Guidance for the Submission of Chemistry, Manufacturing, and Controls Information and Establishment Description for Autologous Somatic Cell Therapy Products; Availability

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 95N-0200]

Guidance for the Submission of Chemistry, Manufacturing, and

Controls Information and Establishment Description for Autologous

Somatic Cell Therapy Products; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the

availability of a guidance entitled ``Guidance for the Submission of

Chemistry, Manufacturing, and Controls Information and Establishment

Description for Autologous Somatic Cell Therapy Products.'' This

guidance, prepared by the Center for Biologics Evaluation and Research

(CBER) in consultation with the Center for Devices and Radiological

Health, is intended to assist applicants in the preparation of the

chemistry, manufacturing, and controls (CMC) section and the

establishment description section of a biologics license application

(BLA) or in the preparation of a product license application (PLA) and

establishment license application (ELA) for all autologous somatic cell

therapy products. This guidance may assist in complying with certain

requirements in the Code of Federal Regulations.

DATES: Written comments may be submitted at any time; however, comments

submitted by April 10, 1997, will be considered for the next revision.

ADDRESSES: Submit written requests for single copies of the guidance

entitled, ``Guidance for the Submission of Chemistry, Manufacturing,

and Controls Information and Establishment Description for Autologous

Somatic Cell Therapy Products'' to the Office of Communication,

Training and Manufacturers Assistance (HFM-40), Center for Biologics

Evaluation and Research, Food and Drug Administration, 1401 Rockville

Pike, Rockville, MD 20852-1448. Send one self-addressed adhesive label

to assist that office in processing your requests. The document may

also be obtained by mail or by calling the CBER Voice Information

System at 1-800-835-4709, or 301-827-1800, or FAX at 1-800-CBER-FAX, or

301-827-3844.

Persons with access to the Internet may obtain the document in

several ways. Users of ``Web Browser'' software, such as Mosaic,

Netscape, or Microsoft Internet Explorer may obtain this document via

the World Wide Web by using the following Uniform Resource Locators:

http://www.fda.gov/cber/cberftp.html

ftp://ftp.fda.gov/CBER/

The document may also be obtained via File Transfer Protocol (FTP).

Requests should connect to the FDA's FTP Server,

FTP.FDA.GOV(192.73.61.21). CBER documents are maintained in a

subdirectory called ``CBER'' on the server. Logins with the user name

of anonymous are permitted, and the user's e-mail address should be

sent as the password. The ``READ.ME'' file in that subdirectory

describes the available documents which may be available as an ASCII

text file (*.TXT), or a Word Perfect 5.1 or 6.x document (*.w51,wp6),

or both. Finally, the guidance can be obtained by ``bounce-back e-

mail''. A message should be sent to: ``[email protected]''.

Submit written comments on the guidance to the Dockets Managements

Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm.

1-23, Rockville, MD 20857. Two copies of any comments are to be

submitted, except that individuals may submit one copy. Requests and

comments should be identified with the docket number found in brackets

in the heading of this document. A copy of the guidance and received

comments are available for public examination in the Dockets Management

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

FOR FURTHER INFORMATION CONTACT: Sharon A. Carayiannis, Center for

Biologics Evaluation and Research (HFM-630), Food and Drug

Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-594-

3074.

SUPPLEMENTARY INFORMATION:

Over the last several years, FDA has worked to clarify its approach

to the

[[Page 1461]]

regulation of products that are comprised in whole or in part of living

cellular materials. Recognizing that sponsors developing tissue and

cell based therapies would soon want to make these products

commercially available, FDA issued a notice in the Federal Register of

October 14, 1993 (58 FR 53248), entitled ``Application of Current

Statutory Authorities to Human Somatic Cell Therapy Products and Gene

Cell Therapy Products;'' this notice explained the regulatory framework

for somatic cell and gene therapy products, but it did not provide

detailed technical guidance. As announced in the Federal Register of

July 18, 1995 (60 FR 36808), FDA held a public hearing on November 16

and 17, 1995, to solicit information on the nature and diversity of a

subset of autologous somatic cell therapy products for structural

repair or reconstruction called manipulated autologous structural cell

products (MAS cell products) and to receive comments on the formulation

and implementation of any new regulatory requirements. As announced in

the Federal Register of March 7, 1996 (61 FR 9185), the agency held a

Commissioner's roundtable public meeting on March 15, 1996, to present

the elements of a planned regulatory framework intended to help ensure

patient safety and confirmation of patient benefit, while accommodating

the development of these therapies and the need for a flexible

regulatory approach. Many of the concepts presented at the meetings

were derived from ongoing FDA Reinventing Government initiatives. In

the Federal Register of May 28, 1996 (61 FR 26523), FDA announced the

availability of a guidance document entitled ``Guidance on Applications

for Products Comprised of Living Autologous Cells Manipulated Ex Vivo

and Intended for Structural Repair or Reconstruction.'' FDA now is

providing the CMC guidance document that describes product

characterization and establishment information for MAS cell products

and other autologous somatic cell therapy products. This document is

intended to assist manufacturers of all autologous somatic cell therapy

products, whether used for structural repair or reconstruction, or for

other purposes.

