ANDAs Stability Testing of Drug Substances and Products Q&A

Guidance for Industry

ANDAs: Stability Testing of

Drug Substances and Products

Questions and Answers

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

May 2014

Generics

Guidance for Industry

ANDAs: Stability Testing of

Drug Substances and Products

Questions and Answers

Additional copies are available from:

Office of Communications

Division of Drug Information, WO51, Room 2201

Center for Drug Evaluation and Research

Food and Drug Administration

10903 New Hampshire Ave., Silver Spring, MD 20993

Phone: 301-796-3400; Fax: 301-847-8714

druginfo@

/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

May 2014

Generics

TABLE OF CONTENTS

I.

II.

B.

1

QUESTIONS AND ANSWERS ....................................................................................... 1

Drug Master File ............................................................................................................................ 5

A. General ............................................................................................................................................ 1

C. Drug Product Manufacturing and Packaging ............................................................................. 6

D. Amendments to Pending ANDA Application ............................................................................ 12

E. Stability Studies ............................................................................................................................ 13

Contains Nonbinding Recommendations

Guidance for Industry1

ANDAs: Stability Testing of Drug Substances and Products

Questions and Answers

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It

does not create or confer any rights for or on any person and does not operate to bind FDA or the public.

You can use an alternative approach if the approach satisfies the requirements of the applicable statutes

and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate

number listed on the title page of this guidance.

I.

INTRODUCTION

This guidance provides answers to questions from the public comments we received on the draft

guidance for industry on ANDAs: Stability Testing of Drug Substances and Products2 (FDA

stability guidance) that published in the Federal Register of September 25, 2012. The final

guidance for industry of the same title published in the Federal Register of June 20, 2013.

Comments received on the draft of this guidance published in the Federal Register of August 27,

2013 have also been incorporated. General issues; drug master files (DMFs); drug product

manufacturing and packaging; and stability studies are discussed in this guidance and are

intended to clarify the stability testing data recommendations for abbreviated new drug

applications (ANDAs). In this document, the terms drug substance and active pharmaceutical

ingredient (API) are used interchangeably.

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.

II.

QUESTIONS AND ANSWERS

A. General

Q1: What is the scope of and implementation date for the FDA stability guidance?

A1: The FDA stability guidance covers all new ANDAs under the Federal Food,

Drug, and Cosmetic Act, section 505 (j), and DMFs (Type II for drug

1 This guidance has been prepared by the Office of Generic Drugs and Office of Pharmaceutical Science in the

Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.

2 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA

Drugs guidance Web page at

/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/.

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Contains Nonbinding Recommendations

substances that support the ANDAs). It does not apply to postapproval

changes.

The implementation date is June 20, 2014.

Q2:

How will this guidance affect the President’s Emergency Plan for AIDS Relief

(PEPFAR) and positron emission tomography (PET) ANDAs?

A2: For chemistry, manufacturing, and controls (CMC) information, PEPFAR

ANDAs should follow the guidance for industry on Fixed Dose

Combinations, Co-Packaged Drug Products, and Single-Entity Versions of

Previously Approved Antiretrovirals for the Treatment of HIV.3

For PET ANDAs, the Agency recommends a minimum of three batches at or

near the upper end of the proposed radio-concentration. If different

synthesizers (methods of synthesis) are used, three batches from each method

of synthesis at or near the upper end of the proposed radio-concentration are

recommended. Batches do not have to be made in the same facility. For any

additional manufacturing facilities, applicants should provide stability data on

at least one batch at or near the upper end of the proposed radio-concentration

from each facility, although bracketing approaches may be submitted for

review. For additional information, the Agency has published a guidance for

industry on FDA Oversight of PET Products, Questions and Answers.4

Q3(i): Can an ANDA be submitted with 6 months of accelerated stability and 6 months of

long-term stability data?

A3(i): Yes. An ANDA applicant should submit 6 months of accelerated stability

data and 6 months of long-term stability data at the time of submission.

