Susan Rosencrance, PhD is with the Center for Drug Evaluation and Research, FDA

Susan Rosencrance

Approval of generic drugs can be slowed down by deficiencies in abbreviated new drug applications (ANDAs). Srinivasan 

 (1-4) published a series of articles on common deficiencies in ANDAs that provide clarification, intention, and criticality of common deficiencies found in the Chemistry, Manufacture, and Controls (CMC) section of ANDAs. Liu 

 (5) also published an article on common deficiencies with “Bioequivalence Submissions in Abbreviated New Drug Applications Assessed by Food and Drug Administration (FDA)”. All the authors, including Srinivasan

hope that the generic-drug companies take steps toward eliminating recurring deficiencies. In their articles, they offer opportunities for generic-drug firms to look into FDA’s mindset for regulatory considerations. Advice from FDA can help companies overcome common pitfalls in research stages, development steps, and document filing. The approval of generic drugs can be accelerated for the companies that pay special attention to these common deficiencies and consistently submit high-quality ANDAs.

	In general, the deficiencies discussed in these articles can be applied to generic topical dermatologic products. Because of the uniqueness and potential complexity of topical products, however, it is required to focus on additional areas to ensure their regulatory success for ANDA filing. This article is an addendum to the aforementioned articles. Because a detailed and thorough discussion on regulatory filing pitfalls for each section of modules was given in the preceding publications, a review focusing on section-by-section of ANDAs again would be redundant. The shortcomings for ANDAs specifically for topical dermatologic products are the main focus of this article.

	Shortcomings in ANDAs of topical dermatologic drug products 

 It is important for the sponsor to provide the maximum daily dose (MDD) for their drug product. Without an estimated MDD, FDA cannot judge the appropriateness of any impurity specification limits proposed by the sponsor. In many cases, the MDD for topical dermatologic products cannot be estimated in a plain, straightforward way. Because of this difficulty, sponsors often disregard MDD intentionally in their applications. If the sponsor does not provide an estimated MDD, it may force reviewers to over-estimate MDD. For example, the MDD may be estimated using the largest pack size (if the treatment duration is not in the package insert) or using the largest pack size divided by the treatment duration (if the treatment duration is available in the package insert). A reviewer may also assume the entire body surface as affected area to calculate the initial MDD. Forty finger-tip units (approximately 0.5 g/finger-tip unit) are required to cover the entire body surface (6), and MDD is calculated as 40 fingertip units x 0.5 g/finger-tip unit x 0.01 (drug concentration of the formula).

	It is advantageous for the applicant to provide their estimated MDD with an estimating equation, which will assist in justifying proposed impurity limits upon review of the ANDA.

	Quality attributes related to microstructure and arrangement of matters (Q3 properties) 

	Because there are many risks associated with changes in formulation, FDA encourages that generic-drug companies submitting ANDAs match the reference-listed drug (RLD) both qualitatively (Q1) and quantitatively (Q2). This can be done through reverse engineering the formulation of the RLD. The generic topical product is not required to be Q1/Q2 the same as the RLD, but non-Q1/Q2 products will face more regulatory scrutiny. This is because composition differences in excipients could change physicochemical properties, skin permeability properties, and solubility and thermodynamic activity of the drug formulation. In other words, some excipients themselves can penetrate skin and act as a drug solubility modifier to alter the solubility of the API, as a lipid mobilizer to alter the ordered intercellular lipid structure, and as a tight junction modulator to affect the intercellular gaps of skin barrier. In turn, these changes can influence diffusion and permeability properties of the drug.

