FDA Perspectives: Common Deficiencies in Abbreviated New Drug Applications: Part 3 - Control of the Drug Product and Stability

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-02-02-2011, Volume 35, Issue 2

Chemistry reviewers in FDA's Office of Generic Drugs provide an overview of common deficiencies cited throughout the CMC section of ANDAs.

As part of the FDA's Office of Generic Drugs' (OGD) ongoing effort to streamline the review process and reduce the number of deficiencies cited for the applications, a series of articles are being published to provide transparency and clarity to applicants submitting applications in the Question-based Review (QbR) format. The articles highlight the need and significance of science based justification in establishing drug substance (DS) and drug product (DP) specifications, in-process controls for both DS/DP, choice of formulation, selection of a product design and selection of the manufacturing processes. Part 1 of this series, which dealt with the deficiencies cited in the drug substance section, was published in January 2010 (1). Part 2 of the series dealing with drug product composition and excipients was published in August 2010 (2).

The current article is intended to provide clarification with respect to intent and criticality of common deficiencies cited in the control of the drug product (3.2.P.5) and stability (3.2.P.8) portions of abbreviated new drug application (ANDA) submissions using the Common Technical Document (CTD) and Question-based Review–Quality Overall Summary (QbR–QOS) format as a guide. Please refer to the sidebar for a list of some of the deficiencies and comments. This is not an all inclusive list of comments and deficiencies pertaining to the drug product specifications and drug product stability, but includes questions that are cited frequently.

Examples of commonly cited drug product and stability deficiencies and comments**

2.3.P.5 Control of the drug product*

The P.5 sections of the QbR–QOS and the body of data, in submitted ANDAs, should include all the proposed controls for routine analysis of the drug product batches including the proposed specifications, analytical methods with associated validations, batch analysis data for exhibit batches, and justifications for all proposed criteria. Much of the information provided in this section is relevant to both release testing (P.5) and stability or shelf-life testing (P.8). We will address the stability section later in the article.

The QbR–QOS includes two sets of questions with respect to control of the drug product. The questions are as follows:

  • What is the drug product specification? Does it include all the critical drug product attributes?

  • For each test in the specification, is the analytical method(s) suitable for its intended use and, if necessary, validated? What is the justification for the acceptance criterion?

The intent of the first set of questions is for the applicant to provide the specifications for routine release testing of the drug product; and to ensure that all critical drug product quality attributes are included in the specifications. The critical quality attributes (CQA) are linked to the intended use, function and performance of the product and are chosen based on the desired quality target product profile (QTPP). The CQAs may be based on compendial specifications and/or the attributes of the reference listed drug (RLD); and also information in the associated labeling. Development studies may be conducted by the ANDA holder to assure that the drug product meets the attributes of identity, purity, potency, assay, and quality. Examples of typical CQAs for solid oral and solution dosage forms are provided in ICH Q6A (3) and the QbR–FAQ (4).

Specifications are defined per ICH Q6A as "a list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a new drug substance or new drug product should conform to be considered acceptable for its intended use"(3). Based on this definition, the typical information provided is a table or list of proposed tests, acceptance criteria, and analytical procedures for the drug product analysis. An all too common deficiency, which should always be avoided, is related to inconsistencies in the specifications listed in the QbR–QOS (CTD module 2.3) versus the body of data (CTD module 3.2). It is imperative that the two sets of specifications match. If there are differences, the CMC reviewer will be unable to ascertain which of the specifications are the final proposed product controls. The information provided in the QOS should be a summary of the detailed information found in the body of data.

The remaining comments and deficiencies will fit into specific categories related to drug product controls including impurities and degradation products, specific controls for specific dosage forms, and analytical methods.

Impurities/Degradation products. There are a number of common deficiencies with respect to impurities and degradation products in the drug product. These include inappropriate criteria and unacceptable justifications.

With respect to setting justified specifications, a commonly cited deficiency is related to control of process impurities in the drug product. In many cases the recommended ICH Q3B (R2) (5) qualification threshold (QT) is used for all specified impurities. This may be appropriate for degradation products; however, it is not appropriate for impurities that are solely linked to the drug substance synthetic route (i.e., process impurities). The drug product limits for a specified impurity that is process impurity should be set at no higher than that proposed in the drug substance limit.

