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generalguidanceholdtimeqas13-521rev320augskclean

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Goutam Dutta
Goutam Dutta

This document provides guidance on conducting "hold-time" studies to establish maximum acceptable holding periods for intermediates and bulk products during pharmaceutical manufacturing. It outlines key aspects to consider in the design of hold-time studies, including identifying critical stages of production, testing relevant quality attributes, establishing acceptance criteria, storage conditions and sampling plans. The goal is to generate data demonstrating materials remain stable and of appropriate quality when held for defined periods before further processing.

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Working document QAS/13.521/Rev.3 August 2014 Document for comment 1 2 3 4 GENERAL GUIDANCE5 ON ¡°HOLD-TIME¡± STUDIES6 7 REVISED DRAFT FOR COMMENT8 (August 2014)9 10 11 12 13 14 15 16 17 18 19 20 21 ___________________________________________________________________________22 ? World Health Organization 201423 All rights reserved.24 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The25 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in26 whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned27 staff and member organizations) without the permission of the World Health Organization. The draft should not be28 displayed on any website.29 Please send any request for permission to:30 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of31 Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22)32 791 4730; email: kopps@who.int.33 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion34 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or35 area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent36 approximate border lines for which there may not yet be full agreement.37 The mention of specific companies or of certain manufacturers¡¯ products does not imply that they are endorsed or38 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.39 Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.40 All reasonable precautions have been taken by the World Health Organization to verify the information contained in41 this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied.42 The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health43 Organization be liable for damages arising from its use.44 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.45 46 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: kopps@who.int; fax: (+41 22) 791 4730 (kopps@who.int) and to Ms Marie Gaspard (gaspardm@who.int), 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 bonnyw@who.int) and we will add it to our electronic mailing list.
Working document QAS/13.521/Rev.3 page 2 SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/13.52147 GENERAL GUIDANCE ON ¡°HOLD-TIME¡± STUDIES48 49 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 WHO Prequalification Programme May 2013 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 WHO Expert Committee on Specifications for Pharmaceutical Preparations 14-18 October 2013 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 ¨C Inspections Group October 2013¨CJanuary 2014
Working document QAS/13.521/Rev.3 page 3 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 feedback received End September 2014 Presentation to forty-ninth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations October 2014 Further follow-up action as required ¡­ 50 51
Working document QAS/13.521/Rev.3 page 4 GENERAL GUIDANCE ON ¡°HOLD-TIME¡± STUDIES52 53 CONTENTS54 55 1. INTRODUCTION AND BACKGROUND56 2. GLOSSARY57 3. SCOPE58 4. ASPECTS TO BE CONSIDERED59 60 61 62 63 1. INTRODUCTION AND BACKGROUND64 65 Manufacturers should ensure that the products that they manufacture are safe, effective66 and of the quality required for their intended use. Products should be consistently67 manufactured to the quality standards appropriate to their intended use and as required by68 the marketing authorization. Systems should ensure that pharmaceutical products are69 produced according to validated processes and to defined procedures. Manufacturing70 processes should be shown to be capable of consistently manufacturing pharmaceutical71 products of the required quality that comply with their specifications.72 73 Arrangements should exist to ensure that the dispensed raw materials and packaging74 materials, intermediate products, bulk and finished products are stored under appropriate75 conditions. Storage should not have any significant negative effect on the processing,76 stability, safety, efficacy or quality of the materials, intermediate products and bulk77 products prior to final packing. Good manufacturing practices (GMP) require that a78 maximum acceptable holding period should be established to ensure that intermediates79 and bulk product can be held, pending the next processing step, without any significant80
