Questions and Answers on Quality Related Controlled Correspondence Guidance for Industry: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Questions and Answers
on Quality Related
Controlled
Correspondence
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
September 2021
Pharmaceutical Quality

Questions and Answers
on Quality Related
Controlled
Correspondence
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4 th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
September 2021
Pharmaceutical Quality

Contains Nonbinding Recommendations
i
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 1
III. 	QUESTIONS & ANSWERS ............................................................................................ 2
1. 	Bracketing/Matrixing .................................................................................................................... 2
2. 	Container-Closure Changes .......................................................................................................... 2
3. 	Dissolution ...................................................................................................................................... 4
4. 	Microbiology (Endotoxin testing) ................................................................................................. 5
5. 	Number of Batches ......................................................................................................................... 7
6. 	Orientation ..................................................................................................................................... 7
7. 	Packaging ........................................................................................................................................ 8
8. 	Scoring and Split Tablet Testing .................................................................................................. 9
9. 	Size and Shape of Generic Solid Oral Dosage Forms ............................................................... 10

Contains Nonbinding Recommendations
1
Questions and Answers on Quality Related Controlled
Correspondence
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
I. 	INTRODUCTION
This questions and answers (Q&A) guidance provides FDA’s current thinking on quality-related
scientific and regulatory topics that appear frequently in controlled correspondence submissions.
The contents of this document do not have the force and effect of law and are not meant to bind
the public in any way, unless specifically incorporated into a contract. This document is
intended only to provide clarity to the public regarding existing requirements under the
law. FDA guidance documents, including this guidance, should be viewed only as
recommendations, unless specific regulatory or statutory requirements are cited. The use of the
word should in Agency guidance means that something is suggested or recommended, but not
required.
II. 	BACKGROUND
The Office of Pharmaceutical Quality (OPQ) reviews correspondence from generic drug
manufacturers and related industry or their representatives related to generic drug development
(i.e., controlled correspondence submissions) requesting information regarding chemistry,
manufacturing, and controls, as well as product quality microbiology for generic drugs. OPQ
also reviews controlled correspondence inquiries related to Type II drug master files for drug
substances submitted in support of generic drug applications. OPQ has observed that the same
questions are frequently received in multiple controlled correspondence submissions. These
Q&A are intended to proactively respond to those scientific and regulatory topics that appear
frequently in controlled correspondence addressed by OPQ, thereby allowing industry to move
forward with certain generic drug development activities without the need to submit controlled
correspondence to FDA.
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and
Research at the Food and Drug Administration. You may submit comments on this guidance at any time. Submit
comments to Docket No. FDA-2017-D-6821 (available at https://www.regulations.gov/docket?D=FDA-2017-D-
6821). See the instructions in that docket for submitting comments on this and other Level 2 guidances.

Contains Nonbinding Recommendations
2
III. 	QUESTIONS & ANSWERS
The Q&A below were derived from numerous controlled correspondence submissions addressed
by OPQ. We recommend that these Q&A be reviewed before submitting a controlled
correspondence for one of the scientific and regulatory topics denoted below.
1. 	Bracketing/Matrixing
Question:
Is it acceptable to use a bracketing approach for the manufacture of the exhibit batches of a
generic drug product with multiple strengths produced from common bulk granulations (or
blends)? Do all of these exhibit batches need to be put into the stability program?
Answer:
A bracketing approach is acceptable for a drug product with multiple strengths, as long as the
active and inactive ingredients are in the same proportion between the different strengths (i.e.,
the strengths are dose proportional). According to the FDA guidance for industry ANDAs:
Stability Testing of Drug Substances and Products Questions and Answers (May 2014), for
abbreviated new drug applications (ANDAs), 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. Three bulk granulations (or blends)
should be used to manufacture the strength(s) tested in the bioequivalence (BE) studies.
Stability data should be provided for three batches of the highest strength and three batches of
the lowest strength, and three batches of the strength(s) tested in the BE studies if the strength
used in the BE study was not the highest or lowest strength. Release data should be provided for
all the batches that were manufactured.
Section Reference:
FDA guidance for industry ANDAs: Stability Testing of Drug Substances and Products
Questions and Answers (May 2014)
2. 	Container-Closure Changes
Question 1:
If the reference listed drug (RLD) is a sterile injectable drug product packaged in an ampule, can
the generic product be packaged in a vial?
Answer 1:
A proposed generic drug product is not required to have the same container closure system
(CCS) as the RLD. However, the ANDA generally must contain information to show that the
proposed generic drug product has the same conditions of use and the same labeling, with certain

