Stability Testing of Drug Products Scientific Criteries, guidelines and officiel state requirements in Europe, Japan and USA Edited by Dr. Wolfgang Grimm, Dr. Karl Thomae GmbH, D-Biberach International APV Symposium on Stability Testing of Pharmaceutical Products, Munich, December 2-4, 1985 Organized by Dr. P. Fischer, CH-Bern Prof. Dr. H. Feltkamp, Bayer AG, D-Leverkusen Dr. W. Grimm, Dr. Karl Thomae GmbH, D-Biberach Prof. Dr. H. Sucker, Sandoz AG, CH-Basel with 104figuresand 8 tables runiversstatsbibl1othek HANNOVER, TECKNISCHE i INFORMATIONS3IBLIOTHEK VOOCs Wissenschaftliche Verlagsgesellschaft mbh Stuttgart 1987
Contents Address of the authors: 12 Introduction (W. Grimm) 13 I. Physico-chemical changes from a molecular-galenical view point (R. Huttenrauch) 17 1. Introduction 17 2. Solid and semi-solid dosage forms, solids in suspensions 21 3. Liquid dosage forms 32 4. Final remarks 39 II. Physicochemical Criteria for semi-solid dosage forms (S.S. Davis) 40 1. Introduction 40 2. The various types of semi-solid forms 40 2.1 Suspensions 40 2.2 Emulsions 41 2.3 Suppositories 41 2.4 Gels 41 2.5 Ointments and creams 41 3. Evaluation of physicochemical properties 42 3.1 Crystalline properties 43 3.2 Sedimentation and creaming 43 3.3 Consistency 44 4. Accelerated tests 50 5. Predictive methods 51 6. Protocols for the evaluation of physical stability 53 7. Stability limits and conclusions 54 m. Physico-chemical Criteria for the stability and stability forcast of solid dosage forms (M. Baltezor) 57 1. Introduction 57 2. Sensory properties 58 3. Hardness 58 4. Retained moisture 59
Contents 5. Disintegration 61 6. Dissolution 61 7. Conclusions 63 IV. Changes in medicinal products and the consequences for their therapeutic application (A. Verain) 64 1. Introduction 64 2. Notation of stability 64 3. Stability and production 66 3.1 The formulation process 67 3.1.1 Structural changes 67 3.1.2 Reactivity 69 3.1.3 Sensibility to humidity 69 3.2 Production 70 3.2.1 Polymorphism 70 3.2.2 Reactivity 71 3.2.3 Humidity 71 3.2.4 Mechanical manipulation 72 4. Medicinal accidents due to faulty fabrication techniques or instabilities 72 4.1 Incidents independent of the chemical structure of the active molecule 72 4.2 Incidents related to the active molecule 74 5. Conclusions 76 V. Japanese Guideline for Stability Testing (T. Nagai) 77 1. Introduction 77 2. Cooperative investigation on the establishment of the method for stability test for pharmaceutical preparations 78 3. General matters concerning the data of stability testing to be submitted when applying for approval to manufacture (or import) new drugs 79 4. Standards for stability testing of new drugs (March 31, 1980) 80 5. Accelerated test standards 82 6. Additional Guideline concerning the standards for stability testing of new drugs (June 8, 1984) 83 VI. Proposed FDA Guideline for Stability Testing (R. C. Shultz) 86 1. Introduction 86 2. Drug substance 87 3. Drug product 89 3.1 Statistical evaluation of an expiration dating period 90
Contents 7 3.2 Design consideration for longterm studies under ambient conditions 91 3.2.1 Selection of the batches 91 3.2.2 Number of batches 91 3.2.3 Selection of samples 91 3.2.4 Testing sequence 92 4. General product information 94 5. Specifications and test methodology information 95 6. Study design and study conditions 95 7. Stability data information 95 8. Data analysis and conclusions 96 VII. State of the official regulations concerning stability testing of pharmaceutical products in the EEC (B. Huyghe) 97 1. Official regulations concerning stability testing of Belgium 97 2. General introduction 97 3. What can be said about in raw materials 98 4. What can be said in 1985 about medicinal products in pharmaceutical form 99 4.1 Acceptability of accelerated testing 99 4.2 Number of batches required to perform the stability tests 99 4.3 Number of temperatures required in stability tests 100 4.4 Desirability to require stability tests in a high humidity atmosphere and/or in the presence of sufficient light 101 5. Conclusions 101 VIII. Requirements of the Licensing Authority of the Federal Republic of Germany concerning the Stability Testing of Drug Products, with special reference to Phytopharmaceuticals (F.W. Hefendehl) 104 1. Stability Tests according to the draft of a Drug Testing Guideline, Section dealing with Quality 104 2. General requirements of stability tests 104 2.1 Number of batches to be tested 105 2.2 Duration of testing 105 2.3 Equivalence of tests that were carried out under other conditions 105 2.4 Testing frequency 106 2.5 Test parameters 106 2.6 Stability specificity 106 2.7 Stability overages 106 3. Foreign documentation and responsibility of the Pharmaceutical Manufacturer 107
