Elsanhouty Pharma Notes, Cairo , Egypt.

Hold Time Studies

Title: Hold Time Study Protocol

1. Objective \ Scope
1.1. Hold time study data shall give the assurance the maximum allowable hold times for bulk and in-
process drug products. Generally, one lot can be used for validating hold times if any inconsistency
results were observed then another two lots can be used for this study.
1.2. Although there are no specific regulations or guidance documents on bulk product hold times, GMP
dictates that hold times should be validated to ensure that in-process and bulk product can be held,
pending the next processing step, without any adverse effect to the quality of the material. Hold time
study provides the re-assurance of the quality at each in-process stages.
1.3. Although there are no specific regulations or guidance documents on bulk product hold times, GMP
dictates that hold times should be validated to ensure that in-process and bulk product can be held,
pending the next processing step, without any adverse effect to the quality of the material. Hold time
study provides the re-assurance of the quality at each in-process stages.
1.4. Although there are no specific regulations or guidance documents on bulk product hold times, GMP
dictates that hold times should be validated to ensure that in-process and bulk product can be held,
pending the next processing step, without any adverse effect to the quality of the material. Hold time
study provides the re-assurance of the quality at each in-process stages.
1.5. Although there are no specific regulations or guidance documents on bulk product hold times, GMP
dictates that hold times should be validated to ensure that in-process and bulk product can be held,
pending the next processing step, without any adverse effect to the quality of the material. Hold time
study provides the re-assurance of the quality at each in-process stages.
2. Responsibilities
2.1. Validation Officer:
 To prepare protocol and report.
 Sampling as per the approved protocol.
 Conclude the result.
2.2. Quality Control:
 Review of Protocol and report.
 To analyses the hold time study samples as per the approved protocol and report the results.
2.3. Quality Control (Microbiology):

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  Review of Protocol and report.
 To analyses the hold time study samples as per the approved protocol and report the results.
2.4. Head – Quality Assurance:
 Approval of protocol and result
3. Hold time consideration
3.1. Granulation Solutions, Coating Solutions:
 Typically, if these in-process products are used within 24 hours of manufacturing, no bulk holding time
studies are deemed necessary. An in-process product that is hold for longer than 24 hours should
be monitored for physical characteristics and microbial contamination.
 A coating solution should be held for the defined hold period. At the test points, a sample should be
taken from the storage container and tested. Results obtained should be compared with the initial data
of the solution control sample results.
3.2. Powder Blends, Granules:
 In-process products such as Powder blends, granules can be held for up to 30 days from the date of
production without being retested prior to use. An in-process product that is held for longer than 30
days should be monitored for hold time study under controlled storage conditions for the length of the
holding period.
 At the test points, a sample should be taken from the storage container and tested. Results obtained
should be compared with the initial data of the core tablet and pellet control sample results.
3.3. Core Tablets:
 In-process products such as core tablets, extended-release pellets can be held for up to 30 days from
the date of production without being retested prior to use. An in-process product that is held for longer
than 30 days should be monitored for hold time study under controlled storage conditions for the
length of the holding period.
 At the test points, a sample should be taken from the storage container and tested. Results obtained
should be compared with the initial data of the core tablet and pellet control sample results.
3.4. Bulk Tablets and Capsules:
 Bulk tablets and capsules can be held for up to 30 days from the date of production without being
retested prior to use. A bulk product that is held for longer than 30 days should be monitored for hold
time study under controlled storage conditions for the length of the holding period.
 At the test points, a sample should be taken from the storage container and tested. Results obtained
should be compared with the initial data of the tablet and capsule control sample results.
3.5. Oral Liquids and Semi-Solids: (Suspensions, Creams and Ointments).
 Typically, liquid and semi-solid dosage form products should be held for no more than 5 days without
a hold time study. Full scale batches should be used for these studies.

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  Samples should be taken from the holding vessel after transfer from the manufacturing vessel, and
again at the completion of the holding period. Multiple samples should be taken at each time point if
holding can impact product uniformity. Samples would be taken to prove that product uniformity of
actives and preservatives.
4. Hold time stages
 The hold time study for the product shall be carried out on three batches. The validation officer shall
collect the sample as per protocol during the manufacturing of the planned batches.
 The selection of hold time study conditions is very important for starting the hold study. These
conditions are same with the manufacturing area/hold area conditions, so these conditions are may
vary with the product to product. Based on the manufacturing process of the dosage forms hold study
stages can be decided. Hold study required stages are summarized in the table.

