2.

Phases 1 and 2

An assay method including adequate acceptance specifications
for content of the new drug substance (including antibiotic)
in the dosage form should be submitted. The initial limits
need not be overly narrow but should be appropriately
tightened as experience with the drug accumlates. Because
the assay alone might not serve as a satisfactory identity
test, using a different method may be necessary during these
phases. Chemical and physical tests characterizing the
dosage form that should be included for solid oral dosage
forms are wmiformity of dosage unit and dissolution profile
in an appropriate medium. Sterility tests, a measure of
particulate content, and apyrogenicity testing should be

included for injectables.

The assay or other procedure should make use of a reference

standard or interim standard, and analytical data to support

its integrity should be submitted. (See "Guideline for,
_ iN preg Pegcraa lions

Submitting Documentation, for uu ure of Drug

Substances.") 2 th ec

Information should also be submitted to support the

specificity, linearity, precision, and accuracy applicable

to specific quantitative methods used to test the dosage

form.

-16-


Assay and identity specifications using a well-
characterized reference standard and description of physical
characteristics (e.g., appearance, odor, etc., where
applicable) are required. A description of other attributes
should also be considered for inclusion, depending on the
type of dosage form. The following list is advisory, and is
not exhaustive, and the omission of a parameter from the
list should not lead to the conclusion that it cannot be the
subject of a regulatory test under appropriate circumstances.

a. Tablets, capsules, and other solid dosage forms

(1) Uniformity of dosage units.

(2) Rate of release of the active ingredient fran the
dosage form by methodology (e.g., dissolution
rate), as appropriate for the dosage form.

(3) Moisture content, where applicable. Special
consideration should be given to dosage forms in
which a major compoent is known to be hygroscopic.

(4) Softening or melting points for suppositories.

b. Solutions (including sterile solids for injection)

(1) Clarity, limit of particulate matter, assay of
preservative, isotonicity (for injectable and
ophthalmic products), and mi determination.

(2) Sterility of injectable and ophthalmic products.

(3) Apyrogenicity of injectable products.


GUIDELINE FOR SUBMITTING DOCUMENTATION FOR THE

MANUFACTURE OF AND CONTROLS FOR DRUG PRODUCTS

INTRODUCTION

This guideline concerns the documentation of the manufacturing
process used to produce dosage forms and the accompanying quality
control system intended for raw mterials, in-process materials, and
the finished dosage form suitable for administration. It is one of
a series of guidelines covering topics relevant to the manufacturing
and controls portion of investigational new drug applications
(IND's), new drug applications (NDA's), and abbreviated new drug
applications (ANDA's). The guideline does not impose mandatory
requirements [21 CFR 10.90(b)]. It does, however, offer guidance on
acceptable approaches to meeting regulatory requirements. Different
approaches may be followed, but the applicant is encouraged to
discuss significant variations in advance with FDA reviewers to
preclude expending time and effort in preparing a submission that

FDA may later determine to be unacceptable.

The information and data discussed in this guideline relate to the
identity, strength, quality, and purity of the dosage form and the
procedures for assuring that all batches manufactured conform to the
appropriate specifications. Information relating to the container,
closure, stability, and labeling are discussed in separate

guidelines.

-1-


Phase 3

Provide a full description of the identity tests, assay
methods, and acceptance specifications as well as any other
appropriate chemical and physical characteristics of the
dosage form. These should approach NDA requirements in the
level of detail provided, including the suitability of
specifications, and data to confirm the adequacy of the
analytical methodology. In vitro dissolution rate tests and
specifications should be submitted for solid dosage forms.
Information in support of any reference standard should be

comparable to that expected in an NDA submission.

Placebos

For matching placebos used in clinical studies, a full
description should be provided of the precautions that will
be taken to ensure the absence of the new drug substance
fram the placebo preparation. The placebo and active dosage
form should be as similar as possible in physical

characteristics and identical in packaging.

-17-

U.S. Government Printing Uffice + 1990 - $17-023/29009


Each formulation of defined dosage forms, potencies/strengths,
or significant changes of inactive ingredient(s) should be
identified with a formulatio number or other appropriate

designation.

Include all ingredients in the batch formla regardless of
whether they remain in the investigational drug product. The
content of new drug substance indicated in the statements of
composition and the representative batch formula should be on
the basis of 100% potency/strengths as stated om the label. Any
calculated excess of an ingredient over the label declaration
should be designated as such, and percent excess should be
shown. Explain any overage in the batch formula, other than

that added to compensate for losses in manufacturing.

