Drug product testing is generally divided into three stages: 1. In-process testing 2. Finished product testing 3. Shelf-life testing
Evaluation of
capsule drug products
Drug
product testing is generally divided into three stages:
1. In-process testing, during the manufacture of the drug
product. These batteries of tests are carried out at predefined intervals
during the product manufacturing, by the manufacturing personnel, and their results
recorded on the batch record. Adverse findings in these tests can be used as a
guide to alter the manufacturing-process parameters.
2. Finished product testing, after the whole batch has been
manufac-tured. These tests help identify whether the batch is acceptable for
marketing or its intended usage.
3. Shelf-life testing, after the whole batch has been
packaged. These tests are frequently carried out after defined periods of
storage at prede-termined conditions. They help to assign and verify the shelf
life and usability of the drug product.
Visual
inspection of soft gelatin capsules is done to ensure absence of clearly
malformed, damaged, or improperly filled capsules. During the encapsula-tion of
soft gelatin capsules, the following parameters are usually closely monitored
and controlled:
·
Gel ribbon thickness and uniformity across the ribbon
·
Seal thickness
·
Weight of the capsule fill and its variation from
capsule-to-capsule
·
Weight of the capsule shell and its variation from capsule-to-capsule
·
Moisture level of the capsule shell before and after drying
Visual
inspection, fill weight, and fill-weight uniformity are the key in-process
tests used for hard gelatin capsules.
Soft
gelatin capsules are tested for physical integrity (absence of leakage) by
visual inspection. Similarly, hard gelatin capsules are tested for any breach
of physical integrity (breakage or opened cap and body).
All
capsules are tested for drug content (potency, as a percent of label claim). In
addition, most drug products are tested for the related substances or
impuri-ties. These must meet predefined specifications for a batch to be
acceptable.
Ten
hard gelatin capsules are usually weighed individually and the con-tents are
removed. The emptied shells are individually weighed and the net weight of the
contents is calculated by subtraction. The content of active ingredient in each
capsule may be determined by calculation based on the percent drug content in
the formulation for high drug load formulations.
For
soft gelatin capsules, the gross weight of 10 gelatin capsules is deter-mined
individually. Then each capsule is cut open, and the contents are removed by
washing with a suitable solvent (that dissolves the fill but not the shell).
The solvent is allowed to evaporate at room temperature, fol-lowed by weighing
of the individual washed shells. The net contents are calculated by subtraction
and the content of active ingredient in each of the capsules can be determined
by calculation based on the percent drug content in the formulation.
Fill-weight
variation of capsules is often a function of equipment setup and filling
operation. An automated capsule sizing machine and/or weight checker is
frequently used to discard over- or underfilled capsules.
Uniformity
of content of the active ingredient can be determined by weight variation of
the fill of hard or soft gelatin capsules for high drug load (API ≥25% w/w of
the total fill weight), high fill-weight (250 mg/capsule) formu-lations. For
low drug load and low fill-weight formulations, each capsule must be analyzed
individually by the potency method for the content of the active ingredient.
The uniformity of content is assured if predetermined criteria for the range
and variation in the content of the active ingredient are met.
Disintegration
of hard and soft gelatin capsules is evaluated to ensure that the drug substance
is fully available for dissolution and absorption from the GI tract. The
disintegration media varies depending on the type of capsules to be tested.
Drug
absorption and physiological availability depend on the drug sub-stance being
in the dissolved state at the site of drug absorption, viz. the GI fluids. The
rate and extent of dissolution of the drug from the capsule dosage form is
tested by a dissolution test. Dissolution test provides means of quality
control in ensuring that (a) different batches of the drug prod-uct have
similar drug release characteristics and (b) that a given batch has similar
dissolution as the batch of capsules that was shown initially to be clinically
effective.
Water
content of the entire capsule or the capsule contents are determined by Karl
Fisher titrimetry to enable the correlation of water content with the
degradation profile or drug-release characteristics of capsules.
The
capsules are tested to ensure lack of growth of bacteria and mold by
microbiological tests. These tests are usually carried out by incubation of the
capsule contents in a growth medium and counting the colonies formed after a
predefined period of time. Selection of the growth medium and duration of the test,
as well as maintenance of aseptic conditions during the testing, are critical
to successful assessment of microbial contamination by this method.
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