Poor justification for the proposed degradation product is another common area where deficiencies are being cited. There are a number of ways to justify specified degradation product criteria including the following, which are not reported in any specific order:

  • Specified impurity limits are in-line with US Pharmacopeia (USP) monograph criteria for specified impurities.

  • Acceptance criteria are in-line with the qualification threshold (QT) recommended in ICH Q3B(R2) and ANDA Guidance: Impurities in Drug Products (draft) (5, 6) as long as there are no safety concerns. The guidance for calculation of the QT using recommended percentage or total daily intake of specified impurities, whichever is lower, should be followed.

  • Qualification of the proposed criterion may be based on the following:

- Level of impurity observed in the reference listed drug (RLD). Data from multiple batches of the RLD at or near expiration date may be provided for qualification.

- Significant human metabolite of drug substance. Literature references should be provided to verify that the compound is a significant human metabolite.

- Scientific literature: as long as there are no safety concerns with respect to the intended use.

  • Impurities that are structural alerts for genotoxicity need to be controlled at the Threshold of Toxicological Concern (TTC) of 1.5 mcg/day, as found in the European Medicines Agency (EMA) and draft FDA guidance (7, 8). However, a higher limit may be proposed based on safety studies demonstrating that the proposed limit does not pose a safety concern. These studies are typically consulted to reviewers in the Pharmacology–Toxicology division.

With respect to unspecified impurities the proposed limit should be equal to or below the recommended ICH Q3B (R2) identification threshold (IT) based on the maximum daily dose. Please be informed that in most cases when a USP monograph includes a limit for "any impurity" or "any other impurity" for unidentified impurities it is recommended that the IT be used for the criterion instead of the monograph limit.

An additional area that may lead to a deficiency is the setting the same criteria in both the release and stability specifications for a degradation product, where there is an increasing trend during stability studies. If an upward trend is observed, it is recommended that the criteria in the release specifications are set tighter so as to provide better quality assurance that all manufactured batches meet the regulatory criteria throughout the product life cycle.

Stereoisomeric drug products. This is a class of drug products which has been gaining ground over the last two decades. With great strides made in the field of analytical separations and also chiral reagents, use of a specific enantiomer is becoming more of a norm in the field of pharmaceuticals. Insufficient information in the application may lead to deficiencies being cited.

There are two significant guidance documents which may be followed regarding chemistry and manufacturing controls for stereoisomeric drug products, Development of New Stereoisomeric Drugs (9) and ICH Q6A (3). Decision Tree 5 in ICH Q6A summarizes the requirements for the chiral drug substances and drug products.

Control of the chiral impurities. It is preferable to include controls for the enantiomer and also diastereomers in the drug product within the constraints of sensitivity of the analytical procedure, unless adequate pharmaceutical development studies demonstrate that racemization or epimerization is not a possibility during the manufacturing or storage of the drug product. The limits for the chiral impurities may be justified by comparison with the RLD product, published literature or safety studies.

Chiral assay. In cases where racemization is found to be insignificant or a very small amount of chiral impurities are expected to be present, a non-chiral assay may be considered sufficient as a control. However, if the active pharmaceutical ingredient (API) is prone to racemization or formation of other diastereomers during the manufacturing or storage of the drug product, a chiral assay is preferable.


Stereospecific identity. The agency's guidance, Development of New Stereoisomeric Drugs (9), states that drug products which contain enantiomers should have a discriminatory identification test. This is especially important when the racemate of the API is present in an approved drug product. Under such circumstances, a stereospecific identification test is requested, as it clearly demarcates between the enantiospecific drug product and the one containing a racemate.

Another scenario in which a stereospecific identification test is desirable is when the drug substance is prone to racemization under the proposed manufacturing process and storage conditions of the drug product.

Additional issues with drug product controls and information. The following is a discussion of other common deficiencies that are related to inadequate controls or justifications and missing information with respect to the drug product.

Identification. Identity testing of the drug product is a required quality requirement, as well as, a cGMP requirement (10). Most products include a satisfactory test for identity; however, there are cases where deficiencies have been issued based on the fact that another identity test may be necessary, if the proposed identity test is non-specific. In some cases a specific identification test is required, especially when there is a possibility of conversion of the active ingredient into another form (e.g., another salt, polymorph, or stereoisomer) based on the process conditions or during typical storage.

