[Federal Register: January 5, 2007 (Volume 72, Number 3)]
[Page 574-576]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]



Food and Drug Administration

[Docket No. 2006N-0525]

Supplements and Other Changes to an Approved Application; Public 

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public meeting.


SUMMARY: The Food and Drug Administration (FDA) is announcing a public 
meeting to solicit comments on issues that FDA should consider when 
developing revisions to its regulations regarding chemistry, 
manufacturing, and controls (CMC) supplements and other changes to 
approved marketing applications for human drugs. FDA is evaluating how 
it could revise its regulations to allow for consideration of risk-
based approaches based on manufacturing process understanding, 
including prior knowledge of similar products, and overall quality 
systems to provide an enhanced risk-based approach to the CMC 
regulatory process, which would reduce the number of supplements. We 
will consider the input from the public meeting and comments on the 
issues presented in this document as we consider whether to revise our 

DATES: The public meeting will be held on February 7, 2007, from 8:30 
a.m. to 3:30 p.m. Anyone who wishes to speak at the meeting must 
register and submit a summary of the presentation by January 24, 2007, 
and submit an electronic copy of the presentation by January 31, 2007. 
See section III of the SUPPLEMENTARY INFORMATION section of this 
document for details on how to register. Submit written or electronic 
comments by March 7, 2007.

ADDRESSES: The public meeting will be held at the Food and Drug 
Administration, Center for Drug Evaluation and Research Conference 
Room, 7519 Standish Pl., third floor, rm. A, Rockville, MD 20855. There 
is parking near the building. Photo identification is required to clear 
building security.
    Submit written comments to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments

FOR FURTHER INFORMATION CONTACT: David J. Cummings, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 21, rm. 3525, Rockville, MD 20993-0002, 301-796-
2400, e-mail: David.Cummings@fda.hhs.gov.


I. Background

    In the Federal Register of June 28, 1999 (64 FR 34608), FDA 
published a proposed rule to implement section 116 of the Food and Drug 
Administration Modernization Act (FDAMA)\1\ by amending certain 
regulations including Sec.  314.70 (21 CFR 314.70) regarding 
supplements and other changes to approved human new drug and 
abbreviated new drug marketing applications. In the Federal Register of 
April 8, 2004 (69 FR 18728), FDA published the final rule (final rule) 
implementing these changes. Section 314.70, as amended, requires 
manufacturers to assess the effects of manufacturing changes on the 
identity, strength, quality, purity, and potency of a drug as those 
factors relate to the safety or effectiveness of the product, and 
categorizes all changes beyond the established variations in an 
approved NDA or ANDA into one of three groups--major, moderate, or 
minor. Major changes require an applicant to submit and receive FDA 
approval of a supplement before distribution of the product made with 
the manufacturing change. Moderate changes require an applicant to 
submit a supplement at least 30 days before distribution of the product 
or, in some cases, submit a supplement at the time of distribution. 
Minor changes require an applicant to notify FDA of the changes in an 
annual report.

    \1\ Section 116 of FDAMA (Public Law 105-115) amended the 
Federal Food, Drug, and Cosmetic Act (FDCA) by adding section 506A 
(21 U.S.C. 356a), which describes requirements and procedures for 
making and reporting manufacturing changes to certain approved 
marketing applications, including new drug applications (NDAs) and 
abbreviated new drug applications (ANDAs).

    In August 2002, FDA introduced the Pharmaceutical Current Good 
Manufacturing Practices (CGMPs) for the 21st Century Initiative (CGMP 
Initiative, available on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/gmp/index.htm
) to enhance and modernize the regulation of pharmaceutical 

manufacturing and product quality. In September 2004 (after publication 
of the final rule), FDA published a final report on ``Pharmaceutical 
CGMPs for the 21st Century--A Risk-Based Approach'' (http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm
). As explained in 

the report, FDA regulates pharmaceutical manufacturing to ensure that 
the drug supply in the United States is of consistently high quality. 
Because of critical public health implications of drug manufacturing, 
FDA traditionally has exercised extensive control over virtually every 
aspect of the manufacturing process. This regulatory approach has 
contributed to pharmaceutical companies being reluctant to change their 
manufacturing processes and equipment. In recent years, significant 
advances in pharmaceutical manufacturing science, modern quality 
management systems, and risk management approaches have taken place. 
This has yielded new tools that

[[Page 575]]

