Commonly Cited Deficiencies for Topical Dermatologic Drug Products in ANDAs

In the September 2016 issue of Pharmaceutical Technology, the authors of "Common Deficiencies in ANDAs for Dermatologic Drug Products," presented the following examples of commonly cited deficiencies for topical dermatologic drug products cited by FDA during the past four years:

• “We note that you have not provided the maximum daily dose (MDD) for your drug product. In the absence of such information, we have used the largest tube (60 g) to calculate the MDD. Based on an MDD of 60 mg of the active, the ICH [International Council for Harmonization] Q3B guidelines allow an Identification Threshold of 0.2% and a Quantitation Threshold of 0.33%. Your limit for any unidentified impurity in your drug product release and stability specifications is set at 0.5%. Please show us your calculation for the MDD to justify your proposed limit or tighten the specification for any unknown impurities to Not More Than 0.2%.”

• “We acknowledge that you attempt to use the finger-tip unit to estimate the maximum daily dose (MDD) for your drug product. However, because you did not provide the maximum possible affected area for your drug product and your estimating equation is not correct, we have used the entire body surface as the affected area (40 finger-tip units x 0.5 g/finger-tip unit) to calculate the MDD. Based on an MDD of 200 mg and the ICH Q3B guidelines, your limits for any individual unknown impurity and identified impurity in your drug product release and stability specifications are not appropriate. Please show us your corrected calculation for the MDD to justify, or tighten, the specification limits.”   

• “Because your test formula contains many ingredients and you did not provide information regarding your understanding of the critical material attributes that may affect your drug product quality, please discuss critical material attributes and their impact on the drug product quality, if there are high-risk excipients used in your formula. Because your manufacturing process is a complicate one, please discuss your understanding of critical process parameters that may affect your drug product quality attributes. In addition, we notice that you incorporated water soluble surfactant into the lipid phase and you added aqueous phase to the lipid phase to form an emulsion. Please discuss the effect of the order of addition (e.g., adding the surfactant to aqueous phase and adding lipid phase to aqueous phase) on Q3 attributes of your drug product. Also, we encourage that the generic companies adopt the QbD concept in their drug product development. Please comment on your rationale not to apply QbD in your drug product development.”  

• “Because pH, viscosity, particle size, and globule size are potential critical quality attributes for your drug product, we request you include these tests in your drug product release and stability specifications.”

• “Please also include description test for your drug product in the proposed container closure system to evaluate packaging components (i.e., label condition, container product interaction, container integrity, etc.).” 

• “Because your drug substance has ionizable functional groups and ionized/unionized ratio is an important factor for drug performance, pH specification limits should be in line with the RLD [reference listed drug]. We recommend you to tighten the upper limit for your in-process, drug product release and stability specifications to be in line with that of the RLD. In addition, we recommend that the pH be characterized by preparing a dilution of the drug product (e.g., 1:10 dilution with distilled, deionized, CO₂-free water).”

• “We encourage the generic companies to adopt quality by design (QbD) and design of experiment (DoE) in their drug product development, partly because we would like the applicant to elucidate the interaction between variables. Also, we initiated risk-based review in which we view a drastic interaction between two quality attributes as an increased risk. Hence, we request you to provide pH effect on viscosity of your drug product to demonstrate your understanding of your drug product and to mitigate this risk.  Please conduct a viscosity-pH study for your test product to show understanding of your drug product and to justify the limits of viscosity based upon viscosity-pH relationship, if feasible.”

• “The gelling agent used in your ANDA product is known to be pH dependent, and viscosity decreases while pH decreases. In addition, the acidic degradative product from active pharmaceutical ingredient can significantly lower pH and then viscosity of your product. In order to mitigate the risks of pH and viscosity downward trend, we recommend you to provide pH effect on viscosity of your drug product to justify your drug product specification limits of viscosity, if feasible.”

• “Because semisolid preparations commonly have a non-Newtonian flow behavior, please provide comparative rheological characteristics (i.e., upward and downward flow curve of shearing stress vs. shearing rate along with yield value) for both your drug product and the RLD to demonstrate the appropriateness of your selected viscometer.”

• “We notice that your temperature condition for viscosity measurement is excessively higher than that of the storage condition. Please revise your test condition to be ambient to avoid any microstructural change (e.g., melting down of excipient(s)).”

