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

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FDA Perspectives: Common Deficiencies in Abbreviated New Drug Applications: Part 3 - Control of the Drug Product and Stability
Chemistry reviewers in the FDA's Office of Generic Drugs provide an overview of common deficiencies cited throughout the CMC section of ANDAs


Pharmaceutical Technology
Volume 35, Issue 2, pp. 58-67

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).


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