can be used to help ensure manufacturing quality. The 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 paradigm that will 
encourage pharmaceutical manufacturers to use these new tools to 
facilitate their decision making and implementation of manufacturing 
processes to reliably produce pharmaceuticals of high quality. Under 
the new paradigm, as under the current scheme, pharmaceutical 
manufacturers are ultimately responsible for ensuring the quality of 
their products subject to FDA regulatory oversight.
    The current Sec.  314.70 categorizes postapproval CMC changes and 
their associated reporting requirements without consideration of the 
applicant's risk management activities or internal quality systems and 
practices; therefore, Sec.  314.70 reflects a rules-based, or 
prescriptive, approach to regulating postapproval manufacturing 
changes. The current Sec.  314.70 may create regulatory burdens and 
costs that discourage beneficial manufacturing changes and may not 
support a desirable level of innovation, modernization, and flexibility 
for the industry as described in the CGMP Initiative.
    Consistent with the agency's risk-based approach to regulating 
pharmaceutical manufacturing described in the CGMP Initiative, FDA is 
considering possible revisions to Sec.  314.70. In particular, FDA is 
evaluating how it could revise Sec.  314.70 to allow for more 
manufacturing changes to be made without prior FDA approval using a 
firm's internal change control system. FDA also is evaluating how it 
could revise Sec.  314.70 to allow for consideration of risk-based 
approaches based on manufacturing process understanding, including 
prior knowledge of similar products, and overall quality systems to 
provide an enhanced risk-based approach to the CMC regulatory process. 
To accomplish this objective, FDA is considering redefining what FDA 
considers to be a major manufacturing change, reducing the reporting 
burden for certain changes, and creating a new reporting category of 
manufacturing changes that do not require notification to FDA. FDA 
anticipates that these revisions would reduce the number of 
postapproval supplements that are required to be submitted. We 
emphasize that under a new regulatory scheme, although the reporting 
burdens for certain manufacturing changes would be reduced, 
manufacturers will continue to be responsible for ensuring product 
quality. FDA also is considering an approach that would retain aspects 
of the current regulatory scheme to accommodate those manufacturers who 
choose to continue operating within the current regulatory framework. 
FDA is announcing this public meeting to solicit comments on issues 
that should be considered if FDA decides to propose revisions to Sec.  

II. Questions for Discussion and Comment

    FDA has prepared the following questions to help focus the comments 
that will be presented at the public meeting or otherwise communicated 
to the agency. Those who comment are invited to address any or all of 
these questions, or raise other issues.
    1. Is it valuable for the agency to move toward a more risk-based 
and quality systems oriented strategy for regulating postapproval CMC 
changes outside of the formal application review process? What are the 
advantages and/or disadvantages?
    2. Would revising Sec.  314.70 as described in this notice provide 
the same level of protection to the public as the current regulatory 
scheme with respect to ensuring the safety and efficacy of human drugs? 
What inspectional approaches might the agency consider to evaluate 
manufacturing changes while ensuring public safety?
    3. Would revising Sec.  314.70 as described in this notice change 
the regulatory burden on the pharmaceutical industry? If so, how would 
the burden change?
    4. Would reducing the prescriptiveness of Sec.  314.70 provide 
manufacturers with greater regulatory flexibility? Would it encourage 
manufacturers to adopt CMC-related risk management strategies? Would 
there be disadvantages?

III. Registration, Agenda, and Transcript

    Seating is limited and will be available on a first-come, first-
served basis. If you need special accommodations because of a 
disability, please inform David J. Cummings.
    Registration for Speaking Attendees: If you wish to make an oral 
presentation at the meeting, you must register and submit a summary of 
your presentation to David J. Cummings by January 24, 2007, via e-mail 
to: David.Cummings@fda.hhs.gov. When registering, you must provide the 
following information: (1) The specific topic or issue to be addressed; 
(2) your name, title, company or organization, address, phone number, 
and e-mail address; and (3) the approximate time requested to speak. 
FDA encourages persons and groups having similar interests to 
consolidate their information for presentation through a single 
representative. After reviewing the requests to present, we will notify 
each participant by e-mail or telephone of the amount of time allotted 
and the approximate time the participant's presentation is scheduled to 
begin. Presenters must send electronic copies of their presentations in 
Microsoft PowerPoint, Microsoft Word, or Adobe Portable Document Format 
(PDF) to David J. Cummings by noon on January 31, 2007.
    Agenda and Transcript: The agenda for the public meeting will be 
available February 2, 2006, on FDA's Center for Drug Evaluation and 
Research (CDER) Web site at: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/meeting/OPS_20070207.htm.
 After the meeting, the agenda, presentations, and 

transcript will be placed on file in the Division of Dockets Management 
(see ADDRESSES) under the docket number found in the heading of this 
document and on CDER's Web site identified previously.
    You may examine the meeting transcript Monday through Friday 
between 9 a.m. and 4 p.m. in the Division of Dockets Management Public 
Reading Room (see ADDRESSES) and on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm.
 You may also request a copy of the 

transcript from the Freedom of Information Office (HFI-35), Food and 
Drug Administration, 5600 Fishers Lane, rm. 6-30, Rockville, MD 20857, 
approximately 20 working days after the meeting at a cost of 10 cents 
per page or on compact disc at a cost of $14.25 each.

IV. Comments

    Regardless of attendance at the meeting, interested persons may 
submit to the Division of Dockets Management (see ADDRESSES) written or 
electronic comments related to the questions and the focus of this 
public meeting by March 7, 2007. All relevant data and information 
should be submitted with the written comments. Submit a single copy of 
electronic comments or two paper copies of any mailed comments, except 
that individuals may submit one copy. Comments are to be identified 
with the docket number found in brackets in the heading of this 
document. The received comments are available for public examination in 
the Division of Dockets Management

[[Page 576]]

between 9 a.m. and 4 p.m., Monday through Friday.

    Dated: December 26, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-22588 Filed 1-4-07; 8:45 am]