Color. This control may be especially important for solutions. A quantitative control for color based on comparison with the innovator's product is desirable. A quantitative control for color is often requested for oral solutions and injections, especially where degradation of the API may occur during storage; or where there is evidence that interactions of the API with the excipients, manufacturing equipment or interaction amongst excipients may cause a change in color of the drug product. Again, adequate pharmaceutical development studies demonstrating the absence of these interactions may justify not including a quantitative control for color for solutions.

Reconstitution time. For products that are intended to be reconstituted, such as powders for injection, a meaningful criterion for reconstitution time should be proposed. In many ANDA submissions this test is either not proposed or the limit is unreasonable based on the observed data, the RLD, or the intended use (e.g. for emergency administration). Most importantly, the limit should be based on a comparison with the RLD product. Additionally, ICH Q6A (3) states that test for reconstitution time can also be omitted based on development studies, however, these studies should be clearly referenced in the appropriate P.5 section.

Disintegration. Many submissions include disintegration limits that are not reasonable based on the data and also the intended use. In general, if disintegration testing is included in the drug product release specifications, the criteria should be based on data generated from analysis of the exhibit batches. Also the disintegration time in release and stability should be commensurate with that proposed in the in-process control during manufacturing of the drug product.

If the product is an Orally Disintegrating Tablet (ODT), it is recommended that, in most cases, a criterion of NMT 30 seconds is proposed based on the current guidance (11). However, a higher criterion may be allowed for disintegration time if justified based on comparison to the RLD.

Scoring. It is generally required that the scoring configuration of generic tablets be the "same as" that of the reference listed drug. For more information regarding scoring requirement, please refer to the CDER MAPP 5223.2, Scoring Configuration of Generic Drug Products (12). Other sources of information regarding scoring may be obtained in British Pharmacopeia (BP) (13) and a recent USP stimuli article (14).

Applicants have frequently been asked questions based on the fact that the tablets are scored. In order to ensure the quality of the split tablets, information regarding uniformity of dosage based on content uniformity or weight variation on each half of the tablet is generally requested, based on drug load. Regarding the breakability of the drug product, applicants are often requested to provide the mass loss after splitting. In certain cases, where breakability is in question based on the shape and size of the tablet, the reviewer may also request the applicant to provide the score depth as a fraction of the tablet thickness. For modified release tablets with score, a one time demonstration of the comparability of the dissolution on whole vs. split tablets is recommended. The aforementioned studies on split tablets should be performed during product and process development. As the dosage form becomes more complex, the necessity of routine testing during drug product release and stability analysis is more critical to the overall control strategy.

Water content. In many cases a control for water content is either not proposed or is poorly justified. An appropriate limit for water content takes into consideration contributions from the formulation components, the manufacturing process (e.g., a wet or dry process) and the product stability. The proposed limit should be reasonable based on the observed data for the exhibit batch(es). The criticality of the limit is heightened for products that contain API or excipients that are sensitive to residual moisture, which may lead to degradation or product performance issues.

Microbiological controls–nonsterile products. A common comment that may come from the Agency during the review is with respect to microbiological control for non-sterile products. Based on the formulation components (e.g., lactose, other sugars) and product's water content, it may be prudent to include standard microbiological tests including aerobic microbial count, total yeasts and molds or specific pathogens. In some cases data on water activity of the product can be used to justify not performing microbial limits testing. The term 'water activity' (aw) describes the (equilibrium) amount of water available for hydration of materials (15). Published literature shows that absolute limit of microbial growth is about aw = 0.6. Thus, pharmaceutical development studies showing the water activity of the formulation is below this level during typical storage may justify not including microbiological controls for non-sterile, solid oral dosage forms. Additional references for microbial testing for non-sterile products and water activity may be found in ICH Q6A and USP <1111> (3, 16); and USP <1112> (16), respectively.

Osmolality/Osmolarity/Tonicity. For injectables (especially intravenous products) comparison of osmolality/osmolarity to RLD should be provided. If the results differ, then justification may be needed. As buffer systems may be different based on 21 CFR 314.94(a)(9)(iii) (17), differences in the osmolality/osmolarity compared to the reference product may be observed. The applicant needs to address this difference, as noted in the CFR, which states that the difference in formulation should not affect the safety of the proposed product. If the acceptance criterion for osmolarity/osmolality is listed in the RLD labeling, it is recommended that it be included in the product specification.