However, if 6 months of accelerated data show a significant change5 or failure

of any attribute, the applicant should also submit 6 months of intermediate

data at the time of submission.

Q3(ii): When do intermediate stability studies need to be initiated in the event of failure at

accelerated condition?

A3(ii): An ANDA applicant should start accelerated, intermediate, and long-term

stability studies at the same time so the data are available at the time of

submission if the accelerated stability study fails.

34 See footnote 2.

Ibid.

5 See the International Conference on Harmonisation (ICH) guidance to industry on Q1A(R2) Stability Testing

of New Drug Substances and Products, section 2.2.7.1.

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Contains Nonbinding Recommendations

Q3(iii): If one among the three batches in accelerated conditions shows a significant

change, what should be done?

A3(iii): If accelerated data show a significant change or failure of any attribute in one

or more batches, an applicant should submit intermediate data for all three

batches. In addition, the submission should contain a failure analysis (i.e.,

discussion concerning the observed failure(s)).

Q4: Can stability bracketing and/or matrixing be used to determine the packaging

configurations to be placed on stability for an original ANDA without prior approval

from the Office of Generic Drugs (OGD)?

A4: Yes. You should follow the International Conference on Harmonisation (ICH)

guidance for industry on Q1D Bracketing and Matrixing Designs for Stability

Testing of New Drug Substances and Products6 and its example tables.

Q5(i): If an application that qualifies for the Generic Drug User Fee Act (GDUFA) 10-month

review is filed with 6 months of accelerated and 6 months of long-term data, and there

are no blocking patents or exclusivities, will 24 months of shelf life be granted?

Q5(ii): During the review cycle, will the application need to be updated with 12 months of

long-term data?

A5(i,ii):

FDA will grant a shelf life period of two times the available long-term data at

the time of approval (up to 24 months) following the recommendation of the

ICH Q1E Evaluation of Stability Data (ICH Q1E) guidance,7 provided the

submitted data are satisfactory, and data evaluation and appropriate

commitments are provided in accordance with ICH Q1E. Please refer to the

decision tree (Appendix A) in ICH Q1E. The ANDA should be updated with

12 months of long-term data during the review cycle.

Q6: Can only two lots of finished product at pilot scale batch size ever be considered

sufficient to support the stability of an ANDA for simple dosage forms?

A6: According to the FDA stability guidance, the applicant should submit data

from three pilot scale batches or should submit data from two pilot scale

batches and one small scale batch. This applies to all dosage forms. If the size

of the pilot scale batch does not follow ICH recommendations, the applicant

should provide a justification. See also section C, question 20 for additional

information regarding exceptions.

67 See footnote 2.

Ibid.

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Contains Nonbinding Recommendations

Q7: How is the proposed shelf life supposed to be calculated? Will 6 months of accelerated

data equal 24 months at long-term?

A7: ICH Q1E principles will help in the calculation of shelf life. Data from the

three ANDA submission batches (i.e., 6 months), accelerated data meeting all

criteria (without significant change per ICH Q1A(R2)), and 12 months long-term data without variability will not need statistical evaluation, and with

appropriate post approval stability commitments, can be used to support

extrapolation to a 24 months shelf life.

If there is a significant change in the accelerated data, ICH Q1E, Appendix A,

provides more details regarding when intermediate condition stability data are

recommended.

Q8: Will the recommendation for 6 months accelerated data be met by providing 24 weeks

of data as 12 weeks is typically accepted as equivalent to 3 months?

A8: No. FDA, following the recommendations of ICH stability guidances refers

to timeframes in terms of months and not weeks.

Q9: When a patent is due to shortly expire and there are no approved ANDAs, can we file

with 3 months stability data with a commitment to supply 6 months data when

available?

A9: No. Data recommendations in the FDA stability guidance should be followed

irrespective of patent status.

