Working document QAS/13.521/Rev.

3
August 2014
Document for comment

1
2
3
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5 GENERAL GUIDANCE
6 ON “HOLD-TIME” STUDIES
7
8 REVISED DRAFT FOR COMMENT
9 (August 2014)
10
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 30 September 2014.
17
Working documents are sent out electronically and they will also be placed on the
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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
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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 Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of
32 Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22)
33 791 4730; email: kopps@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
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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
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47 SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/13.521

48 GENERAL GUIDANCE ON “HOLD-TIME” STUDIES
49
Date
Preparation of draft by Dr A.J. van Zyl,
November-December 2012
South Africa, based on need identified by
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.3
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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 August 2014

document

Compilation of comments and evaluation of End September 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 GENERAL GUIDANCE ON “HOLD-TIME” STUDIES

53
54 CONTENTS
55
56 1. INTRODUCTION AND BACKGROUND
57 2. GLOSSARY
58 3. SCOPE
59 4. ASPECTS TO BE CONSIDERED
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61
62
63
64 1. INTRODUCTION AND BACKGROUND
65
66 Manufacturers should ensure that the products that they manufacture are safe, effective
67 and of the quality required for their intended use. Products should be consistently
68 manufactured to the quality standards appropriate to their intended use and as required by
69 the marketing authorization. Systems should ensure that pharmaceutical products are
70 produced according to validated processes and to defined procedures. Manufacturing
71 processes should be shown to be capable of consistently manufacturing pharmaceutical
72 products of the required quality that comply with their specifications.
73
74 Arrangements should exist to ensure that the dispensed raw materials and packaging
75 materials, intermediate products, bulk and finished products are stored under appropriate
76 conditions. Storage should not have any significant negative effect on the processing,
77 stability, safety, efficacy or quality of the materials, intermediate products and bulk
78 products prior to final packing. Good manufacturing practices (GMP) require that a
79 maximum acceptable holding period should be established to ensure that intermediates
80 and bulk product can be held, pending the next processing step, without any significant
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81 adverse effect to the quality of the material. Such a holding period should be underwritten
82 by data, but need not be extended to find the edge of failure.
83
84 2. GLOSSARY
85
86 Bulk product
87 Any pharmaceutical product which has completed all processing stages up to, but not
88 including, final packaging.
89
90 Intermediate
91 Partly processed product that must undergo further manufacturing steps before it becomes
92 a bulk product.
93
94 3. SCOPE
95
96 This guideline focus primarily on aspects that should be considered in the design of the
97 hold-time studies during the manufacture of solid dosage forms. Many of the principles
98 herein also apply to other dosage forms such as liquids, creams and ointments. This
99 guideline does not cover aspects for hold times in cleaning validation or the
100 manufacturing of active pharmaceutical ingredients (APIs).
101
102 This guideline is intended as a basic guide for use by pharmaceutical manufacturers and
103 GMP inspectors. This document does not intend to prescribe a process for establishing
104 hold times, but reflects aspects that should be considered in the design of the hold-time
105 study.
106
107 Manufacturers should gather scientific and justifiable data to demonstrate that the
108 dispensed raw materials and packaging materials, intermediate and bulk products:
109
110 - remain of appropriate quality before processing to the next stage;
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111 - meet the acceptance criteria and release specification for the finished product.
112
113 4. ASPECTS TO BE CONSIDERED
114
115 Hold time can be considered as the established time period for which materials
116 (dispensed raw materials, intermediates and bulk dosage form awaiting final packaging)
117 may be held under specified conditions and will remain within the defined specifications.
118
119 Data to justify the hold time can be collected, but not limited to:
120 - during development on pilot-scale batches,
121 - during scale up,
122 - during process validation, or
123 - as part of an investigation of a deviation that occurred during manufacture.
124 Hold-time studies establish the time limits for holding the materials at different stages of
125 production to ensure that the quality of the product does not deteriorate significantly
126 during the hold time. The design of the study should reflect the holding time at each
127 stage. Hold times should normally be determined prior to marketing of a product and
128 following any significant changes in processes, equipment, starting and packaging
129 materials and represent actual processing. Hold time studies should be included during
130 process validation (Ref: Process validation guideline).
131
132 Manufacturers may use a flow chart to review the manufacturing procedure of a product
133 and then break up the critical stages of manufacturing process on the basis of time
134 duration required for the particular storage and processing stages, typical pauses in the
135 manufacturing campaign, and the potential impact of storage with reference to
136 environmental and storage conditions. An example for a flow chart is given below.
137
138 For example, for oral tablets that are coated the following stages may be considered:
139
140 - binder preparation to granulation – consider the granulate;
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141 - wet granulation to drying – the dried granulate;

