Working document QAS/13.521/Rev.

2
February 2014
Document for comment

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2
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5 GENERAL GUIDANCE
6 ON “HOLD-TIME” STUDIES
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8 REVISED DRAFT FOR COMMENT
9 (February 2014)
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11
12 Should you have any comments on the attached text, please send these to
13 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards
14 and Norms, World Health Organization, 1211 Geneva 27, Switzerland; email:
15 kopps@who.int; fax: (+41 22) 791 4730 (kopps@who.int) and to Ms Marie Gaspard
16 (gaspardm@who.int), by 15 April 2014.
17
Working documents are sent out electronically and they will also be placed on the
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19 guidelines please let us have your e-mail address (to bonnyw@who.int) and we will
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21
22 ___________________________________________________________________________
23 © World Health Organization 2014
24 All rights reserved.
25 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The
26 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in
27 whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned
28 staff and member organizations) without the permission of the World Health Organization. The draft should not be
29 displayed on any website.
30 Please send any request for permission to:
31 Dr Deus Mubangizi, Group Leader, Prequalification Team – Inspections, Regulation of Medicines and other Health
32 Technologies, Department of Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva
33 27, Switzerland; e-mail: mubangizid@who.int.
34 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion
35 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or
36 area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent
37 approximate border lines for which there may not yet be full agreement.
38 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or
39 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.
40 Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
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43 The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health
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45 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
46
 Working document QAS/13.521/Rev.2
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47 SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/13.521

48 GENERAL GUIDANCE FOR INSPECTORS ON “HOLD-TIME” STUDIES
49
Date
Preparation of draft by Dr A.J. van Zyl,
South Africa, based on need identified by November-December 2012
the WHO Prequalification Programme
inspectors

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 30 May 2013

consultation with Prequalification
Inspection team and inspectors from
national inspectorates

Follow-up of e-Discussion of Subgroup June 2013

with expert inspectors to finalize new draft
of working document for comments

Recirculation of working document for July 2013

comments

Compilation of comments and feedback September 2013

Review of feedback received with September 2013

Prequalification Inspection team

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 October 2013–January 2014

WHO Expert Committee on Specifications
for Pharmaceutical Preparations and
subsequently with Dr A.J. van Zyl and the
Prequalification Team – Inspections Group
 Working document QAS/13.521/Rev.2
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Further follow-up action as required …

