Guidance for Industry

Format and Content for the

CMC Section of an Annual

Report

Center for Drug Evaluation and Research (CDER)

September 1994
 This guidance has been prepared under the auspices of the Chemistry Manufacturing Controls 1

Coordinating Committee (CMC CC) of the Center for Drug Evaluation and Research at the Food and

Drug Administration. Although this guidance does not create or confer any rights for or on any person

and does not operate to bind FDA or the industry, it does represent the agency’s current thinking on the

submission of chemistry, manufacturing, and controls information in an annual report. For additional

copies of this guidance, contact the Division of Communications Management, HFD-210, CDER, FDA,

5600 Fishers Lane, Rockville, MD 20857 (Phone: 301-594-1012). Send one self-addressed adhesive

label to assist the offices in processing your request. An electronic version of this guidance is also

available via Internet using FTP, Gopher or the World Wide Web (WWW). For FTP, connect to the

CDER anonymous FTP server at CDVS2.CDER.FDA.GOV and change to the “guidance” directory. For

Gopher, connect to the CDER Gopher server at GOPHER.CDER.FDA.GOV and select the “Industry

Guidance” menu option. For WWW, connect to the FDA Home Page at WWW.FDA.GOV/CDER.

GUIDANCE FOR INDUSTRY1

FORMAT AND CONTENT

 FOR THE CMC SECTION OF AN ANNUAL REPORT

I. PURPOSE

To describe the information requested by the Center for Drug Evaluation and Research

(CDER) in an Annual Report to a New Drug Application (NDA), Abbreviated New Drug

Application (ANDA), or Abbreviated Antibiotic Application (AADA) submitted pursuant

to 21 CFR 314.81(b)(2).

The primary objective is to ensure consistency and completeness of information in the

Annual Reports submitted by the pharmaceutical industry and to standardize the

general format.

II. BACKGROUND

The FDA regulations for the submission of Annual Reports are described in 21 CFR

314.70(d) and 21 CFR 314.81(b)(2). In the past, the reports submitted under these

regulations have exhibited wide variability from firm to firm, and at times the information

submitted has been inconclusive or insufficient.

This guidance addresses information that should be included in an Annual Report. It

may also be helpful to consult other Center guidances for information on the depth of

technical information requested. For example, CDER's Guideline for Submitting

Documentation for the Stability of Human Drugs and Biologics provides information on

the design of stability protocols, the amount of stability data that should be provided to

support specific changes to the application (e.g., packaging changes submitted under
314.70(d)(6)), and guidance on the extension of the expiration dating period. Complete

information submitted in an easy to follow format will assist the reviewer in conducting

an efficient review.

CDER encourages the applicant to contact the appropriate office or division if there is

uncertainty whether the information should be submitted in an annual report or as a

supplemental change to the approved application. 

III. POLICY

The NDA/ANDA/AADA holder should follow the procedure outlined in Form FDA 2252

when filing an Annual Report. Annual Reports should be filed for all approved NDA's,

ANDA's and AADA's (including those for bulk antibiotic drugs), regardless of their

activity status. For NDA's filed with the Offices of Drug Evaluation I or II, applicants

should submit sufficient copies of the Annual Report for the jacket of each affected

discipline so as to assure concurrent review.

The applicant should follow the format described below and include all information

when preparing an Annual Report. If no changes were made in a particular section

during the reporting period, the applicant should state "No changes were made during

the reporting period." Please note that even though the format described below may

not be entirely complete, the firm remains responsible for complying with all

requirements under current regulations. 

IV. FORMAT

SECTION I. SUMMARY OF NEW INFORMATION 

The firm should include a brief summary of all changes made to the application during

the reporting period, including changes made in accordance with approved

supplements under 21 CFR 314.70(b) and special supplements under 21 CFR

314.70(c). All changes should be highlighted or annotated within the Annual Report

and should be included in the list of approved chemistry, manufacturing and control

information described in Section IV of this document.

SECTION II. DISTRIBUTION DATA [21 CFR 314.81(b)(2)(ii)] 

The firm should provide:

A. The quantity distributed of each currently approved strength by package

size (e.g. number of 30's, 100's for drug products or kg for bulk antibiotic

drugs), or
B. The statement "None distributed" along with the corresponding approved

package size(s) if there is no distribution for that package size.

C. Quantities distributed for domestic use and quantities distributed for

foreign use.

D. For bulk antibiotic drug AADA's, a current list of all persons authorized to

reference the application and any person whose authorization has been

withdrawn.

Distribution information should be distributor-specific.

SECTION III. LABELING [21 CFR 314.70(d), 21 CFR

 314.81(b)(2)]

Generally, any labeling change submitted in an Annual Report should include

supportive documentation (e.g. submission of a statement of the currently approved

composition to support upgrading insert labeling to include previously unlisted inactive

ingredients).

Information submitted under 21 CFR 314.81(b)(2)(iii), should include the following:

A. All currently used labeling, including a representative sample of package

labels. This should include all package inserts and examples of the

immediate container labels. It may be useful to include labels of

distributors. Samples of all labeling which has undergone a change

during the reporting period, including immediate container labels, carton

labeling, and insert labeling, should be provided in the Annual Report.

B. A summary of any changes made in the labels/labeling since the last

Annual Report, listed chronologically by implementation date. 