Contains Nonbinding Recommendations
3
permissible differences, as the RLD.2 Refer to FDA guidance for industry Determining Whether
to Submit an ANDA or a 505(b)(2) Application (May 2019).
The proposed CCS will be evaluated during the review process.3 In the assessment of an
ANDA’s proposed CCS, the Agency will, among other things, evaluate any differences in the
proposed CCS relative to the RLD CCS and determine whether these differences would result in
the proposed generic drug product not having the same conditions of use and the same labeling
(with certain permissible differences) as the RLD.
You should follow the recommendations in the FDA guidance for industry Container Closure
Systems for Packaging Human Drugs and Biologics: Chemistry, Manufacturing, and Controls
Documentation (July 1999) for the chemistry, manufacturing, and controls (CMC) information
that should be submitted in the ANDA.
Question 2:
Should a proposed generic ophthalmic drug product have the same cap color as the RLD when
that color is not in line with the American Academy of Ophthalmology (AAO) recommendation?
Answer 2:
As described in the guidance for industry Container Closure Systems for Packaging Human
Drugs and Biologics (July 1999), the cap color of ophthalmic drug products should follow AAO
color codes, or the applicant should provide adequate justification for deviations from the AAO
color coding system. For the proposed generic drug product, the Agency recommends that the
color be in accordance with AAO recommendations.
Section References:
Section 505(j)(2)(A)(i) and (j)(2)(A)(v) of the FD&C Act
American Academy of Ophthalmology (AAO) recommendations:
https://www.aao.org/about/policies/color-codes-topical-ocular-medications
FDA guidance for industry Container Closure Systems for Packaging Human Drugs and
Biologics: Chemistry, Manufacturing, and Controls Documentation (July 1999)
FDA guidance for industry Determining Whether to Submit an ANDA or a 505(b)(2) Application
(May 2019)
2 See section 505(j)(2)(A)(i) and 505(j)(2)(A)(v) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)(21
U.S.C. 355(j)(2)(A)(i) and 21 U.S.C. 355(j)(a)(A)(v)).
3 In this Q&A, the term review also means assessment, which is the term that CDER’s Office of Pharmaceutical
Quality and Office of Generic Drugs will generally use in place of review. Assessment means the process of both
evaluating and analyzing submitted data and information to determine whether the application meets the
requirements for approval and documenting that determination.

Contains Nonbinding Recommendations
4
3. 	Dissolution
Question:
If the dissolution method for a proposed generic drug product is not available in the FDA
Dissolution Methods Database or in the United States Pharmacopeia (USP), can the Agency
provide the dissolution method for the product?
Answer:
When neither the USP dissolution method nor the FDA’s Dissolution Methods Database provide
a dissolution method for a product, the Agency recommends that applicants develop an
appropriate and discriminating dissolution method for the proposed drug product, taking into
consideration the method development and validation principles described in the USP General
Chapter <711> Dissolution or General Chapter <724> Drug Release, and USP General Chapter
<1092> The Dissolution Procedure: Development and Validation.
Please note that the Agency considers that dissolution should be product-specific and therefore
the selection of the dissolution method and setting of the acceptance criterion/criteria should be
based on the dissolution data generated for the proposed drug product. Therefore, for the in vitro
dissolution method to be used for quality control (QC) of your proposed drug product, the
Agency recommends that irrespective of the source of the proposed dissolution method (USP,
FDA, or in-house), additional dissolution studies be conducted to demonstrate the suitability of
the selected method for the proposed drug product. For this purpose, the Agency recommends
that the report for the development and validation of an in-house method or verification of a USP
method being proposed for dissolution QC testing be provided in the drug product’s ANDA
submission, specifically in Module 3.2.P.5.4 The report should include complete
information/data on: i) solubility of the drug substance(s); ii) adequacy of the selected
dissolution testing conditions (i.e., apparatus, rotation speed, medium, volume, sampling times,
etc.); iii) validation/verification of the robustness of the selected dissolution method; iv)
validation/verification of the analytical method used to assay the dissolution samples; and v)
demonstration of the discriminating ability of the dissolution method [for modified release
products and immediate release drug products containing low soluble drug substance(s)].
Additionally, for generic immediate release solid oral drug products including a highly soluble
drug substance (per the Biopharmaceutics Classification System (BCS) definition5), the Agency
recommends that dissolution QC testing be conducted as described in FDA’s guidance for
industry Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage
Form Drug Products Containing High Solubility Drug Substances (August 2018). The
information/data supporting the high solubility of the drug substance(s), as described in the BCS
guidance (ICH guidance for industry M9 Biopharmaceutics Classification System-Based
Biowaivers (May 2021)) should be included in the ANDA submission (Module 3.2.P.5 or
Module 3.2.S.1.3), in addition to the proposed drug product’s dissolution data.
4 See FDA guidance for industry ANDA Submissions: Content and Format of Abbreviated New Drug Applications
(June 2019).
5 See ICH guidance for industry M9 Biopharmaceutics Classification System-Based Biowaivers (May 2021).

