Stability Testing of Drug Products

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Jerome Stewart
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1 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

2 Contents Address of the authors: 12 Introduction (W. Grimm) 13 I. Physico-chemical changes from a molecular-galenical view point (R. Huttenrauch) Introduction Solid and semi-solid dosage forms, solids in suspensions Liquid dosage forms Final remarks 39 II. Physicochemical Criteria for semi-solid dosage forms (S.S. Davis) Introduction The various types of semi-solid forms Suspensions Emulsions Suppositories Gels Ointments and creams Evaluation of physicochemical properties Crystalline properties Sedimentation and creaming Consistency Accelerated tests Predictive methods Protocols for the evaluation of physical stability Stability limits and conclusions 54 m. Physico-chemical Criteria for the stability and stability forcast of solid dosage forms (M. Baltezor) Introduction Sensory properties Hardness Retained moisture 59

3 Contents 5. Disintegration Dissolution Conclusions 63 IV. Changes in medicinal products and the consequences for their therapeutic application (A. Verain) Introduction Notation of stability Stability and production The formulation process Structural changes Reactivity Sensibility to humidity Production Polymorphism Reactivity Humidity Mechanical manipulation Medicinal accidents due to faulty fabrication techniques or instabilities Incidents independent of the chemical structure of the active molecule Incidents related to the active molecule Conclusions 76 V. Japanese Guideline for Stability Testing (T. Nagai) Introduction Cooperative investigation on the establishment of the method for stability test for pharmaceutical preparations General matters concerning the data of stability testing to be submitted when applying for approval to manufacture (or import) new drugs Standards for stability testing of new drugs (March 31, 1980) Accelerated test standards 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) Introduction Drug substance Drug product Statistical evaluation of an expiration dating period 90

4 Contents Design consideration for longterm studies under ambient conditions Selection of the batches Number of batches Selection of samples Testing sequence General product information Specifications and test methodology information Study design and study conditions Stability data information Data analysis and conclusions 96 VII. State of the official regulations concerning stability testing of pharmaceutical products in the EEC (B. Huyghe) Official regulations concerning stability testing of Belgium General introduction What can be said about in raw materials What can be said in 1985 about medicinal products in pharmaceutical form Acceptability of accelerated testing Number of batches required to perform the stability tests Number of temperatures required in stability tests Desirability to require stability tests in a high humidity atmosphere and/or in the presence of sufficient light 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) Stability Tests according to the draft of a Drug Testing Guideline, Section dealing with Quality General requirements of stability tests Number of batches to be tested Duration of testing Equivalence of tests that were carried out under other conditions Testing frequency Test parameters Stability specificity Stability overages Foreign documentation and responsibility of the Pharmaceutical Manufacturer 107

5 Contents 4. Stability tests of phytopharmaceuticals Definition Peculiarities of crude drugs and crude drug preparations Stability tests of crude drugs and crude drug preparations Single crude drugs and crude drug preparations with known active substances Single crude drugs or crude drug preparations, whose active substances are not known Crude drug mixtures or mixed crude drug preparations with known active substances Crude drug mixtures or mixtures of crude drug preparations with unknown active substances Quality assessment of the general characteristics of various dosage forms of Phytopharmaceuticals during stability tests Ill Special provision for the stability testing of Phytopharmaceuticals Ill 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) Introduction Stability - study schedule Setting up the study Investigation of the active principle Reactivity of the molecule General study procedures Pharmaceutical dosage form stability test Moisture Antioxidants Functional group analysis and prediction of stability Forced oxidation Interpretation of the results and conclusions Analytical aspects Technical aspects, Conclusions 129 X. Great Britain, the DHSS Medicines Devision Requirement (A.G. Stewart) Introduction The underlying philosophy The pharmaceutical assessors 132

6 Contents 9 4. The guidelines Discussion Some effects of instability The drug substance/active constituent The dosage form The headings on stability Batches examined Conditions and duration of storage testing Containers Analytical methods Parameters tested Results Proposed shelf life Storage conditions, user instructions and pharmaceutical precautions On-going stability testing Conclusions 139 XL Stability and Stability Testing of Medicinal Products APV Guideline and Commentary APV Guideline Application and purpose Definition of stability Content of active ingredient Purity, degradation products Organoleptic, physico-chemical and microbiological characteristics Stability overage Storage time, shelf life Storage conditions Normal storage conditions Defined storage conditions Labelling Packaging Stability Testing Container and closure Accelerated studies Long term studies Storage conditions for long term studies Duration of studies Testing intervals Test criteria Test methods 144

7 10 Contents On-going stability Commentary on the APV Guideline (W. Grimm) Stability and stability testing of medicinal products Definition of stability Active ingredient Purity, degradation products Organoleptic, physico-chemical and microbiological characteristics Stability overage Stability period, shelf life Storage conditions Packaging Stability testing Accelerated stability tests Long term studies 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) Introduction Content of stability tests Description of the individual phases in a stability testing programme Tests with the drug substance Screening during pharmaceutical development Accelerated studies with the chosen formulation Long term testing Follow-up studies Tests after alterations to routine production Critical assessment of stability test programmes Cooperation with the Authorities The future of stability testing 169 XIV. Analytical methods of Stability Testing for chemically defined substances (S. Ebel) Introduction High pressure liquid chromatography Thin layer chromatography UV-spectrometry Voltammetry Titration procedures Conclusions 184

8 Contents 11 XV. Analytical procedures for stability testing of phytopharmaka and pharmaceutical products derived from natural compounds (G. Harnischfeger) Introduction General requirements Procedure for the planning of a stability test Predictable chemical change Redox reactions Interconversions Hydrolysis Condensations and polymerisations Isomerisations Photochemical processes Predictable galenical changes Technical limitations in stability testing of phytopharmaka Methods and their limitations Combination products Examples Final remarks :. 208 XVI. Stability Testing during development (K. Krummen) Introduction Drug substance reactivities Excipient compatibility Formulation comparison Stability of proposed product Conclusions 226 XVII. Packaging materials and shelf life (D. Herrmann) Introduction, General remarks Permeation, Plastic bottles Lyophilisates/Freeze-drying stoppers Glass Light protection Elastomeres/Rubber materials Plastics/General categories Collapsible tubes/aluminium Conclusions summary 239

GUIDANCE FOR INDUSTRY ON FIXED DOSE COMBINATIONS (FDCs)

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