	Topical dermatologic drug products generally tend to be complex dosage forms that require complex manufacturing processes. Because of this complexity, one cannot solely rely on traditional quality batch release testing to ensure drug product quality. In addition, the drug product equivalence and similarity in terms of the microstructure/arrangement of matters quality attributes (Q3) from exhibit batch to commercial batch are not certain. In view of this, it is logical that FDA strongly encourages pharmaceutical companies to adopt a quality-by-design (QbD) concept for their development and manufacturing of topical dermatologic drug products. Q3 attributes are emphasized as part of quality target product profile (QTPP) and critical quality attributes (CQA) due to this paradigm shift from the “equivalence-by-testing” traditional approach to the “equivalence-by-design” QbD approach. If the applicant did not adopt the current regulatory trend, significant numbers of deficiencies may be issued to alert the applicant of the importance of QbD and Q3 attributes as well as the need to adequately characterize the parameters of semisolid drug products (7, 8). The agency remains cautious to adopt an approach for the thorough evaluation of all quality attributes (Q1/Q2/Q3) as well as surrogate markers (i.e., in-vitro release, in-vitro permeation, and/or in-vitro dermal distribution) for which there was known or suspected bioequivalence problem, such as in Acyclovir cream and ointment cases. For the drug product with no known or suspected bioequivalence problem (e.g., AT-rated drug products), the agency focuses on Q3 attributes demonstrating pharmaceutical equivalence and patient acceptability (e.g., guidance on Triamcinolone Acetonide Cream and Ointment). It should be noted that in some occasions, to measure bioavailability or establish bioequivalence for certain topical drug products, the agency recommends 

 study option. This information is available on FDA’s 

 (9). Acceptable comparative physicochemical characterization and/or 

 drug release rates of the generic and RLD products is of importance to be considered as qualified for the in-vitro option.

	The applicant should include a comprehensive, comparative quality attribute evaluation of both the RLD and the generic-drug candidate. Ideally, an evaluation of three separate lots of the RLD with different expiry dates (i.e., a fresh lot and lots close to expiry) is recommended to provide a complete understanding of the variability of each quality attributes for the RLD. These Q3 attributes may include the following: pH, globule size, drug particle size, rheological behavior, drug polymorphic form, and in-vitro release rate. Some common concerns regarding Q3 attributes are discussed in the following sections.

	Appearance descriptions. Some applicants offer incomplete appearance descriptions. More detailed descriptions (e.g., free of lumps, free of foreign matter, homogeneous consistency, no phase separation, etc.) should be included in the drug product specification. Also, the description for the drug product in its container closure system should be included as part of appearance test (e.g., package appearance [inner and outer wall]) to check for seal integrity and any discoloring of inner wall as well as label evaluation.

 pH can affect many parameters, such as: ionization state of the drug substance, solubility of the drug substance, drug-product stability, viscosity, preservative efficacy, performance, etc. Generally, conventional pH meters are designed to measure the pH of aqueous solutions. Topical dermatologic drug products, however, may contain limited quantities of aqueous phase and may instead contain solvents and lipoidic materials in larger quantities. Dilution of the preparation using an appropriate medium may be necessary to keep the pH sensor in an aqueous phase and measure pH accurately. It is recommended to use a 1:10 dilution with distilled, deionized, CO

-free water for pH determination, when direct measurement is not feasible.

 Rheological behavior of the test drug product and the RLD needs to be characterized using an appropriate viscometer/rheometer for semisolid texture material. Because semi-solid dosage forms usually display non-Newtonian flow behavior, it is prudent that the upward and downward flow curve (shear rate vs. stress plot) for the test drug product and RLD product be generated to demonstrate that the selected viscometer is appropriate for semi-solid texture material analysis. If the material tested has plastic flow behavior, it is important to report yield value. The flow curve should consist of multiple data points. The number of data points for the flow curve depends on the selected viscometer’s capability, but should be comprehensive enough to characterize the flow curve. Viscosity values at specific test conditions for multiple lots of the test product and the RLD should be generated as a foundation to set the viscosity acceptance criteria for the generic-drug product. In special cases, apparent viscosity specifications at more than one set of conditions may be required to monitor product viscosity properly. Also, note that viscosity measurement of the molten state of the product under an elevated temperature is not acceptable as a drug product quality attribute.

 Polymorphs can vary in their physicochemical properties, which may in turn affect the quality, safety, and efficacy of the final product. Demonstrating the equivalence of polymorphic form of a generic product to that of the RLD is critical, if applicable. Identification of the specific polymorph of drug substance in the generic drug may be performed through x-ray diffraction, Raman spectroscopy, or other appropriate techniques. In these cases, it is necessary to compare analyses of the drug substance in the semi-solid product for both the RLD and generic products with the aid of drug substance polymorphic standards and placebo matrix. This direct analysis of the drug product is the preferred method to identify and quantify the polymorphic form. It can be technically challenging to measure polymorphic changes in drug products. However, the applicant needs to show their proper due diligence in analyzing the polymorphic form of the drug substance in dermatologic products, either by analysis of drug products or isolated drug particles. In addition, the applicant should refer to the #4 Polymorphic Forms section of the International Council for Harmonization’s (ICH) Q6A decision tree to discuss their drug substance and drug product situation to alleviate regulatory polymorphic form concern (10).