Contents 4. Stability tests of phytopharmaceuticals 107 4.1 Definition 107 4.2 Peculiarities of crude drugs and crude drug preparations 107 4.3 Stability tests of crude drugs and crude drug preparations 108 4.3.1 Single crude drugs and crude drug preparations with known active substances 108 4.3.2 Single crude drugs or crude drug preparations, whose active substances are not known 109 4.3.3 Crude drug mixtures or mixed crude drug preparations with known active substances 110 4.3.4 Crude drug mixtures or mixtures of crude drug preparations with unknown active substances 110 4.3.5 Quality assessment of the general characteristics of various dosage forms of Phytopharmaceuticals during stability tests Ill 4.3.6 Special provision for the stability testing of Phytopharmaceuticals Ill 4.3.7 Summary and outlook 112 IX. Stability testing of pharmaceutical products: Official state requirements in France, Analytical approach and schema for the study of stability (F. Pellerin) 113 1. Introduction 113 2. Stability - study schedule 114 3. Setting up the study 116 3.1 Investigation of the active principle 116 3.1.1 Reactivity of the molecule 117 3.1.2 General study procedures 118 3.2 Pharmaceutical dosage form stability test 123 3.2.1 Moisture 124 3.2.2 Antioxidants 124 3.2.3 Functional group analysis and prediction of stability 125 3.2.4 Forced oxidation 126 4. Interpretation of the results and conclusions 128 4.1 Analytical aspects 128 4.2 Technical aspects, 129 4.3 Conclusions 129 X. Great Britain, the DHSS Medicines Devision Requirement (A.G. Stewart) 131 1. Introduction 131 2. The underlying philosophy 131 3. The pharmaceutical assessors 132
Contents 9 4. The guidelines 134 5. Discussion 135 5.1 Some effects of instability 135 6. The drug substance/active constituent 135 7. The dosage form 136 8. The headings on stability 137 8.1 Batches examined 137 8.2 Conditions and duration of storage testing 139 8.3 Containers 137 8.4 Analytical methods 137 8.5 Parameters tested 138 8.6 Results 138 8.7 Proposed shelf life 138 8.8 Storage conditions, user instructions and pharmaceutical precautions 139 8.9 On-going stability testing 139 9. Conclusions 139 XL Stability and Stability Testing of Medicinal Products APV Guideline and Commentary 140 1. APV Guideline 140 1.1 Application and purpose 140 1.2 Definition of stability 140 1.2.1 Content of active ingredient 140 1.2.2 Purity, degradation products 141 1.2.3 Organoleptic, physico-chemical and microbiological characteristics 141 1.3 Stability overage 141 1.4 Storage time, shelf life 141 1.5 Storage conditions 141 1.5.1 Normal storage conditions 141 1.5.2 Defined storage conditions 142 1.5.3 Labelling 142 1.6 Packaging 142 1.7 Stability Testing 142 1.7.1 Container and closure 143 1.7.2 Accelerated studies 143 1.7.3 Long term studies 143 1.7.3.1 Storage conditions for long term studies 143 1.7.3.2 Duration of studies 143 1.7.3.3 Testing intervals 143 1.7.3.4 Test criteria 143 1.7.3.5 Test methods 144
10 Contents 1.7.4 On-going stability 144 2. Commentary on the APV Guideline (W. Grimm) 144 2.1 Stability and stability testing of medicinal products 144 2.2 Definition of stability 145 2.2.1 Active ingredient 145 2.2.2 Purity, degradation products 146 2.2.3 Organoleptic, physico-chemical and microbiological characteristics 146 2.3 Stability overage 146 2.4 Stability period, shelf life 146 2.5 Storage conditions 147 2.6 Packaging 148 2.7 Stability testing 148 2.7.1 Accelerated stability tests 148 2.7.2 Long term studies 149 2.7.3 On-going Studies 150 XII. APV Guideline: Stability and Stability testing. State of the art in the field of stability and stability testing (W. Oeser) 151 Xm. Stability Testing in Industry (W. Grimm) 157 1. Introduction 157 2. Content of stability tests 158 3. Description of the individual phases in a stability testing programme 159 3.1 Tests with the drug substance 159 3.2 Screening during pharmaceutical development 160 3.3 Accelerated studies with the chosen formulation 161 3.4 Long term testing 162 3.5 Follow-up studies 165 3.6 Tests after alterations to routine production 166 4. Critical assessment of stability test programmes 167 5. Cooperation with the Authorities 168 6. The future of stability testing 169 XIV. Analytical methods of Stability Testing for chemically defined substances (S. Ebel) 171 1. Introduction 171 2. High pressure liquid chromatography 171 3. Thin layer chromatography 176 4. UV-spectrometry 180 5. Voltammetry 182 6. Titration procedures 183 7. Conclusions 184
Contents 11 XV. Analytical procedures for stability testing of phytopharmaka and pharmaceutical products derived from natural compounds (G. Harnischfeger) 188 1. Introduction 188 2. General requirements 189 3. Procedure for the planning of a stability test 190 3.1 Predictable chemical change 192 3.1.1 Redox reactions 193 3.1.2 Interconversions 193 3.1.3 Hydrolysis 194 3.1.4 Condensations and polymerisations 194 3.1.5 Isomerisations 195 3.1.6 Photochemical processes 195 3.2 Predictable galenical changes 196 4. Technical limitations in stability testing of phytopharmaka 198 5. Methods and their limitations 198 6. Combination products 203 7. Examples 204 8. Final remarks :. 208 XVI. Stability Testing during development (K. Krummen) 210 1. Introduction 210 2. Drug substance reactivities 211 3. Excipient compatibility 212 4. Formulation comparison 215 5. Stability of proposed product 220 6. Conclusions 226 XVII. Packaging materials and shelf life (D. Herrmann) 227 1. Introduction, General remarks 227 2. Permeation, Plastic bottles 229 3. Lyophilisates/Freeze-drying stoppers 230 4. Glass 230 5. Light protection 233 6. Elastomeres/Rubber materials 235 7. Plastics/General categories 238 8. Collapsible tubes/aluminium 238 9. Conclusions summary 239