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Hold Time Study Protocol

TABLE OF CONTENTS
  1. Table of Contents
  2. Introduction
  3. Objective
  4. Scope
  5. Responsibility
  6. Holding Time Considerations
  7. Hold Time Study Stages
  8. Stages, Study Times and Tests to be Considered
  9. Conclusion
  10. Revalidation

INTRODUCTION
  • 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.

OBJECTIVE
  • 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.

SCOPE
  • This Protocol provides the guidance for 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.

RESPONSIBILITY

Validation Officer:
  • To prepare protocol and report.
  • Sampling as per the approved protocol.
  • Conclude the result.

Quality Control:
  • Review of Protocol and report.
  • To analyses the hold time study samples as per the approved protocol and report the results.

Quality Control (Microbiology):
  • Review of Protocol and report.
  • To analyses the hold time study samples as per the approved protocol and report the results.

Head – Quality Assurance:
  • Approval of protocol and result

Production:
  • To review the protocol and report.

HOLDING TIME CONSIDERATIONS:

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.

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.
PEOPLE ALSO READ: SOP for Hold Time Study

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.

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.

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. 
  • 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.

HOLD TIME STUDY 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 1.
Figure 1 - Example of a flow chart for reviewing the manufacturing procedure – Tablets


Figure 2 - Example of a flow chart for reviewing the manufacturing procedure – Capsules


Figure 3 - Example of a flow chart for reviewing the manufacturing procedure – Liquid Oral

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



STAGES, STUDY TIMES AND TESTS TO BE CONSIDERED:

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


Table 2: Hold time study requirements for all types of dosage forms.

CONCLUSION:
The conclusion should state whether the outcome of the activity was successful or not.

REVALIDATION:
The hold time study shall be performed again in case of any major change in product specification.

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