Guidance

ANDAs:

for Industry

Blend Uniformity

Analysis

DRAFT GUIDANCE
This guidance document

is being distributed

for comment

purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft guidance.
Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.
For questions on the content of the draft document contact Devinder S. Gill, 301-827-5848.

U.S. Department of Health and Human Services

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 1999
OGD

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Guidance
ANDAs:

for Industry

Blend Uniformity

Additional copies are available from:

Drug Information Branch (HFD-21O),
Center for Drug Evaluation and Research (CDER),
5600 Fishers Lane, Rockville, MD 20857 (Te~ 301-827-4S70

(Intemetj http://wwwfda.gov/cder/guidance/index.htm

U.S. Department of Health and Human Services

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 1999
OGD

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Analysis

Table of Contents
I.

INTRODUCTION

II.

SCOPE

III.

SAMPLING

IV.

ACCEPTANCE

. .**...*..

.......................................... 1

............................................................2
SIZE AND PROCEDURES
CRITERIA

. . . . . . . . . . . ...*....

AND ANALYTICAL

PROCEDURES

...............3
. . . . . . . . . ...4

ATTACHMENT
A . . . . . . . . . . ...**.*..
. . . . . . . . . . . . . . . . . . . . . ...*...
Blend Uniformity Analysis Recommendations
for Simple Dosage Forms

. . . . ...*

.5

ATTACHMENT
B . . . ...*..
................................................6
Blend Uniformity Analysis Recommendations
for Complex
Dosage Forms and Complex Processes
GLOSSARY

..............................................................7

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GUIDANCE
ANDAs:

I.

FOR INDUSTRY1

Blend Uniformity

Ana1ysis2

INTRODUCTION

This guidance is intended to provide recommendations

to applicants of abbreviated new drug

applications (ANDAs) on establishing in-process acceptance criteria for blend uniformity analysis
(BUA).3 This guidance provides recommendations on when BUA should be performed and how
to perform BUA. The recommendations apply to original ANDAs and supplemental ANDAs for
formulation and process changes.
FDAs regulations state that the information submitted to support applications must include inprocess controls for the drug products (21 CFR314.50(d)(l)(ii)(a)
and 314.94(a)(9)(i)). The
Center for Drug Evaluation and Research (CDER) guidance for industry on Submitting
Documentation for the Manufacture of and Controls for Drug Products (February 1987) states
that 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 can include, but should not be limited to, representative
master/batch production and control records. BUA is an in-process test that is useful for
ensuring the adequacy of the mixing of active pharmaceutical ingredients (APIs) with other
components of the drug product. The in-process testing requirement for adequacy of mixing to
ensure uniformity and homogeneity is established at 21 CFR 211.11 O(a)(3).

1This guidance has been prepared under the direction of the Chemistry, Manufacturing, and Controls
Coordinating Committee (CMC CC) in the Center for Drug Evaluation and Research (CDER) at the Food and Drug
Administration. This guidance represents the Agencys current thinking on blend uniformity analysis for ANDAs. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative
approach may be used if such approach satisfies the requirements of the applicable statutes, regulations, or both.
2 The primary application of this guidance is expected to be in the manufacture of solid oral dosage forms,
although certain other dosage forms are covered by the document. To simplifj the document, blend uniformity analysis
has been discussed in this guidance in the context of solid oral dosage products. The principles discussed in this
guidance apply equally to other types of blends and dosage forms.
3 An earlier guidance entitled Submitting Documentation for the Manufacture of and Controls for Drug
Products (February 1987) is currently being revised. When that document is finalized, the contents of this guidance will
eventually be incorporated and extended, as appropriate, to new drug applications (NDAs).
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Recommendations

are provided in this guidance on the following:

BUA testing for certain dosages, based on their composition, according to strength
(mg of active) and weight to weight percent (w/w?? of the active)

Sample size and procedures

Acceptance criteria for blend uniformity analysis

FDA intends to seek the support of the Product Quality Research Institute on blend uniformity.
This guidance will be updated based on the outcome of any research.

II.

SCOPE

BUA is recommended for those drug products for which the U.S. Pharrnacopeia (USP) requires
content uniformity analysis. USP requires this test when the drug product contains less than 50
milligrams of the active ingredient per dosage form unit, or when the active ingredient is less than
50 percent of the dosage form unit by weight. BUA is recommended for bioequivalence, test, and
commercial production batches of a drug product.
BUA or homogeneity testing can be applied to all dosage forms, but is recommended for those
dosage forms for which the USP requires content uniformity testing. These dosage forms
include:4

Coated tablets, other than film coated tablets

Transdermal systems
Suspensions in single-unit containers or in soft capsules
Pressurized metered-dose inhalers
Suppositories

If the composition of the drug product is greater than or equal to 50 milligrams of the active
ingredient per dosage form unit or the active ingredient is greater than or equal to 50 percent of
the dosage form unit by weight, blend uniformity analysis is not usually necessary (see Attachment
A). For complex dosage forms, such as modified-release tablets or capsules, and complex
processes (e.g., multistep granulation processes), applicants are advised to consult the appropriate

