[Federal Register Volume 73, Number 128 (Wednesday, July 2, 2008)]
[Notices]
[Pages 37972-37974]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-14999]


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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: [email protected].

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

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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