Analytical methods related to the drug substance.
Verification of compendial methods: If a compendial analytical method is used, the ANDA sponsor is not required to provide complete validation. However, documentation
of suitability of use needs to be established based on 21 CFR 211.194(a)(2) of the current good manufacturing practice (CGMP) regulations, which states that "the suitability of all testing
methods used shall be verified under actual conditions of use" (16). ANDA sponsors are requested to refer to USP <1226> for
verification of compendial methods (8).
USP methods versus in-house methods:
In cases where there is an USP monograph for the drug substance and the sponsor decides to use an in-house method, a comparison to demonstrate the equivalence
of the methods is considered valuable. Again, the impurity profile of the API used by the sponsor may be significantly different
from the source of the USP monograph, based on the synthetic route. Thus, it is important to demonstrate that the USP method is capable of separating all the possible process impurities and degradants since in the event of any dispute the
USP method is considered the method of resolution.
Adoption of DMF holder's method: ANDA sponsors frequently state that they have adopted the DMF holder's methods for analysis of the drug substance and refrain
from providing the details of validation. It is acceptable to adopt the DMF holder's methods for analysis of the API. However,
because the ANDA is a standalone document, the information regarding validation of the method needs to be complete. The sponsor
may provide details of the validation from the DMF holder with additional information regarding its own verification of the
HPLC method versus titration for assay of the active pharmaceutical ingredient:
It is generally recommended that a specific, stability-indicating procedure is included for assay of the API. In many cases
it is possible to employ the same procedure (e.g., high-performance liquid chromatography) for both assay of the API and quantification
In some cases where use of a nonspecific assay is justified, other supporting analytical procedures should be used to achieve
overall specificity. For example, where titration is adopted to assay the drug substance, the combination of the assay and
a suitable impurities test could be used. However, there may be occasions, when a non-specific titration assay is not preferred
due to the inherent nature of the API and the impurities. For example, when the API is basic in nature and so are most of
the impurities, a perchloric acid titration may yield to a "false–high" assay result due to non-specific titration of the
API and the major impurities. In these cases, the ANDA sponsors may be requested to revert to a specific assay method.
ANDA sponsors frequently report results of analysis as "conforms" versus providing the quantitative figures. This may only
be acceptable in case of limit tests. In all quantitative analysis, results above limit of quantitation need to be reported
Occasionally, sponsors provide quantitative values that are below the limit of quantitation (LOQ). We recommend that sponsors
in these cases not report numerical values below the LOQ, as they have minimal significance. Additionally, the limit of detection
(LOD) and limit of quantitation (LOQ) should be provided for all methods used to control impurities and residual solvents
in the API.
2.3.S.5 Reference Standards
Most ANDA sponsors provide satisfactory information when it comes to API reference standards. However, one common deficiency
is cited with respect to the impurity reference standard used in the proposed methods and/or the standards used during method
validation. The sponsor should provide at a minimum the source, lot number, and purity of the impurity standards. This information
is often found in the method validation report, and if this is the case, a reference to the relevant section or report can
be provided in section 2.3.S.5.
Two other common questions from the reviewers' regard standard spectra and revision of secondary or qualified standard specifications.
Representative spectra and chromatograms should be provided for reference standards used. With respect to revision of secondary
or qualified standards, any applicable changes to the drug substance specifications should be made to the specifications of
the reference standard. An additional recommendation is that reference standards meet all relevant acceptance criteria.
2.3.S.6 Container Closure System and 2.3.S.7 Stability
With respect to the last two sections of 2.3.S, questions are not routinely asked as these portions usually reference the
associated DMF(s). Questions that do arise regarding the drug substance container closure systems (section 2.3.S.6) are often
prompted by "repackaging" of the drug substance by the ANDA sponsor. This action shifts the responsibility of storage and
stability of the drug substance from the DMF holder to the ANDA sponsor, and the sponsor may have to provide detailed information
and justification for the proposed container closure system and its effect on the drug substance's stability. Stability studies
used to support the container closure system should be included in sections 2.3.S.7 and 3.2.S.7 of the ANDA. Additionally,
if storage conditions differ from what is recommended (e.g. temperature, inert atmosphere, etc.) and/or justified by the DMF
holder, drug substance stability data are recommended to support the conditions.