142 - dried granules to lubrication/blending – the lubricated blend;
143 - blend to compression;
144 - compression to coating – the tablet cores;
145 - coating solution to preparation – the coating solution;
146 - coating to packing – consider the bulk coated tablets;
147 - coating to packing in bulk or FDF;
148 - packing in bulk to FDF.
149
150 Example for a flow chart :
151
152 Dispensing
153
154
155 Sifting
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Dry
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Mixing
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160
161 Granulation Binder
Granules: Sample withdrawn for
162 Sample withdrawn for analysis
163 analysis

164 Drying
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166 Lubrication Blend:
167 Sample withdrawn for
&Blending analysis
168
Core tablets:
169 Sample withdrawn for
170 analysis

171 Compression
172
173
174
175 Coated tablet: Coating Solution:
176 Sample withdrawn for
Coating Sample withdrawn for
analysis analysis
177
178
179
180 Packing
Drying
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181
182 A written protocol, procedure or programme should be followed which includes the
183 activities to be performed, test parameters and acceptance criteria appropriate to the
184 material or product under test. The protocol and report should generally include the
185 following: a title; reference number; version; date; objective; scope; responsibility;
186 procedure; description of the material/product; sample quantities; sampling method and
187 criteria; acceptance limits; frequency for sampling; sampling locations; pooling of
188 samples; storage conditions; type of container; methods of analysis; results; conclusion;
189 recommendation; signatures and dates. Acceptance criteria are typically more stringent
190 than registered specifications to provide assurance that the material is well within control.
191 When setting the specifications any known stability trends will need to be taken into
192 account.
193
194 For certain products microbiological aspects should also be considered and included
195 where appropriate.
196
197 Typically one or more batches of a material, intermediate or product can be used for
198 determining hold times. A risk-based approach can be used to determine the appropriate
199 number of batches, considering inter alia the characteristics of the materials A
200 representative sample of the batch of material or product subjected to the hold-time study
201 should be held for the defined hold period. The maximum hold period for each category
202 of material should be established on the basis of the study by keeping the material in
203 either the original or simulated container used in production. The containers used in
204 which hold-time samples are stored should be the same pack as used in production unless
205 the pack is exceptionally large, in which case one that is equivalent (same material of
206 construction and closure system to the production packaging system) may be used.
207 Reducing the size of container when necessary for testing holding time, should be
208 justified. Where head space is important the hold-time samples should represent the
209 maximum possible head space (worst-case scenario) to bulk stored in
210 manufacturing/quarantine. The sample storage environmental conditions should be same
211 as that of the quarantine area/manufacture stage.Asampling plan should be established
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212 and followed for taking samples for testing at the different intervals. The required sample
213 amount should be calculated based on the batch size, the intervals and tests to be
214 performed. Results should be compared with the initial baseline data of the control
215 sample . Samples may be pooled for analysis where appropriate, e.g. when the analysis of
216 a composite sample will not miss issues expected in the variation of the product.
217
218 Where appropriate, statistical analysis of the data generated should be performed to
219 identify trends and to justify the limits and hold time set.
220
221 Batches of finished products made from intermediates or bulk products and subjected to a
222 hold-time study should be considered for long-term stability testing if data show adverse
223 trending or shifting patterns during the intermediate time points up to the end of the
224 shelf-life. The shelf-life of the product – irrespective of hold times – should be measured
225 from the time the active ingredients are mixed with other ingredients. Normally
226 intermediate and bulk products should not be stored beyond the established hold time. All
227 testing of bulk intermediates and product should be performed using validated stability-
228 indicating methods.
229
230 The following table provides examples of stages and tests that may be considered.
231
232 Table: Examples of stages and tests that may be considered, based on risk assessment
233 and specific product needs
Stage Test to be carried out as per Study time
specification

Binder preparation Microbial test Initial, 2hrs, 5hrs, 8hrs.

In case of starch: initial,
2hrs, 5hrs

Solution prepared Physical appearance, Specific Initial, 12, 24, 36, 48,
(including granulation gravity, Viscosity, Sedimentation, 60, 72 hours
pastes, coating solution pH, Microbial test
and coating suspensión
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Granule Description, Assay, Related Initial, 30th day, 45th

substances, Loss on drying, Water day
content, Particle size distribution,
Bulk density, Tap density, Angle
of repose.

Blend Microbial test, Loss on drying, Initial, 30th day, 45th

Blend uniformity, Particle size, day
Bulk/Tapped density

Core tablets – uncoated Description, Hardness, Thickness, Initial, 30th day, 60th
(in bulk container Friability, Disintegration, day & 90th day
Dissolution or Dissolution profile,
assay, Degradation products/
related substance, Uniformity of
dosage units, Microbial test.
Coated tablets (in bulk Description, Hardness, Thickness, Initial, 30th day, 60th
container) Friability, Disintegration, day & 90th day
Dissolution or Dissolution profile,
Assay, Degradation products/
related substance, Uniformity of
dosage units , Moisture content,
Microbial test.
234
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236 ***