Contains Nonbinding Recommendations
5
Please note that the acceptability of the proposed dissolution method and acceptance criterion(a)
will be determined during the ANDA review process based on the totality of the provided
dissolution data/information and additional data/information may be requested during the
submission review process.
Section References:
USP General Chapter <711> Dissolution
USP General Chapter <724> Drug Release
USP General Chapter <1092> The Dissolution Procedure: Development and Validation.
Guidance for industry ANDA Submissions: Content and Format of Abbreviated New Drug
Applications (June 2019)
Guidance for industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms
(August 1997)
Guidance for industry Dissolution Testing and Acceptance Criteria for Immediate-Release Solid
Oral Dosage Form Drug Products Containing High Solubility Drug Substances (August 2018)
International Council for Harmonisation (ICH) guidance for industry M9 Biopharmaceutics
Classification System-Based Biowaivers (May 2021)
4. 	Microbiology (Endotoxin testing)
Question 1:
How should a bacterial endotoxins test acceptance criterion be determined for the finished drug
product?
Answer 1:
The finished drug product bacterial endotoxins test acceptance criterion should be determined
based on the maximum dose that can be delivered within one hour as interpreted from the
package insert. Special considerations can include:
• 	Additional doses that may be administered after the initial dose,
• 	Maintenance doses administered after an initial bolus dose,
• 	Incremental dose increases, and
• 	For anesthetics or other drugs for which repeat doses are administered until a desired
clinical outcome is achieved, the maximum number of potential doses at the minimum
specified time interval between doses that could be administered in a one-hour period.
The USP General Chapter <85> Bacterial Endotoxins Test recommended maximum endotoxin
exposure is NMT 5 EU/kg (interpreted as within 1 hour) for most drugs based on an average

Contains Nonbinding Recommendations
6
patient weight of 70 kg. For drugs administered to pediatric patients, consult the WHO-CDC
growth charts6 for average weight at the youngest patient age for the proposed generic drug.
For drug products administered topically on a body surface area basis, the recommended
maximum endotoxins exposure is 100 EU per square meter.
For drug products administered intrathecally (or epidurally due to risk of inadvertent intrathecal
administration), the maximum recommended exposure is 0.2 EU/kg (in 1 hour).
Please note that USP monographs may contain historical bacterial endotoxins test acceptance
criteria that may not reflect the maximum dose that can be interpreted from the current drug
package insert of the RLD. The proposed endotoxin limit for a proposed generic product should
be based on dosing in the current RLD package insert. If the calculated limit is higher than the
USP monograph limit, we recommend that applicants submit a controlled correspondence to
confirm acceptability with the Agency prior to submission of the ANDA.
Question 2:
Is it acceptable to omit bacterial endotoxin limits in the proposed specification for a topical
ophthalmic drug product?
Answer 2:
Topical ophthalmic drug products are generally not required to be tested for bacterial endotoxins.
Therefore, the finished product release and stability specifications for topical ophthalmic
products are not required to include testing for bacterial endotoxins unless the labeling indicates
that the product is nonpyrogenic. However, if the labeling for a topical ophthalmic product
includes directions for use on an abraded eye and/or use during surgery, a bacterial endotoxin
specification for the drug product may be appropriate.7
Please note that this answer is specific to this question and does not address other ophthalmic
drug products, dosage forms, or combination products that include an ophthalmic drug product
component.
Section References:
Centers for Disease Control and Prevention (CDC) growth charts:
https://www.cdc.gov/growthcharts/who_charts.htm
USP General Chapter <85> Bacterial Endotoxins Test
USP <771> Ophthalmic Products — Quality Tests
FDA guidance for industry Pyrogen and Endotoxins Testing: Questions and Answers (June
2012)
6 See https://www.cdc.gov/growthcharts/who_charts.htm for growth charts.
7 See FDA guidance for industry Pyrogen and Endotoxins Testing: Questions and Answers (June 2012).

