General_Guidance_Hold_Time_studies-QAS13.521_20.02.2013_

Working document QAS/13.521

February 2013

RESTRICTED

GENERAL GUIDANCE FOR INSPECTORS

ON “HOLD-TIME” STUDIES

DRAFT FOR COMMENT

Should you have any comments on the attached text, please send these to

Dr Sabine Kopp, Manager, Medicines Quality Assurance Programme, Quality Assurance

and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland;

e-mail: kopps@; fax: (+41 22) 791 4730 (kopps@) and to

Ms Marie Gaspard (gaspardm@), by 12 April 2013.

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___________________________________________________________________________

© World Health Organization 2013

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Please send any request for permission to:

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Assurance and Safety: Medicines, Department of Essential Medicines and Pharmaceutical Policies, World Health

Organization, CH-1211 Geneva 27, Switzerland; e-mail: stahlm@.

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Working document QAS/13.521

page 2

SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/13.521

GENERAL GUIDANCE FOR INSPECTORS ON “HOLD-TIME” STUDIES

Preparation of draft by Dr A.J. van Zyl,

South Africa, based on need identified by

the WHO Prequalification Programme

inspectors

Preliminary internal review of draft

Draft mailed for comments

Collation of comments

Review by inspectors collaborating with the

WHO Prequalification Programme

Recirculation for comments

Collation of comments

Presentation to forty-eighth meeting of the

WHO Expert Committee on Specifications

for Pharmaceutical Preparations

Further follow-up action as required

Date

November-December 2012

January 2013

February 2013

April 2013

May 2013

June 2013

September 2013

14-18 October 2013

Introduction and background

Scope

Introduction and background

Working document QAS/13.521

page 3

CONTENTS

Manufacturers should ensure that the products that they manufacture are safe, effective

and of the quality required for their intended use. Products should be consistently

manufactured to the quality standards appropriate to their intended use and as required by

the marketing authorization. Systems should ensure that pharmaceutical products are

produced according to defined procedures that are validated and monitored.

Manufacturing processes should be shown to be capable of consistently manufacturing

pharmaceutical products of the required quality that comply with their specifications.

Arrangements should exist to ensure that the materials used, intermediate products, bulk

and finished products are stored under appropriate conditions. Storage should not have

any negative effect on the processing, stability, safety, efficacy or quality of the materials,

intermediate products, bulk and finished products. Good manufacturing practices require

that the maximum allowable hold time should be established 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. These time periods must be supported by adequate data to

demonstrate that the product will be stable throughout the approved shelf-life.

Normally bulk products should not be stored for a period of 25% or more of the approved

shelf-life (prior to packing into the final containers) unless these are tested, with stability-indicating methods, prior to packaging.

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Scope

This document does not intend to prescribe a process for establishing hold times, but

reflects aspects that should be considered in the design of the hold-time study.

Manufacturers should gather sufficient data to demonstrate that a product:

- remains stable before processing to the next stage;

- meets the acceptance criteria for the finished product;

- meets its stability specifications.

The quality and stability of starting materials, intermediate products, bulk and finished

products should be ensured at all stages of manufacture.

Maximum allowable hold times should therefore be established for starting materials,

intermediate products, bulk and finished products on the basis of tests related to storage

conditions. Data to justify the hold time can be collected during development on pilot

scale batches, during process validation, or as part of a deviation with appropriate testing.

Hold-time studies establish the time limits of holding the materials at different stages of

production by assuring that the quality of the product does not deteriorate during the hold

time. To validate the hold time under the specified hold-time condition, results obtained

should be within the limits of acceptance criteria throughout the hold time. Hold times

should be determined prior to marketing of a product and following any significant

changes in processes, equipment, packaging materials, etc.

Manufacturers may use a flow chart to review the manufacturing procedure of a product

and then break up the critical stages of manufacturing process on the basis of time

duration required for the particular processing stage and the impact of time period with

reference to environmental conditions and storage conditions.