• “Drug substance polymorphism can be the critical attribute to ensure drug performance. Please demonstrate the drug form for API is the same as that in the RLD [reference listed drug] or discuss the polymorphism form issue following the ICH [International Council for Harmonization] Q6A decision tree for #4 polymorphic form.”

• “Your procedure for analyzing drug product particle size reports an average of very limited crystalline particles. In order to define a better estimation of the particle size distribution, it is recommended that you report the average of ~300 particles. To alleviate this slow and tedious manual procedure, a computerized image analysis method or other appropriate test method can be adopted for particle size measurements.”

• “We notice that you have proposed one tier particle size specification limit in your drug product release and stability specifications. It is recommended that you establish a three-tier particle size distribution for your proposed drug product.”

• “Your drug product is an oil-in-water cream. The globule size is a potential critical quality attribute. Please include globule size test in your drug product release and stability specifications with appropriate limits, based on the test results of your test products and the RLD.”

• “We recommend that comparative in-vitro release test for your drug product and the RLD be conducted using a validated test method, and the data generated can be used as a baseline for future potential formulation and process changes for your drug product.” 

• “We notice that you only test top, middle, and bottom (three samples), which is not sufficient to demonstrate the homogeneity of bulk product. Please acknowledge this inadequate sample number for bulk content uniformity test and commit to increase the sample number (at least 10 samples) collected from appropriately spaced locations for your future batches to attain statistically meaningful results.”

• “What additional in-process controls and tests are in place during filling and packaging? Specifically, provide specific details on the controls in place for fill weight, sealing and capping of the tubes. Also, seal integrity or tube leaking test should be performed to ensure adequate protection for the drug product.”

• “Your drug product contains the solvent (ethyl alcohol), penetration enhancer (isopropyl myristate), and chelating agent (edetate disodium); however, your drug product release and stability specifications do not include assay tests for these important components of your formulation. Please modify your DP release and stability specifications to include ethyl alcohol assay, isopropyl myristate assay, and edetate disodium content.”

• “Please include weight loss test in your drug product stability specification with a footnote to reflect such a test for developmental batches (exhibit and validation batches) only to qualify the proposed container closure system.”

• “Because your test formula contains large amount of ethyl alcohol and the solvent has powerful extraction ability, we request you conduct the extractables/leachables studies for your container closure system. Please investigate and demonstrate the absence of benzophenone in the drug product stability samples using an established analytical method. In case benzophenone is detected in the drug product, we recommend including a leachable specification to limit its amount in your drug product release and stability specifications. Also, note that benzophenones have been named the American Contact Dermatitis Society’s 2014 Contact Allergen of the year.”

• “The thermal cycling studies you conducted are not acceptable in their current forms. One of the purposes to a conduct thermal cycling (freeze-thaw) study is to assess the effects of transportation on the quality of the drug product. The temperature range you selected does not adequately simulate the actual transportation conditions, which routinely span a temperature range of 40 °C to -20 °C. Please also note that the thermal cycling study is part of the stability studies. Therefore, all quality attributes of the stability specifications should be evaluated and the results reported. Please revise your thermal cycling study protocol and provide all relevant data according to your stability specifications.”

• “Please refer to FDA Guidance for Industry: ANDAs: Stability Testing of Drug Substances and Products Questions and Answers (May 2014), specifically to Section E Q2 and A2, for FDA’s recommendations on the storage positions for stability samples in the stability program. Please note that we recommend that for semi-solid drug product the stability samples should be placed into two orientations: an inverted (or horizontal) position and an upright (or vertical) position. We ask that you comply with our recommendation in any future ANDA submissions. For your current ANDA application, we recommend that you adopt the required two (2) sample orientations for at least one of the validation batches. Once you demonstrate that the products in one orientation do not have significant greater impact on stability over the other, you may discontinue the testing with samples stored in upright orientation for routine stability studies.”

Article Details

Pharmaceutical Technology

Vol. 40, No. 9

September 2016

Pages: 70, 72, 74

Citation

When referring to this article, please cite it as R. Chang et al., Sidebar to "Common Deficiencies in ANDAs for Dermatologic Drug Products," Pharmaceutical Technology 40 (9) 2016.