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).
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
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).