Contains Nonbinding Recommendations
7
5. 	Number of Batches
Question 1:
If an applicant intends to have more than one drug product manufacturing site in an abbreviated
new drug application (ANDA), how many exhibit batches should be provided for each site?
Answer 1:
Stability data from three exhibit batches manufactured at each drug product manufacturing site
for each strength should be submitted in the ANDA, or a bracketing approach as described in
Section 2 above should be used. The applicant should submit data from at least three batches of
drug product that can include any one of the following batch sizes:
‒ 	Three pilot scale batches, three batches that meet the minimum dosage form batch
recommendations, whichever is larger, or three commercial scale batches
‒ 	Two pilot scale batches or two batches that meet the minimum dosage form batch
recommendations, whichever is larger, and one small scale batch
‒ 	Two commercial scale batches and one small scale batch
This data should be submitted from each drug product manufacturing site.
Section References:
FDA guidance for industry ANDAs: Stability Testing of Drug Substances and Products (June
2013)
FDA guidance for industry ANDAs: Stability Testing of Drug Substances and Products
Questions and Answers (May 2014)
FDA guidance for industry on Q1A(R2): Stability Testing of New Drug Substances and Products
(November 2003)
6. 	Orientation
Question 1:
If the generic drug product is a “for injection” (sterile lyophilized powder), can stability data for
exhibit batches be generated using only one orientation?
Answer 1:
According to the FDA guidance for industry ANDAs: Stability Testing of Drug Substances and
Products Questions and Answers (May 2014), “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.” Since lyophilized powders do not fall under one of these
categories, exhibit batches for drug products that are sterile lyophilized powders may be placed
on stability in one orientation alone, provided that the ANDA submission includes an adequate
justification for the orientation selected.

Contains Nonbinding Recommendations
8
Question 2:
If a product is packaged using blow-fill-seal technology and the container is composed of a
single material, can stability data for exhibit batches be generated using only horizontal or
upright orientation?
Answer 2:
For products packaged using blow-fill-seal technology, stability studies on exhibit batches may
be performed in one orientation alone, as long as the orientation provides maximal contact for
the drug product with container closure system components, including the seal and neck. See
guidance for industry Nasal Spray and Inhalation Solution, Suspension, and Spray Drug
Products — Chemistry, Manufacturing, and Controls Documentation (July 2002).
Therefore, stability testing conducted in the horizontal position would be acceptable if adequate
justification is provided in the submission to demonstrate that the position selected represents the
maximum contact of the drug product and container closure system components. Stability testing
conducted only in the upright or vertical position would generally be unacceptable due to the
lack of exposure of the drug product to the seal and the twist-off neck area.
Section References:
FDA guidance for industry ANDAs: Stability Testing of Drug substances and Products –
Questions and Answers (May 2014)
FDA guidance for industry Nasal Spray and Inhalation Solution, Suspension, and Spray Drug
Products — Chemistry, Manufacturing, and Controls Documentation (July 2002)
7. 	Packaging
Question 1:
Should the three exhibit batches for a generic product be fully packaged in the proposed
marketed packaging?
Answer 1:
In accordance with FDA guidances for industry on Q1A(R2): Stability Testing of New Drug
Substances and Products (November 2003) and ANDAs: Stability Testing of Drug Substances
and Products Questions and Answers (May 2014), one of the three exhibit batches should be
completely packaged using all the proposed marketed configurations. This batch could be either
a pilot scale or a small scale batch. The other two exhibit batches should be packaged in
sufficient quantity to comply with 21 CFR 211.166(a)(1-5) and 211.166(b). All batches,
including the small scale batch, should be packaged using commercial packaging equipment or
similar equipment. Different batches of packaging material should be used where the packaging
material could affect drug product performance and/or delivery.