Q10: How long do the three pilot scale batches, submitted as a part of an ANDA, need to be

stored before destruction?

A10: Sample storage times are discussed in 21 CFR 320.38 and 21 CFR 320.63 in

connection with bioequivalence study samples. In general, ANDA

submission batch samples should be stored for 1 year after approval of the

ANDA, and samples of the drug product used for bioequivalence studies must

be stored following the requirements listed in 21 CFR 320.38 and 21 CFR

320.63. In addition, the guidance for industry on Handling and Retention of

BA and BE Testing Samples8 may be helpful regarding the procedure for

handling reserve samples from relevant bioavailability and bioequivalence

studies. Additional information on sample quantities (for retention purposes)

is discussed in 21 CFR 211.170 (a) and (b), Reserve Samples.

8 See footnote 2.

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Contains Nonbinding Recommendations

B. Drug Master File

Q1: Please clarify the effect of the FDA stability guidance on Drug Master File (DMF)

holders.

Q1(i): How many months of long-term and accelerated data are required when a

“Completeness Assessment” is performed on the DMF? Also, what should the DMF

stability section contain for a Completeness Assessment?

A1(i):

To pass the Completeness Assessment, DMFs should include the stability

protocol, commitments, and data demonstrating that stability studies have

started. The initial and one additional time point for the accelerated studies

and long-term studies are sufficient. If the DMF does not meet the

recommendations under A1(ii) below at the time of the Completeness

Assessment the DMF holder should amend the DMF with updated stability

data to prepare for full scientific review.

Q1(ii): Are stability data from three current good manufacturing practice (CGMP) batches

required to be filed in the DMF to support the API retest date? Also, how many months

of long-term and accelerated data are required for pilot scale batches?

A1(ii): Yes. Per ICH Q1A(R2) data from formal stability studies should be provided

on at least three primary batches9 and the batches should be manufactured to a

minimum of pilot scale10 for the drug substance to be filed in the DMF. These

batches should be made under CGMPs. The FDA stability guidance

recommends 6 months of accelerated data and 6 months of long-term data for

the pilot scale batches to be submitted for a full scientific review of the DMF.

Additional long-term data for all three batches, as the data becomes available

through the proposed retest period, should be submitted as an amendment.

Q2: Will submissions to DMFs be accepted based on stability data from production scale

batches?

A2: Yes. Per ICH Q1A(R2), section II, A, 8, Stability Commitment (2.1.8), the

submission is appropriate if satisfactory stability data from at least three

production batches made under CGMP are filed in the DMF with 6 months of

accelerated data and data for samples stored under long-term conditions that

cover the proposed retest period.

Q3: Should executed batch records for the three batches be included in the DMF

submission?

A3: One representative executed batch record will be sufficient.

910 “Primary batch” is defined in ICH Q1A(R2) Glossary.

See ICH Q1A(R2) Glossary.

5

Contains Nonbinding Recommendations

C. Drug Product Manufacturing and Packaging

Q1: Can the split bulk solution filled into different fill volumes be considered discrete

batches?

To be consistent with ICH Q1A(R2), we recommend that discrete finished

A1:

product batches be produced that represent different batches of bulk solution.

Split filling one batch of bulk solution into different fill volume sizes would

not constitute discrete batches.

Q2: Can you clarify the packaging recommendations for the submission batches for blow-fill-seal containers?

A2:

Blow-fill-seal containers are not an exception from regular packaging and are

usually packaged inside a secondary container or a carton. The secondary

packaging should be included in all three batches. ICH Q1A(R2) addresses

secondary packaging usefulness (see section II, B, 4, Drug Product Container

Closure System (2.2.4)).

Q3: Should all three batches be stored in final proposed packaging?

A3: Yes. You should package all three batches in the container closure system

proposed for marketing. ICH Q1A(R2) addresses this question (see section II,

B, 4, Drug Product Container Closure System (2.2.4)).