 If the drug product contains a dispersion of drug substance, then the particle size of the active ingredient in the drug product base needs to be monitored. In general, the particle size of the active ingredient in a drug product should be generated by microscopic measurement of at least 300 particles to obtain an accurate estimate of particle size distribution. The drug product specifications should include a particle size distribution test with three-tier specification limits (e.g., D10%, D50%, and D90%). To avoid this slow and tedious manual procedure, computerized image analysis methods or other validated methods are permitted for particle size measurements. If the drug product contains the drug in a molecular state, it is prudent to microscopically ensure lack of crystallization of the active ingredient during the drug product development stage. If the drug product is emulsion-type cream, the apparent distribution of particles between aqueous phase and oil phase should be evaluated microscopically.

 Topical preparations in the form of either oil-in-water cream (vanishing cream) or water-in-oil cream (cold cream) are commonly used to deliver APIs to the epidermis or upper dermis to elicit their pharmacological effects. Globule size can influence the drug product quality and performance. Because emulsions are inherently thermodynamically unstable, the measurement of globule size and size distribution is a crucial test item for monitoring the stability of emulsion type products.

 drug release tests (IVRT) are rarely included in finished drug product release and stability specifications for generic dermatologic products. If the drug product is a complex semisolid preparation (e.g., emulsion type cream), however, it is imperative to submit comparative IVRT data in the application. In specific cases (e.g., the formula containing microsphere, a novel excipient), IVRT was included in the drug product specifications. FDA has several reasons to implement the inclusion of the in-vitro drug release test as a required drug product release and stability specifications in the future. The main reason is that the IVRT can reflect the combined effect of several physicochemical characteristics (e.g., solubility of API, pH, particle size, globule size, viscosity, and diffusion resistance of the vehicle). Recently, FDA has recommended that IVRT method development be started early in the drug product development  phase for all topical drug products, if applicable. For new drug applications (NDAs), Ghosh (11) pointed out that FDA is facing challenges in bringing discontinued products back to the market in the absence of current reference products; an established IVRT method and specification could alleviate this problem. Likewise, in ANDAs, the authors have concerns that there is no historical IVRT data as a baseline to assess product “sameness” during scale-up and post-approval changes for dermatologic drug products. As FDA continues to request IVRT data for NDAs and NDA supplements of dermatologic drug products, this trend also applies to ANDA products. Currently, the authors encourage that comparative 

 release test for generic drug product and the RLD be conducted particularly during product development and the data can be used as a baseline for future potential formulation and process changes for a drug product.

 permeation test (IVPT) across human skin is perhaps the most useful, versatile and insightful in vitro information in development of a topical drug product. The authors encourage generic-drug applicants to adopt this technique in their drug product development; the knowledge gained can give better understanding of impact of any difference in the Q3 attributes.

	In the ANDA pharmaceutical development stage, it is important to have complete documentation for all stages of drug development and production. This documentation includes complete batteries of quality testing in the drug substance, as well as complete examinations of in-process and drug product specifications as described in this section. This thorough investigation will ensure the quality, safety, and efficacy of the generic topical-drug product. Through this extensive testing, it will be possible to work backwards to pinpoint any manufacturing steps for trouble shooting, if necessary. The proposed in-process tests should render adequate monitoring and control of the high risk attributes (e.g., assay, impurities, blend uniformity, pH, viscosity, globule size, and particle size distribution), if applicable. For the blend uniformity test, the authors recommended that the sample size should be at least 10 to attain statistically meaningful results. In-process controls and tests during filling and packaging are frequently missing in submissions.

	All topical semi-solid drug products, if applicable, should be monitored for, but not limited to the following characteristics: description, identification, assay, impurities (known impurities, individual unknown impurity, and total impurities), pH, viscosity, API particle size distribution, globule size, minimum fill, microbial limits, uniformity in container, non-aqueous solvent assay, anti-oxidant assay, antimicrobial preservative assay, penetration enhancer assay, water content, weight loss, and leachables. The applicant should refer to 

 (USP) chapter <3> Topical and Transdermal Drug Products-Product Quality Tests to meet compendial requirements (12).