Recirculation of working document for February 2014

comments

Compilation of comments April 2014

Discussion of feedback during informal 28-30 April 2014

consultation on medicines quality: GXPs,
inspection guides and risk management

Recirculation of updated working May 2014

document

Compilation of comments and evaluation of July 2014

feedback received

Presentation to forty-ninth meeting of the October 2014

WHO Expert Committee on Specifications
for Pharmaceutical Preparations

Further follow-up action as required …

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52 CONTENTS
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54 1. Introduction and background
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56 2. Scope
57
58 3. Aspects to be considered
59
60 1. INTRODUCTION AND BACKGROUND
61
62 Manufacturers should ensure that the products that they manufacture are safe, effective
63 and of the quality required for their intended use. Products should be consistently
64 manufactured to the quality standards appropriate to their intended use and as required by
65 the marketing authorization. Systems should ensure that pharmaceutical products are
66 produced according to validated processes and to defined procedures. Manufacturing
67 processes should be shown to be capable of consistently manufacturing pharmaceutical
68 products of the required quality that comply with their specifications.
69
70 Arrangements should exist to ensure that the dispensed raw materials and packaging
71 materials, intermediate products, bulk and finished products are stored under appropriate
72 conditions. Storage should not have any significant negative effect on the processing,
73 stability, safety, efficacy or quality of the materials, intermediate products and bulk
74 products prior to final packing. Good manufacturing practices (GMP) require that a
75 maximum acceptable holding period should be established to ensure that intermediates
76 and bulk product can be held, pending the next processing step, without any significant
77 adverse effect to the quality of the material. Such a holding period should be underwritten
78 by data, but need not be extended to find the edge of failure for holding
79
80
81
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82 2. SCOPE
83
84 This guideline focus primarily on aspects that should be considered in the design of the
85 hold-time studies during the manufacture of solid dosage forms. Many of the principles
86 herein also apply to other dosage forms such as liquids, creams and ointments. This
87 guideline does not cover aspects for hold times in cleaning validation or the
88 manufacturing of active pharmaceutical ingredients (APIs).
89
90 This guideline is intended as a basic guide for use by pharmaceutical manufacturers and
91 GMP inspectors. This document does not intend to prescribe a process for establishing
92 hold times, but reflects aspects that should be considered in the design of the hold-time
93 study.
94
95 Manufacturers should gather scientific and justifiable data to demonstrate that the
96 dispensed raw materials and packaging materials, intermediate and bulk products:
97
98 - remain of appropriate quality before processing to the next stage;
99 - meet the acceptance criteria and release specification for the finished product.
100
101 3. ASPECTS TO BE CONSIDERED
102
103 Hold time can be considered as the established time period for which materials
104 (dispensed raw materials, intermediates, bulk, and finished products under quarantine)
105 may be held under specified conditions and will remain within the defined specifications.
106
107 The quality and stability of dispensed raw materials, intermediate products, bulk (and
108 finished products in quarantine) should be ensured at all stages of manufacture.
109
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110 Data to justify the hold time can be collected during development on pilot-scale batches,
111 during process validation, or as part of an investigation of a deviation that occurred
112 during manufacture.
113
114 Hold-time studies establish the time limits for holding the materials at different stages of
115 production to ensure that the quality of the product does not deteriorate significantly
116 during the hold time. To validate the hold time under the specified hold-time condition,
117 results obtained should be within the limits of acceptance criteria throughout the hold
118 time. Hold times should normally be determined prior to marketing of a product and
119 following any significant changes in processes, equipment, starting and packaging
120 materials. However, for products already marketed retrospective risk-based, hold-time
121 studies should be performed.
122
123 Manufacturers can consider following a “most probable” approach opposed to a “worst-
124 case approach”, For example, in a worst case situation where a product has a maximum
125 hold time of seven days as granulate, 30 days as uncoated tablets, and six months as
126 coated bulk tablets, will probably not represent any actual batch that is intended for
127 commercial sale. A “most probable” approach would reflect actual hold times at each
128 stage, and apply the worst actual case, spreading the total hold time over the different
129 stages. A combination approach might also be appropriate.
130
131 Manufacturers may use a flow chart to review the manufacturing procedure of a product
132 and then break up the critical stages of manufacturing process on the basis of time
133 duration required for the particular processing stage and the potential impact of storage
134 with reference to environmental and storage conditions.
135
136 For example, for oral tablets the following stages may be considered:
137
138 - binder preparation to granulation – consider the granulate;
139 - wet granulation to drying – the dried granulate;
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140 - dried granules to lubrication/blending – the lubricated blend;