Q4: What is the Agency’s position on using different lots of APIs and/or packaging

materials? How many API lots should be used in the manufacture of finished product

lots used to support the ANDA?

A4: It is not necessary to use different lots of packaging material, except in cases

where the packaging material could affect drug product performance and/or

delivery. A minimum of two lots of the drug substance should be used to

prepare the three primary batches of drug product.11

Q5: Should the small scale batches be packaged with commercial equipment? Also, is it

acceptable to package using research equipment or by hand?

A5: Yes. Small scale batches should be packaged with commercial equipment, or

the packaging equipment should be similar to that proposed for use prior to

market distribution. No, it is not recommended to package small scale batches

using research equipment or by hand. Please refer to ICH Q1A(R2) section II,

B, 3, Selection of Batches (2.2.3) and the glossary definition for primary

batches.

11 For nasal aerosols and nasal sprays, you should use three different lots of drug substance.

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Contains Nonbinding Recommendations

Q6: What will the recommendation for secondary packaging be?

A6: We recommend following ICH Q1A(R2) section II, B, 4, Drug Product

Container Closure System (2.2.4).

Q7: What are the recommendations for stability testing data of modified release dosage

forms?

A7: Per ICH Q1A(R2) the applicant should provide data on three batches of all

dosage forms including modified release dosage forms. ICH stability

guidances do not distinguish among different dosage forms.

Q8: What are the recommendations for the submission of oral solutions, ophthalmic

solutions, oral and ophthalmic suspensions, transdermal patches, ointments, creams,

granules for reconstitution, and parenterals?

A8: The applicant should provide three discrete batches and 6 months of

accelerated data and 6 months of long-term data at the time of submission for

all dosage forms. Also, refer to other questions and corresponding answers

that specifically discuss other dosage forms included in this document (e.g.,

questions Q7, Q13).

Q9: Are 6 months of stability data required on all three batches, or would one batch at 6

months and two lots at 3 months be acceptable?

A9: Following ICH stability guidances, 6 months accelerated stability data on all

three submission batches should be provided.

Q10: Should the executed batch records for the three batches be included in the ANDA

submission?

A10: Yes.

Q11: Does all relevant CMC batch information for the three stability batches need to be

included in the application?

A11: Yes. When more than one lot of API or excipients is used, the corresponding

section in Module 3 should contain appropriate CMC information.

Q12: If you are an applicant submitting an ANDA with two API sources, are you required to

perform stability on three batches of drug product for each API source?

A12: If you propose to add additional sources of API for the same drug substance,

you should provide the following CMC information:

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Contains Nonbinding Recommendations

•

•

•

Comparison and justification of comparability (by the applicant) of the

physico-chemical properties and impurities of the drug substance from

each source.

Appropriate stability data on three batches of drug product qualifying

the first API source used in the bioequivalence (BE) studies as

recommended by the FDA stability guidance.

A single pilot scale batch of the drug product bio-strength(s)

manufactured using the second or each of the other proposed API

source(s) used to support the ANDA application, along with

comparative dissolution data.

Appropriate stability data (accelerated and long-term for 6 months at

the time of filing) on the strength(s) manufactured for each API

source. Appropriate stability data may in some cases include

intermediate condition stability data.

•

Q13: What is meant by “small” scale? “Small” is not a defined word in ICH guidance.

What are the packaging expectations from the small batch, as well as from the two

pilot scale batches? Traditionally, ANDAs are submitted with 100,000 units for solid

oral dosage forms. Is this still applicable?

A13: The interpretation of what constitutes a small scale batch for the purpose of

filing ANDAs is further elaborated below for various dosage forms and their

packaging recommendations. Unless specifically noted below, one primary

batch should be fully packaged.

