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HoldTimeStudies1 PDF
HoldTimeStudies1 PDF
3
August 2014
Document for comment
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5 GENERAL GUIDANCE
6 ON “HOLD-TIME” STUDIES
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8 REVISED DRAFT FOR COMMENT
9 (August 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 30 September 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 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
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.
41 All reasonable precautions have been taken by the World Health Organization to verify the information contained in
42 this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied.
43 The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health
44 Organization be liable for damages arising from its use.
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.3
page 2
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
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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.
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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;
Working document QAS/13.521/Rev.3
page 6
111 - meet the acceptance criteria and release specification for the finished product.
112
113 4. ASPECTS TO BE CONSIDERED
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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;
Working document QAS/13.521/Rev.3
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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
Working document QAS/13.521/Rev.3
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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
Working document QAS/13.521/Rev.3
page 9
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.
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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
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
Working document QAS/13.521/Rev.3
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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.
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