Antimicrobial preservative and antioxidants. Antimicrobial preservatives and antioxidants may be essential for establishing an acceptable shelf life of drug products. Antimicrobial preservatives by preventing microbial proliferation and antioxidant by preventing oxidation of the API, as well as, the excipients. In a parenteral formulations, based on 21 CFR 314.94(a)(9)(iii) (17) an applicant may choose to substitute or add antimicrobial preservative or anti-oxidant based on adequate justification. The key term here is "adequate justification". On many occasions deficiencies are cited as the applicant may have failed to rationalize the proposed levels of the antimicrobial preservatives or antioxidants in the proposed drug product. Additionally, there have been instances where applicants have not provided substantial rationale for substituting or adding the antimicrobial preservative or antioxidant in a parenteral formulation, especially when the RLD product does not contain one or the other.

USP <51>, which deals with Antimicrobial Effectiveness Testing, clearly recommends the minimization and justification of the range and/or criteria proposed of antimicrobial preservatives (16). Similarly, the applicants need to justify the chosen level of antioxidant in the formulation. The level of antioxidants is preferably justified based on pharmaceutical development studies demonstrating the minimum level at which the required activity is achieved and supported by the stability data provided in the application. The finished product release and stability specification should include limits for any antioxidant or antimicrobial preservative present in the formulation. The controls should comply with the requirements in ICH Q6A (3).

In some cases, the applicants are also requested to control plausible degradants in the antimicrobial preservatives and antioxidants. Some well known examples of degradants are benzaldehyde and benzoic acid in benzyl alcohol and p-hydroxybenzoic acid in methylparaben and propylparaben. The applicants may be asked to monitor these during routine drug product release and stability analysis. The justification of the criteria for these degradants, in most cases, is consistent with the justifications used for drug product impurities, noted previously.

Rheological properties, redispersibility and particle-size distribution of oral suspensions. There are often questions regarding the above attributes, especially in case of oral and injectable suspensions. The viscosity of a suspension is considered an important attribute, as it is reflective of the settling tendency of the particulate matters in the suspension. It is also an indicator of the ease of pouring a suspension from a bottle or injecting it through a needle (18). The controls should be based on studies that demonstrate that the tendency to segregate during the manufacturing and storage has been minimized and/or controlled. Suitable tests should be included based on comparison with the innovator's product or pharmaceutical development studies.

Suspension stability and particle size. Redispersibility is critical for oral and injectable suspensions if sedimentation occurs during the storage of the suspension. The acceptance criteria should be set based on an appropriate and reproducible method. The time taken for re-suspension should be defined, based on pharmaceutical development studies and have minimal intra and inter-lot variability.

Occasionally, crystal growth in pharmaceutical suspensions is known to cause a drastic change in particle size distribution, which in turn may affect the physical stability of the suspension and sometimes, the bio-availability. Thus, particle size distribution may be a critical quality attribute of some suspensions, which may need to be monitored at release and over shelf life. See also ICH Q6A and the QbR FAQ for additional information (3, 4).

Multilayer tablets. With respect to multilayer tablets, it is incumbent on the applicant to provide development studies and/or suitable controls to ensure tablet integrity. If controls or development studies are not provided, it is likely that applicants will receive a deficiency.

It is recommended that when an applicant develops a multilayer tablet, they should provide data on layer integrity (e.g., radial crushing test). Additionally, during development or through a control strategy the applicant should provided assurance that tablets, throughout the product lifetime, exhibit consistent cohesion. In some cases a routine friability test performed on stability samples may be sufficient.

As the tablet layer integrity may be contingent upon material attributes of the chosen inactive ingredients, if post-approval changes in supplier or grade change; the applicant should be prepared to demonstrate that tablets manufactured with a different supplier or grade of inactive ingredients show multilayer products of comparable quality and performance. This same line of thinking would apply to changes made to the manufacturing equipment or process. Applicants may be asked to provide data to demonstrate that multilayer products of comparable quality and performance are manufactured. Additional considerations may be found in a recent article on multilayer tablets (19).

Transdermal delivery systems and locally acting patches. Although transdermal delivery systems (TDDS) and other patches are not currently common dosage forms, as these products become more popular deficiencies would be cited with respect to specific critical quality attributes (CQAs) if they are not addressed in the submission.

Adhesion is by far of the most critical attribute that should be addressed in applications. Product adhesion is a CQA related not only to product quality and performance, but to product safety. The applicant should be able to measure adhesion in the proposed product with an appropriate, justified test and they should be able to demonstrate that the proposed system shows consistent product quality, performance and safety in terms of adhesion. A good reference on the criticality of adhesion in TDDS is a recent review article (20). Additional literature and guidance is also available on critical attributes of TDDS and patches (21, 22).