Oral dosage forms

(a) Tablets/Capsules (e.g., immediate release, extended release, chewable,

orally disintegrating and delayed release tablets or capsules): Two of the

three batches should be of at least 10 percent of the proposed production batch

or 100,000 finished dosage units, whichever is greater (i.e., pilot scale

batches). The third batch can be smaller than the 10 percent of the proposed

production batch, but should not be less than 25 percent of the pilot scale

batch. We recommend stability data be generated for the three ANDA

submission batches in the proposed marketing container. A minimum of

100,000 units in all proposed presentations is recommended. Representative

samples from all three batches must be packaged in a sufficient number of

proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and

211.166(b)

.

(b) Powders/Solutions/Suspensions: Two of the three batches should be at

least 10 percent of the proposed maximum size commercial batch. The third

batch can be smaller than 10 percent of the proposed commercial batch, but

should not be less than 25 percent of the pilot scale batch. To capture

variability introduced by packaging, the product from all the batches should

be used in the packaging process. We recommend packaging representative

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Contains Nonbinding Recommendations

samples from all three batches of a sufficient number of proposed marketing

presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b)

.

Parenterals

Solutions/Powders for Solutions (lyophilized cakes)/Suspensions/Sterile

Topicals (Ophthalmic and Otic drug products): Two of the three batches

should be at least (a) 10 percent of the proposed maximum size commercial

batch (i.e., pilot scale size), (b) 50 L (per batch if the fill volume

configurations per vial is larger than 2.0 mL), or (c) 30 L (per batch if the fill

volume size is up to 2.0 mL) whichever is larger including packaging.12

When multiple fill volume sizes are proposed by the applicant (e.g., 1 mL, 2

mL, and 3 mL), then 50 L per batch size is recommended. The third batch can

be smaller than 10 percent of the proposed commercial batch, but should not

be less than 25 percent of the pilot scale batch (with packaging).13 To capture

variability introduced by packaging, the product from each of multiple fill

volume batches should be used in the packaging process. We recommend

manufacturing all the batches to meet sterility requirements. Packaging

requirements are also discussed in 21 CFR 211.166(a) (1-5) and 211.166 (b).

Transdermal Patches

Two of the three batch sizes for each strength should be at least 10 percent of

the proposed commercial production batch (with packaging) or 25,000 units

(for each strength), whichever is greater. The third batch can be smaller than

10 percent of the proposed commercial batch (with packaging), but should not

be less than 60 percent of the pilot scale batch (with packaging). For

transdermal matrix products, where different strengths are identified by the

transdermal patch size (surface area), to comply with the three batch size

recommendation, we recommend providing data on patches manufactured

using three distinct matrix laminates at the time of submission (each laminate

can be cut to support multiple strengths in the application, where applicable).

We recommend you contact the appropriate OGD review division if you are

manufacturing transdermal patches using other technologies (e.g., reservoir).14

You should include a representative sample from all three batches using

different components of backing, adhesives, release liner, and other critical

excipients used in packaging a sufficient number of proposed marketing

presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b).

1213 Amount packaged = 50 L or 30 L –(minus) filling/flushing loss.

Ibid.

14

See the guidance for industry on Residual Drug in Transdermal and Related Drug Delivery Systems.

9

Contains Nonbinding Recommendations

Topicals

(a) Creams/Lotions/Gels: For nonsterile semi-solid dosage forms,15 the two

pilot scale batches should be at least 100 Kg or 10 percent of the production

batch, whichever is larger, packaged.16 The third batch can be smaller than 10

percent of the proposed commercial batch, but not less than 40 percent of the

pilot scale batch, packaged.17 Packaging requirements are also discussed in

21 CFR 211.166(a) (1-5) and 211.166 (b).

(b) Inhalation Solutions/Nasal Sprays (nasal nonmetered dose atomizer):

Please refer to the following guidances for industry for information: Nasal

Spray and Inhalation Solution, Suspension, and Spray Drug Products –

Chemistry, Manufacturing, and Controls Documentation, and Bioavailability

and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local

Action.18

Please contact OGD to discuss other dosage forms and/or routes of

administration not covered in this document.