Working document QAS/13.521/Rev.3 page 5 adverse effect to the quality of the material. Such a holding period should be underwritten81 by data, but need not be extended to find the edge of failure.82 83 2. GLOSSARY84 85 Bulk product86 Any pharmaceutical product which has completed all processing stages up to, but not87 including, final packaging.88 89 Intermediate90 Partly processed product that must undergo further manufacturing steps before it becomes91 a bulk product.92 93 3. SCOPE94 95 This guideline focus primarily on aspects that should be considered in the design of the96 hold-time studies during the manufacture of solid dosage forms. Many of the principles97 herein also apply to other dosage forms such as liquids, creams and ointments. This98 guideline does not cover aspects for hold times in cleaning validation or the99 manufacturing of active pharmaceutical ingredients (APIs).100 101 This guideline is intended as a basic guide for use by pharmaceutical manufacturers and102 GMP inspectors. This document does not intend to prescribe a process for establishing103 hold times, but reflects aspects that should be considered in the design of the hold-time104 study.105 106 Manufacturers should gather scientific and justifiable data to demonstrate that the107 dispensed raw materials and packaging materials, intermediate and bulk products:108 109 - remain of appropriate quality before processing to the next stage;110
Working document QAS/13.521/Rev.3 page 6 - meet the acceptance criteria and release specification for the finished product.111 112 4. ASPECTS TO BE CONSIDERED113 114 Hold time can be considered as the established time period for which materials115 (dispensed raw materials, intermediates and bulk dosage form awaiting final packaging)116 may be held under specified conditions and will remain within the defined specifications.117 118 Data to justify the hold time can be collected, but not limited to:119 - during development on pilot-scale batches,120 - during scale up,121 - during process validation, or122 - as part of an investigation of a deviation that occurred during manufacture.123 Hold-time studies establish the time limits for holding the materials at different stages of124 production to ensure that the quality of the product does not deteriorate significantly125 during the hold time. The design of the study should reflect the holding time at each126 stage. Hold times should normally be determined prior to marketing of a product and127 following any significant changes in processes, equipment, starting and packaging128 materials and represent actual processing. Hold time studies should be included during129 process validation (Ref: Process validation guideline).130 131 Manufacturers may use a flow chart to review the manufacturing procedure of a product132 and then break up the critical stages of manufacturing process on the basis of time133 duration required for the particular storage and processing stages, typical pauses in the134 manufacturing campaign, and the potential impact of storage with reference to135 environmental and storage conditions. An example for a flow chart is given below.136 137 For example, for oral tablets that are coated the following stages may be considered:138 139 - binder preparation to granulation ¨C consider the granulate;140
Working document QAS/13.521/Rev.3 page 7 - wet granulation to drying ¨C the dried granulate;141 - dried granules to lubrication/blending ¨C the lubricated blend;142 - blend to compression;143 - compression to coating ¨C the tablet cores;144 - coating solution to preparation ¨C the coating solution;145 - coating to packing ¨C consider the bulk coated tablets;146 - coating to packing in bulk or FDF;147 - packing in bulk to FDF.148 149 Example for a flow chart :150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 Sifting Dry Mixing Granulation Drying Lubrication &Blending Compression Coating Packing Drying Binder Sample withdrawn for analysis Granules: Sample withdrawn for analysis Blend: Sample withdrawn for analysis Core tablets: Sample withdrawn for analysis Coating Solution: Sample withdrawn for analysis Coated tablet: Sample withdrawn for analysis Dispensing
Working document QAS/13.521/Rev.3 page 8 181 A written protocol, procedure or programme should be followed which includes the182 activities to be performed, test parameters and acceptance criteria appropriate to the183 material or product under test. The protocol and report should generally include the184 following: a title; reference number; version; date; objective; scope; responsibility;185 procedure; description of the material/product; sample quantities; sampling method and186 criteria; acceptance limits; frequency for sampling; sampling locations; pooling of187 samples; storage conditions; type of container; methods of analysis; results; conclusion;188 recommendation; signatures and dates. Acceptance criteria are typically more stringent189 than registered specifications to provide assurance that the material is well within control.190 When setting the specifications any known stability trends will need to be taken into191 account.192 193 For certain products microbiological aspects should also be considered and included194 where appropriate.195 196 Typically one or more batches of a material, intermediate or product can be used for197 determining hold times. A risk-based approach can be used to determine the appropriate198 number of batches, considering inter alia the characteristics of the materials A199 representative