Specifications and Analytical Methods for Inactive Components

See section II. C. above.

Manufacturer

See section II. D. above.

Methods of Manufacturing and Packaging

A document describing proposed production and packaging
operations should be submitted for IND phases. Although it
would lack certain features of the final record, it should be as

complete as possible under the circumstances.

-14-


Reprocessing due to deviations not anticipated in the
original NDA should be covered by a supplemental
application. Approval of reprocessing procedures must be
cdbtained before release of the reprocessed drug or drug
product. These supplements may be directed to the
reprocessing of a specific lot/batch or my be submitted as
a new procedure. Supplemental applications for reprocessing
should include the following:
a. A specific and complete descriptiom of the rejected
material including a statement of the deviation(s) from

the specification(s).

b. A detailed description of the proposed reprocessing
procedure, including controls beyond those established

for routine production.
c. A statement of the maximum time elapsed between the
initial manufacture and the time of reprocessing, and

the storage conditions during this interval.

F. Specifications and Analytical Methods for the Drug Product

1. Introduction
The goal of drug product manufacture is reproducibility
within all specified limits. The significant chemical and

physical parameters important to clinical response of the

-6-


include a complete statement of composition and other
information that will properly describe and identify these
materials. Justify proposed alternatives for any listed
substances by demonstrating that the use of these alternatives
does not significantly alter the stability and bioavailability
of the drug product and the suitability of manufacturing

cantrols.

Composition
1. Statement of Composition

A statement of the quantitative composition should specify,
by unit dose, a definite weight or measure for each active
drug substance and a definite weight, measure, or
appropriate range for all other ingredients contained in the

drug product.

2. Batch Formula
Provide a complete list of the ingredients and their amounts
to be used for the manufacture of a representative batch of
the drug product. Submit a separate batch forma for each
formulation of the drug product. All ingredients should be
included in the batch formula whether or not they remain in

the finished product.


Information included in a Drug Master File (DMF) to satisfy the
documentation needed to evaluate any particular part of the
manufacture and controls for a drug product is acceptable provided
the reference is specific, current, and applicable to the drug
product described in the application. However, the agency will
consider the informtion in a DMF only if written authorization is
granted with specific reference to pertinent sections, including
dates of submissions of the DMF. For information om preparing

DMF's, refer to the Guideline for Drug Master Files.

DRUG PRODUCT (NDA's and ANDA's)

The following information should be included in the application:

A. Components
Provide a list of compments, including all substances and
in-process materials used in producing a defined finished drug
or placebo product. List all substances used in the manufacture
of a drug product whether or not they appear in the finished
product, and state the quality designation or grade for each
material (e.g., Americian Chemical Society (ACS), United States
Pharmacopeia (USP), National Formlary (NF)). Identify each
component by its established name, if any, or by complete
chemical name, using structural formulas when necessary for
specific identificatim. If any proprietary preparations or

other mixtures are used as components, their identity should

~2-


F. Specifications and Analytical Methods for Investigational Drug

Products

1.

Introduction

The product tests and specifications appropriate to
investigational drug products are, understandably, not as
well developed as when an NDA is submitted. However, the
safety of investigational products can be assured only if
appropriate analytical information is provided. It is
necessary to realize that the developmental studies of such
methods are not so clearly separated into Phases 1, 2, and 3
as the clinical studies. ‘The following is presented as a
general IND development sequence intended to provide
guidance for the development of product information during
the investigational phases. The ultimate goal of this
sequence is the development of the product tests and
specifications in the form that will eventually be submitted
with an NDA. The level of detail for specifications and
analytical methods set forth in section II.F of this
guideline must, therefore, be considered as an ultimate
goal. The fact that an item may not be included in this
section of this guideline should not be viewed as
justification for its omission at a later development stage

of the IND.

-15-


detailed description of the production process for a
representative batch. Describe the manufacturing and
packaging process for a representative batch, including a
description of each production step, actual operating
conditions, equipment to be utilized and points of sampling

for in-process controls.

A schematic diagram of the production process is often
helpful. Such a diagram should include a superimposed
materials flow plan, indicating the equipment used and the

points of sampling.

Reprocessing Operations

Before reprocessing a drug product, the applicant should
consider the effects of reprocessing on stability and
bioavailability. To permit approval of the reprocessing of
batches of bulk, in-process, and finished drug products that
do not conform to established specifications, the original
submission of an NDA may include proposals for reprocessing
procedures that cover possible foreseeable deviations from
specifications (e.g., weight variation, content uniformity,
unacceptable tablet coating, etc.). Such reprocessing my
require additional amounts of one or more of the components;
however, the amounts added should not result in a component
being present beyond the reasonable variations provided for

in the formation.