Contains Nonbinding Recommendations
9
Question 2:
For a combination product consisting of a pen injector device with an injectable drug product
filled in a cartridge, is it acceptable to package only the amount required for stability into the
cartridges and pen injector device for the three exhibit batches submitted in the ANDA?
Answer 2:
For a pen injector device used with an injectable drug product filled in a cartridge and other
similar products, we recommend that all three of the exhibit batches be completely filled into
cartridges. As described in FDA guidances for industry Q1A(R2): Stability Testing of New Drug
Substances and Products (November 2003) and ANDAs: Stability Testing of Drug Substances
and Products Questions and Answers (May 2014), one of the three batches should be entirely
assembled into the pen injector devices. The other two primary stability batches should have a
sufficient number of samples packaged and assembled into the pen injector devices for stability
and reserve samples, in accordance with 21 CFR 211.166(a)(1-5), 211.166(b), and 211.170.
Section References:
FDA guidance for industry on Q1A(R2): Stability Testing of New Drug Substances and Products
(November 2003)
FDA guidance for industry ANDAs: Stability Testing of Drug Substances and Products
Questions and Answers (May 2014)
21 CFR 211.166(a)(1-5), 211.166(b), and 211.170
8. 	Scoring and Split Tablet Testing
Question 1:
Is the reference listed drug (RLD) considered to have functional scoring when it is not mentioned
in the labeling and half the tablet does not match the lowest labeled dose?
Answer 1:
Any scoring on the RLD should be considered functional scoring, and therefore, the generic
product should have similar scoring. According to FDA guidance for industry Tablet Scoring:
Nomenclature, Labeling, and Data for Evaluation (March 2013), “scoring configuration of
generic drug products should be the same as the RLD.” We recommend that split tablet testing
be performed and the data submitted in the ANDA; otherwise, the Agency may refuse to receive
the ANDA due to inconsistent scoring configuration between the RLD and the test product.
(FDA guidance for industry ANDA Submissions – Refuse-to-Receive Standards, Rev. 2
(December 2016)).
Question 2:
If the RLD has partial score lines, can the proposed generic product have a full score line(s)?

Contains Nonbinding Recommendations
10
Answer 2:
When the RLD has partial score lines, the generic can have a full score line(s) to produce partial
doses equivalent to that of the RLD as indicated in the approved labeling. Scoring between the
RLD and generic products should be consistent to ensure that the patient is able to adjust the
dose by breaking the tablet in the same manner, such that the patient can switch from the RLD to
the generic product without encountering problems related to the dose. Additionally, consistent
scoring assures that neither the generic product nor the RLD has an advantage in the marketplace
because one is scored and one is not . For additional information, see FDA guidance for industry
Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation (March 2013).
Section References:
FDA guidance for industry ANDA Submissions – Refuse-to-Receive Standards, Rev. 2
(December 2016)
FDA guidance for industry Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation
(March 2013)
9. 	Size and Shape of Generic Solid Oral Dosage Forms
Question:
If the reference listed drug (RLD) has been discontinued and there is no information on its shape
and size, is it acceptable to use the shape and size of the FDA designated reference standard to
design the generic product?
Answer:
In cases where the RLD is not available because it has been discontinued for reasons not
associated with safety and efficacy, FDA may have designated a reference standard. The FDA
designated reference standard is recommended to be used in in-vivo bioequivalence studies as
well as comparative in-vitro studies. In this situation, if information on the size and shape of the
RLD are not available, it is acceptable to use the size and shape of the FDA designated reference
standard to develop the generic product provided it meets the recommendations in the size and
shape guidance.
Section References:
FDA guidance for industry Referencing Approved Drug Products in ANDA Submissions (Oct
2020)
FDA guidance for industry Size, Shape, and Other Physical Attributes of Generic Tablets and
Capsules (June 2015)