___________________ 

Guidance for Industry 

ANDAs: Impurities in Drug 

Products 

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 90 days of 

publication in the Federal Register of the notice announcing the availability of the draft guidance. 

Submit comments to the Division of Dockets Management (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 regarding this draft document, contact Devinder Gill, 301-827-5845 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

August 2005 

OGD 

Revision I

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Guidance for Industry 

ANDAs: Impurities in Drug 

Products 

Additional copies are available from: 

Office of Training and Communication 

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration 

5600 Fishers Lane 

Rockville, MD 20857

(Tel) 301-827-4573

 http://www.fda.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 2005 

OGD 

Revision 1 

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TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND............................................................................................................... 2

III. LISTING OF DEGRADATION PRODUCTS AND SETTING ACCEPTANCE 

CRITERIA FOR DEGRADATION PRODUCTS IN DRUG PRODUCT 

SPECIFICATIONS.................................................................................2

 A. Listing of Degradation Products........................................................2

 B. Setting Acceptance Criteria for Degradation Products............................3

IV. QUALIFICATION OF DEGRADATION PRODUCTS....................................4

 A. Qualification Thresholds.................................................................4

 B. Qualification Procedures.................. ..............................................5

 1. Comparative Analytical Studies... ................................................... 5

 2. Scientific Literature and Significant Metabolite............ ......................5

 3. Toxicity Studies................................................ ................... .........6

ATTACHMENT 1: IDENTIFICATION AND QUALIFICATION OF DEGRADATION 

PRODUCTS IN GENERIC DRUG PRODUCTS...................................................................... 7

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1 Guidance for Industry 

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3 

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ANDAs: Impurities in Drug Products 

5 This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) 

6 current thinking on this topic. It does not create or confer any rights for or on any person and does 

7 not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies 

8 the requirements of the applicable statutes and regulations. If you want to discuss an alternate 

9 approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff, call 

10 the appropriate number listed on the title page of this document.

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If you plan to submit comments on this draft guidance, to expedite FDA review of your comments, 

please: 

• Clearly explain each issue/concern and, when appropriate, include a proposed revision 

and the rationale and/or justification for the proposed revision. 

• Identify specific comments by line numbers; use the pdf version of the document 

whenever possible. 

• If possible, e-mail an electronic copy (Word) of the comments you have submitted to the 

docket to cummingsd@cder.fda.gov.

I. INTRODUCTION 

This guidance provides recommendations on what chemistry, manufacturing and controls (CMC) 

information sponsors should include regarding the reporting, identification, and qualification of 

impurities that are classified as degradation products in drug products when submitting:1, 2

• Original abbreviated new drug applications (ANDAs) 

• ANDA supplements for changes that may affect the quantitative or qualitative 

degradation product profile 

The guidance also provides recommendations for establishing acceptance criteria for degradation

products (specifically, degradation products of the active ingredient or reaction products of the 

active ingredient with an excipient(s) and/or immediate container/closure system) in generic drug 

products. The guidance will replace an existing 1998 draft guidance of the same name. 

This guidance does not apply to an ANDA or ANDA supplement that has been reviewed prior to 

the publication of the final guidance. 

1

 The recommendations in this guidance are limited to drug products that are manufactured from drug substances

produced by chemical synthesis. 

2

 See 21 CFR 314.94(a)(9) 

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FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

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II. BACKGROUND 

We are revising the draft guidance for industry titled ANDAs: Impurities in Drug Products, 

issued in December 1998, for the following reasons: 

1. To update information on listing of degradation products, setting acceptance criteria, 

and qualifying degradation products (thresholds and procedures) in ANDAs in 

conformance with the revision of the guidance for industry (November 2003) on 

Q3B(R) Impurities in New Drug Products. 

2. To remove those sections of the 1998 draft guidance containing recommendations 

that are no longer needed because they are addressed in the more recent Q3B(R) (see 

the list below). 

