Biomedical Engineering Reference
In-Depth Information
compared to parent compound and are used in marketed products
for treatment of open-angle glaucoma. Esters of pilocarpine were
developed with enhanced aqueous stability [
20
-
25
].
The characterization of the physicochemical properties of the
drug substance or active pharmaceutical ingredient (API) is critical
in developing a successful ophthalmic product. Drug substance
storage temperature, humidity, and packaging materials require
evaluation as part of formulation development. Packaging materials
and storage conditions should be evaluated with the assumption
that the package will be opened multiple times for sampling and
subdivision at the manufacturing site. Improper storage conditions
can lead to moisture uptake or product degradation, impacting
potency of the formulation.
Preformulation studies are routinely carried out to characterize
and profile the chemistry and pharmaceutics of the drug substance
[
26
]. Physicochemical information on the compound of interest
(API) is also needed for dossier in regulatory submission. A list of
such studies is provided in Table
2
.
3.2 Preformulation
Studies for Drug
Substance
Code of federal register and FDA guidance related to drug sub-
stance were issued with intention “to provide sponsors with proce-
dures acceptable to the agency for complying with regulations
pertaining to the submission of adequate information on the pro-
duction and control of new drug substances” [
27
,
28
]. Most recent
guidance to industry by regulatory agencies on drug substance CMC
were published in 2010 [
29
-
35
]. According to ICH e-CTD
format, CMC of drug substance constitute section 3.2.S.1-3.2.S.7
(
see
Table
12
), including all aspects of drug substance such as
manufacturing, characterization, control, stability,
3.3 Drug Substance
Chemistry,
Manufacturing,
Control
impurity, and
reference standard.
The DS characterization process involves structural characteri-
zation with NMR, FTIR, UV, MS, and single crystal structure
determination. Physical characterization involves particle size,
morphology (optical microscopy and SEM), XRPD, TGA, DSC,
moisture content, moisture sorption/desorption isotherms, etc.
A detailed crystal form study should be carried out as well to
identify the most stable form for development. Other tests, as
appropriate and as needed, would be conducted on DS to charac-
terize properly and identify uniqueness and risk associated. Accord-
ing to ICH Q3A guidance, impurities in an API can be classified
into three categories as mentioned below [
29
].
Organic impurities constitute process-related impurities and any
associated degradation products. Reporting, identification, and
qualification thresholds of impurities, as per ICH Q3A guidance
[
29
], are provided in Table
3
.
3.3.1 Organic Impurities