Q14: Is it acceptable to use a technical grade of the drug substance for the small scale

batches or one of the two pilot scale batches of finished drug product?

A14: No. The applicant should follow CGMP requirements for ANDA submission

as they relate to drug substance and finished drug product. Because the drug

substance quality can affect the drug product stability, the drug substance used

for the ANDA batches (supporting the application) should be of the same

quality intended for the market product. We would consider data from the use

of a different grade drug substance for a product as supporting data.

Q15: Do the small scale batches need to be manufactured in accordance with all CGMP

regulations, or is it acceptable to manufacture the small scale batches in a research

setting?

A15: All ANDA submission batches should be made following CGMP.

Q16: Should the small scale batches meet the same finished product specification as the pilot

scale batches?

A16: Yes. The finished product specification should be the same for all three

ANDA submission batches submitted.

15 See the CDER Data Standards Manual, Drug Nomenclature Monographs (Dosage Form)

/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/DataStandardsManualmonographs/.

16 Amount packaged = 100 Kg or Larger –(minus) filling/flushing loss.

17 Ibid.

18 See footnote 2.

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Q17: For sterile products, is it acceptable to manufacture the small scale batches in a

nonsterile facility and allow variance from sterility and particulate criteria?

A17: No. To be consistent with ICH Q1A(R2), sterile product small scale batches

should be representative of the manufacturing processes to be applied to a full

production scale batch, and therefore should not be manufactured in a

nonsterile facility. Sterility is a critical quality attribute (CQA) for sterile

products.

Q18: Should small scale batches be produced at the proposed commercial site?

A18: Yes. Small scale batches should be produced at the proposed commercial site.

The primary batch information submitted in the application is used to support

the proposed commercial product manufacture. Product batches produced at a

different site than the proposed commercial site would not be considered as

primary batches.

Q19(i): In cases where an intermediate bulk material is identical between the various

strengths (dose proportional blends, bulk solutions, etc.), is it sufficient to perform

stability on one lot of each strength, when each strength is produced from a separate

intermediate bulk?

A19(i): No. For ANDAs that contain multiple strengths (that are dose proportional),

three separate intermediate bulk granulations (or blends) should be

manufactured. One batch of bulk granulation (or blend) should be used to

manufacture all the strengths proposed. The other two bulk granulations (or

blends) can be used to manufacture only the lowest and the highest strengths,

in addition to the strength used in BE studies (i.e., the strength(s) tested in the

BE studies should have three batches). Stability testing should still use all

three batches of drug product.

Q19(ii): Are differences in the capsule shell (i.e., imprint, color, size, etc.), allowed in cases

where a multi-strength capsule product is dose-proportional across all strengths (based

on common bead blend)?

A19(ii): Yes differences in the capsule shell are allowed in the described case.

Q20: What are the criteria for an exception to the recommendations regarding minimum

size for pilot scale for ANDA submission batches? What justification would be needed

if we wanted to deviate from these guidance recommendations?

A20: The submission ANDA batches can have a smaller size than the established

pilot scale, according to the ICH definition, when any one of the following

circumstances prevails:

• The reference listed drug product has an orphan drug designation.

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•

•

Use of a controlled drug substance is based on a Drug Enforcement

Administration allocation.

The test batch size is the same as the commercial batch size with the

commitment that a prior approval supplement (PAS) will be provided

when there is a scale-up.

Q21: Are scale-up and postapproval changes (SUPAC) level one and two variations and

changes permitted among the three ANDA submission batches for components and

composition?

A21: No. The three ANDA submission batches should maintain the chosen formula

based on product development studies for components and composition.

Q22: Can FDA provide specific examples of cases where statistical analysis is required and

the type of statistical analysis needed?