General drug product information. There are a few pieces of general information that if not provided will lead to deficiencies. As stated previously, this is not intended to be an all inclusive list. Common information not provided in the ANDAs that has lead to deficiencies includes the following:

  • Results for all strengths are not included.

  • Quantitative results are not presented for numerical tests, but general terms such as "complies" or "meets limit" are reported.

  • A USP <467> compliance statement along with option used is not included in the drug product specifications.

  • In case of the drug product label having specific information regarding how the patient may use a drug product, additional controls may be requested in release and stability. For example, if the label of a chewable, dispersible tablet claims that it may be dissolved in water or juice completely before taking, a test may be needed to establish that the generic meets the same criteria.

Methods and validations. There are a variety of common deficiencies regarding the analytical methods used for the drug product analysis, as well as, the associated method validation studies. One common question cited to applicants is related to insufficient method information being provided in the QbR-QOS, especially for non-compendial methods. The applicant should provide a brief summary of each non-USP method. This can be in a tabular or descriptive form and the information should include the critical parameters for the method and system suitability criteria, if applicable. Specifically for impurity methods, it should be clear that impurities (degradation products) are quantified using impurity standards or by the use of relative response factors (RRF).

In some submitted ANDAs, inadequate method validation information is provided. For in-house methods, validation protocols should include all the relevant tests as noted in USP <1225>, including method robustness (16). Typical robustness testing in HPLC methods includes varying chromatographic conditions, chromatographic systems, and/or mobile phase preparations. If a method is transferred then some minimal verification testing should be provided including tests such as intermediate precision (ruggedness) and determination of limit of detection (LOD) or limit of quantification (LOQ), as applicable. Compendial methods may also need to be verified based on the proposed laboratories ability to perform the method. A good reference for method verification can be found in USP <1226> (16).

Some specific studies and information that is often lacking in submitted method validations reports include linearity studies that do not include the proposed limit or the LOQ; inadequate or irrelevant acceptance criteria in the validation protocol, and lack of spiking studies to assess method suitability for detecting specified degradation products that may increase over time. Additionally, stress studies often are insufficient to assess stability indicating nature of the method as no degradation is observed in stressed samples. It is typically recommended to target 10–30% degradation in stressed samples. For molecules that are difficult to degrade, a justification should be provided along with a summary of forced degradation results (i.e., stress conditions that go beyond the usual) or other studies performed to demonstrate specificity (4).

2.3.P.8 Stability

The P.8 sections of the QbR–QOS and the body of data in submitted ANDAs include information with respect to stability studies used to determine the shelf-life of the product. As stated previously, much of the information provided in the P.5 section is relevant to both release testing (P.5) and stability testing (P.8).

There are three QbR–QOS questions noted in P.8. These are as follows:

  • What are the specifications for stability studies, including justification of acceptance criteria that differ from the drug product release specification?

  • What drug product stability studies support the proposed shelf life and storage conditions?

  • What is the post-approval stability protocol?

This article will focus on the first two questions with respect to common deficiencies and comments cited in ANDA submissions.

Stability specifications. Based on ICH Q1A(R2) (23) stability studies should include testing of attributes of the drug product that are susceptible to change during storage and may influence quality, safety, and/or efficacy of the drug product. The testing should cover the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system). Analytical procedures should be fully validated and stability indicating.

Modification of limits for stability. In some cases, the relaxation of the limits of certain quality attributes in stability is necessary based on the nature of the drug product. Applicants should take great care in using realistic, as well as, scientific and regulatory approaches to setting acceptance criteria for the stability studies.

For example, when the API or one of the excipients is hygroscopic, the water content may increase during shelf life for solid oral dosage forms. Similarly, if a hydrolytic degradation pathway related to an API is well documented in literature, the resultant degradant may be controlled at a higher level in stability. This may also be the case with an impurity, which arises due to reaction of the API with one or more of the excipients in the dosage form. However, deficiencies are cited when the relaxation of the specification is not well justified.

In case of water content, in the example noted above, it needs to be demonstrated that the proposed relaxation is not detrimental to the product quality in any way, leading to change in appearance, physical attributes or impurity levels. In case of degradants, the relaxed limit is acceptable as long as it is within the ICH Q3B (R2) qualification threshold (QT) and the impurity is not a structural alert for genotoxicity. However, if a limit higher that the QT is proposed, it needs to be justified by comparison with several lots of RLD, close to or at expiration date. In case of artifacts arising due to interaction of the API with the excipients, the levels need to be at ICH Q3B (R2) proposed QT or adequately justified based on safety data.