	It is essential to include thermal cycling studies as a part of stability studies to assess the effects of transportation temperature conditions on the quality of dermatologic drug products. The authors also recommend two storage orientations (i.e., horizontal or inverted vertical and upright vertical) for the exhibit batches to support the ANDA filing (13).

	Leachables/extractables studies are required for injectables, inhalation products, and ophthalmic products. They are, however, not required for dermatologic drug products in most cases (14). When a dermatologic drug product contains significant amounts of solvents, reviewers tend to inquire about leachables/extractables studies due to the high extractability of the solvents in the formula, which is supported by a published article (15). The applicant should refer to 

 chapters <1663> and <1664> for further guidance (16, 17).

	Furthermore, benzophenones are given more attention because they have been named the Contact Allergen of 2014 by the American Contact Dermatitis Society (18-20). In addition, benzophenones are used in many industries, ranging from UV light absorber, adhesives, and plastics. Hence, reviewers often ask applicants to demonstrate the absence of benzophenones in the drug product.

	Increased sharing of internal policy assists in increasing FDA’s transparency, which is crucial to minimize the problems and pitfalls in ANDAs. Hopefully, increased transparency and clarity about FDA’s internal review processes will help generic-drug companies avoid the aforementioned pitfalls. For ANDA sponsors, careful attention to these insights will improve quality of ANDA documents, increase chances of regulatory success, and benefit in expediting approval of their dermatologic drug products.

 34 (1), 50-59 (January 2010).
	2. A. Srinivasan, R. Iser, and D. Gill, 

 34 (8), 45-51 (August 2010).
	3. A. Srinivasan, R. Iser, and D. Gill, 

35 (2), 58-67 (February 2011).
	4. A. Srinivasan and R. Iser, 

 35 (4), 62-68 (April 2011).
	5. Q. Liu et al., 

 14 (1), 19-22 (2012), DOI: 10.1208/s12248-011-9312-7.
	6. C.C. Long and A.Y. Finlay, 

16 (6), 444-7 (1991).
	7. R.K. Chang et al., 

, 16 (1), 41-52 (2013), DOI: 10.1208/s12248-012-9411-0.
	8. R.K. Chang et al., 

, 15 (3), 674-83 (2013), DOI: 10.1208/s12248-013-9472-8.
	9. FDA, “Product-Specific Recommendations for Generic Drug Development,” 

Q6A Specifications: Test Procedure and Acceptance Criteria for New Drug Substances and New Drug Products, Chemical Substances

 (ICH, 1999).
	11. T.K. Ghosh, “Topical Drug Delivery: U.S. Regulatory Perspectives from Biopharmaceutics and Related Disciplines,” presented in USP Workshop on Quality Attributes of Drug Products Applied to the Skin, Sept. 21-22, 2015.
	12. USP, Chapter <3> Topical and Transdermal Drug Products-Product Quality Tests, 

 Vol. 1, page 81-86 and Official from August 1, 2016.
	13. FDA, 

Guidance for Industry, ANDAs: Stability Testing of Drug Substances and Products, Questions and Answers

Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics, Chemistry, Manufacturing and Controls Documents

 (CDER, CBER, May 1999).
	15. J.B. Haverkamp et al., 

70 (3), 921-8 (2008).
	16. USP, Chapter <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems, USP 39-NF 34, Vol 1, page 1835-1848, Official from August 1, 2016.
	17. USP, <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging Delivery Systems 

, Vol. 1, page 1850, Official from August 1, 2016.
	18. A. Heurung, S. Raju, and E. Warshaw, Dermatitis 25 (1): 3-10, (2014), DOI:10.1097/DER.0000000000000025.
	19. D. Brunk, “Benzophenones Named 2014 Contact Allergen of the Year,” Dermatology News Digital Network (March 14, 2014), www.skinandallergynews.com/single-view/benzophenones-named-2014-contact-allergen-of-the-year/cb086f7e351cccbcfd9dbf5fa806762b.html
	20. A Vazirnia and S. E. Jacob, 

, 22 (11) (2014), www.the-dermatologist.com/content/review-acds’-allergen-od-year-2000-2015 

The opinions expressed in this commentary by the authors do not necessarily reflect the views or policies of the United States Food and Drug Administration.


