. . not exceed four; then only one batch of one str ngth needs to be These made for the second and subsequent sources of N batch(es) should be prepared for the same strength product as the batch used in the bioequivalency study in support of approval of The applicant should submit three (3) months of the application. accelerated stability data and comparative dissolution profile approved NDS sourcze batch)However, data (against the primary, if the applicant is seeking authorization to market more than four (4) strengths of the product, then for the second and each subsequent source of ND5 one test batch needs to be prepared for each strength product upon which a bioequivalency study was conducted with the initial source of NDS. 6 _ If no b vivo bioequivalency study is required for a product, then only one batch of one strength needs to be prepared, regardless of the number of strengths for the product. F. It remains the responsibility of the company to be able to demonstrate that any scale-up does not result in a change in the If all the above conditions are met, one method of manufacture; or more increases in production batch size that do not 1 the cum at've size of the test batch on which bioequivalence has been established and that do not exceed the batch size described in the application as a full scale batch will ordinarily be acceptable to the OGD and will not be regarded as a manufacturing change requiring prior approval through a supplemental application [21 CFR 314.70(b)(2)]. In the event that the OGD objects to scale-up of this magnitude, it will communicate to the applicant its objection with specific reasons for the concern. It will remain the responsibility of the applicant to validate and to report on such scale-up as a part of the applicant's required annual reporting [21 CFR 314.70(d)]. approval of an ANDA, a company wishing to G. Following initial increase its batch size beyond the maximum-approved batch size covered by its application is responsible for evaluating whether the proposed increase is a change .affecting the drug product that would require prior approval of a supplemental application [Zl The OGD is concerned that changes in batch CFR 314.70(b)(2)]. size requiring use of larger-size pieces of equipment may be It is manufacturing changes that affect the drug product. recognized that this point of guidance does not offer a clear decision rule that companies may use to meet their However, the review staff of -&e Office of responsibilities. on a case by case basis, a&dress any specific Generic Drugs will, Supplemental applications inquiries made on this issue. proposing a change in manufacturing by inmea&ng batch size should also address the requirements of 21 CFR 320,21(b) et seq. regarding changes in bioavailability and bioequivalence.
been offered as advice to any applicant who has requested advice Therefore, the Office expects that all on batch size. applications submitted after September 1, 1989, will be &apported In by batches of a size that is consistent with this policy. addition, the Office expects all applications to contain the appropriate demonstration batches for multiple strengths and However, some specific sources of NDS as described here. interpretations in this guide are new points and could reasonably be expected to be addressed only in newly filed applications.
including the 5. IMPLEMENTATION: Many elements of this policy, were annminced in a speech key element of a minimum batch Size, to NAPM in January of 1988 and confirmed in an April 1989 meeting In addition, for more than one year these points have with GPIA.
The Office recognizes that this guide is not a rule or guideline our bes$ opinion at this on an informal basis, but merely offers, Therefore, the Office is prepared to consider and review, time. alternative-approaches to providing --on a case by case basis, evidence that data from demonstration batches that: are not full production batches and that do not meet the parameters of this guide may be adequate to support an application for approval. Sponsors who wish to make such a case shuuld provide a rationale and data documenting that the alternative approach they wish to comparable to that derived from the use will provide confidence, product approach described here, that the test batch of their will be comparable to the proposed production batches of their attention should be paid In making such a case, special product. to bioavailability, dissolution profile, stability, content uniformity, production yield and physical characteristics of the
dosage unit.
D. B. Burlington, Acting Director,.
Date
Office
E.D.
'
of Generic
Drugs
Subject:
Submission
of
Reprocessing
Procedures
by
ANDA and
AADA
Applicants.
1.