An additional question that arises in section 2.3.S.7 asks the ANDA sponsor to provide the justification for the retest or
expiry date if these are not supported by the DMF holder information provided. For example, if the DMF holder certificate
of analysis reports a 2-year expiry date and the ANDA sponsor lists a 5-year retest date, the discrepancy will need to be
clarified and justified. Sometimes, based on DMF review, the chemist is aware that the expiration date proposed by the DMF
holder is not justified by the information submitted in the DMF. In these cases, the deficiency cited to the ANDA sponsor
may be commensurate to that cited by the DMF holder.
It is well known that successful development of a drug product begins by understanding the drug substance's physico-chemical
characteristics as well as adequate control of the properties, which are critical to the drug product's quality, efficacy,
and safety. The authors hope that the information provided in this article will shed some light on the common deficiencies
cited during the review of ANDAs. The information provided herein is intended to assist ANDA sponsors in building quality
into their submissions so that they may convey meaningful drug-substance information to FDA, with the goal of reducing instances
of these common deficiencies from being cited.
1 Numbering in section heads correspond to those in the Common Technical Document (CTD).
The authors wish to acknowledge Lawrence Yu, PhD, OGD Deputy Director for Science, and Vilayat A. Sayeed, PhD, Director Division
III, OGD, for their encouragement and invaluable insight.
The views and opinions expressed in this article are only those of the authors and do not necessarily reflect the views or
policies of FDA.
Aloka Srinivasan, PhD*, and Robert Iser, M.S., are team leaders at the Office of Generic Drugs within the Office of Pharmaceutical Science, under the US Food and Drug
Administration's Center for Drug Evaluation and Research, Aloka.Srinivasan@fda.hhs.gov
*To whom all correspondence should be addressed.
1. P. Schwartz, Journ. of Generic Medicines,
3 (4), 280–286, (2006).
2. FDA, OGD, Guidance for Industry, ANDAs: Pharmaceutical Solid Polymorphism: Chemistry, Manufacturing, and Controls Information (Rockville, MD, July 2007).
3. L Yu et al., Pharma. Res.
20 (4) 531–536 (2003).
4. ICH, Q3A Impurities in New Drug Substances (R2) (Geneva, June 2008).
5. FDA, OGD, Guidance for Industry, ANDAs: Impurities in Drug Substances (R1) (Rockville, MD, June 2009).
6. FDA, Guidance for Industry, Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches, Draft
(Rockville, MD, December 2008).
7. ICH, Q3C Impurities: Residual Solvents (Geneva, December 1997).
8. USP 32–NF 27 (US Pharmacopeial Convention, Rockville, MD, 2009).
9. FDA, Residual Solvents in ANDAs: Questions and Answers (Oct. 28, 2008).
10. FDA, Guidance for Industry, Residual Solvents in Drug Products Marketed in the United States (Rockville, MD, November 2009).
11. EMEA, Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents, Committee for Medicinal Products for
human Use (CHMP), European Medicines Agency (Doc. Ref. EMEA/CHMP/SWP/4446/2000), Feb. 21, 2008.
12. USP Ad Hoc Advisory Panel on Inorganic Impurities and Heavy Metals and USP Staff, "Stimuli to the Revision Process: General
Chapter on Inorganic Impurities: Heavy Metals," Pharmacop. Forum
34 (5), (September-October, 2008).
13. ICH, Q6A, Federal Register: 65(251) (Dec. 29, 2000).
14. FDA, Guidance for Industry, Development of New Stereoisomeric Drugs (Rockville, MD, May 1992).
15. S. Zhigang et al., Amer. Pharma. Rev., in press.
16. FDA, "21 CFR 211 Current Good Manufacturing Practices for Finished Pharmaceuticals, Subpart J," [Records and Reports, Sec. 211.194 (a)(2)].
This article represents the views of the authors and not of FDA.