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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.

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• 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.

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.

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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

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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

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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 Proposed Hold Time Study Tests Required

Study Hold Time Points
Required Time

Core Tablets (Direct Compression/ Dry Granulation)

Granules 45 days Initial, 15, 30 and 45 Description, Loss on Drying and

days Assay

Lubrication 45 days Initial, 15, 30 and 45 Loss on Drying, Content Uniformity,

days Particle Size, Bulk/Tapped Density

Core Tablets 90 days Initial, 30, 45, 60 and Description, Hardness, Thickness,
90 days Friability, Disintegration, Dissolution,
Assay

Core Tablets (Wet Granulation)

Binder 8 hours Initial, 2, 5, 8 hours Appearance

solution In case of
starch: initial, 2, 5
hours

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Dried 45 days Initial, 15, 30 and 45 Description and LOD

Granules days

Lubrication 45 days Initial, 15, 30 and 45 Loss on Drying, Content Uniformity,

days Particle Size, Bulk/Tapped Density

Core Tablets 90 days Initial, 30, 45, 60 and Description, Hardness, Thickness,
90 days Friability, Disintegration, Dissolution,
Assay

Coated Tablets (Direct Compression/ Dry Granulation)

Granules 45 days Initial, 15, 30 and 45 Description, LOD and Assay

days

Lubrication 45 days Initial, 15, 30 and 45 Loss on Drying, Content Uniformity,

days Particle Size, Bulk/Tapped Density

Core Tablets 90 days Initial, 30, 45, 60 and Description, Hardness, Thickness,
90 days Friability, Disintegration, Dissolution,
Assay

Coating 72 hours Initial, 12, 24, 36, 48, Physical Appearance, Specific
Solution 60 and 72 hours Gravity, Viscosity, Sedimentation, pH

Coated 90 days Initial, 30, 45, 60 and Description, Hardness, Thickness,

Tablets 90 days Friability, Disintegration, Dissolution,
Assay

Coated Tablets (Wet Granulation)

Binder 8 hours Initial, 2, 5, 8 hours Appearance

solution In case of
starch: initial, 2, 5
hours

Dried 45 days Initial, 15, 30 and 45 Description and LOD

Granules days

Lubrication 45 days Initial, 15, 30 and 45 Loss on Drying, Content Uniformity,

days Particle Size, Bulk/Tapped Density.

Core Tablets 90 days Initial, 30, 45, 60 and Description, Hardness, Thickness,
90 days Friability, Disintegration, Dissolution,
Assay

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Coating 72 hours Initial, 12, 24, 36, 48, Physical Appearance, Specific
Solution 60 and 72 hours Gravity, Viscosity, Sedimentation, pH

Coated 90 days Initial, 30, 45, 60 and Description, Hardness, Thickness,

Tablets 90 days Friability, Disintegration, Dissolution,
Assay

Dispersible/ Orally Disintegrating Tablets

Granules 45 days Initial, 15, 30 and 45 Loss on Drying, Content Uniformity,

days Particle Size, Bulk/Tapped Density

Compressed 90 days Initial, 30, 45, 60 and Description, Hardness, Thickness,

Tablets 90 days Friability, Disintegration, Dissolution,
Assay

Capsules (Power Filling)

Lubrication 45 days Initial, 15, 30 and 45 Loss on Drying, Content Uniformity,

days Particle Size, Bulk/Tapped Density.

Filled 90 days Initial, 30, 45, 60 and Description, Disintegration,

capsules 90 days Dissolution, Assay.

Capsules (Pellets Filled)

Drug Pellets 45 days Initial, 15, 30 and 45 Description and assay.

days

Lubrication 45 days Initial, 15, 30 and 45 Loss on Drying, Content Uniformity,

days Particle Size, Bulk/Tapped Density.

Filled 90 days Initial, 30, 45, 60 and Description, Disintegration,

capsules 90 days Dissolution, Assay,

Liquids (Syrups, Oral Solutions, Suspensions)

Un-filtered 7 days 1, 2, 5 and 7days Description, pH, Specific Gravity,

solution Assay and Microbial Limit

Filtered 7 days 1, 2, 5 and 7days Description, pH, Specific Gravity,

solution Assay and Microbial Limit

Ointments / Gels / Creams

Bulk stage 72 hours Initial, 12, 24, 36, 48 Description, pH, Specific Gravity and
and 72 hours assay

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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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