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Companies may potentially accelerate the approval of generic drugs by avoiding deficiencies in ANDA submissions.
Approval of generic drugs can be slowed down by deficiencies in abbreviated new drug applications (ANDAs). Srinivasan et al. (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 et al. (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 et al. and Liu et al. 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.
Maximum daily dose. 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.
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 in-vitro or in-vivo study option. This information is available on FDA’s website (9). Acceptable comparative physicochemical characterization and/or in-vitro 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. 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, CO2-free water for pH determination, when direct measurement is not feasible.
Viscosity. 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.
Polymorph equivalence. 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).
API particle size. 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.
Globule size. 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. Currently, in-vitro 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 in-vitro 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 tests.In-vitro 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 United States Pharmacopeia (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 USP 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.
1. A. Srinivasan and R. Iser, Pharm. Technol. 34 (1), 50-59 (January 2010).
2. A. Srinivasan, R. Iser, and D. Gill, Pharm. Technol. 34 (8), 45-51 (August 2010).
3. A. Srinivasan, R. Iser, and D. Gill, Pharm. Technol. 35 (2), 58-67 (February 2011).
4. A. Srinivasan and R. Iser, Pharm. Technol. 35 (4), 62-68 (April 2011).
5. Q. Liu et al., AAPS Journal 14 (1), 19-22 (2012), DOI: 10.1208/s12248-011-9312-7.
6. C.C. Long and A.Y. Finlay, Clin. Exp. Dermatol. 16 (6), 444-7 (1991).
7. R.K. Chang et al., AAPS Journal, 16 (1), 41-52 (2013), DOI: 10.1208/s12248-012-9411-0.
8. R.K. Chang et al., AAPS Journal, 15 (3), 674-83 (2013), DOI: 10.1208/s12248-013-9472-8.
9. FDA, “Product-Specific Recommendations for Generic Drug Development,” FDA.gov.
10. ICH, 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, USP 39-NF 34 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 (CDER, May 2014).
14. FDA, 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., Eur. J. Phrm.Biopharm. 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 USP 39-NF 34, 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, The Dermatologist, 22 (11) (2014), www.the-dermatologist.com/content/review-acds’-allergen-od-year-2000-2015
Editor’s Note: 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
When referring to this article, please cite it as R. Chang et al., "Common Deficiencies in ANDAs for Dermatologic Drug Products," Pharmaceutical Technology 40 (9) 2016.