[Federal Register Volume 60, Number 236 (Friday, December 8, 1995)]
[Notices]
[Pages 63048-63049]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-29960]



-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 95N-0371]


Interim Definition and Elimination of Lot-by-Lot Release For 
Well-Characterized Therapeutic Recombinant DNA-Derived and Monoclonal 
Antibody Biotechnology Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is announcing an 
interim definition for well-characterized therapeutic recombinant DNA-
derived and monoclonal antibody biotechnology products. FDA is also 
announcing that FDA is eliminating lot-by-lot release for licensed 
well-characterized therapeutic recombinant DNA-derived and monoclonal 
antibody biotechnology products. After approval, manufacturers of such 
products are no longer requested to submit samples and protocols for 
individual lots of products to the Center for Biologics Evaluation and 
Research (CBER) for routine lot-by-lot release. Manufacturers may begin 
distributing products affected by this policy after notification by 
CBER and without awaiting approval of a supplement to their product 
license applications. This notice is intended to reduce unnecessary 
burdens for industry without diminishing public health protection.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. Comments should be identified with the docket 
number found in brackets in the heading of this document. Two copies of 
any comments are to be submitted, except that individuals may submit 
one copy. 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:
    Regarding lot release: Jerome A. Donlon, Center for Biologics 
Evaluation and Research (HFM-200), Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852-1448, 301-594-2200.
    Regarding the definition of a well-characterized therapeutic 
recombinant DNA-derived and monoclonal antibody biotechnology product: 
Jean M. Olson, Center for Biologics Evaluation and Research (HFM-630), 
Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-
1448, 301-594-3074.
SUPPLEMENTARY INFORMATION: This notice is being issued in accordance 
with the principles set forth in Executive Order 12866. Executive Order 
12866 directs Federal agencies to implement measures that will reform 
and streamline the regulatory process to avoid unnecessary regulatory 
burdens. In the November 1995 ``Reinventing the Regulation of Drugs 
Made from Biotechnology'' report, the President and Vice President 
announced a series of regulatory reform initiatives, including FDA's 
intention to issue a notice eliminating lot-by-lot release for licensed 
well-characterized therapeutic recombinant DNA-derived and monoclonal 
antibody biotechnology products. FDA made a commitment to issue the 
notice within 30 days of the report.

Elimination of Lot-by-Lot Release

    Biologics have traditionally been complex mixtures of substances 
produced primarily from living organisms, and have been difficult to 
characterize by precise tests. They include vaccines, products made 
from human or animal blood, and other products made from a variety of 
materials. Because of the inherent variability of these products, each 
individual lot of most biological products has been subject to 
evaluation and testing by CBER prior to release.
    Under Sec. 610.2 (21 CFR 610.2), the Director of CBER may require, 
at any time, that samples of a licensed product, protocols, and test 
results be submitted to CBER for official release. FDA has invoked lot-
by-lot release to help ensure that products continue to meet 
established standards before they are distributed.
    Historically, lot-by-lot release has served an important role in 
the regulation of biotechnology products and has prevented the 
distribution of unacceptable lots. However, greater control has been 
achieved by manufacturers over the production of biotechnology products 
through in-process controls, process validation, and advances in 
analytical techniques. For well-characterized therapeutic recombinant 
DNA-derived and monoclonal antibody biotechnology products, as defined 
below, FDA has found that once a company has demonstrated its ability 
to consistently produce acceptable lots, and has procedures in place 
that will prevent the release of lots that do not meet release 
specifications, it is not necessary for FDA to verify that each 