141 - compression to coating – the tablet cores;
142 - coating solution to preparation – the coating solution;
143 - coating to packing – consider the bulk coated tablets;
144 - coating to packing in bulk or FDF;
145 - packing in bulk to FDF.
146
147 A written protocol, procedure or programme should be followed which includes the
148 activities to be performed, test parameters and acceptance criteria appropriate to the
149 material or product under test. The protocol and report should generally include the
150 following: a title; reference number; version; date; objective; scope; responsibility;
151 procedure; description of the material/product; sample quantities; sampling method and
152 criteria; acceptance limits; frequency for sampling; sampling locations; pooling of
153 samples; storage conditions; type of container; methods of analysis; results; conclusion;
154 recommendation; signatures and dates.
155
156 For certain products microbiological aspects should also be considered and included
157 where appropriate.
158
159 Typically one or more batches of a material, intermediate or product can be used for
160 determining hold times. A risk-based approach can be used to determine the appropriate
161 number of batches. A representative sample of the batch of material or product subjected
162 to the hold-time study should be held for the defined hold period. The maximum hold
163 period for each category of material should be established on the basis of the study by
164 keeping the material in either the original or simulated container used in production. The
165 containers used in which hold-time samples are stored should be the same pack as used in
166 production unless the pack is exceptionally large, in which case one that is equivalent
167 (same material of construction and closure system to the production packaging system)
168 may be used. Reducing the size of container when necessary for testing holding time,
169 should be justified. Where head space is important the hold-time samples should
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170 represent the maximum possible head space (worst-case scenario) to bulk stored in
171 manufacturing/quarantine. The sample storage environmental conditions should be same
172 as that of the quarantine area/manufacture stage. (Note: Where appropriate, a sampling
173 plan should be established and followed for taking samples for testing at the different
174 intervals. The required sample amount should be calculated based on the batch size, the
175 intervals and tests to be performed.) At the test points a sample should be taken from the
176 storage container and tested. Results obtained should be compared with the initial
177 baseline data of the control sample results. Samples may be pooled for analysis where
178 appropriate. Where necessary, individual samples may be tested and compared.
179
180 Statistical analysis of the data generated should be performed to identify trends and to
181 justify the limits and hold time set.
182
183 Batches of products subjected to a hold-time study should be considered for long-term
184 stability testing if data show trending or shifting patterns during the intermediate time
185 periods up to the end-time. The shelf-life of the product – irrespective of hold times –
186 should be measured from the time the actives are mixed with other ingredients. Normally
187 intermediate and bulk products should not be stored beyond the established hold time. All
188 testing of bulk intermediates and product should be performed using validated stability-
189 indicating methods.
190
191 The following table provides examples of generally accepted hold times for materials,
192 intermediate, bulk or finished products packed and stored in suitable containers, based on
193 product knowledge. Specific cases may necessitate other storage periods based on data.
194
195
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196 Table 1. Example of maximum storage times without hold-time data

197
198 (1. Delete table? 2. Remove lower limits for the maximum hold times.
199 Dispensed raw materials: 30 days
200 Solutions: 24 h
201 Granules: 30 days
202 Blend: 2 days ?)
203
Stage Suggested maximum storage period

Dispensed raw materials storage 5 to 30 days1

Solutions prepared 8 to 12 (or 8 to 24?) hours (related with a

(including granulating pastes, coating specific temperature of storing)
solutions and coating suspensions)
Granules 2 to 30 days2

Blend 1 to 2 days

Core tablets – uncoated (in bulk 30 days

containers)
Coated tablets (in bulk containers) 30 days

204
205 The maximum processing time (time from dispensing of the ingredients to the final top
206 coating) should normally not exceed 30 days. Hold-time periods beyond those in the
207 above table or what is considered necessary for a specific product/material should be
208 justified through a formal study. Risk assessment (product specific) may further assist

1
Dispensed materials stored in containers similar to those in which material was supplied from the original
manufacturer and under the same controlled conditions.
2
Appropriate to the formulation of the granule.
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209 manufacturers to determine which stage, tests, intervals and storage periods should be
210 considered for a hold-time study.
211
212 The cumulative hold time should be scientifically justified. Generally a 90-day
213 cumulative hold time would be acceptable without further supportive data. In the case
214 where cumulative hold times individually add to >90 days, but there is an additional
215 provision that time from dispensing of the ingredients to the final top coating will not
216 exceed 30 days, further justification of the cumulative hold time is considered
217 unnecessary.
218
219 Table 2 below provides examples of stages and tests that may be considered.
220
221 Table 2. Examples of stages and tests that may be considered, based on risk assessment
222 and specific product needs
223
Stage Examples of tests to be considered3

Dispensed raw 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
Moisture content (loss on drying)

3
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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Water content
Particle size distribution
Bulk density
Tap density
Angle of repose
Blend Microbial test
Moisture content (loss on drying)
Blend uniformity
Particle size
Bulk/tapped density
Core tablets – uncoated (in bulk Description
containers) Hardness
Thickness
Friability
Appearance
Dissolution
Disintegration
Assay
Degradation products/related substances
(where applicable)
Uniformity of dosage units
Microbial test
Coated tablets (in bulk containers) Description
Hardness
Thickness
Friability
Appearance
Dissolution/dissolution profile
Disintegration
Assay
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Degradation products/related substances

(where applicable)
Uniformity of dosage units
Moisture content
Microbial test
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227 ***