 

The Q3B(R) was developed by the International Conference on Harmonisation (ICH) to provide 

guidance on impurities in drug products for new drug applications (NDAs). However, the 

Agency believes that many of the recommendations provided on impurities in drug products also 

apply to ANDAs. Please refer to the following specific sections in the Q3B(R) for these 

recommendations: 

• Section I, Introduction 

• Section II, Rationale for the Reporting and Control of Degradation Products 

• Section III, Analytical Procedures 

• Section IV, Reporting Degradation Products, Content of Batches 

• Attachment 1, Thresholds for Degradation Products 

III. LISTING OF DEGRADATION PRODUCTS AND SETTING ACCEPTANCE 

CRITERIA FOR DEGRADATION PRODUCTS IN DRUG PRODUCT 

SPECIFICATIONS 

A. Listing of Degradation Products 

We recommend that the specification for a drug product include a list of degradation products. 

Stability studies, chemical development studies, and routine batch analyses can be used to 

predict the degradation profile for the commercial product. It is important that the list of 

degradation products for the drug product specification be based on degradation products found 

in the batch(es) manufactured by the proposed commercial process. 

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We recommend that you include in your submission a rationale for the inclusion or exclusion of 

degradation products in the drug product specification. It is important that the rationale include a 

discussion of the degradation profiles observed in stability studies and in the degradation profiles 

observed in the batch(es) under consideration together with a consideration of the degradation 

profile of the batch(es) manufactured by the proposed commercial process. 

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Individual degradation products with specific acceptance criteria that are included in the 

specification for the drug product are referred to as "specified degradation products" in this 

guidance. Specified degradation products can be identified or unidentified.

We recommend that specified identified degradation products be included in the list of

degradation products along with specified unidentified degradation products that are estimated to 

be present at a level greater than the identification threshold given in Q3B(R). For degradation 

products known to be unusually potent or to produce toxic or unexpected pharmacological 

effects, we recommend that the quantitation and/or detection limit of the analytical procedures 

correspond to the level at which the degradation products are expected to be controlled. 

For unidentified degradation products to be listed in the drug product specification, we 

recommend that you clearly state the procedure used and assumptions made in establishing the 

level of the degradation product. It is important that specified unidentified degradation products 

be referred to by an appropriate qualitative analytical descriptive label (e.g., unidentified A, 

unidentified with relative retention of 0.9). We recommend that you also include general 

acceptance criteria of not more than the identification threshold (see Q3B(R), Attachment 1) for 

any unspecified degradation product and acceptance criteria for total degradation products. 

We recommend that the drug product specification include, where applicable, a list of the 

following types of degradation products: 

• Each specified identified degradation product 

• Each specified unidentified degradation product 

• Any unspecified degradation product with an acceptance criterion of not more than (≤) 

the figure in the identification threshold in Attachment 1, Q3B(R)

• Total degradation products 

B. Setting Acceptance Criteria for Degradation Products 

We recommend that the acceptance criterion be set no higher than the qualified level (see section 

IV, Qualification of Degradation Products). In establishing degradation product acceptance 

criteria, the first critical consideration is whether a degradation product is specified in the United 

States Pharmacopeia (USP). If there is a monograph in the USP that includes a limit for a 

specified identified degradation product, we recommend that the acceptance criterion be set no 

higher than the official compendial limit. 

If the level of the degradation product is above the level specified in the USP, we recommend 

qualification. Then, if appropriate qualification has been achieved, an applicant may wish to 

petition the USP for revision of the degradation product’s acceptance criterion. 

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If the acceptance criterion for a specified degradation product does not exist in the USP and this 

degradation product can be qualified by comparison to an FDA-approved human drug product, 

the acceptance criterion should be consistent with the level observed in the approved human drug 

product. In other circumstances, the acceptance criterion may need to be set lower than the 

qualified level to ensure drug product quality. For example, if the level of the metabolite 

impurity is too high, other quality attributes, like potency, could be seriously affected. In this 

case, we would recommend that the degradation product acceptance criterion be set lower than 

the qualified level. 

