Pharmaceutical Manufacturing Handbook: Production and

organisms, stability (shelf life), toxicity, sensitizing effects, and compatibility with
other ingredients in the dosage form [57] . Typical antimicrobial preservatives include
m - cresol, phenol, parabens, thimerosal, sorbic acid, potassium sorbate, benzoic acid,
chlorocresol, and benzalkonium chloride. Cationic agents such as benzalkonium
chloride are typically not utilized for peptide and protein formulations because they
may be inactivated by other formulation components and their respective charges
may induce conformational changes and lead to physical instability of the API.
Further, excipients intended for other applications, such as chelating agents, may
exhibit some antimicrobial activity. For instance, the chelating agent ethylenediaminetetraacetic
acid (EDTA) may exhibit antimicrobial activity, as calcium is required
for bacterial growth.
Identifying an optimal antimicrobial preservative is based largely on the effectiveness
of that preservative at the concentration chosen. In short, it is not enough to
assess the compatibility of the preservative of choice with the API and formulation
and processing components. There also needs to be a determination of whether the
preservative concentration is suffi cient to kill certain standard test organisms. The
USP presents standard protocols for assessing the relative effi cacy of a preservative
in a formulation using the antimicrobial effectiveness test (AET) [58] . Briefl y, by
comparing the relative kill effi ciency of the formulation containing varying concentrations
of the preservative, the formulator can determine the minimal concentration
required for preservative effi cacy and design the formulation accordingly.
1.1.5
DRUG PRODUCT STABILITY
DRUG PRODUCT STABILITY 21
1.1.5.1 Defi ning Drug Product Storage Conditions
From a regulatory standpoint, the primary objective of formulation development is
to enable the delivery of a safe and effi cacious drug product to treat and/or mitigate
a disease state throughout its proposed shelf life. The effi cacy and in many cases the
safety of a product are directly related to the stability of the API, both neat and in
the proposed formulation under processing, storage, and shipping conditions as well
as during administration. As such, the concept of drug stability for biotechnology -
derived products does not change substantially from that of small molecules,
although the level of complexity increases commensurate with the increased complexity
of the APIs in question and the formulation systems utilized for their
delivery.
Stability study conditions for biotechnology - derived APIs and their respective
drug products are not substantially different from those studies conducted for small
molecules. Temperature and humidity conditions under which to conduct said
studies are outlined in ICH Q1A(R2), which incorporates ICH Q1F, stability study
conditions for zones III and IV climactic conditions [59] . Additional guidance specifi
c to conducting stability studies on biopharmaceutical drug products is given in
ICH Q5C [1] . However, the intention of ICH Q5C is not to outline alternate temperature
and humidity conditions to conduct primary stability studies; rather it
provides guidance with respect to the fact that the recommended storage conditions
and expiration dating for biopharmaceutical products will be different from product
to product and provides the necessary fl exibility in letting the applicant determine