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

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).


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