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We recommend that ANDA sponsors develop robust formulations and manufacturing processes 

that are based on sound state-of-the-art scientific and engineering principles and knowledge. 

Although routine manufacturing variations are expected, significant variation in batch-to-batch 

degradation product levels or an unusually high level of degradation products may indicate that 

the manufacturing process of the drug product is not adequately controlled or designed. 

IV. QUALIFICATION OF DEGRADATION PRODUCTS 

Qualification is the process of acquiring and evaluating data that establish the biological safety 

of an individual degradation product or a given degradation profile at the level(s) being 

considered. When appropriate, we recommend that applicants provide a rationale for establishing 

degradation product acceptance criteria that includes safety considerations.

A degradation product is considered qualified when it meets one or more of the following 

conditions: 

• When the observed level and proposed acceptance criterion for the degradation product 

do not exceed the level observed in an FDA-approved human drug product. 

• When the degradation product is a significant metabolite of the drug substance. 

• When the observed level and the proposed acceptance criterion for the degradation 

product are adequately justified by the scientific literature. 

• When the observed level and proposed acceptance criterion for the degradation product 

do not exceed the level that has been adequately evaluated in toxicology studies. 

Although Quantitative Structure Activity Relationships (QSAR) programs may be used for 

prediction of toxicity of an individual degradation product or a given degradation profile, the 

results are not generally considered conclusive for qualification purposes. 

A. Qualification Thresholds 

Recommended qualification thresholds3 for degradation products based on the maximum daily 

dose of the drug are provided in ICH Q3B(R). When these qualification thresholds are exceeded,

we recommend that degradation product levels be qualified. In some cases, it may be 

3 Qualification threshold is defined as a limit above (>) which a degradation product should be qualified.

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appropriate to increase or decrease the qualification threshold for qualifying degradation 

products. For example, when there is evidence that a degradation product in certain drug classes 

or therapeutic classes has previously been associated with adverse reactions in patients, it may be 

important to establish a lower qualification threshold. Conversely, when the concern for safety is 

low, a higher threshold for qualifying degradation products may be appropriate. The FDA will 

consider proposals for applications for alternative qualification thresholds on a case-by-case 

basis after considering issues such as patient population, drug class effects, and historical safety 

data. 

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B. Qualification Procedures 

The decision tree in Attachment 1 describes considerations for the qualification of degradation 

products when the usual qualification threshold recommended in ICH Q3B(R) is exceeded. In 

some cases, decreasing the level of the degradation product below the threshold rather than 

providing additional data can be the simplest course of action. Alternatively, adequate data 

could be available in the scientific literature to qualify the degradation product. The studies 

considered appropriate to qualify the degradation product will depend on a number of factors, 

including the patient population, daily dose, and route and duration of drug administration. Such 

studies can be conducted on the drug product containing the degradation product to be controlled,

although studies using isolated degradation products can sometimes be appropriate. The 

following are descriptions of methods for qualifying degradation products. 

1. Comparative Analytical Studies 

A degradation product present in a drug product covered by an ANDA can be qualified by 

comparing the analytical profiles of a generic drug product with those in an approved human 

drug product using the same validated, stability-indicating analytical procedure (e.g. comparative 

HPLC studies). This approved human drug product is generally the reference listed drug (RLD). 

However, you may also compare the profile to a different drug product with the same route of 

administration and similar characteristics (e.g., tablet versus capsule) if samples of the reference 

listed drug are unavailable or in the case of an ANDA submitted pursuant to a suitability petition. 

It is essential that maximum daily doses of the degradation product and routes of administration 

should be taken into account for qualification by comparative analytical studies. The qualified 

threshold of a degradation product in a dosage form may not be applicable to all drug products 

containing that degradation product if the maximum daily doses or the routes of administration 

are different. We recommend that you conduct the stability studies on comparable samples (e.g., 

age of samples) to get a meaningful comparison of degradation profiles. 

