_ _

I, 1993 / Notkxs 38771

Dated: july 14.199z
hfichacl R. Taylor,
Dapu ty Commirsionerjor Po/~cY.
(FR Dot. 9347088 Filed 7-1093: 8.45 am~
B(l.UNG cooe 416euI-F
I__-
Docket No. 93N-O3202]
t
Guidenca on Alternatives to Lot
Release for Ucensed BIologIcat
Products
AGENCY: Food and DIU~ Administratiop,
HHS.
ACTION: Notice.
\
SUMMARY: The Food and Drug
Administration (FDA) is describing its
current practices govemin lot release
for licensed biological pro ti ucts. This
documenl describes the information that
should be submitted by manufacturers
of licensed biological products and the
approach that FDA’s Center for
Biologics Evaluaffon and Resedkh
(CBER) is using when evaluating
alternatives to lot release. CBER’s
decisions in this regard are based on a
continued assurance that the safety,
urity, and potency of the producl will
Ii e maintained. This action is being
taken in response to request2 for
guidance on alternatives to lot release.
FDA invites coqunents on this guidance
statement.
DATES: .Submit written commenls by
September 20.1993.
ADDRESSES: Submit written comments
and information to the Dockets
Management Branch (HFA-3051, Food
and Drug Administration, rm. 1~23, -.
’ 12420 Parklawn Dr., Rockville, MD *
20857. Submit product license
a pkatiop amendments e&g
a Ptematives to ldt release Tan sample
submission re uirements to the diiactor
of the applica d on division within the
office having prim jusisdiction over
’ the product (e.g., 03 ce pf Thera eutics.
Office of Vt~adnes,or Office pf BPood).
Food and Drug AdmhWratfon. Center
for Biolo its Evaluation and kesearch, .
1401 Rot L lle Pike, Rockville, MD
20852-1448.
FOR .FURTHER INFORMAnON COWACT:
JoAnn M. Minor. Center for Biologics
Evaluation and Research (HFM-835),
Food and Drug Administration, 1401
Rockville Pike, Rockvifle, MD 20852-
1448.301-295-9074.
SUPPLEMENTARY INFORMATION: FDA is
describing its current procedure for
considering requests fkom .
manufadturers regardin #k-natives to
the submission of sarpp‘I es a114of
protocols that show results of applicable
tests (commonly called “lot release”) as
set forth in 21 CFR 610.2. This notice
 38772 Federal Register / Vol. 58, No. 137 / Tuesday, July 20, 1993 / Notices