SECTION IV. CHEMISTRY MANUFACTURING AND CONTROLS CHANGES

CDER requests that a current list of approved chemistry, manufacturing and control

information be provided yearly in the Annual Report to better document the changes

occurring in applications. This index is not for review purposes, but will serve as a

reviewer aid. The list should include all information shown in Attachment 1 and the use

of the format in the attachment is encouraged. The information should include the

type and date of each change to each component, the type of submission used to

report the change (Original, Supplemental or Annual Report), and the date the change

was reported and approved, if it was.
Regulatory specifications and analytical methods for the drug substance and drug

product should be listed individually as illustrated below:

III. SPECIFICATIONS AND METHODS FOR THE DRUG SUBSTANCE

Test Specification Method (#, Reference)

Description Clear, Colorless Visual (CZT2001,

Liquid Original[2-3-86])

Assay 98 - 102% HPLC (CZT2019,

S-003[4-11-81])

* * *

Examples of chemistry, manufacturing and controls changes that should be reported

include but should not be limited to the following information:

A. Compendial Changes [21 CFR 314.70(d)(1)]

Changes made to comply with changes in an official compendium should

include:

(1) Full description of changes in test methods and limits.

(2) Data demonstrating the suitability of the compendial change for the

drug product.

B. Formulation [21 CFR 314.70(d)(4)]

Deletion of an ingredient intended only to affect the color of the drug

product should be reported and include:

(1) A comparative component and composition statement, with all

changes highlighted or annotated.

(2) A statement of the current component and composition in

subsequent Annual Reports, including reference to the change (i.e.

date, Annual Report Number, or Supplement Number).
(3) Revised labeling as required by 21 CFR 314.70(d)(2) reflecting the

change in formulation.

C. Expiration Period [21 CFR 314.70(d)(5)]

Extension of the expiration dating period should be accompanied by full

shelf-life stability data for the proposed expiry dating on a minimum of

three production lots and a justification for the change in the expiration

date. The data should be obtained using the stability protocol approved

in your application.

D. Container/Closure [21 CFR 314.70(d)(6)]

Changes within the approved container and closure system for a solid

oral dosage form may be included in the annual report (e.g., one HDPE to

another HDPE). The description of this change should be accompanied

by the following information:

(1) Components and manufacturer. Letters of authorization allowing

reference to other documents (e.g., DMFs) should be included if

appropriate.

(2) Testing results that demonstrate the equivalency of the changed

container and closure system to the original system in accordance

with compendial requirements or a protocol approved in the

application.

(3) A Statement of Commitment to place the drug product using the

changed container and closure system in stability studies using the

approved stability protocol.

E. Test Methods [21 CFR 314.70(d)(7)]

The applicant should submit the following information for the addition or

deletion of an alternate method:

(1) A brief statement explaining the reason for the deletion.

(2) Data demonstrating the suitability and validation of the new

alternate method compared to the reference method. The data

should demonstrate the alternate method is equivalent or superior

to the current regulatory method.
F. Container/Closure [21 CFR 314.70(d)(8)]

A change in the size of a container for a solid oral dosage form, without a

change from one container and closure system to another, should be

consistent with the Center for Drug Evaluation and Research Guideline

for Submitting Documentation for the Stability of Human Drugs and

Biologics.

G. Status Report [21 CFR 314.81(b)(2)(vii)]

CDER strongly recommends that the stability report format for the Annual

Report include the following information along with the data accumulated

from your ongoing stability studies:
STABILITY REPORT

NAME/STRENGTH: BATCH #/STUDY #: BATCH/SIZE:

DATE MANUFACTURED: MANUFACTURING SITE: CONTAINER SIZE/SUPPLIER:

DATE PACKAGED: PACKAGER/SITE: CONTAINER RESIN:

DATE STUDY STARTED: PURPOSE OF STUDY: CLOSURE/SUPPLIER:

DATE OF EXPIRY: STORAGE CONDITIONS SEAL/SUPPLIER:

(INCLUDE ORIENTATION):

DRUG SUBSTANCE

MANUFACTURER/SITE/LOT#:

FILLER:

ATTRIBUTES METHODS SPECIFICATIONS TIME (MONTHS)

SOP# (LOW/HIGH)

0 3 6 9 12 18 ...

APPEARANCE

ASSAY

PURITY

 DEG PROD A

 DEG PROD B

 DEG PROD C

pH

ETC...

ACTUAL TEST xxxxxxxxx xxxxxxxxxxxxxxx

DATES

The actual date that the sample(s)were tested should be included in the bottom

row of the table.

If there was no product distribution during the reporting period, the firm should

state the status of the ongoing stability program as stated in the approved

protocol.
Approved by CMC CC:

__________________________ __________________________

Charles Kumkumian, Ph.D. Roger L. Williams, M.D.
ATTACHMENT 1

NDA/ANDA/AADA ######

INDEX OF APPROVED CHEMISTRY, MANUFACTURING AND CONTROLS

INFORMATION

 SUBMISSION APPROVAL 

 TYPE DATE DATE

I. DRUG SUBSTANCE

A. Manufacturer(s) ________ 

B. Method(s) of Manufacture ________

C. Container and Closure ________

D. Stability Protocol ________

E. Specifications and Analytical Methods *

II. DRUG PRODUCT

A. Composition ________

B. Manufacturer(s) ________

C. Method(s) of Manufacture and Packaging ________

D. Specifications and Analytical Methods *

E. Container(s) and Closure(s) ________

F. Expiration Dating Period Months ________

G. Stability Protocol ________

Please attach a complete listing of the Specifications and Analytical *

Methods for the drug substance and drug product in the format provided.
III. SPECIFICATIONS AND METHODS FOR THE DRUG SUBSTANCE

 TEST SPECIFICATION METHOD ( #, Reference)

IV. RELEASE SPECIFICATIONS AND METHODS FOR THE DRUG PRODUCT

 TEST SPECIFICATION METHOD ( #, Reference)