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.

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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.

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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

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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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