	Vol. 40, No. 9
	September 2016
	Pages: 68-76

	When referring to this article, please cite it as R. Chang et al., "Common Deficiencies in ANDAs for Dermatologic Drug Products," 

Articles

Companies may potentially accelerate the approval of generic drugs by avoiding deficiencies in ANDA submissions.

Common Deficiencies in ANDAs for Dermatologic Drug Products

Controlled correspondence provides a crucial communication mechanism between FDA and the generic pharmaceutical industry. Such a mechanism allows the industry to seek for the agency’s input prior to the submission of an abbreviated new drug application (ANDA). On average, FDA has received more than 1000 controlled correspondences every year since the agency began responding to inquiries in 1992.

	Controlled correspondence is defined as “a correspondence submitted to the agency, by or on behalf of a generic drug manufacturer or related industry, requesting information on a specific element of generic drug product development” (1). An effort has been made to data-mine correspondences related to generic-drug chemistry that were submitted in the past 10 years with the goal of identifying major categories of interest and determine areas where FDA can improve communication with the industry. This effort is expected to increase efficiency and thereby assure the fulfillment of the agency’s Generic Drug User Fee Amendments of 2012 (GDUFA) commitment to the industry, as elaborated below.

	Under the GDUFA commitment (2), FDA will respond to:

		70% of controlled correspondence in four months from date of submission in fiscal year (FY) 2015

		70% in two months from date of submission in FY 2016

		90% in two months from data of submission in FY 2017.

	If the controlled correspondence requires input from the clinical division, one additional month will be added to the goals outlined above.

	Several years ago, FDA established a webpage (3) and provided instructions to better guide the industry in submitting controlled correspondence. To further improve the efficiency of processing controlled correspondence, a draft guidance for industry entitled 

Controlled Correspondence Related to Generic Drug Development

 (1), was published in August 2014. In this guidance, controlled correspondence is defined and criteria are given for what correspondence is acceptable for submission to FDA. Pre-ANDA meeting requests,-questions related to pending ANDAs under review, inquiries not directly related to generic-drug development, or general, open-ended, or insufficiently detailed questions will not be considered as controlled correspondence. Requestors inquiring on matters under consideration by FDA (e.g., approval standards for complex products) will be notified, but no conclusive information will be given until the matter is settled by the agency. Moreover, the guidance states that requests for review of clinical protocols for 

 bioequivalence studies will remain excluded from GDUFA goal dates as these recommendations are covered by individual guidances. These well-defined limits are anticipated to reduce the volume of inquiries and allow allocation of FDA resources to providing timely answers to appropriate inquiries.

	This retrospective analysis of chemistry-related controlled correspondence is another tool to aid in improving the agency’s response to the industry. Understanding trends in the content of these correspondences will allow FDA to improve communication, address gaps in guidance interpretation, and inform future guidance development. Increased clarity from FDA will further increase efficiency by reducing the volume of correspondences each year, thereby reducing strain on the agency’s resources.


	The agency’s correspondence database was data-mined to identify chemistry-related correspondence received between January 2004 and May 2014. Preliminary search identified 754 correspondences labeled as chemistry related; among these, 173 were sub-labeled as meeting requests, biowaivers, bioequivalence, and citizen petition. However, they were not included in the further data analysis because they are not considered as chemistry-related correspondences under the new definition. Therefore, the final sample size was 581.

	These correspondences were reviewed and assigned one of 15 categories and a number of relevant keywords. The questions and answers provided by the agency were summarized in a master spreadsheet based on receipt dates. The most frequently asked questions were identified and are discussed in this publication. A Python-based natural language processing tool (4) was then used to count keywords for further analysis of the categories and to generate a lexical dispersion plot to determine the location of each category within the text in a chronological order. In addition, review outcomes and commonly seen issues have been summarized and suggestions for improvement are provided.


	On average, the agency receives approximately 1200 correspondences yearly. Approximately 5-10% are related to generic-drug chemistry. The number of chemistry-related correspondences has increased steadily since 2011, as shown in 

. Topics in these correspondences can be loosely grouped into 11 categories:

	Each correspondence was assigned to one category, and the number of correspondences under each category was counted and summarized in 

. Categories with the highest number of counts include formulation, stability, specifications, and post-approval changes.

