[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]
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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.
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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