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 Dosages Form Hold Study Required Stages
Binder
Dried Granules
Lubricated Blend
Tablets
Core Tablet
Coating Solution
Coated Tablets
Blending Powder
Capsules
Filled Capsules
Un-Filtered Solution
Liquids
Filtered Solution
Semi Solids Bulk Sample

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5. Tests to be considered
Proposed
Hold Time Hold Time Study Time
Hold Tests Required
Study Required Points
Time
Core Tablets (Direct Compression/ Dry Granulation)
Description, Loss on Drying and
Granules 45 days Initial, 15, 30 and 45 days
Assay
Loss on Drying, Content Uniformity,
Lubrication 45 days Initial, 15, 30 and 45 days
Particle Size, Bulk/Tapped Density
Description, Hardness, Thickness,
Initial, 30, 45, 60 and 90
Core Tablets 90 days Friability, Disintegration, Dissolution,
days
Assay
Core Tablets (Wet Granulation)
Initial, 2, 5, 8 hours
Binder solution 8 hours In case of starch: initial, 2, Appearance
5 hours
Dried Granules 45 days Initial, 15, 30 and 45 days Description and LOD
Loss on Drying, Content Uniformity,
Lubrication 45 days Initial, 15, 30 and 45 days
Particle Size, Bulk/Tapped Density
Description, Hardness, Thickness,
Initial, 30, 45, 60 and 90
Core Tablets 90 days Friability, Disintegration, Dissolution,
days
Assay
Coated Tablets (Direct Compression/ Dry Granulation)
Granules 45 days Initial, 15, 30 and 45 days Description, LOD and Assay
Loss on Drying, Content Uniformity,
Lubrication 45 days Initial, 15, 30 and 45 days
Particle Size, Bulk/Tapped Density
Description, Hardness, Thickness,
Initial, 30, 45, 60 and 90
Core Tablets 90 days Friability, Disintegration, Dissolution,
days
Assay
Initial, 12, 24, 36, 48, 60 Physical Appearance, Specific
Coating Solution 72 hours
and 72 hours Gravity, Viscosity, Sedimentation, pH
Description, Hardness, Thickness,
Initial, 30, 45, 60 and 90
Coated Tablets 90 days Friability, Disintegration, Dissolution,
days
Assay
Coated Tablets (Wet Granulation)
Initial, 2, 5, 8 hours
Binder solution 8 hours In case of starch: initial, 2, Appearance
5 hours
Dried Granules 45 days Initial, 15, 30 and 45 days Description and LOD
Loss on Drying, Content Uniformity,
Lubrication 45 days Initial, 15, 30 and 45 days
Particle Size, Bulk/Tapped Density.
Description, Hardness, Thickness,
Initial, 30, 45, 60 and 90
Core Tablets 90 days Friability, Disintegration, Dissolution,
days
Assay
Initial, 12, 24, 36, 48, 60 Physical Appearance, Specific
Coating Solution 72 hours
and 72 hours Gravity, Viscosity, Sedimentation, pH
Initial, 30, 45, 60 and 90 Description, Hardness, Thickness,
Coated Tablets 90 days
days Friability, Disintegration, Dissolution,

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 Assay
Dispersible/ Orally Disintegrating Tablets
Loss on Drying, Content Uniformity,
Granules 45 days Initial, 15, 30 and 45 days
Particle Size, Bulk/Tapped Density
Description, Hardness, Thickness,
Compressed Initial, 30, 45, 60 and 90
90 days Friability, Disintegration, Dissolution,
Tablets days
Assay
Capsules (Power Filling)
Loss on Drying, Content Uniformity,
Lubrication 45 days Initial, 15, 30 and 45 days
Particle Size, Bulk/Tapped Density.
Initial, 30, 45, 60 and 90 Description, Disintegration,
Filled capsules 90 days
days Dissolution, Assay.
Capsules (Pellets Filled)
Drug Pellets 45 days Initial, 15, 30 and 45 days Description and assay.
Loss on Drying, Content Uniformity,
Lubrication 45 days Initial, 15, 30 and 45 days
Particle Size, Bulk/Tapped Density.
Initial, 30, 45, 60 and 90 Description, Disintegration,
Filled capsules 90 days
days Dissolution, Assay,
Liquids (Syrups, Oral Solutions, Suspensions)
Un-filtered Description, pH, Specific Gravity,
7 days 1, 2, 5 and 7days
solution Assay and Microbial Limit
Description, pH, Specific Gravity,
Filtered solution 7 days 1, 2, 5 and 7days
Assay and Microbial Limit
Ointments / Gels / Creams
Initial, 12, 24, 36, 48 and Description, pH, Specific Gravity and
Bulk stage 72 hours
72 hours assay
6. Conclusion :
6.1. The conclusion should state whether the outcome of the activity was successful or not.

7. Revalidation Criteria:
7.1. The hold time study shall be performed again in case of any major change in product specification.

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Dr. Hassan Elsanhouty