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., 4th 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 
 
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 
i  Contains Nonbinding Recommendations 
 
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 FDAs 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. 
 
  1  Contains Nonbinding Recommendations 
 
 
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 
  2  Contains Nonbinding Recommendations 
 
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 
ANDAs 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 CDERs 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.  
  3  Contains Nonbinding Recommendations 
 
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 FDAs 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 products 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 FDAs 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 products 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). 
  4  Contains Nonbinding Recommendations 
 
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 
  5  Contains Nonbinding Recommendations 
 
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). 
  6  Contains Nonbinding Recommendations 
 
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.  
  7  Contains Nonbinding Recommendations 
 
 
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. 
   
   
  8  Contains Nonbinding Recommendations 
 
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)? 
 
   
  9  Contains Nonbinding Recommendations 
 
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)  
 
  10