PUTlfSOSE: To establish
timing and procedures
a consistent content of submissions of by ANDA and AADA applicants.
policy regarding reprocessing formal
the
RACKr,ROr_lND: Under 21 Code of Federal Regulations section Zi1.115. it is required that manufacturers must devise formal reproceasing procedures. When in the application review and sppraval cycle manufacturers must submit those procedures for Some inrluaion in their applications has not been clear. reviewers have expected submission within the original ANDA or AADA. other3 have asked that rework procedures be deleted untiraly from an original application and be the subject of a post-approval supplement--if needed. No regulation or policy atatementexists to specify a time for submission; however, no disagreement exists on the fact that prior approval must be given
fnr reprocessing. "RePrscessing"
2
II - - - batches zpecifications-.." %he approved stance (for FDA's
Manufacture 21 states:
in 21 CFR 211.115 is reworking as stated do not conform to standards or It does not concern normal repetition within sequence of processing according to FDA's compliance example, Eli Lilly agreement. Nov., 1989. page 81. that
and
current
of
"Guide for Submitting Documentation Controls for Drug Products,"
-,% -provided to the chemistry-review branch and cited in the NA letter generated as a conseQuence or of
the chemistry review. there are circumstances that may However, justify not waiting until the chemistry review is completed-requiring immediate communication to the firm--the most common being when the labeling of the listed (pioneer) drug undergoes major revision following issuance of several ANIIA/AADA NA letters and amendments yet a few chemistry deficiencies remain unresolved. The labeling reviewer will ordinarily direct the applicant to start the process over, either citing the specific innovator insert as a reference or by providing detailed instructions for The ability to communicate this information as quickly change. as possible would allow the applicant to promptly~amend the application and permit DGD to review the amendment prior to issuance of the next action letter by the chemist. A second example of reasonable cause for providing a specific labeling letter concerns the review of final printed labeling which uncover8 a new deficiency, not previously recognized. Again, the ability to convey this promptly would likely result in one-less NA letter being issued. This policy and procedure is to be implemented immediately.
Actj(ng
Directob,
Division
of
Generic
Drugs
Office Policy
of Generic Drugs and Procedure Guide
Guide fzs-90 Date 9/20/90 AADA"s, and
Previously-reviewed material in ANDA*s, Subject: DMF@s with respect to reassigned cases. PURPOSE: repetition. To reduce review time by eliminating
needless
who have been assigned amended BACKGROUND: Some reviewers d and reviewed by submitt applications that have been previously others have expressed a feeling of need to exp ore alreadycovered ground in order to have full confidence in the total being While caution is generally a ood quality, review product. overly cautious in review work cause needless loss of a reviewers need to Therefore, reviewer's valuable time. understand where the office management expeczts them to draw the line between each individual reviewer's desire to having full confidence in the total review package and the need for appropriate time management on the part of our professional review staff. of Generic: Drugs' policy POLICY AND PROCEDURE: It is the Office for its reviewers to routinely accept as corre& the results of Current review efforts are previous reviews completed by others. Newly intended to assess only currently-pending submissions. assigned reviewers will not be held responsible ,for unrecognized This policy of defects that may exist in previous reviews. However, the acceptance of completed work is a general one. following circumstances are identified as those for which newly reviewers should audit previous reviews: assigned 1. To assure that applicants have complied with earlier commitments or requests for information from the Division that have not been previously reviewed and found satisfactory. To pursue ad hoc subjects impact on prior decisions or FDA standard/policy.) that (for arise and which example, change have an in a USP
2.
3.
To assure the adequacy of previous reviews that were completed by a reviewer who has been indicted or has pleaded guilty to illegal activities related to his/her job. To assure compliance with batch sizes and conditions current pcrlicy of manufacture. regarding
4.
2 5. To assure that all review elements necessary for a complete review are present in the final favorable review of an application. Other special circumstances not listed above but that are considered by the OGD and DGD management or Review Branch Supervisors to be appropriate for rereview.