4 USP 23, Supplement 7,<905>, Uniformity of Dosage Units.

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chemistry reviewing division to determine if BUA is recommended (see Attachment B).
Under current good manufacturing practices (CGMPS), an applicant is required to perform a test
or examination on each commercial batch of all products to monitor the output and validate the
performance of processes that could be responsible for causing variability, which includes
adequacy of mixing to ensure uniformity and homogeneity (21 CFR 211.11 O(a)(3)). A BUA test
for commercial batches in an approved application meets this requirement. An applicant should
not submit a supplemental application requesting the deletion of BUA testing from commercial
batches when the BUA testis also used to ensure compliance with CGMPS. A supplement
requesting deletion of BUA testing should include supportive information justifying that the test
would not be considered necessary under CGMPS. Requests for deletion of BUA testing as an
approved in-process specification do not relieve a fmn of its responsibilities for compliance with
CGMPS. Where an approved application does not include a BUA for commercial batches,
conformance with the CGMP requirement will be evaluated under the drug CGMP regulatory
program.

III.

SAMPLING

SIZE AND PROCEDURES

The recommended sample size of the blend material is no more than three times the weight of an
individual dose. If the firm experiences problems in collecting small samples equivalent to 1 to 3
dosage units and demonstrates that small samples give lower values for BUA due to sampling
bias, larger samples (usually no more than 10 dosage units) can be collected. Justification for
larger samples should be specific to the application under review. Justification based on literature
references is usually not adequate.
Samples for BUA can be collected either from the drums or the blenders. For more than one
drum or blender, analysis from each drum or blender is encouraged for the bioequivalence ardor
test batches. The batch size, number of samples (usually 6 to 10), locations of sampling, and
equipment should be specified as part of the in-process controls for BUA or homogeneity.
Potential differences in mixing efficiency associated with specific types of equipment should be
considered when determining sampling locations.
BUA is recommended for all active ingredients present in the drug product. Since the purpose of
BUA is to assess the uniformity and homogeneity of a blend, composite sampling from various
sites is not appropriate. The weight of the sample tested should be equivalent to the dosage used.
If a common blend is used for the manufacture of multiple strengths of the drug product, the
weight of the sample used should be equivalent to the weight of the lowest strength of the drug
product. For a drug product where different strengths are not made from the same common
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blend, BUA for each blend is recommended.

IV.

ACCEPTANCE

CRITERIA

AND ANALYTICAL

PROCEDURES

Manufacturing records for bioequivalence batches, test batches, and commercial production
batches for drug products for which BUA is recommended should include documentation of test
results and acceptance criteria for BUA. Analytical procedures for BUA can be described
separately in the section of the ANDA application (Section XII) on in-process controls.5
Acceptance criteria of 90.0 percent to 110.0 percent of the expected quantity of active ingredient
(mean of individual test results) with a relative standard deviation (RSD) of no more than 5.0
percent are recommended for BUA. This will allow compensation for any potential loss in blend
uniformity during subsequent manufacturing steps and also ensure compliance with USP
acceptance criteria for content uniformity. The BUA results should be reported as individual test
results, mean value, and calculated RSD. Rounding of BUA results to whole numbers is not
recommended. Additional levels of testing through the use of two-tier acceptance criteria are also
not recommended.

5 See the FDA guidance for industry on Organization

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of an ANDA (February 1999).

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ATTACHMENT

Blend Uniformity

Analysis Recommendations

Weight of Active Pharmaceutical

Ingredient(s)

for Simple Dosage Forms

Per Dosage Form Unit

50 mg ~~~~

Omg ~j~~

Blend Uniformity Analysis

recommended

o%

WPD

Ingredient(s)

x mg

Blend Uniformity Analysis not

usually needed

+50%

Active Pharmaceuticals

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100%

as a Percentage of Dosage Form Unit by Weight

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ATTACHMENT

Blend Uniformity Analysis Recommendations

for Complex
Dosage Forms and Complex Processes

Weight of Active Pharmaceutical

o mg

Ingredient(s)

Per Dosage Form Unit

50 mg ~~~>

~~

Consult Division of Chemistry I or II, Office of Generic

Drugs for Guidance Regarding Blend Uniformity Analysis

t-

o%

~50%

Active Pharmaceutical

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Ingredient(s)

x mg

100%

as a Percentage of Dosage Form Unit by Weight

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GLOSSARY

Acceptance Criteria:
Acceptance criteria are numerical limits or other suitable measures for
acceptance of the results of analytical procedures.
Active Pharmaceutical
Ingredient/Drug
Substance: The active pharmaceutical ingredient or
drug substance is the ingredient that is intended to furnish pharmacological activity or other direct
effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the
structure or any function of the human body (21 CFR 3 14.3).
Batch: A batch is a specific quantity of a drug or other material that is intended to have uniform
character and quality, within specified limits, and is produced according to a single manufacturing
order during the same cycle of manufacture (21 CFR 2 10.3(b)(2)).
Drug Product: A drug product is a finished dosage form (e.g., a tablet or capsule that contains a
drug substance) generally, but not necessarily, in association with one or more other ingredients
(21 CFR 214.3).
In-Process Controls: In-process controls are tests that can be performed during the manufacture
of either the drug substance or drug product, rather than as part of the formal battery of tests that
are conducted prior to release (ICH draft guidance Q6A, Step 2).
In-Process Material: In-process material is any material fabricated, compounded, blended, or
derived by chemical reaction that is produced for, and used in, the preparation of the drug product
(21 CFR 210.3(b)(9)).

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