—5-


CENTER For Druc EvALuaTION AND RESEARCH

Guidance for Industry

The FDA published Good Guidance Practices in February 1997.
This guidance was developed and issued prior to that date.

Additional copies are available from:
Office of Training and Communications
Division of Communications Management

Drug Information Branch, HFD-210

5600 Fishers Lane
Rockville, MD 20857

(Tel) 301-827-4573
(Internet) http://www.fda. gov/cder/guidance/index.hitm

U.S. DerarTMENT OF HEALTH AND HumAN SERVICES, Foop AND DRUG ADMINISTRATION



may include, but should not be limited to, representative
master/batch production and control records. In particular,
when these records are submitted in support of a
supplemental application that proposes the deletion or
broadening of specifications, the records should cover a
consecutive series of batches. Information on in-process
controls in manufacturing is essential to a thorough review

of the manufacturing and processing of the drug.

Regulatory Specifications and Methods for Drug Products

Regulatory specifications are the defined limits (e.g.,
physical, chemical, biological, microbiological) within
which test results for a drug substance or drug product
should fall when determined by the regulatory methodology.
The regulatory methodology is the procedure or set of
procedures used by the FDA to ascertain whether or not the
drug substance or drug product is in conformance with the
approved regulatory specifications in the NDA. (See
“Guideline for Submission of Samples and Analytical Data for

Methods Validation.")

The regulatory tests and specifications should be designed
to ensure that the dosage form will meet acceptable
therapeutic and physicochemical standards throughout the

shelf life of the marketed product. As such, regulatory


2.

drug product should be defined at an early stage in the
investigational studies, so that the transition to routine
production lot manufacture may be conducted rationally. A
well-organized drug application should demonstrate that the
manufacturing, sampling, and control processes have been
designed to provide a consistent product that, within any
lot and om a lot-to-lot basis, does not vary beyond the

established specifications.

Sampling Methods

Describe the sampling plan that will be used to assure that
the sample of the drug product obtained is representative of
the batch. The plan should include both the sampling of
production batches and the selection of sub-samples for
analytical testing. This plan will, of course, be
applicable only to batches of that particular size, s0
procedures for scale-up or scale-down of this sampling plan
to other batch sizes must also be provided. If samples are

pooled, a justification mist be given for pooling them.

In-Process_ Controls

The analytical controls used during the various stages of
manufacturing and processing of the dosage form should be
fully described. Where feasible, the in-process

specifications should be supported by appropriate data that

-7-


Cc.

Specifications and Analytical Methods for Inactive Components

Provide acceptance specifications and the corresponding
analytical methods for all inactive camponents of the
formilation, regardless of whether they remain in the finished
product. Limits and methods (applicable to the finished dosage
form) for compments that are removed in the manufacturing
Process should be included. Limits and methods must be included

for potentially toxic compments.

Manufacturer

State the name, location and, where appropriate, building number

of each facility having a part in the manufacture or controls of

the drug product. This includes the following, as appropriate:

1. Manufacturer(s) of the bulk drug substance(s).

2. Manufacturer(s) of the drug product.

3. Contract packager(s) and/or labeler(s).

4. . Contract laboratories performing quality control tests on
raw materials, drug substance, or the finished drug product.

5. Suppliers of compments used in the manufacture of the drug

product.

Methods of Manufacturing and Packaging

1. Production Operations
To facilitate the evaluation of the production and control

of the drug product, submit a copy of the proposed or actual

master/batch production and control records or a comparably


INTRODUCTION... 2. er

II. DRUG PRODUCT (NDA's and ANDA's). 2. 2 2 2 eee ee ee ee ee ee

Til.

A.
B.

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2. Reprocessing Operations .. 1... 2.6.6 ee eee ee eee

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1. Introductim .........-. Pe ee
2. Sampling Methods ...... ee ee ee ee
3. In-Process Controls... 1 1 1 ee ee ee ee eee
4. Regulatory Specifications and Methods for Drug Products . .

a.
b.
c.
a.
e.
£.
g.
h.