[[Page 63049]]
manufactured lot is acceptable for release.
    Accordingly, as provided under Sec. 610.2, the Director of CBER is 
no longer requiring that manufacturers of well-characterized 
therapeutic recombinant DNA-derived and monoclonal antibody 
biotechnology products submit samples and protocols to CBER. FDA will 
continue to monitor companies' compliance with the requirement in 
Sec. 610.1 ( 21 CFR 610.1) that they assay each lot and release only 
those lots that meet release specifications.
    FDA intends to revise the guidance entitled, ``Guidance on 
Alternatives to Lot Release for Licensed Biological Products,'' (58 FR 
38771, July 20, 1993) to reflect the new procedures. Manufacturers who 
do not receive a letter, but think that one of their licensed products 
meets the interim definition, may contact Jerome A. Donlon (address 
above).
    Eliminating FDA lot-by-lot release should not compromise the 
safety, purity, or potency of licensed well-characterized therapeutic 
recombinant DNA-derived and monoclonal antibody biotechnology products. 
Because of process validation and current in-process controls and 
testing for these products, identity, purity, and potency can be 
controlled and measured. In addition, the in-process and end-product 
release specifications can be validated for these products. Therefore, 
submission of lot release samples and protocols are no longer viewed by 
FDA as essential to the ongoing assurance of safety for these products.
    Eliminating lot-by-lot release for these products furthers FDA's 
harmonization of its regulation of well-characterized therapeutic 
recombinant DNA-derived and monoclonal antibody biotechnology products 
between CBER and the Center for Drug Evaluation and Research.
    Manufacturers are still required under Sec. 610.1 to test each lot 
and release only those that meet release specifications. During 
inspections, FDA will monitor compliance with those requirements. 
Manufacturers continue to be required to maintain adequate records and 
retention samples under 21 CFR 211.170 and 211.180.

Interim Definition

    FDA has prepared the following interim definition for a well-
characterized therapeutic recombinant DNA-derived and monoclonal 
antibody biotechnology product:
    A chemical entity(ies) whose identity, purity, impurities, 
potency, and quantity can be determined and controlled. -
    Identity:
    a. Recombinant DNA Biotechnology Products
    The primary structure is known (i.e., amino acid sequence), and
    The secondary structure is known (e.g., disulfide linkage), and
    Post-translational modifications are known (e.g., 
glycosylation), or
    b. Monoclonal Antibodies
    The identity can be determined by rigorous physicochemical and 
immunochemical characterization without fully knowing its chemical 
structure.
    Purity and impurities:
    The purity is quantifiable.
    The impurities are quantifiable, and identified if feasible.
    Potency and quantity:
    The biological activity is measurable.
    The quantity is measurable.
    Well-characterized therapeutic recombinant DNA-derived or 
monoclonal antibody biotechnology products require proper raw material 
controls, process validation and controls, and sensitive and validated 
test methods and specifications. FDA intends to use the definition to 
determine which products may be exempted from lot-by-lot release and to 
help determine which products may be eligible for other regulatory 
initiatives directed at well-characterized biotechnology products.
    FDA invites comments on its proposed definition for well-
characterized therapeutic recombinant DNA-derived and monoclonal 
antibody biotechnology products. In particular, FDA invites comments on 
whether the proposed definition for well-characterized therapeutic 
recombinant DNA-derived and monoclonal antibody biotechnology products 
should be expanded to include other categories of products that would 
be considered to be well-characterized and should be categorically 
exempted from lot-by-lot release.
    In the Federal Register of October 25, 1995 (60 FR 54695), FDA 
announced that it is sponsoring a public scientific workshop on 
December 11 through 13, 1995. At the workshop participants will be 
asked to refine the definition of a well-characterized therapeutic 
recombinant DNA-derived and monoclonal antibody biotechnology product 
as set forth above. After considering the information presented at the 
workshop, FDA may modify the interim definition given above. 
Manufacturers of well-characterized therapeutic recombinant DNA-derived 
and monoclonal antibody biotechnology products affected by this change 
in policy will be notified by letter. -
    CBER does not intend for this notice to be comprehensive. If a 
manufacturer has questions concerning application of this policy to one 
of its licensed products or the interim definition, it can discuss the 
matter with CBER. Although the interim definition for well-
characterized therapeutic recombinant DNA-derived and monoclonal 
antibody biotechnology products in this notice is not binding on either 
FDA or manufacturers of biological products and does not create or 
confer any rights for or on any person, it does represent the agency's 
current thinking on that definition.

    Dated: December 4, 1995.
 William B. Schultz,
 Deputy Commissioner for Policy.
[FR Doc. 95-29960 Filed 12-5-95; 2:43 pm]
BILLING CODE 4160-01-F