	Formulation is a broad category, but generally consists of inquiries about API-related topics such as allowable particle size, salt stoichiometry, or synthetic route deviations from the reference listed drug (RLD); the presentation of the dosage form; and other allowable deviations from the RLD.

	The specifications, post-approval changes, and stability categories were broken down into sub-categories to further elucidate trends.

	Specifications is a broad topic, which includes questions related to residual solvents, identity, limits, drug master file (DMF), test method, validation, and impurity (see 

). While the counts in many of the subcategories were distributed relatively evenly, test method and impurity stood out as major topics. Test method questions were highly varied and case-specific. These questions sought specific recommendations on the procedure and/or data requirements for stability testing; API/excipient characterization and compatibility; in-process testing; quality requirements; and ANDA submission data requirements.

	Inquiries about residual solvents or impurities generally requested advice on the limits or the types of solvents/impurities found with a particular API. The limits category catches all other inquiries regarding limits that are not pertaining to residual solvents or impurities; these questions largely requested advice on the setting of assay limits for the API.

	Inquiries regarding post-approval changes (see 

) revolved almost exclusively around questions about which post-approval reporting category was most appropriate, followed by requests for advice on any other information or data that should be filed with the supplement(s). Questions in this category will no longer be considered as controlled correspondence; the draft Guidance for Industry: Controlled Correspondence Related to Generic Drug Development (August 2014) considers any questions related to a pending or approved ANDA as a review issue and outside the scope of controlled correspondence (1). However, the agency is trying to establish some mechanism to address general questions for approved ANDAs during the post-approval phase.

	Stability questions were divided into subcategories (see 

) and pertained to requirements for batch size and requests for approval of bracketing or matrixing protocols. Batch number questions generally seek to clarify how many primary stability batches are required for supporting the ANDA submission given the requirements set forth in the June 2013 Guidance for Industry, ANDAs: Stability Testing of Drug Substances and Products (5). Because the release of this guidance and the subsequent May 2014 Guidance for Industry, ANDAs: Stability Testing of Drug Substances and Products Questions and Answers (6) generated many questions and represents a relatively major shift in FDA’s approach, further analysis of these controlled correspondences will be elaborated in a future publication.


	The most commonly posed questions across all categories were compiled in 

. The most popular question was about reduced batch size(s): Firms requested for the agency’s concurrence on reduced primary batch sizes compared to the established pilot-scale size according to the International Conference on Harmonisation (ICH) definition. The criteria for an exception to the recommendations regarding minimum size for pilot scale for ANDA submission batch size reduction were established in the agency’s guidance (6):

		The RLD has an orphan drug designation.

		Use of a controlled substance allocated by the Drug Enforcement Administration.

		The test batch size is the same as the commercial batch size with the commitment that a prior approval supplement (PAS) will be provided when there is scale-up.

	FDA did concur with the proposals for reduced batch sizes when they met one of the above criteria; however, in cases where the proposals used the high API cost or other financial/logistical constraints as justifications, the agency normally denied concurrence.

	The second most popular question was regarding multiple API sources. The specific questions were broad, but generally related to whether different routes of synthesis are acceptable from two API sources in the same ANDA submission, whether it is acceptable to have different specifications and test methods for different sources of API, and how many exhibit/stability batches should be manufactured using the API from the alternate source(s). For the first two scenarios, FDA typically concurs with the proposals while recommending sufficient justifications to be included in the ANDA submission(s). Regarding the number of batches, the agency recommends comparative stability and release data from at least one batch of finished drug product produced from each alternate API source. It should be noted that the APIs in discussion are limited to small molecules; recommendations for complex drug substances or products (e.g., peptides, low molecular weight heparins, and biologics) can be different and would require considerations on case-by-case basis.

	Another common question is the reporting mechanism for post-approval changes. Nearly all questions in the post-approval changes category were related to reporting category or what data should be submitted in support of the change. These questions have been addressed using a risk-based -approach following the general principles prescribed by the agency’s guidances on post-approval changes (7, 8).