Accelerated stability data on RLD samples. Deficiencies are often cited when the relaxation of specifications of impurities in stability is justified by comparison with RLD, which has been subjected to degradation under accelerated stability conditions. Since accelerated storage conditions are not the normal storage condition of the drug product, it is recommended that the comparative batch analysis is conducted at controlled room temperature conditions to demonstrate similarity of behavior between the RLD and the generic.

Specific studies or tests on stability samples.

Water loss. Per ICH Q1A(R2) (23), it is recommended that aqueous-based products packaged in semi-permeable containers should be evaluated for potential water loss during stability studies. Deficiencies have been cited with respect to applicants using semi-permeable containers with no evaluation of potential water loss. It is recommended that the ICH Q1A guidance approach be used with respect to performing studies under low relative humidity conditions. Alternative approaches to determine water loss based on differing stability conditions can also be used, per the guidance.

Dissolution. The responsibility of reviewing the adequacy of the dissolution specification rests with the Division of Bioequivalence (DBE). However, a frequent deficiency provided to the applicants is to update the drug product release and stability specification based on DBE recommendations. It is also imperative that the applicants conduct the dissolution test by using the DBE recommended method on retained 3rd month accelerated stability samples for all packaging configurations and ensure that the exhibit batch meets the proposed specification. If accelerated stability samples are not available, testing should be conducted on samples placed in controlled room temperature. In this case, typically, the age of the samples at the time of testing will be the tentative expiration dating period that OGD will grant to the drug product. As such, updated stability protocols should be provided reflecting the reduced tentative expiration date. To avoid the reduction of shelf life, it is recommended that samples, which have already been taken out from the accelerated stability study chamber be retained until approval of the ANDA.

Photostability studies. The information regarding photostability studies for the drug product is often absent from the application. As ICH Q1B (24) states, the studies on the photostability of drug product need to be done in a sequential manner, starting with the fully exposed product and proceeding, if necessary to the immediate pack and then to the marketing pack, until results demonstrate that the drug product is adequately protected from exposure to light. In some cases, the ANDA holder justifies not performing photostability studies for the drug product based on the fact that the drug substance did not show photo-degradation during the forced degradation studies. However, this is may not be acceptable, in some cases, since the excipients or impurities there in, may catalyze photo-degradation of the API in the drug product. In these cases the applicant will need to scientifically justify why photostability studies are not necessary.

Alternatively, if the applicant demonstrates that the generic product packaging provides a comparable level of protection to the RLD packaging, photostability studies may be exempted.

Thermal cycling. Thermal cycling studies or freeze-thaw cycling studies are recommended for certain dosage forms such as solutions, suspensions and emulsions to ascertain the effect of extreme temperature fluctuations during shipping through various climatic zones, seasonal fluctuation in temperature and mode of transport on the physical stability of the drug products. These studies are generally desirable for those drug products which may undergo phase separation, loss of viscosity, precipitation, and change in particle size distribution. However, we frequently see deficiencies cited in the ANDA due to lack of thermal cycling studies. It is desirable that the ANDA holders carry out thermal cycling studies during product development to assure a robust formulation. Also, a one time thermal cycling stability study needs to be conducted on the exhibit lot of the drug product to verify its physical stability, when applicable.

Diluent studies. Stability testing of the pharmaceutical product after constitution or dilution, where applicable, should be conducted based on the information in the labeling of the RLD. This testing should be performed on the constituted or diluted product through the proposed in-use period on exhibit batches as part of the ANDA submission.

Accumulated data/studies. Usually, satisfactory results of three months accelerated studies justify a tentative expiration date of 24 months. However, based on trends observed in the accelerated stability data, the expiry date for some products may be based solely on the accumulated full long-term stability data.

There are drug products, due to their inherent nature show a significant change during the accelerated stability studies. In these cases, the expiration date is based on the long term stability data, though the ANDA holder may demonstrate that the RLD exhibits similar behavior under accelerated stability conditions. In cases were significant changes occur in accelerated conditions, applicants may also need to demonstrate (e.g., intermediate storage conditions) that excursions in temperature during routine shipping and storage have no detrimental impact on the product quality.