sample of the batch of material or product subjected to the hold-time study200 should be held for the defined hold period. The maximum hold period for each category201 of material should be established on the basis of the study by keeping the material in202 either the original or simulated container used in production. The containers used in203 which hold-time samples are stored should be the same pack as used in production unless204 the pack is exceptionally large, in which case one that is equivalent (same material of205 construction and closure system to the production packaging system) may be used.206 Reducing the size of container when necessary for testing holding time, should be207 justified. Where head space is important the hold-time samples should represent the208 maximum possible head space (worst-case scenario) to bulk stored in209 manufacturing/quarantine. The sample storage environmental conditions should be same210 as that of the quarantine area/manufacture stage.Asampling plan should be established211
Working document QAS/13.521/Rev.3 page 9 and followed for taking samples for testing at the different intervals. The required sample212 amount should be calculated based on the batch size, the intervals and tests to be213 performed. Results should be compared with the initial baseline data of the control214 sample . Samples may be pooled for analysis where appropriate, e.g. when the analysis of215 a composite sample will not miss issues expected in the variation of the product.216 217 Where appropriate, statistical analysis of the data generated should be performed to218 identify trends and to justify the limits and hold time set.219 220 Batches of finished products made from intermediates or bulk products and subjected to a221 hold-time study should be considered for long-term stability testing if data show adverse222 trending or shifting patterns during the intermediate time points up to the end of the223 shelf-life. The shelf-life of the product ¨C irrespective of hold times ¨C should be measured224 from the time the active ingredients are mixed with other ingredients. Normally225 intermediate and bulk products should not be stored beyond the established hold time. All226 testing of bulk intermediates and product should be performed using validated stability-227 indicating methods.228 229 The following table provides examples of stages and tests that may be considered.230 231 Table: Examples of stages and tests that may be considered, based on risk assessment232 and specific product needs233 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 suspensi¨®n Physical appearance, Specific gravity, Viscosity, Sedimentation, pH, Microbial test Initial, 12, 24, 36, 48, 60, 72 hours
Working document QAS/13.521/Rev.3 page 10 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 ¨C uncoated (in bulk container Description, Hardness, Thickness, Friability, Disintegration, Dissolution or Dissolution profile, assay, Degradation products/ related substance, Uniformity of dosage units, Microbial test. Initial, 30th day, 60th day & 90th day Coated tablets (in bulk container) 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 234 235 ***236

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generalguidanceholdtimeqas13-521rev320augskclean

  • 1. Working document QAS/13.521/Rev.3 August 2014 Document for comment 1 2 3 4 GENERAL GUIDANCE5 ON ¡°HOLD-TIME¡± STUDIES6 7 REVISED DRAFT FOR COMMENT8 (August 2014)9 10 11 12 13 14 15 16 17 18 19 20 21 ___________________________________________________________________________22 ? World Health Organization 201423 All rights reserved.24 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The25 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in26 whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned27 staff and member organizations) without the permission of the World Health Organization. The draft should not be28 displayed on any website.29 Please send any request for permission to:30 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of31 Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22)32 791 4730; email: kopps@who.int.33 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion34 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or35 area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent36 approximate border lines for which there may not yet be full agreement.37 The mention of specific companies or of certain manufacturers¡¯ products does not imply that they are endorsed or38 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.39 Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.40 All reasonable precautions have been taken by the World Health Organization to verify the information contained in41 this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied.42 The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health43 Organization be liable for damages arising from its use.44 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.45 46 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: kopps@who.int; fax: (+41 22) 791 4730 (kopps@who.int) and to Ms Marie Gaspard (gaspardm@who.int), 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 bonnyw@who.int) and we will add it to our electronic mailing list.