	Questions on overage were almost exclusively related to whether or not the firm could produce a drug product with an overage of the API. In most circumstances, the overage proposal was not approved. As set forth in the Guidance for Industry: Q8(R2) Pharmaceutical Development (January 2009) (9), the use of an overage to compensate for degradation during manufacture or a product’s shelf life, or to extend shelf life, is discouraged. Many firms claim to have found an overage in the RLD; however, this may not be a sufficient justification for overage because the RLDs may have used a different product design and/or manufacturing processes. Given that only a limited amount of information is typically provided in these correspondences, FDA typically considers the use of overage as a review issue to be evaluated within the full context of the ANDA(s); therefore, the firms should provide sufficient justifications in the ANDA submission(s) if overage is used.

	The fifth most popular question was whether it is acceptable to formulate a tablet or capsule size larger than that of the RLD. It is generally recommended to formulate generic solid oral dosage forms to be similar in size to the RLD to increase patient compliance and reduce the risk of dysphagia. Further details are discussed in the Guidance for Industry: Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules (10). Somewhat similar to the use of overage, the agency typically states in the responses that deviations (especially when larger) should be justified in the ANDA submission. Proper justifications should at least include why a larger size is necessary, and how the firm will circumvent dysphagia and patient-compliance issues. Arguments based on patent infringement or manufacturing limitations are not considered appropriate.


	It is helpful to visualize when a topic becomes popular in time. These time points can signal when guidances have accurately conveyed information or may alert the agency about unclear guidance language or recommendations. A lexical dispersion plot (

) displays words in sequential order within a text to visualize the location of keywords within the text. Each stripe represents the instance of a word (the category) and each row represents the entire text. Simultaneously identifying the location of the years 2004-2014 within the text allowed for correlation between the occurrence of each category to the date that the correspondence was submitted.

	This type of chronological correlation shows a heightened interest in specification, formulation, and overage questions beginning in 2012. Questions regarding post-approval changes have remained fairly steady. The Guidance for Industry: CMC Postapproval Manufacturing Changes to Be Documented in Annual Reports (8) was published in May 2014; correspondences will be monitored using such a chorological correlation to assess how well such a guidance document would guide the industry. 

 shows a sharp increase in stability-related controlled correspondence beginning in late 2012, which loosely correlated with the publication of the stability guidance document (5) and its companion question and answer document (6). Given that many questions were about the number and sizes of primary stability batches, FDA may use this information to guide further policy/guidance development or updates.

Furthermore, the evaluation of the frequency of inquiries on a topic over time can indicate how well the agency’s guidance/policy addressed the related topics. For example, questions regarding acceptable limits for and test methods of residual solvents (see 

) were most popular in 2008 and 2009 and then decreased after 2009, corresponding to the release of the 

Guidance for Industry: Residual Solvents in Drug Products Marketed in the United States

 (11) in November 2009. From 2012, no more residual solvents inquiries are recorded. Similarly, the number of questions on impurities dramatically dropped in 2009 and 2010, concurrent with the publication of two impurity-related guidance documents (12, 13).


	Based on the observations during the review of these correspondences, commonly seen submission issues include:

		Vague, general, or poorly-worded questions

		Imprecise language and/or misused terms

		Questions that make incorrect assumptions

		Too much unnecessary information provided.

	The agency strongly recommends the firms:

		Thoroughly research the question before drafting the controlled correspondence, including visiting the FDA website for published guidances and materials

		Provide relevant information clearly in the letter, including, at a minimum, dosage form

		Do not assume that the agency will correct any incorrect assumptions/information.

	With these recommendations considered, a general workflow for proper assembly of controlled correspondences is provided in 


	Controlled correspondence is a crucial route of communication between FDA and the generic-drug industry to facilitate the development of generic-drug products. Therefore, the agency has agreed to specific program enhancements and performance goals for addressing these correspondences, as set forth in the GDUFA Commitment Letter (2). As part of the effort, this data-mining exercise was conducted to identify gaps and potential continual improvements in chemistry-related correspondences. The findings and observations here can provide valuable reference to both FDA and the generic-drug industry. From these observations, the agency can gain better understanding of how its guidances and policies are received and further gauge the needs and concerns of the industry. Further interpretation of certain guidances and policies are provided here so that the industry can be more efficient in submitting correspondences and developing generic-drug products.

An analysis of controlled correspondence between generic-drug manufacturers and FDA reveals patterns in questions about specific drug chemistry topics and the response to information provided in FDA guidance documents.