6.
reviews of pending amended Consistent with this policy, applications should ordinarily not repeat the documentation of review comments on issues evaluated and found sa.tisfactory during Where there is in the administrative record a earlier reviews. standard review format--that has written review-- in the current found one or more descriptive or review areas satisfactory, then the review of the current amendment or supplement should not repeat or comment again on those previously-reviewed, those satisfactory, items; it should simply cross reference completed,.. final reviews. If, in the opinion of the reviewer, a troubling situation arises which has not been explicitly covered by this Guide, he/she should present the facts to his/her supervisor who will then make a decision regarding an appropriate response. If reviewers, this policy not withstanding,, re-review material that has been previously reviewed and found satisfactory and they find any issue(s) where they disagree with previouslyreviews completed reviews, they should note in their written They should then seek the decision of these specific concerns. their supervisor as to which position --the previously-completed Such supervisory or the current review--should prevail. decisions should be documented in the administrative record.
Date
"DEPARTXENTOFHEALTH JIXMANSERVICES
%blic
Heaith S%wce
HAR2t %
1990
Foad ana Drug Admtnisuation iiockville MD 2W57
Mr. Robert Millanese,
National
747 Third Avenue New.York, New York Dear Mr. Millanese:
This
Pharmaceutical
Association
Manufacturers
President of
10017
concerning discontinuing the letter clarifies FDA procedures This use of FDLC Red No. 3 and its lakes in drug products. clarification follows publication on February 1, X999, of a final rule terminating the provisional listing of FD&C Red No. 3 for in externally applied drugs and the use, among other things, The final. rule prohibits, lakes of FDCC Red No. 3 for all uses. of the lakes of FD&C Red after January 29, 1990, the addition It also No. 3 to any drug or drug component (e.g., capsules)h prohibits the addition of the straight color addi iv@ , FD&C Red No. 3, to a-ally applies FDA,is noi requiring recall from the market or destruction of an~%xternally applied drug to which the color additive had been added or any drug product to I which FD&C Red No. 3 lakes had been added before January 29,, 1990. For drug products requiring premarket approval, under FDA drug approval regulations (21 CFR 314,70(b)), a manufacturer is permitted to delete a color additive without FDA approval of a Drugs subject to the OTC Review supplement covering the change. may be reformulated consistent with the policies and requirements of that process.
Because of the prohibition on adding FD&C Red No. 3 to drugs or drug components after January 29, 1990, and the r:e irement. in the drug approval regulations for premarket approval of a * supplemental new drug application to add a new color to certain
FDA is adopting the following drug products, policie3 for the use of FD&C Red No, 3 lakes disruptlpn of the supply of those drugs. transitional to minixuize
(1). Formulations to which FD&C Red No. 3 was added arior January 29, 1990.
The February
to
1 action applies to m manufacturing and Consistent with prior production of affected products. manufacturers may exhaust supplies of drug agency policy, products or components, including capqules, colored powders, and coating solutions to which FD&C Red No. 3 or its lakes was added'priox to Januam 29, 1990,
armroval
(2) Expedited
of suunlements.
To prevent unnecessary disruption in the marketing of the agency is assigning a high priority affected products, for the review and to reviewing manufacturers g requests
-
.._
_...
I
apprxal of all supplemental applications proposing new FDA formulations involving color chbmges in such products. requires manufacturers to submit a minimum of 3-months accelerated data to establish the stability of a new manufacturers submit these data in Ordinarily, formulation. supplemental applications upon completion of the full 3
In this case, however, to months of accelerated tests. expedite the review process, the agency will permit manufacturers to submit their supplemental applications containing the necessary supporting information, but This will initially containing 2 months of stability data. allow early initiation of FDA review, and the agency will make every effort to complete review of these applications as ouickly as possible after receipt of the third month's stability data.
Manufacturers who wish expedited review of new submissions of such supplements should submit a request for expedited In the case review, specifying the reason for the request. of previously' G&omitted suppl&eX%; -applicants who wish to obtain expedited review should contact the appropriate F review division within the Center for Drug Evaluation and Any manufacturer who has.questions about the data Research. necessary to support a supplemental application should likewise contact the appropriate review division. (3) &rucs botentiallvin short stmt~lv. The agency is concerned about the consequences of a disruption in the supply of approved drugs to the public as a result of the interaction between (1) the immediate effective date of the February 1 rule and (2) the needifor approval of supplements for formulation changes required by The agency is the deletion of FD&C Red No. 3, and its lakes. basis, on a case-by-case therefore willing to consider,
by manufacturers and continued supply of wishing to make such a request Compliance, CDER, 301-295-8054. measures must demonstrate why inadequate to ensure continued &'&zests
ensure the
others for additional steps to Any person approved drugs. should contact the Office of A request for additional the steps mentioned above are
supply.