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Generally, for oral solid dosage forms, the following stages should be considered:

- binder preparation to granulation;

- wet granulation to drying;

- dried granules to lubrication/blending;

- lubrication/blending to compression;

- compression to coating;

- aqueous coating solution preparation to coating;

- coating to packing.

A written protocol, procedure or programme should be followed which includes elements

and test parameters appropriate to the material or product under test. The protocol and

report should include a title, reference number, version, date, objective, scope,

responsibility, procedure, description of the material/product, sample quantities, sampling

method and criteria, acceptance limits, frequency for sampling, sampling locations,

pooling of samples, storage conditions, type of container, methods of analysis, results,

conclusion, recommendation, signatures, dates, etc.

Typically one or more batches of a material, intermediate or product can be used for

determining hold times. A representative sample of the batch of material or product

subjected to the hold-time study should be held for the defined hold period. The

maximum storage period for each category of material should be established on the basis

of the study by keeping the material in a simulated container used in production. The

containers used in which hold-time samples are stored should be of the same material of

construction as those used in manufacturing/quarantine. Hold-time samples should have

head space in proportion to bulk stored in manufacturing/quarantine. The sample storage

environmental conditions should be same as that of the quarantine area/manufacture

stage. (Note: Where appropriate, a sampling plan should be established and followed for

taking samples for testing at the different intervals. The required sample amount should

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be calculated based on the intervals and tests to be performed.) At the test points a

sample should be taken from the storage container and tested. Results obtained should be

compared with the initial baseline data of the control sample results. Samples may be

pooled for analysis where appropriate. Where necessary, individual samples may be

tested and compared statistically. Statistical calculations should be done and trends

identified and discussed to prove a reliable hold time.

Batches of products subjected to a hold-time study should also be subjected to long-term

stability testing.

Risk assessment

In general the following table provides examples of generally accepted hold times for

materials, intermediate, bulk or finished products packed and stored in suitable

containers, based on product knowledge. However, specific cases may necessitate other

storage periods based on data.

Table 1. Example of maximum storage times without hold-time data

Stage Suggested maximum storage period

Dispensed materials storage 5 to 30 days1

Solutions prepared 8 to 24 hours

(including granulating pastes, coating

solutions and coating suspensions)

Granules 2 to 30 days

Blend 1 to 2 days

Core tablets – uncoated (in bulk 30 days

containers)

Coated tablets (in bulk containers) 30 days

1

Dispensed materials stored in containers similar to those in which material was supplied

from the original manufacturer and under the same controlled conditions.

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Hold times should be established where materials, intermediate, bulk or finished products

are stored for extended periods. Risk assessment (product specific) may further assist

manufacturers to determine which stage, tests, intervals and storage periods should be

considered for a hold time study. Table 2 below provides examples of stages and tests

that may be considered.

Table 2. Examples of stages and tests that may be considered, based on risk assessment

and specific product needs

Stage Examples of tests to be considered2

Dispensed materials storage Microbial test

Solutions prepared Physical appearance

(including granulating pastes, coating Specific gravity

solutions and coating suspensions) Viscosity

Sedimentation

pH

Microbial test

Granules Description

Assay

Loss on drying

Water content

Particle size distribution

Bulk density

Tap density

Angle of repose

Blend Microbial test

Moisture content

Blend uniformity

Particle size

Bulk/tapped density

Core tablets – uncoated (In bulk Description

containers) Hardness

Thickness

Friability

Appearance

2

These parameters are examples. Manufacturers have to identify and justify the selection

of stages and parameters selected or excluded from a hold-time study.

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Dissolution

Disintegration

Assay

Degradation products/related substances

(where applicable)

Uniformity of dosage

Units

Microbial test

Description

Hardness

Thickness

Friability

Appearance

Dissolution/dissolution profile

Disintegration

Assay

Degradation products/related substances

(where applicable)

Uniformity of dosage units

Moisture content

Microbial test

Coated tablets (in bulk containers)

Hold-time data under specified conditions should demonstrate comparable stability to the

dosage form in the marketed package.

Interim storage of the dosage form in bulk containers should generally not exceed six

months.

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