As outlined in the President's November 1995, National Performance

Review, ``Reinventing the Regulation of Drugs Made From

Biotechnology,'' and as part of FDA's continuing effort to reduce

unnecessary burdens for industry without diminishing public health

protection, FDA committed to using a standardized, single application

format for drug and biological product approvals. An interim form for

submission of the BLA, FDA Form 3439, is available from the Office of

Communication, Training and Manufacturers Assistance (address above).

Use of this form is voluntary. Establishments wishing to engage in

clinical studies of autologous somatic cell therapy products, including

MAS cell products, should submit an investigational new drug

application (IND). Establishments seeking approval of autologous

somatic cell therapy products for clinical use should either submit, as

appropriate, a BLA or a product license application (PLA) and companion

establishment license application (ELA).

The information FDA received at the public hearing of November 16

and 17, 1995, as well as comments received on the FDA Commissioner's

roundtable meeting of March 15, 1996, were considered in developing the

guidance for preparation of the CMC and establishment description

sections of the BLA for autologous somatic cell therapy products.

The guidance document is divided into three parts. The general

information section provides background information. Part 1, the CMC

section, is divided into the following sections: (1) Introduction; (2)

Biological Substance/Product, including discussions of Description and

Characterization, Manufacturer(s), and Method(s) of Manufacture,

Process Controls, Specifications/Analytical Methods, Container and

Closure Systems/Shipping Containers, and Biological Substance

Stability; (3) Biological Product, including discussions of Method(s)

of Manufacture and Packaging, Specifications and Test Methods for Final

Biological Product, Biological Product Stability, Container and Closure

System, and Microbiology; (4) Environmental Assessment; and (5) Method

Validation. Part 2, the establishment description section, provides a

description of establishment information that should be submitted and

related good manufacturing practice (GMP) controls for the manufacture

of autologous somatic cell therapy products. Part 2 is divided into the

following sections: (1) Introduction; (2) General Information; (3)

Water Systems, including discussions of General Description of Water

System, Validation Summary and Routine Monitoring; (4) Heating,

Ventilation and Air Conditioning Systems; and (5) Contamination/Cross

Contamination Issues, including discussions of Cleaning Procedures and

Validation and Containment Features. This document provides guidance to

manufacturers for providing the information describing establishment

standards and GMP controls that would be submitted as part of the BLA

or PLA and ELA.

As with other procedural guidance documents, FDA does not intend

that this guidance would be all-inclusive. Alternative approaches could

be warranted in specific situations, and certain aspects might not be

applicable in all situations. If an applicant believed a procedure

described in this guidance was inapplicable to a specific situation for

a particular product, the applicant could provide, for CBER's

consideration, information supporting an alternative process. If an

applicant chooses to use alternative processes, the applicant may wish

to discuss the matter further with the agency to prevent expenditure of

money and resources on activities that later might be determined to be

inappropriate by FDA. Additionally, FDA intends to further revise this

guidance, as needed. FDA also encourages applicants who use the BLA to

contact CBER to discuss use of the application further inasmuch as the

agency's experience with its use will evolve. Although this guidance

document does not create or confer any rights for or on any person, and

does not operate to bind FDA or the public, it does represent the

agency's current thinking on the CMC and establishment description

sections of a BLA or PLA and ELA submitted for an autologous somatic

cell therapy product.

Interested persons may, on or before April 10, 1997, submit written

comments on the guidance document to the Dockets Management Branch

(address above). Two copies of any comments are to be submitted, except

that individuals may submit one copy. Comments and information are to

be identified with the

docket number found in brackets in the heading of this document. The

guidance and received comments may be seen in the office above between

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

Written comments on this document will be considered in determining

whether revisions to the guidance are warranted.

Dated: January 6, 1997.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 97-579 Filed 1-9-97; 8:45 am]

BILLING CODE 4160-01-F