(a) Additional use _ or its lakes,
of nreviouslv
certified
FD&C Red No. 3
Given the'agency's limited resources and the importance of avoiding significant disruptions in the drug supply, the agency will concentrate its enforcement e,fforts during the next 6 months on those illegal products that can be removed, Thus, from the market without a significant disruption. manufacturers who submit requests for additional measures to ensure the continued supply of their approved drugs should
’
.
3 demonstrate to FDA why immediate regulatory ?ctfon against .sDecific drugs would be contrary to the public Interest. FDA will consider requests from manufacturers who seek to add previously certified FD&C Red No. 3 or its lakes already approved drugs during this 6 month period on hand to their to have while they are taking the steps necessary
Manufacturers are encouraged formulation changes approved, to take all appropriate steps to obtain approval of reformulated products during this initial enforcement phase so as to avoid the possibility of future disruptions as, at the agency will be prepared the end of the +-month period, to take regulatory action against any formulation marketed in violation of the February 1 rule. (b) New formulations containing other
colors.
l
If other steps are found inadequate to ensure the continued marketing of an approved drug, the agency will consider a for a waiver of the requirement of request by a manufacturer . : 'L \ change a'?7a supplement for a formulation 21cFR 314'~'--crri ) (other than the deletion of a color) be formally approved by Under such a' the agency prior to marketing the new product. waiver, the submission of a complete supplement containing data will be deemed the necessary 3-months" stability set forth in approved under the procedures and requirements The agency does not intend to grant such 21 CFR 314.70(c). waivers for products with (a) a narrow therapeutic range (list attached),"(b) an FD&C Red No. 3 conte?t greater than 10 percent of the active ingredient(s) by werght, or (c) an increase or decrease of greater than 10 percent of the in the approved formulation. allowable range of excipients Any request for such a waiver must be accompanied by a+ signed agreement that the manufacturer wrll recall the product from the market upon being informed by the agency that the supplement has been found defzclent. rF
As stated in the February 1, 1990, final rule, the marketing-of ingested drugs containing permanently listed FD&C Red No. 3 is still allowed pending further agency action to delist. Please share these policies with Sincerely your member companies. yours,
&&el L, Michels Director Office of Compliance Center for Drug Evaluation
and Research
.---
_ -.--. _-- -
/
‘
,,
,.
’
4
This
letter
w;;s also
addressed
to
the
following
people:
Szxce J. Brennan Senior Vice President and General Counsel Pharmaceutical Manufacturers Association 110~ Fifteenth Street, N-W . 20005 Washington, D-C. Dee Fensterer, President Generic Pharmaceutical Industry 200 Madison Avenue, Suite 2404 New York, New York 10016 James D. Cope, President Nonprescription Drug Manufacturers 1150 Connecticut Avenue, N.W . 20036 Washington, D.C. Association
Association
5
. , ..
‘ ;
Druss with Narrow Theraneutic Ranae of Low Therapeutic Index Generic Name Tabs Tabs
Aminophylline Carbamazepine Clindamycin Clonidine Dyphyfline Disopyramide Ethinyl Guanethidine Isoetharine Isoproterenol Lithium
Caps Tabs Tabs Caps 30 & 35 mcg (in comb. oral contraceptive tabs) Tabs MD1 MD1 Caps & Tabs . Tabs release
Estradiol
Carbonate
Metaproterenol Minoxidil Oxtriphylline Phenytoin Prazocin Primidone Tabs
Tabs delayed Caps - extended
Caps Tabs hydrochloride Caps & SR Tabs
Procainamide Guanidine Theophylline Valproic Valproate Warfarin
Sulfate
& Gluconate Release Tabs
Tabs & Controlled - sodium
- acid
Sodium Tabs