This concludes our discussion on the commonly cited deficiencies for control of the drug product (3.2.P.5) and stability (3.2.P.8). This is by far the most active area when it comes to deficiencies and comments cited to ANDA applicants. The prevalence of deficiencies speaks to the criticality of the information with respect to controls proposed for routine release and stability analysis of the drug product. Applicants should endeavor to provide sound scientific and regulatory justification for all specifications (tests, methods, and criteria) that are proposed.

As stated in the beginning of the paper, this is not an exhaustive list of deficiencies in the drug product release and stability sections. However, the authors have attempted to provide the underlying reasons for common deficiencies related to the control of the drug product during release and stability testing. Our goal is to shed light on the rationale for citing these deficiencies and demonstrating how pharmaceutical development studies, performed during the initial development of the product, may reduce the instances of these deficiencies being cited.

* 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 Chemistry, for his encouragement and invaluable insight.


The views and opinions in this article are only those of the authors and do not necessarily reflect the views or policies of the FDA.

Aloka Srinivasan, PhD,* is a team leader, Devinder S. Gill, PhD, is a deputy director, and Robert Iser, M.S., is an acting director, 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.


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3. ICH, Q6A, Federal Register: 65(251) (Dec. 29, 2000).

4. FDA, QbR Frequently Asked Questions (June 4, 2007).

5. ICH, Q3B Impurities in New Drug Products (R2) (Geneva, July 2006)

6. FDA, OGD, Guidance for Industry, ANDAs: Impurities in Drug Products (draft) (Rockville, MD, August 2005).

7. EMA, Guideline on the Limits of Genotoxic Impurities, Committee for Medicinal Products for Human Use (CHMP) (Doc. Ref EMEA/CHMP/QWP/251344/2006), Jan. 1, 2007.

8. FDA, Guidance for Industry, Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches (draft) (Rockville, MD, December 2008).

9. FDA, Development of New Stereoisomeric Drugs (Rockville, MD, 1992).

10. FDA, "21 CFR 211 cGMPs for Finished Pharmaceuticals" [Testing and Release for Distribution, Sec. 211.165 (a)], revised Apr. 1, 2010.

11. FDA, Guidance for Industry, Orally Disintegrating Tablets (Rockville, MD, December 2008).

12. FDA, MAPP 5223.2, Scoring Configuration of Generic Drug Products (Rockville, MD, Nov. 1, 1995).

13. British Pharmacopeia, Formulated Preparations: General Monographs—Tablets Volume III, Ph. Eur. monograph 0478 (2010).

14. USP Stimuli Article, Pharmacopeial Standards for the Subdivision Characteristics of Scored Tablets, Pharmacopeial Forum 35 (6) (Rockville, MD, Nov–December 2009).

15. B. Snider, P. Liang, and N. Pearson, Pharm. Technol. 31 (2), 56–71, (2007).

16. USP 33–NF 28 (USP, Rockville, MD, 2010).

17. "21 CFR 314 Applications for FDA Approval to Market a New Drug," [Content and Format of an Abbreviated New Drug Application, Sec. 314.94 (9)], revised Apr. 1, 2010.

18. A. Gupta, V.A. Sayeed, and M.A. Khan, "The Science and Regulatory Perspectives of Pharmaceutical Suspensions," in Pharmaceutical Suspensions, From Formulation Development to Manufacturing, Eds. A.K. Kulshreshtha, O.N. Singh, G.M. Wall (Springer, New York-Dordrecht -Heidelberg-London, 2010), pp. 265–284.

19. S. Vaithiyalingam et al., Internat. Jrnl. of Pharmaceut. 398 (1–2) 2010

20. M. Wokovich et al., Euro. Jrnl. of Phrm. and Biophrm. 64 (1), 1–8 (2006).

21. FDA, Guidance for Industry, Residual Drug in Transdermal and Related Drug Delivery Systems (draft) (Rockville, MD, August 2009).

22. N. Sadrieh, B. Michniak-Kohn, and R. Harapanhalli, presentation at the Pharmaceutical Science and Clinical Pharmacology Advisory Committee, Aug. 5, 2009, Topic 2, www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/ucm178925.htm.

23. ICH, Q1A(R2) Stability Testing of New Drug Substances/Products (2003).

24. ICH, Q1B Photostability of New Drug Substances and Products (1996).

This article represents the views of the authors and not of FDA.