- Table of Contents
- Introduction
- Objective
- Scope
- Responsibility
- Holding Time Considerations
- Hold Time Study Stages
- Stages, Study Times and Tests to be Considered
- Conclusion
- Revalidation
- 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.
- 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.
- Hold time study is the determination of time period for which the product can be held at a particular stage & period during processing, under defined storage conditions. Such study will support the maximum time period between various stages during the manufacturing of the product.
- This protocol will provide the guideline to determine the hold time for different manufacturing stages for products.
- This Protocol provides the guidance for the determination of time limitation up to which bulk can be stored before taken for next processing stage up to which time it can be stored in stipulated storage container at stipulated storage conditions.
- To prepare protocol and report.
- Sampling as per the approved protocol.
- Conclude the result.
- Review of Protocol and report.
- To analyses the hold time study samples as per the approved protocol and report the results.
- Review of Protocol and report.
- To analyses the hold time study samples as per the approved protocol and report the results.
- Approval of protocol and result
- To review the protocol and report.
- 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 held 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. The results obtained should be compared with the initial data of the solution control sample results.
- In-process products such as Powder blends, and 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.
- In-process products such as core tablets and extended-release pellets can be held for up to 30 days from the date of production without being retested before 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. The results obtained should be compared with the initial data of the core tablet and pellet control sample results.
- 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.
- 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.
- 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.
- Interim storage of the dosage form in bulk containers should generally not exceed six months.
- 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 1.
Dosages Form | Hold Study Required Stages |
Tablets | Binder |
Dried Granules | |
Lubricated Blend | |
Core Tablet | |
Coating Solution | |
Coated Tablets | |
Capsules | Blending Powder |
Filled Capsules | |
Liquids | Un-Filtered Solution |
Filtered Solution | |
Semi Solids | Bulk Sample |
Table 1: All pharmaceutical dosage forms hold study stages
Hold Time Study Required | Proposed Hold Time | Hold Time Study Time Points | Tests Required |
Core Tablets (Direct Compression/ Dry Granulation) | |||
Granules | 45 days | Initial, 15, 30 and 45 days | Description, Loss on Drying and Assay |
Lubrication | 45 days | Initial, 15, 30 and 45 days | Loss on Drying, Content Uniformity, Particle Size, Bulk/Tapped Density |
Core Tablets | 90 days | Initial, 30, 45, 60 and 90 days | Description, Hardness, Thickness, Friability, Disintegration, Dissolution, Assay |
Core Tablets (Wet Granulation) | |||
Binder solution | 8 hours | Initial, 2, 5, 8 hours In case of starch: initial, 2, 5 hours | Appearance |
Dried Granules | 45 days | Initial, 15, 30 and 45 days | Description and LOD |
Lubrication | 45 days | Initial, 15, 30 and 45 days | Loss on Drying, Content Uniformity, Particle Size, Bulk/Tapped Density |
Core Tablets | 90 days | Initial, 30, 45, 60 and 90 days | Description, Hardness, Thickness, Friability, Disintegration, Dissolution, Assay |
Coated Tablets (Direct Compression/ Dry Granulation) | |||
Granules | 45 days | Initial, 15, 30 and 45 days | Description, LOD and Assay |
Lubrication | 45 days | Initial, 15, 30 and 45 days | Loss on Drying, Content Uniformity, Particle Size, Bulk/Tapped Density |
Core Tablets | 90 days | Initial, 30, 45, 60 and 90 days | Description, Hardness, Thickness, Friability, Disintegration, Dissolution, Assay |
Coating Solution | 72 hours | Initial, 12, 24, 36, 48, 60 and 72 hours | Physical Appearance, Specific Gravity, Viscosity, Sedimentation, pH |
Coated Tablets | 90 days | Initial, 30, 45, 60 and 90 days | Description, Hardness, Thickness, Friability, Disintegration, Dissolution, Assay |
Coated Tablets (Wet Granulation) | |||
Binder solution | 8 hours | Initial, 2, 5, 8 hours In case of starch: initial, 2, 5 hours | Appearance |
Dried Granules | 45 days | Initial, 15, 30 and 45 days | Description and LOD |
Lubrication | 45 days | Initial, 15, 30 and 45 days | Loss on Drying, Content Uniformity, Particle Size, Bulk/Tapped Density. |
Core Tablets | 90 days | Initial, 30, 45, 60 and 90 days | Description, Hardness, Thickness, Friability, Disintegration, Dissolution, Assay |
Coating Solution | 72 hours | Initial, 12, 24, 36, 48, 60 and 72 hours | Physical Appearance, Specific Gravity, Viscosity, Sedimentation, pH |
Coated Tablets | 90 days | Initial, 30, 45, 60 and 90 days | Description, Hardness, Thickness, Friability, Disintegration, Dissolution, Assay |
Dispersible/ Orally Disintegrating Tablets | |||
Granules | 45 days | Initial, 15, 30 and 45 days | Loss on Drying, Content Uniformity, Particle Size, Bulk/Tapped Density |
Compressed Tablets | 90 days | Initial, 30, 45, 60 and 90 days | Description, Hardness, Thickness, Friability, Disintegration, Dissolution, Assay |
Capsules (Power Filling) | |||
Lubrication | 45 days | Initial, 15, 30 and 45 days | Loss on Drying, Content Uniformity, Particle Size, Bulk/Tapped Density. |
Filled capsules | 90 days | Initial, 30, 45, 60 and 90 days | Description, Disintegration, Dissolution, Assay. |
Capsules (Pellets Filled) | |||
Drug Pellets | 45 days | Initial, 15, 30 and 45 days | Description and assay. |
Lubrication | 45 days | Initial, 15, 30 and 45 days | Loss on Drying, Content Uniformity, Particle Size, Bulk/Tapped Density. |
Filled capsules | 90 days | Initial, 30, 45, 60 and 90 days | Description, Disintegration, Dissolution, Assay, |
Liquids (Syrups, Oral Solutions, Suspensions) | |||
Un-filtered solution | 7 days | 1, 2, 5 and 7days | Description, pH, Specific Gravity, Assay and Microbial Limit |
Filtered solution | 7 days | 1, 2, 5 and 7days | Description, pH, Specific Gravity, Assay and Microbial Limit |
Ointments / Gels / Creams | |||
Bulk stage | 72 hours | Initial, 12, 24, 36, 48 and 72 hours | Description, pH, Specific Gravity and assay |
