[Federal Register: July 2, 2008 (Volume 73, Number 128)]
[Notices]
[Page 37972-37974]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr02jy08-89]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2008-N-0355]
Submission of Quality Information for Biotechnology Products in
the Office of Biotechnology Products; Notice of Pilot Program
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is seeking volunteers
from pharmaceutical companies to participate in a pilot
[[Page 37973]]
program involving the submission of quality (chemistry, manufacturing,
and controls) information for biotechnology products in an Expanded
Change Protocol, consistent with the principles of quality by design
and risk management in pharmaceutical manufacturing. The purpose of the
pilot program is to gain more information on and facilitate agency
review of quality-by-design, risk-based approaches for manufacturing
biotechnology products. This pilot will focus on products reviewed by
FDA's Office of Biotechnology Products (OBP), in the Office of
Pharmaceutical Science (OPS), Center for Drug Evaluation and Research
(CDER). This pilot program will assist FDA in developing guidance for
industry on quality by design and risk management in pharmaceutical
manufacturing. The pilot is open to original submissions of and
supplements to biologic license applications (BLA) or new drug
applications (NDA) reviewed by OBP.
DATES: Submit written and electronic requests to participate in the
pilot program by September 30, 2009. Comments on this pilot program can
be submitted until December 31, 2008.
ADDRESSES: Submit written requests to participate in and to comment on
the pilot program to the Division of Dockets Management (HFA-305), Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852. Submit electronic requests to participate in the pilot to http:/
/www.regulations.gov.
FOR FURTHER INFORMATION CONTACT: Marilyn Welschenbach, Center for Drug
Evaluation and Research, Food and Drug Administration,Bldg. 21, rm.
1514, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002,301-796-
1773, e-mail: Marilyn.Welschenbach@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
OPS, in FDA's CDER, is establishing a quality-by-design, risk-based
approach to pharmaceutical quality, which is based on FDA's final
report on ``Pharmaceutical cGMPs for the 21st Century--A Risk-Based
Approach'' (http://www.fda.gov/cder/gmp/gmp2004/GMP_
finalreport2004.htm). The new quality-by-design approach will focus on
critical quality attributes related to chemistry, formulation, and
process design. Under quality by design, manufacturing will depend on a
risk-based approach linking attributes and processes to product
performance, safety, and efficacy.
The principles underlying this new approach to a quality-by-design,
risk-based assessment can be found in the International Conference on
Harmonisation (ICH) guidances: ``Q8 Pharmaceutical Development,'' May
2006 (http://www.fda.gov/cder/guidance/6746fnl.pdf), and ``Q9 Quality
Risk Management (ICH),'' June 2006 (http://www.fda.gov/cder/guidance/
7153fnl.pdf), and FDA's guidances for industry entitled ``PAT-- A
Framework for Innovative Pharmaceutical Development, Manufacturing, and
Quality Assurance,'' September 2004 (http://www.fda.gov/cder/guidance/
6419fnl.pdf), and ``Quality Systems Approach to Pharmaceutical CGMP
Regulations,'' September 2006 (http://www.fda.gov/cder/guidance/
7260fnl.pdf). Quality-by-design and risk-based approaches are also
described in the following draft guidances: ``Q8(R1) Pharmaceutical
Development Revision 1'' (http://www.fda.gov/cder/guidance/8084dft.pdf)
and ``Q10 Pharmaceutical Quality Systems'' (http://www.fda.gov/cder/
guidance/7891dft.pdf).
The agency's Office of New Drug Quality Assessment (ONDQA) in OPS,
CDER, initiated a pilot program (70 FR 40719, July 14, 2005) to gain
experience in assessing chemistry, manufacturing, and controls (CMC)
sections of NDAs that demonstrate an applicant's product knowledge and
process understanding at the time of submission. This pilot was
extremely useful in helping identify appropriate information to be
shared regarding quality by design for small molecules. Although many
of the principles of quality by design apply equally to small molecules
and more complex pharmaceuticals, the ability to assess relevant
attributes is a much greater challenge for complex pharmaceuticals.
The OBP pilot described in this document focuses on defining
clinically relevant attributes for complex products and linking them to
the manufacturing process. In addition to considering quality by design
for an entire original application, this pilot also will consider
quality-by-design approaches to unit operations in supplements.
Finally, this pilot will explore the use of protocols submitted under
Sec. Sec. 314.70(e) and 601.12(e) (21 CFR 314.70(e) and 601.12(e)).
Sections 314.70 and 601.12(e) allow for the use of protocols
describing the specific tests and studies and acceptance criteria to be
achieved to demonstrate the lack of adverse effect for specified types
of manufacturing changes on the identity, strength, quality, purity,
and potency of the drug product. A particular type of protocol is a
Comparability Protocol. In many cases, Comparability Protocols have
been used for a single manufacturing change. Protocols based on
quality-by-design submissions will focus on critical quality attributes
related to chemistry, formulation, and process design. Such protocols
will be referred to as Expanded Change Protocols. Expanded Change
Protocols will describe the quality-by-design, risk-based approach
linking attributes and processes to product performance, safety, and
efficacy.