  • 2. Working document QAS/13.521/Rev.3 page 2 SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/13.52147 GENERAL GUIDANCE ON ¡°HOLD-TIME¡± STUDIES48 49 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 WHO Prequalification Programme May 2013 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 WHO Expert Committee on Specifications for Pharmaceutical Preparations 14-18 October 2013 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 ¨C Inspections Group October 2013¨CJanuary 2014
  • 3. Working document QAS/13.521/Rev.3 page 3 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 feedback received End September 2014 Presentation to forty-ninth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations October 2014 Further follow-up action as required ¡­ 50 51
  • 4. Working document QAS/13.521/Rev.3 page 4 GENERAL GUIDANCE ON ¡°HOLD-TIME¡± STUDIES52 53 CONTENTS54 55 1. INTRODUCTION AND BACKGROUND56 2. GLOSSARY57 3. SCOPE58 4. ASPECTS TO BE CONSIDERED59 60 61 62 63 1. INTRODUCTION AND BACKGROUND64 65 Manufacturers should ensure that the products that they manufacture are safe, effective66 and of the quality required for their intended use. Products should be consistently67 manufactured to the quality standards appropriate to their intended use and as required by68 the marketing authorization. Systems should ensure that pharmaceutical products are69 produced according to validated processes and to defined procedures. Manufacturing70 processes should be shown to be capable of consistently manufacturing pharmaceutical71 products of the required quality that comply with their specifications.72 73 Arrangements should exist to ensure that the dispensed raw materials and packaging74 materials, intermediate products, bulk and finished products are stored under appropriate75 conditions. Storage should not have any significant negative effect on the processing,76 stability, safety, efficacy or quality of the materials, intermediate products and bulk77 products prior to final packing. Good manufacturing practices (GMP) require that a78 maximum acceptable holding period should be established to ensure that intermediates79 and bulk product can be held, pending the next processing step, without any significant80
  • 5. Working document QAS/13.521/Rev.3 page 5 adverse effect to the quality of the material. Such a holding period should be underwritten81 by data, but need not be extended to find the edge of failure.82 83 2. GLOSSARY84 85 Bulk product86 Any pharmaceutical product which has completed all processing stages up to, but not87 including, final packaging.88 89 Intermediate90 Partly processed product that must undergo further manufacturing steps before it becomes91 a bulk product.92 93 3. SCOPE94 95 This guideline focus primarily on aspects that should be considered in the design of the96 hold-time studies during the manufacture of solid dosage forms. Many of the principles97 herein also apply to other dosage forms such as liquids, creams and ointments. This98 guideline does not cover aspects for hold times in cleaning validation or the99 manufacturing of active pharmaceutical ingredients (APIs).100 101 This guideline is intended as a basic guide for use by pharmaceutical manufacturers and102 GMP inspectors. This document does not intend to prescribe a process for establishing103 hold times, but reflects aspects that should be considered in the design of the hold-time104 study.105 106 Manufacturers should gather scientific and justifiable data to demonstrate that the107 dispensed raw materials and packaging materials, intermediate and bulk products:108 109 - remain of appropriate quality before processing to the next stage;110
  • 6. Working document QAS/13.521/Rev.3 page 6 - meet the acceptance criteria and release specification for the finished product.111 112 4. ASPECTS TO BE CONSIDERED113 114 Hold time can be considered as the established time period for which materials115 (dispensed raw materials, intermediates and bulk dosage form awaiting final packaging)116 may be held under specified conditions and will remain within the defined specifications.117 118 Data to justify the hold time can be collected, but not limited to:119 - during development on pilot-scale batches,120 - during scale up,121 - during process validation, or122 - as part of an investigation of a deviation that occurred during manufacture.123 Hold-time studies establish the time limits for holding the materials at different stages of124 production to ensure that the quality of the product does not deteriorate significantly125 during the hold time. The design of the study should reflect the holding time at each126 stage. Hold times should normally be determined prior to marketing of a product and127 following any significant changes in processes, equipment, starting and packaging128 materials and represent actual processing. Hold time studies should be included during129 process validation (Ref: Process validation guideline).130 131 Manufacturers may use a flow chart to review the manufacturing procedure of a product132 and then break up the critical stages of manufacturing process on the basis of time133 duration required for the particular storage and processing stages, typical pauses in the134 manufacturing campaign, and the potential impact of storage with reference to135 environmental and storage conditions. An example for a flow chart is given below.136 137 For example, for oral tablets that are coated the following stages may be considered:138 139 - binder preparation to granulation ¨C consider the granulate;140