A22: The FDA stability guidance recommends analysis of data in accordance with

ICH Q1E, Appendix A. The flowchart in that guidance provides clear

situations where analysis is normally recommended or unnecessary. In

addition, ICH Q1E B.7 figures provide example diagrams for assay and

degradation products that illustrate how plots should be generated for the three

batches using regression lines and upper and lower confidence limits.

Q23: How many batches of drug product should be tested for split-portions of scored tablets?

A23: In general, one batch testing for each scored strength on the split tablets will

suffice, as recommended in the guidance for industry, Tablet Scoring:

Nomenclature, Labeling, and Data for Evaluation.19

Q24: For drug products that include placebo tablets, how many batches (of placebo tablets)

are required for submission? Is 6 months of stability data on the placebo tablets needed

if the ANDA is submitted after the June 2014 deadline?

A24: One batch of placebo tablets with full CMC information should be included at

the time of ANDA submission; however, the final packaging presentation

(containing the placebo tablets) should have data from accelerated and long-term stability testing. Six months of accelerated and long-term stability data

are recommended for the entire packaging presentation including placebo

tablets, where applicable, at the time of submission.

D. Amendments to Pending ANDA Application

Q1: What are the recommendations for amendments and responses filed to pending

ANDAs after issuance of the final FDA stability guidance?

19 See footnote 2.

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A1: All amendments submitted to pending ANDAs after the effective date of the

final FDA stability guidance will be held to the standards in place concerning

stability data at the time of the original ANDA submission, unless there is a

concern with the submitted stability data.

Stability Studies

E.

Q1: What will be the expected testing time points on accelerated conditions?

A1: The applicant should test at 0 (initial release), 3, and 6 months; for additional

time points on accelerated conditions, please follow ICH Q1A(R2)

recommendations for all ANDAs.20

Q2: Can the Agency clarify expectations for the storage positions for products placed into

the stability program?

A2: For primary batches of liquids, solutions, semi-solids, and suspensions, the

product should be placed into an inverted (or horizontal) position and an

upright (or vertical) position. For routine stability studies, the applicant

should pick the worst case orientation for the study.

Q3: When and how are reconstitution/dilution studies performed?

A3: Recommendations listed in ICH Q1A(R2), section II, B, 7, Storage Conditions

(2.2.7) should be followed for all three batches. These studies should be

performed when the drug product is labeled for reconstitution or dilution.

Q4: What types of containers are classified as semipermeable containers, and can the

Agency clarify the stability expectations for the drug products in semipermeable

containers?

A4: Examples of semipermeable containers are provided in the ICH Q1A(R2)

glossary. The recommendations for stability expectations for semipermeable

containers are detailed in ICH Q1A(R2) section II, B, 7, c. Drug products

packaged in semipermeable containers (2.2.7.3).

Q5: Can the Agency clarify expectations around the number of batches to support tests

such as preservative effectiveness and extractable leachable testing?

A5: One of the primary batches of the drug product should be tested for

antimicrobial preservative effectiveness (in addition to preservative content) at

the end of the proposed shelf life. The drug product specification should

20 This recommendation also applies to nasal spray, inhalation solution, suspension, aerosols, and liposomal drug

products.

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include a test for preservative content, and this attribute should be tested in all

stability studies.

Extraction/leachable studies are generally one-time studies; however, if

multiple types of containers/closures are employed for packaging, then

additional studies could be recommended.

Q6: When are in-use stability studies needed?

A6: Please refer to response A3 under section E, Stability Studies.

Q7: Are there changes to postapproval protocols and commitments when ICH stability

guidances are implemented because of scale or type of batches submitted?

A7: ICH Q1A(R2), section II, B, 8, Stability Commitment (2.2.8) addresses this

question. Section 2.1.8 provides information regarding stability commitment

for drug substances.

Also, ANDAs and DMFs should include a commitment to place one batch of

drug product and drug substance, respectively, into the annual long-term

stability program, and to provide stability data in the annual reports.

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