Tablets, capsules, and other solid dosage forms . .
Solutions (including sterile solids for injection)
Suspensions . 2. 2... 1 1 ee ee ee ee ee ae
Creams, emilsions, and ointments ........-.
Transdermal delivery systems ...... ry
Diluent solutions . 2... 6. 6 ee ee ee eee ee ee
Sterile plastic devices containing active drugs... .
Placebos .......-. oe ee we eee ee ee ee

INVESTIGATIONAL FORMULATIONS (IND's) .....-.--- ry

A.
B.
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D.
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CompanentS . 6 6 ee ee ee ee ee ee
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ComponentS . 6 6 ee ee ee et te ee se eee
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Specifications and Analytical Methods for

Investigational Drug Products ..,..-.-.--2+ + ee ee
1. Introduction 2... 6 1 ee eee ee ee ee ee
2. Phases land2 ......2..22.. eee ee ee eee
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4. Placebos ..... Pr a a a ry eee eee

ab

an au


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da.

e.

(4) Leakage test for ampules, aerosols, pouch packets,
strips, tubes, etc.

(5) Metering tests and specifications (if metered
dosage) and container pressure for aerosols.

(6) Completeness and clarity of constituted solutions.

Suspensions

(1) Assay of preservative and pi determination.

(2) Sterility of injectable and ophthalmic products.

(3) Apyrogenicity of injectable products.

(4) Particle size specifications, resuspendability,
viscosity, sedimentation rates, caking, and
syringability of suspensions.

(5) Metering tests and specifications (if metered

dosage) and container pressure for aerosols.

Creams, emulsions, and ointments

(1) Assay of preservative and pil determination.
(2) Sterility where required.
(3) Homogeneity.

(4) Uniformity of dosage mits as appropriate.

Transdermal delivery systems

(1) In vitro release rates.

(2) Uniformity of dosage units.

-11-


drug product or placebo product. List all substances used in
the manufacture of a drug product whether or not they appear in
the dosage form and state the quality designation or grade for

each mterial (e.g., ACS, USP, NF).

Each camponent should be properly identified by its established
name, if any, or by complete chemical name, using structural
formulas when necessary for specific identification. If any
proprietary preparations or other mixtures are used as
components, their identity should include a complete statement
of composition and other information that will properly describe
and identify them. Justify proposed alternatives for any listed
substances. An amendment should be filed for any significant

changes in formulation not proposed in the initial IND.

Composition

Submit a quantitative statement of composition. It should
specify an appropriate range or a definite weight or measure for
each ingredient contained in the investigational drug product,
whether active or not, and contain a batch formula
representative of that to be used for the manufacture of the

investigational drug product.

-13-


For further information regarding the guideline please contact:

Food and Drug Administration
Center for Drugs and Biologics
Office of Drug Research and Review (HEFN-100)
5600 Fishers Lane
Rockville, Maryland 20857
(301-443-4330)


Center for Drugs and Biologics
Food ami Drug Administration
Department of Health and Human Services

GUIDELINE FOR SUBMITTING DOCUMENTATION FOR THE

MANUFACTURE OF AND CONTROLS FOR DRUG PRODUCTS

February 1987


specifications normally include all criteria that apply to
the bulk dosage form, those related to the packaged product,
and those that indicate the presence or absence of

degradation.

Regulatory specifications may differ from in-house product
release specifications. All drug products require assay and
identity tests and specifications. For compendial products,
the specifications and tests in the United States
Pharmacopeia/National Formilary (USP/NF) monographs may
satisfy relevant requirements. Additional specifications or
alternate analytical methods (e.g., tests for impurities, a
stability-indicating assay, a second identity test, etc.)
may be required as necessary. Broader limits than those in
the USP/NF monograph will not ordinarily be approved as
regulatory specifications unless the labeling indicates that
the product differs from the official monograph. When
alternate analytical methods that are equivalent to, or that
are an improvement over, the compendial methods are
submitted to the agency, the applicant is encouraged to
simultaneously ask the United States Pharmacopeial
Convention (USPC) to change or modify the methodology in the

monograph.

-9~


£. Diluent solutions
Full acceptance specifications and analytical methods,
including assays for preservatives, should be included

for diluents with dry solids or for liquid concentrates.

g. Sterile plastic devices containing active drugs

(1) In vitro release rates, sterility, and limits for
residual ethylene oxide and its decomposition
products, as applicable, in addition to the
identity of all plastic components.

(2) Additional physical tests such as frame memory,
resiliency, tensile strength, and seal integrity of
the immediate package.

h. Placebos
A suitable test demonstrating the absence of the drug

substance in the placebo.

III. INVESTIGATIONAL FORMULATIONS (IND's)

The following information should be included in the application:
A. ents
Provide a list of components, including all substances and

in-process materials used in producing a defined investigational

-12-