Drugs

Questions and Answers

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

 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.

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 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).

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 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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Page Last Updated: 12/17/2014
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