspections of manufacturers of human and animal drugs
when the inspectional observations demonstrate that the firm does not
meet the requirements of the regulations concerning Current Good
Manufacturing Practices (21 CFR Parts 210 and 211). They also have the
authority for Type A medicated articles (21 CFR Part 226), and Medicated
Feeds (21 CFR Part 225).
6. When does the rescission of Direct Reference Authority begin?
FDA District Offices are being advised that Direct Reference
Authority for issuing Warning Letters will be rescinded on February 28,
2003. Beginning in March 2003, the Centers will begin reviewing warning
letters proposed by the District Offices.
7. Why are all drug cGMP Warning Letters now going to be reviewed by
the Centers?
This will help identify possible program inconsistencies and resolve
them before warning letters are issued.
8. Will the Centers/FDA be doing any kind of evaluation of the
inspectional information supporting proposed Warning Letters?
Yes, regular analysis of these data will aid the Centers in
identifying trends used to further develop a risk-based strategy towards
cGMP enforcement practices. FDA can also use this knowledge to enhance
policy, provide guidance, and establish training for the FDA field staff
and regulated industry.
9. What are some of the inconsistencies that FDA is trying to
eliminate and why?
As innovative manufacturing and control technologies are adopted in
the pharmaceutical industry, it is important that FDA regulate them in a
consistent way. Some of these technologies will be first encountered in
FDA's inspection program and Center review of Warning letters will help
assure that FDA responds to any deficiencies in a consistent manner.
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Dispute Resolution Process
10. What are the specific details for the dispute resolution process
being contemplated, such as the timelines and mechanics for submitting
and resolving disputes?
Specific details are outlined in our progress
report FDA welcomes comments and
suggestions from stakeholders, including suggestions on how to best
implement the concepts described in the progress report. Within 90 days,
the agency intends to seek further public comment on a draft guidance
document that identifies further details on the procedures being
considered.
11. How will the dispute resolution panel operate and what kinds of
disputes would be considered by the panel?
As described in the progress report, the working group is considering
a panel that would consist of representatives from each of the program
Centers, the Office of the Chief Counsel, the Office of Regulatory
Affairs, and the Office of the Commissioner. As needed, external
experts, serving as special government employees, could be included.
12. How would improving the transparency help the regulatory process
for resolving disputes?
A more transparent process should be more easily understood and used.
Such a process should make it easier to raise scientific and technical
issues early on to avoid misunderstandings and reduce inconsistent
agency action. In addition, sharing the outcome of technical and
scientific issues/disputes should provide greater clarity about
regulatory requirements and facilitate the development and revision of
guidance documents. Further, dissemination of the results, both
internally and externally, should preclude future disputes on the same
and related subjects.
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Effective Communications (FDA Form 483)
13. What reaction does FDA anticipate in response to the added
language clarifying the status of observations on the FDA Form 483?
We anticipate a positive reaction because it clarifies what the
document represents. For the firm undergoing inspection, it illustrates
that the Agency has a regulatory process and the FDA-483 is only one
aspect of that process. Further, it decreases the likelihood that
inspectional observations will be misused or misunderstood.
14. Is this effort in response to industry complaints about how the
press and public perceive the FDA Form 483 they obtain through the FOIA
process?
The external and internal interviews we conducted demonstrated a
general lack of understanding as to what the FDA Form 483 represents. It
is only one piece of the overall inspection process that the Agency
employs to make its decisions on the compliance status of the inspected
firm.
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Risk Management Workplanning
15. What are the factors for high risk?
For the current fiscal year (FY 2003), FDA identified three factors
to help identify pharmaceutical manufacturing establishments where FDA
oversight would likely have the greatest impact: (1) sterile drug
manufacturing, (2) Rx drug manufacturing, and (3) newly registered
facilities that have not previously been inspected. For the following
fiscal year, FDA intends to develop a more detailed risk model to help
predict where FDA inspections are most likely to achieve the greatest
public health impact. Among the factors FDA is reviewing include those
pertaining to manufacturing complexity, product exposure (e.g., volume),
and compliance history.
16. Why doesn't FDA inspect all pharmaceutical manufacturers at least
every two years?
For many years, FDA has been unable to consistently achieve biennial
inspections of all drug manufacturers because of the combination of the
increasing number of manufacturing-related establishments and declining
resources available for such inspections. A risk-based approach seeks to
ensure that high risk facilities are inspected as often as needed to
protect the public health and to apportion resources commensurate with
the risks associated with non-compliance.
17. What about bringing risk-based approaches to other areas of the
cGMP and pre-approval programs?
Although our first step was to initiate a risk-based approach for FDA
workplanning for the cGMP inspectional program, this initiative, Pharmaceutical
cGMPs for the 21st Century, is intended to bring risk
assessment and risk management principles to all aspects of the
regulation of drug quality. Resource limitations prevent uniformly
intensive coverage of all aspects of pharmaceutical products and
production. To provide the most effective public health protection, FDA
must match its level of effort against the magnitude of the risk. As FDA
and stakeholders enhance their risk assessment capacities and
manufacturing process knowledge, both will be better equipped to oversee
manufacturing quality through risk management approaches. Risk
management will play a central role in enhancing the scientific basis of
FDA's regulatory policies and standards.
18. Does this mean that FDA will stop inspecting "low risk"
products and manufacturing?
No. FDA intends to reserve adequate resources to ensure appropriate
oversight of products that are not currently known to be high risk to ensure
that these products do not deteriorate in quality.
19. Will FDA suspend enforcement of all cGMP requirements until it
completes its effort to bring risk management concepts to cGMP
requirements?
No. FDA will continue strong enforcement of current regulatory
requirements, even as it is examining and revising its approach to the
regulation of pharmaceutical quality.
20. What does the reorganization of CDER's Office of Compliance have
to do with risk management?
CDER's Office of Compliance recently created a new division of
Compliance Risk Management and Surveillance to enhance the Office's
capacity to implement risk management approaches. The responsibilities
for this division will include analysis of the data documenting
manufacturing and drug quality problems to identify trends and patterns
to better focus scarce inspectional resources on areas where FDA
oversight and intervention are most likely to have the greatest public
health impact.
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Product Specialists
21. Will the increased use of 'Specialists' on pre-approval
inspections affect PDUFA deadlines/timelines for application review
processes?
We are very sensitive to this issue and believe specialists can be
incorporated on pre-approval inspections without jeopardizing
achievement of PDUFA performance goals. Additional scientific input into
the inspection process will assist in resolving many potential issues up
front, with the potential to help minimize any delays in the review
process. In the biologic area, product specialists play an integral part
in pre-approval and biennial inspections.
22. How will it be determined when to utilize a
'Specialist' on
inspections (pre-approval, biennial, for cause)?
We are developing appropriate criteria to assist in the decision
making process. It is envisioned that a needs assessment will be
developed that considers the purpose and scope of the inspection. The
appropriate expertise, as necessary, will be incorporated into the team
to achieve the goals of the inspection. The focus of this effort is to
synergistically bring more scientific and technical expertise to the
process and will complement efforts within other areas of the overall
cGMP initiative.
23. Does this mean that current FDA inspectors have no specialized knowledge of what they are inspecting?
Not at all. FDA's review and inspection staffs have different but
complementary backgrounds and responsibilities. Our investigators
receive extensive classroom and on-the-job training before they
independently inspect facilities. However, some products or
manufacturing and control technologies can present unique technical
issues. FDA believes that making product or technical specialists
available for inspections of such products and processes will enhance
the agency's inspection program.
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Enhancing Expertise
24. Does this support external criticism
that the review burden
doesn't allow for FDA employees to keep up-to-date with science and
technology involved in the products that they're reviewing?
Continuing education is essential for FDA staff to keep up-to-date
with science and technology and this is currently accomplished to
various degrees. Under this initiative, FDA is proposing to bring a
broader focus on this issue and will develop programs that will focus on
improving FDA's scientific and engineering understanding of
pharmaceutical manufacturing.
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International
25. How is this drug product quality initiative being coordinated with
our international colleagues and major trading partners so that public
health advances have global benefits?
FDA is working with its ICH partners: the European Commission (EC, EU),
European Federation of Pharmaceutical Industries and Associations (EFPIA),
Ministry of Health, Labor and Welfare (MHLW, Japan), Japan
Pharmaceutical Industry Association (JPMA), Pharmaceutical Research and
Manufacturers of America (PhRMA), WHO, Health Canada and the European
Free Trade Area to ensure coordinated international approach to the Drug
Product Quality initiative. In September 2002, Dr. Janet Woodcock
presented the broad outline of the initiative to the ICH Steering
Committee, and at the time interest was expressed in undertaking topics
that would promote or encourage technical innovation pertaining to
science and public health via the ICH process. The initiative has been
further discussed in greater details in December 2002 and it continues
to have broad based support from the ICH partners. Additional
information will be provided on the current situation both to industry
and regulatory authorities. This information will be exchanged before
the next ICH meeting in Brussels, Belgium. It is anticipated that a core
group of product quality and GMP experts from the 3 ICH regions will
meet in Brussels, focus their discussion on the information exchanged
prior to the meeting and propose specific topics for ICH to consider.
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21 CFR Part 11
26. Why did FDA withdraw the draft guidance titled "Guidance for
industry, 21 CFR Part 11 Electronic Records; Electronic Signatures,
Electronic Copies of Electronic Records"?
We wanted to avoid loss of time spent by industry in an effort to
review and comment on the draft guidance when that draft guidance may no
longer be representative of FDA's approach under the new CGMP
initiative.
27. Why is a new draft guidance being published?
FDA is embarking on a re-examination of part 11 as it applies to all
FDA regulated products. We may revise provisions of part 11 as a result
of that reexamination. The draft guidance explains that while this
re-examination is under way, we intend to exercise enforcement
discretion with respect to certain part 11 requirements.
28. Are firms still required to have secure and reliable records?
We suggest that the decision on how to maintain records be based on
predicate rule requirements and that you base your decision on a
justified and documented risk assessment and a determination of the
value of the records over time.
29. What does the agency mean when saying "...it intends to
interpret the scope of Part 11 narrowly."?
Under the narrow interpretation of the scope of Part 11, with respect
to records required to be maintained or submitted, when persons choose
to use records in electronic format in place of paper format, Part 11
would apply. On the other hand, when persons use computers to generate
paper printouts of electronic records, those paper records meet all the
requirements of the applicable predicate rules, and persons rely on the
paper records to perform their regulated activities, the merely
incidental use of computers in those instances would not trigger
Part 11. In such instances, FDA would generally not consider persons to
be "using electronic records in lieu of paper records" under
§§ 11.2(a) and 11.2(b).
30. The agency is announcing in the draft guidance on Part 11 the use of
"enforcement discretion." How will that be implemented and
clarified in the future?
After receipt and assimilation of the comments received, the agency
will publish a final guidance implementing the enforcement discretion
for those areas covered. The Agency will then embark on a re-examination
of part 11 as it applies to all FDA regulated products. We may revise
the provisions of part 11 as a result of that reexamination.
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Date created: February 20, 2003 |