A degradation product present in the generic drug product is considered qualified if the amount 

of identified degradation product in the generic drug product reflects the levels observed in the 

corresponding approved human drug product. 

2. Scientific Literature and Significant Metabolites 

If the level of the specified identified degradation product is adequately justified by the scientific 

literature, no further qualification is considered necessary. In addition, a degradation product 

that is also a significant metabolite of the drug substance is generally considered qualified. 

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If the level of the specified identified degradation product is adequately justified by the scientific 

literature, no further qualification is considered necessary. In addition, a degradation product 

that is also a significant metabolite of the drug substance is generally considered qualified. 

3. Toxicity Studies 

Toxicity tests are the least preferred method to qualify degradation products. We recommend the 

tests be used only when degradation products cannot be qualified by either of the above 

procedures (section IV.B.1 or 2). The tests are designed to detect compounds that induce general 

toxic or genotoxic effects in experimental systems. If performed, such studies should be 

conducted on the drug product or drug substance containing the degradation products to be 

controlled, although studies using isolated degradation products may also be used. 

 

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ATTACHMENT 1: IDENTIFICATION AND QUALIFICATION OF DEGRADATION 

PRODUCTS IN GENERIC DRUG PRODUCTS 

doc 

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Is degradation

product greater

than identification

thresholda?

Yes No

No action

No action 

Yes 

No 

Yes 

Reduce to

safe level

Any

known human 

relevant risksb

?

Structure 

identified?

No Greater than 

qualification

thresholda? No further

action 

Reduce 

to not more than

(≤) identification

thresholda

? 

Yes 

Yes 

No Action 

Yes 

No

Is the degradation product

observed in an FDA-approved human 

drug productc

 at a similar level or is

it adequately qualified by other 

acceptable approachesd

? 

Reduce

to not more than

(≤) qualification

thresholda

? 

No 

Yes 

No

No 

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Consider patient population and duration of use 

and consider conducting: 

• Genotoxicity studies (point mutation, 

chromosomal aberration)e

• General toxicity studies (one species, usually

14 to 90 days)

f

• Other specific toxicity endpoints, as 

appropriate 

Qualified Reduce to Yes No

safe level 

Any

clinically

relevant adverse 

effects?
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Notes on Attachment 1

a Lower thresholds can be appropriate if the degradation product is unusually toxic. 

b For example, do known safety data for this degradation product or its structural class preclude human exposure at

the observed level?

c In this context, an FDA-approved human drug product generally refers to the reference listed drug. It may also 

include a different drug product with the same route of administration and similar characteristics such as tablet 

versus capsule

. 

d A degradation product is considered qualified for ANDAs when one or more of the following conditions are met: 

• When the observed level and proposed acceptance criterion for the degradation product do not exceed the 

level justified by an FDA-approved human drug product.

• When the degradation product is a significant metabolite of the drug substance. 

• When the observed level and the proposed acceptance criterion for the degradation product are adequately 

justified by the scientific literature. 

• When the observed level and proposed acceptance criterion for the degradation product do not exceed the 

level that has been adequately evaluated in toxicity studies. 

e If considered desirable, a minimum screen (e.g., genotoxic potential) should be conducted. A study to detect point

mutations and one to detect chromosomal aberrations, both in vitro, are considered an appropriate minimum

screen for genotoxicity. 

f If general toxicity studies are appropriate, one or more studies should be designed to allow comparison of

unqualified to qualified material. The study duration should be based on available relevant information and

performed in the species most likely to maximize the potential for detecting the toxicity of a degradation product. 

On a case-by-case basis, single-dose studies can be appropriate, especially for single-dose drugs. In general, a 

minimum duration of 14 days and a maximum duration of 90 days would be considered appropriate. 

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