also responds to requests for guidance approval of alternalives to the lot release release or an in-process. or bulk lot or
on what information should be provided requirements set forth in their license, batch was rejected.
when submitting such requests- Sum& roduct license application (3) A summary listing of all pmduct
. - Inlductiaa amen x ments may be submitted once a complaints which include, but are sot
manufacturer has documented an limited lo. presence of labeling errors.
Under section 351(d) of the Public acceptable history of lot release and decreased potency, contamination,
Hea1t.h Service Ad (42 U.S.C. 262(d)) WI control ofhe manufacturing facility, ptiicuiatdmatter, adverse reactions,
establishment may be issued a license to sthe definition of acceptable lot release and defect reuorts. The actions taken bv
manufacture a biological product only history will vary according to the the manufa&er for each identified- -’
ah showing hat the ~ab~s~ent and pduct and the completities of the production lot or batch should be
product meat standards designed to manufacturing us. CBER amsiders described.
ensure that product’s continued safety, granting requests for &srnatives to lot (4) A iistiug of any lot(s) which was
purity, end poten . Thereafter, a release only upon demonstration that subject to recall or market cormct~ve
manufacturer of aT iological product the alternative approach does not action following distribution.
subject to a license must demonstrate compromise the safety, u&y, and (5) A description of any major process
supervision and control of the entire potency of the blot cap roduct. change. including when the process
~~ufact~ pr-s to M.m% among Specific questions Ta s oul be addressed change was implemented and a list of
other thin s. i%at contaminants are not to the office with product responsibility lots manufactured using the new .
introdu UJ during production end that prior to submission of an amendment procedure.
there ia lot-lo-lot consistenllcy in the re uesting alternatives to lot release. After evaluating a lianse amendmen&
quality of the llc4msed product (sea 21 h moug the factors that CBER assesses requesting permission to use’
CFR part 600 ei seq.). in detwnintag whether to approve such alternatives to lot reiaase, CBER may
Under 5 610.2, mUfact=n UUYbe -endmat uests are caIJfoLnlMce to
required to submit samples brn all lots ),icena& - 3 ad&g pdW and determine that routine submission of lot
release protocols and samples tpat
of a lie bIolor$~ product together the ability of the manufacturer to necessary if the qbmission describes
with the rotocols showing results of consistentIy demonstrate
applicab B tests when deemed necessary p~ty, otency, ad st& alternatives wbkh provide continued
by the Director, CBER. For most In ad k- tron. thira should assurance of safety, purity, and potency.
biological products, CBER has required of FDA rstablishznent inspectlone that CBER may consider whether there is a
the stirnfssion of this information both ’ have shown comp&mce with apphble need for manufacturers to submlt
in support of a license ap lication and regulations during the period covered. samples and protocols at speciiic
for continued lot release Pallowing The period considered may vary hy intervals (e.g.. quarterly] for surveiilanca
product license application approvaL In product, because the number of lots purposes. Such Iots should be random1
these instances, a manufactures may not produced in a given time may vary, as selected in each period, or as inshucte B
distribute any product until tie . may the &tent to which lot r&ase by the D-or, CEER Regardless d
Director, CBEEt, issues an official release pmcadtues am viewed as important for CBER’s determination on submitting lot
for the lot. oonc?inR assuranm of sefetv and efficacv. release protocols and/or sampls’the
CB-j?Rrkgnizes that the rkd for - manufacturer is requhwd to maintain
Guidance and Rationale sufficient xxxcords,retentkm samples
submlssinn of lot r&ase protocols and/
Biological roducts historically have or samph may be greater for some and stability test samples as required by
been primari Py complex mixtures products than others, e.g.. pmducb 21CFR211.I70 and 211.160. -
produced by living organisms. The where main tenana, of consistent The approech described above is
products have ranged &XII whole blood specScations from lot-*lot Is d.iflkuIt based upon a retrospective analysis of
for transfusion to allergenic extracts, and/or where insuflident axrelstion is lot release history at CBER, including a
vaccines, and recombinant therapeutics. available between measuIsment of comparison of the number of lot failures
Current technology enables tndnstial potepcy and biological activity. The to the total number of lots tested. Whexx~
scale production of biological products e erienoe dieded in both the number a major change in mciaufMuring .
which are more easily characterized of“p ots produced and the period of recess or establishment is proposed or
using reprodudble methodology. In production is import8nt to assess the Ii as occurmd wJ3kh requires an
addition, improved analytical potential value of the Id release amendment, CBER may consider
techniques are available for procadums for a partirxlar product or reimposing the requirement far
ch-don of staxtin makriaL9 as product&s. - - submissiun of lots for release in
well as Anal products, an di efficient The followinn data should be addition to lots subldttted &I nippo$ of .
methods of purificatton can reduce submltted in thz fwm of a product the amendment. Furthermore, if a
levels of process-related impurities to a license application amendment covering product surveillance sample is tested
minimum. an adequate period of time and a . and fails a m ired test or established
Current technology combined with sufficient number of product lofs: specification, the product may be
the experience dertved from years of (11A well-orgtid table containing subject to recall by the manufacturer
product-specific inspections and testing a testing summary of all lots and/or the 88quirement for Iut release
in CBER laboraturies has demonstrated manutactured, including lots may be reimposed.
that. for some biological products, manufactured in sup ort of licensure. CBER is currently a plying the
alternatives to requiring a CBER release This testing history sl-iould include both approach set forth in % s notice. This
ection for every lat provide ddequate lots submitted to CBER for release notice provides information about. but
control to ensure continued safety, action and lots ar batches rejected does not set forth spedfic mquimmmts
purity, and potency (including during in-process, bulk, ur final testing for, the submission of a product licenso
effcctivonass). Therefore, manufacturers at the manufacturing ostablishmont. amendment requesting permission to
meeting the assurances described in this (2) A summary of the disposition of use alternatives ta lot release. FDA doa
document may submit product license the above lots, including the reason a not intend tar this guidance to be
application amendments requesting final lot was not submitted to CBER for comprehensive. All information in this
‘. . FcderaI Register I

guidance may not be applicable to all

silualions.
This nolice is intended as guidance to
manufacturers of biological roducts
filing product license amen &l ents to
request alternatives to lot release. If a
manufacturer believes that the factors
described in this guidance are
inappltcable to a particular product and
other factors are appropriate for CBWs
consideration, the manufacturer may’
wish to discuss the matter further with
the agency to revent expenditure of
money and ef Fort on activities that later
ma be determined to be unacceptable
by b A.
This guidance does not bind the
agency and does not create or amfer’any
rights, privileges, or benefits for or upon
any person, manufacturer, or
orEEE~~?persons may, on or before
September 20.1~93 submit to the
Dockets Management Branch (address
above) written comments and
information on this guidance statement.
Two copies of any comments ate to be *
submitted, except that lndivfduals may
submit one copy. Comments and
information should be idantified with
the docket number found in brackets In
the heading of this document. The
notice and received information and
comments are available for public
examination in the office above between
9 a.m. and 4 p.m., Monday through
Friday.
FDA will consider any comments
received in determining whether
amendments to the @danat statement
are warranted. As warranted, FDA wiU
announce the availability of any revised
guidance statement in&e Federal
Register.
Dated: July 14,196.
Michael R Taylor,
- Deputy Commissioner/or Policy.

Advisory Commlttees; Nollce of

Meetinga
AGENCYj Food and Drug Administration. *
* HHS.
ACTtON: No&e.
SlJMMAflY: This notice announces
forthcoming meetings of pubIic advisory
committees of the Food and Drug’
Administration (FDA). This notice also
summarizes the procedures for the
meetings. and methods by which
interested persons may participate in
o en public hearings before FDA’s
a ii visory Cdmmittees.
MEETINGS: The following advisory
committee meetings are announced: