Working document QAS/13.521/Rev.3
August 2014
Document for comment
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GENERAL GUIDANCE
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ON “HOLD-TIME” STUDIES
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REVISED DRAFT FOR COMMENT
(August 2014)
Should you have any comments on the attached text, please send these to
Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards
and Norms, World Health Organization, 1211 Geneva 27, Switzerland; email:
[email protected]; fax: (+41 22) 791 4730 ([email protected]) and to Ms Marie Gaspard
([email protected]), by 30 September 2014.
Working documents are sent out electronically and they will also be placed on the
Medicines web site for comment. If you do not already receive directly our draft
guidelines please let us have your e-mail address (to [email protected]) and we will
add it to our electronic mailing list.
___________________________________________________________________________
© World Health Organization 2014
All rights reserved.
This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The
draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in
whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned
staff and member organizations) without the permission of the World Health Organization. The draft should not be
displayed on any website.
Please send any request for permission to:
Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of
Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22)
791 4730; email: [email protected].
The designations employed and the presentation of the material in this draft do not imply the expression of any opinion
whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or
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This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
Working document QAS/13.521/Rev.3
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SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/13.521
GENERAL GUIDANCE ON “HOLD-TIME” STUDIES
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Date
Preparation of draft by Dr A.J. van Zyl,
South Africa, based on need identified by
the WHO Prequalification Programme
inspectors
November-December 2012
Preliminary internal review of draft
January 2013
Draft mailed for comments
February 2013
Collation of comments
April 2013
Review by inspectors collaborating with the May 2013
WHO Prequalification Programme
Discussion during the joint informal
consultation with Prequalification
Inspection team and inspectors from
national inspectorates
30 May 2013
Follow-up of e-Discussion of Subgroup
with expert inspectors to finalize new draft
of working document for comments
June 2013
Recirculation of working document for
comments
July 2013
Compilation of comments and feedback
September 2013
Review of feedback received with
Prequalification Inspection team
September 2013
Presentation to forty-eighth meeting of the 14-18 October 2013
WHO Expert Committee on Specifications
for Pharmaceutical Preparations
Review of comments with subgroup of
WHO Expert Committee on Specifications
for Pharmaceutical Preparations and
subsequently with Dr A.J. van Zyl and the
Prequalification Team – Inspections Group
October 2013–January 2014
Working document QAS/13.521/Rev.3
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Further follow-up action as required
…
Recirculation of working document for
comments
February 2014
Compilation of comments
April 2014
Discussion of feedback during informal
consultation on medicines quality: GXPs,
inspection guides and risk management
28-30 April 2014
Recirculation of updated working
document
August 2014
Compilation of comments and evaluation of End September 2014
feedback received
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Presentation to forty-ninth meeting of the
WHO Expert Committee on Specifications
for Pharmaceutical Preparations
October 2014
Further follow-up action as required
…
Working document QAS/13.521/Rev.3
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GENERAL GUIDANCE ON “HOLD-TIME” STUDIES
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CONTENTS
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1. INTRODUCTION AND BACKGROUND
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2. GLOSSARY
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3. SCOPE
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4. ASPECTS TO BE CONSIDERED
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1.
INTRODUCTION AND BACKGROUND
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Manufacturers should ensure that the products that they manufacture are safe, effective
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and of the quality required for their intended use. Products should be consistently
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manufactured to the quality standards appropriate to their intended use and as required by
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the marketing authorization. Systems should ensure that pharmaceutical products are
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produced according to validated processes and to defined procedures. Manufacturing
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processes should be shown to be capable of consistently manufacturing pharmaceutical
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products of the required quality that comply with their specifications.
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Arrangements should exist to ensure that the dispensed raw materials and packaging
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materials, intermediate products, bulk and finished products are stored under appropriate
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conditions. Storage should not have any significant negative effect on the processing,
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stability, safety, efficacy or quality of the materials, intermediate products and bulk
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products prior to final packing. Good manufacturing practices (GMP) require that a
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maximum acceptable holding period should be established to ensure that intermediates
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and bulk product can be held, pending the next processing step, without any significant
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adverse effect to the quality of the material. Such a holding period should be underwritten
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by data, but need not be extended to find the edge of failure.
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2. GLOSSARY
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Bulk product
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Any pharmaceutical product which has completed all processing stages up to, but not
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including, final packaging.
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Intermediate
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Partly processed product that must undergo further manufacturing steps before it becomes
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a bulk product.
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3.
SCOPE
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This guideline focus primarily on aspects that should be considered in the design of the
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hold-time studies during the manufacture of solid dosage forms. Many of the principles
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herein also apply to other dosage forms such as liquids, creams and ointments. This
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guideline does not cover aspects for hold times in cleaning validation or the
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manufacturing of active pharmaceutical ingredients (APIs).
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This guideline is intended as a basic guide for use by pharmaceutical manufacturers and
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GMP inspectors. This document does not intend to prescribe a process for establishing
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hold times, but reflects aspects that should be considered in the design of the hold-time
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study.
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Manufacturers should gather scientific and justifiable data to demonstrate that the
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dispensed raw materials and packaging materials, intermediate and bulk products:
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remain of appropriate quality before processing to the next stage;
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meet the acceptance criteria and release specification for the finished product.
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4.
ASPECTS TO BE CONSIDERED
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Hold time can be considered as the established time period for which materials
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(dispensed raw materials, intermediates and bulk dosage form awaiting final packaging)
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may be held under specified conditions and will remain within the defined specifications.
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Data to justify the hold time can be collected, but not limited to:
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during development on pilot-scale batches,
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during scale up,
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during process validation, or
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as part of an investigation of a deviation that occurred during manufacture.
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Hold-time studies establish the time limits for holding the materials at different stages of
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production to ensure that the quality of the product does not deteriorate significantly
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during the hold time. The design of the study should reflect the holding time at each
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stage. Hold times should normally be determined prior to marketing of a product and
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following any significant changes in processes, equipment, starting and packaging
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materials and represent actual processing. Hold time studies should be included during
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process validation (Ref: Process validation guideline).
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Manufacturers may use a flow chart to review the manufacturing procedure of a product
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and then break up the critical stages of manufacturing process on the basis of time
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duration required for the particular storage and processing stages, typical pauses in the
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manufacturing campaign, and the potential impact of storage with reference to
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environmental and storage conditions. An example for a flow chart is given below.
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For example, for oral tablets that are coated the following stages may be considered:
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binder preparation to granulation – consider the granulate;
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wet granulation to drying – the dried granulate;
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dried granules to lubrication/blending – the lubricated blend;
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blend to compression;
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compression to coating – the tablet cores;
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coating solution to preparation – the coating solution;
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coating to packing – consider the bulk coated tablets;
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coating to packing in bulk or FDF;
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packing in bulk to FDF.
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Example for a flow chart :
Dispensing
Sifting
Dry
Mixing
Granules:
Sample withdrawn for
analysis
Granulation
Binder
Sample withdrawn for
analysis
Drying
Lubrication
&Blending
Blend:
Sample withdrawn for
analysis
Core tablets:
Sample withdrawn for
analysis
Compression
Coated tablet:
Sample withdrawn for
analysis
Coating
Packing
Drying
Coating Solution:
Sample withdrawn for
analysis
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A written protocol, procedure or programme should be followed which includes the
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activities to be performed, test parameters and acceptance criteria appropriate to the
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material or product under test. The protocol and report should generally include the
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following: a title; reference number; version; date; objective; scope; responsibility;
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procedure; description of the material/product; sample quantities; sampling method and
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criteria; acceptance limits; frequency for sampling; sampling locations; pooling of
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samples; storage conditions; type of container; methods of analysis; results; conclusion;
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recommendation; signatures and dates. Acceptance criteria are typically more stringent
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than registered specifications to provide assurance that the material is well within control.
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When setting the specifications any known stability trends will need to be taken into
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account.
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For certain products microbiological aspects should also be considered and included
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where appropriate.
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Typically one or more batches of a material, intermediate or product can be used for
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determining hold times. A risk-based approach can be used to determine the appropriate
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number of batches, considering inter alia the characteristics of the materials A
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representative sample of the batch of material or product subjected to the hold-time study
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should be held for the defined hold period. The maximum hold period for each category
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of material should be established on the basis of the study by keeping the material in
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either the original or simulated container used in production. The containers used in
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which hold-time samples are stored should be the same pack as used in production unless
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the pack is exceptionally large, in which case one that is equivalent (same material of
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construction and closure system to the production packaging system) may be used.
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Reducing the size of container when necessary for testing holding time, should be
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justified. Where head space is important the hold-time samples should represent the
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maximum
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manufacturing/quarantine. The sample storage environmental conditions should be same
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as that of the quarantine area/manufacture stage.Asampling plan should be established
possible
head
space
(worst-case
scenario)
to
bulk
stored
in
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and followed for taking samples for testing at the different intervals. The required sample
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amount should be calculated based on the batch size, the intervals and tests to be
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performed. Results should be compared with the initial baseline data of the control
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sample . Samples may be pooled for analysis where appropriate, e.g. when the analysis of
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a composite sample will not miss issues expected in the variation of the product.
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Where appropriate, statistical analysis of the data generated should be performed to
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identify trends and to justify the limits and hold time set.
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Batches of finished products made from intermediates or bulk products and subjected to a
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hold-time study should be considered for long-term stability testing if data show adverse
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trending or shifting patterns during the intermediate time points up to the end of the
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shelf-life. The shelf-life of the product – irrespective of hold times – should be measured
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from the time the active ingredients are mixed with other ingredients. Normally
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intermediate and bulk products should not be stored beyond the established hold time. All
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testing of bulk intermediates and product should be performed using validated stability-
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indicating methods.
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The following table provides examples of stages and tests that may be considered.
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Table: Examples of stages and tests that may be considered, based on risk assessment
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and specific product needs
Stage
Test to be carried out as per
specification
Study time
Binder preparation
Microbial test
Initial, 2hrs, 5hrs, 8hrs.
In case of starch: initial,
2hrs, 5hrs
Solution prepared
(including granulation
pastes, coating solution
and coating suspensión
Physical appearance, Specific
gravity, Viscosity, Sedimentation,
pH, Microbial test
Initial, 12, 24, 36, 48,
60, 72 hours
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Granule
Description, Assay, Related
substances, Loss on drying, Water
content, Particle size distribution,
Bulk density, Tap density, Angle
of repose.
Initial, 30th day, 45th
day
Blend
Microbial test, Loss on drying,
Blend uniformity, Particle size,
Bulk/Tapped density
Initial, 30th day, 45th
day
Core tablets – uncoated
(in bulk container
Description, Hardness, Thickness,
Friability, Disintegration,
Dissolution or Dissolution profile,
assay, Degradation products/
related substance, Uniformity of
dosage units, Microbial test.
Description, Hardness, Thickness,
Friability, Disintegration,
Dissolution or Dissolution profile,
Assay, Degradation products/
related substance, Uniformity of
dosage units , Moisture content,
Microbial test.
Initial, 30th day, 60th
day & 90th day
Coated tablets (in bulk
container)
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***
Initial, 30th day, 60th
day & 90th day