II. Description of Pilot Program
This pilot will focus on quality-by-design approaches to the
manufacturing of biotechnology products through the use of Expanded
Change Protocols. The pilot program will provide additional information
to FDA for use in facilitating quality-by-design, risk-based approaches
for complex molecules. OBP will work with each participant on an
individual basis. Pilot submissions will be either original
applications or manufacturing supplements subject to the Prescription
Drug User Fee Act (PDUFA) Performance Goals; we expect that
participation in the pilot program will not adversely affect our
ability to meet the review goal. The process will include appropriate
coordination between agency quality review staff and staff from other
disciplines (such as compliance, clinical pharmacology, toxicology,
clinical review, as needed) based on the scope of the submission. Based
on experience gained during the pilot program and prior knowledge, FDA
will develop procedures to facilitate implementing a quality-by-design,
risk-based approach for complex products. In addition, the experience
gained by FDA under this pilot is expected to facilitate the
development of guidance for industry.
A. Scope
The pilot program will include both original applications and
postapproval supplements. A pilot program submission should demonstrate
the applicant's increased knowledge of product attributes and link the
product attributes to process parameters in an Expanded Change
Protocol. Acceptance into this pilot program will depend on the
soundness of the applicant's proposal as described in their written
request to participate in the pilot and the potential of the proposed
application to affect the development of a quality-by-design, risk-
based approach for complex products. Considerations for acceptance into
the pilot may include sponsor approaches to risk management and use of
prior knowledge. Considerations for original
[[Page 37974]]
applications may also include quality-by-design approaches to multiple
unit operations and the stage of product development. For original
applications, it would be of value to enter the pilot well in advance
of submitting the application. Entry during the appropriate stage of
development, as an investigational new drug (IND), would facilitate
working with the agency on quality-by-design approaches.
Because the number of biotechnology product applications submitted
is relatively low compared to small-molecule drugs, the pilot will have
an extended submission period. Written requests to participate in this
pilot program for products regulated by OBP may be submitted from the
date of the publication of this notice until September 30, 2009. This
pilot program will be limited to 10 supplements to be submitted by
March 31, 2010, and 5 original applications for products reviewed by
OBP (BLA or NDA) in Common Technical Document (CTD) format, paper or
electronic. As noted in the previous paragraph, it is preferable for
original applications to enter the pilot as INDs. The INDs must be
submitted before March 31, 2010. Due to resource considerations,
participation in the program may be limited to a total of three pilot
submissions to OBP per quarter.
Every effort will be made to ensure that a variety of
pharmaceutical companies and complex biotechnology product types are
included in this pilot program. This pilot affects the CMC section of
the submission; however, supportive data may relate to other
disciplines. Existing regulations and requirements for the submission
of a supplement or marketing application (BLA or NDA) will not be
waived, suspended, or modified for purposes of this pilot program.
Participants must submit the application supplement or original
application, paper or electronic, in accordance with 21 CFR parts 314
and 601 and other relevant regulations.
B. Process and How to Request Participation in the Pilot
Interested parties should submit to the Division of Dockets
Management (see ADDRESSES) a written request to participate in the
pilot program (identified with the docket number found in brackets in
the heading of this document). The request should include the following
information: (1) The contact person's name, company name, company
address, and telephone number; (2) the name of the drug product and a
brief description of the drug substance, dosage form, indication, and
stage of development; (3) a summary of the approaches that define
relevant attributes and process parameters; (4) a statement describing
the manufacturing changes to be included in an Expanded Change
Protocol; and (5) a timeline for requested premeetings and for the
submission. All pharmaceutical companies requesting participation in
the pilot program will be notified of their acceptance in writing by
OBP within 60 days of receipt of the request.
Potential participants are encouraged to discuss their plans to
participate in this pilot program with OBP. Discussions with potential
applicants can facilitate appropriate pilot applications. Meeting
requests for potential applicants should be submitted in accordance
with FDA's guidance for industry on ``Formal Meetings With Sponsors and
Applicants for PDUFA Products,'' February 2000 (http://www.fda.gov/
cder/guidance/2125fnl.htm). Once an application is selected for
participation in this program, the applicant can meet with OBP as
needed before the submission and during the review process by sending
requests directly to OBP.
The quality assessment under this pilot program will be conducted
under the direct oversight of the OBP Office Director by a team of
experienced OBP scientists who have a strong scientific background in
product quality, biochemistry, biology and structure/function
relationships. OBP will be assisted by the Office of Compliance on
proposed current good manufacturing practices (CGMP) and facility
approaches and other disciplines, as appropriate. ONDQA and FDA's
Center for Biologics Evaluation and Research will also coordinate with
OBP to facilitate a consistent general approach to quality-by-design
principles.
After the application or amendment has been submitted into the
pilot program, the submission may be withdrawn or amended within an
agreed upon timeframe to not delay approval.
III. Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
Submit a single copy of electronic comments or two paper copies of any
mailed comments, except that individuals may submit one paper copy.
Comments are to be identified with the docket number found in brackets
in the heading of this document. Received comments may be seen in the
Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday.
Please note that on January 15, 2008, the FDA Web site transitioned
to the Federal Dockets Management System (FDMS). FDMS is a Government-
wide, electronic docket management system. Electronic submissions will
be accepted by FDA through FDMS only.
Dated: June 24, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-14999 Filed 7-1-08; 8:45 am]
BILLING CODE 4160-01-S