  • 7. Working document QAS/13.521/Rev.3 page 7 - wet granulation to drying ¨C the dried granulate;141 - dried granules to lubrication/blending ¨C the lubricated blend;142 - blend to compression;143 - compression to coating ¨C the tablet cores;144 - coating solution to preparation ¨C the coating solution;145 - coating to packing ¨C consider the bulk coated tablets;146 - coating to packing in bulk or FDF;147 - packing in bulk to FDF.148 149 Example for a flow chart :150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 Sifting Dry Mixing Granulation Drying Lubrication &Blending Compression Coating Packing Drying Binder Sample withdrawn for analysis Granules: Sample withdrawn for analysis Blend: Sample withdrawn for analysis Core tablets: Sample withdrawn for analysis Coating Solution: Sample withdrawn for analysis Coated tablet: Sample withdrawn for analysis Dispensing
  • 8. Working document QAS/13.521/Rev.3 page 8 181 A written protocol, procedure or programme should be followed which includes the182 activities to be performed, test parameters and acceptance criteria appropriate to the183 material or product under test. The protocol and report should generally include the184 following: a title; reference number; version; date; objective; scope; responsibility;185 procedure; description of the material/product; sample quantities; sampling method and186 criteria; acceptance limits; frequency for sampling; sampling locations; pooling of187 samples; storage conditions; type of container; methods of analysis; results; conclusion;188 recommendation; signatures and dates. Acceptance criteria are typically more stringent189 than registered specifications to provide assurance that the material is well within control.190 When setting the specifications any known stability trends will need to be taken into191 account.192 193 For certain products microbiological aspects should also be considered and included194 where appropriate.195 196 Typically one or more batches of a material, intermediate or product can be used for197 determining hold times. A risk-based approach can be used to determine the appropriate198 number of batches, considering inter alia the characteristics of the materials A199 representative sample of the batch of material or product subjected to the hold-time study200 should be held for the defined hold period. The maximum hold period for each category201 of material should be established on the basis of the study by keeping the material in202 either the original or simulated container used in production. The containers used in203 which hold-time samples are stored should be the same pack as used in production unless204 the pack is exceptionally large, in which case one that is equivalent (same material of205 construction and closure system to the production packaging system) may be used.206 Reducing the size of container when necessary for testing holding time, should be207 justified. Where head space is important the hold-time samples should represent the208 maximum possible head space (worst-case scenario) to bulk stored in209 manufacturing/quarantine. The sample storage environmental conditions should be same210 as that of the quarantine area/manufacture stage.Asampling plan should be established211
  • 9. Working document QAS/13.521/Rev.3 page 9 and followed for taking samples for testing at the different intervals. The required sample212 amount should be calculated based on the batch size, the intervals and tests to be213 performed. Results should be compared with the initial baseline data of the control214 sample . Samples may be pooled for analysis where appropriate, e.g. when the analysis of215 a composite sample will not miss issues expected in the variation of the product.216 217 Where appropriate, statistical analysis of the data generated should be performed to218 identify trends and to justify the limits and hold time set.219 220 Batches of finished products made from intermediates or bulk products and subjected to a221 hold-time study should be considered for long-term stability testing if data show adverse222 trending or shifting patterns during the intermediate time points up to the end of the223 shelf-life. The shelf-life of the product ¨C irrespective of hold times ¨C should be measured224 from the time the active ingredients are mixed with other ingredients. Normally225 intermediate and bulk products should not be stored beyond the established hold time. All226 testing of bulk intermediates and product should be performed using validated stability-227 indicating methods.228 229 The following table provides examples of stages and tests that may be considered.230 231 Table: Examples of stages and tests that may be considered, based on risk assessment232 and specific product needs233 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 suspensi¨®n Physical appearance, Specific gravity, Viscosity, Sedimentation, pH, Microbial test Initial, 12, 24, 36, 48, 60, 72 hours
  • 10. Working document QAS/13.521/Rev.3 page 10 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 ¨C uncoated (in bulk container Description, Hardness, Thickness, Friability, Disintegration, Dissolution or Dissolution profile, assay, Degradation products/ related substance, Uniformity of dosage units, Microbial test. Initial, 30th day, 60th day & 90th day Coated tablets (in bulk container) 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 234 235 ***236