Introduction:
Manufacture should ensure that
the products they are manufacture are safe, effective and quality required for
intended use. System should be in-place and in-use to ensure that the products
manufactured as per validated process.
As per Good manufacturing
practices, manufacture should ensure that the dispensing raw materials and
packing materials, intermediates products, bulk and finished product are stored
under suitable conditions.
Storage arrangement should be such which safeguard the subsequent processing, stability, safety, efficacy or quality of starting materials, intermediate products, and bulk drug prior to final packing. Maximum hold time should be established to ensure that intermediate and bulk product can be held without producing results outside the acceptance criteria for the quality of the material. Intermediate and bulk product should not be store beyond the established hold time. The choice of maximum hold time should be supported by relevant data. manufacture should collect scientific and justifiable data to demonstrate that the dispensed raw/packing material, intermediate and bulk product remain of appropriate quality before processing to the next stage.
Definition:
Bulk drug: Any
pharmaceutical product that has completed all processing stages up-to, but not
including final packaging.
Intermediate:
Partly processed product that must undergo further manufacturing steps before
it becomes a bulk product.
Fact to be considered:
Hold time can be considered as the established time period
for which materials may be held under specified condition and will remain
within specification. The design of this study should reflect the holding time
of each stage. Hold time should be determined prior to marketing of the
product. Risk assessment should be done if any change in process, equipment,
storage condition, starting and packing material. Hold time studies performed
during development on pilot-scale batches or during scale-up should be
confirmed during process validation of commercial batches. Manufacturer can use
a flow chart for review of manufacturing procedure for the product and then
breakup the critical stages.
A written protocol, procedure should be followed. Acceptance
criteria are typically more stringent than registered specification, to provide
assurance that the material is well within control. While setting the
specification any known stability trends will need to be taken into account. In
certain product microbiological should also be considered and included where
appropriate. A representative sample of the batch of material or product
subjected to the hold-time study should be held for the defined hold period.
The hold period of each category of material should be established on the basis
of the study by keeping the material in either the original or simulated
container used in production. Reducing the size of container, when this is
necessary for testing holding, should be justified.
Where the headspace of containers used for bulk storage in
manufacturing and/or quarantine is important (eg. Because of the risk of
potential degradation as a result of oxidation), then the hold-time studies
should represent worst case conditions. In such cases, the ratio of headspace
to content in the test container should be at least as great as the maximum
that is possible in routine production.
The environmental condition should be maintained same as
those of the quarantine area and/or manufacturing stage.
The amount of sample required should be calculated based on
the batch size, the intervals, and the tests to be performed. Results should be
compared with the initial results.
Statistical analysis of the data generated should be
performed to identify trends and to justify the limits on hold time set.
 |
| General process flow of Tablet Manufacturing |
As per WHO guidance Annexure 4 “General guidance on Hold
time studies”
Example
|
Stage |
Test
to be carried out as per specification |
Study time |
|
Binder
preparation |
Microbial test, appearance, viscosity |
Initial, 2, 5, 8 hours. In case of starch Initial, 2, 5 hours |
|
Dispersion
preparation (including granulation paste, coating solution and coating
suspension) |
Physical appearance, specific gravity, viscosity, sedimentation, pH, microbial test |
Initial, 15th day, 30th day, 45th day |
|
Blend |
Microbial test, loss of drying, Blend uniformity, partial size, bulk/tapped density |
Initial, 15th day, 30th day, 45th day |
|
Core
tablets – uncoated (in bulk container) |
Description, hardness, thickness, friability, disintegrating, dissolution profile, assay,, degradation products/ related substance, uniformity of dosage unit, microbial test |
Initial, 30th day, 45th day, 60th day and 90th day |
|
Coated
tablets (in bulk container) |
Description, appearance or visual examination, hardness, thickness, friability, disintegration, dissolution or dissolution profile, assay degradation products/ related substance, moisture content, microbial test |
Initial, 30th day, 45th day, 60th day and 90th day |
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