Ich guidelines
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This document discusses guidelines for stability testing of pharmaceuticals according to the International Conference on Harmonization (ICH). It describes the ICH guidelines for stability testing, including stability protocols, reports, and studies. The key points covered include stability testing procedures, factors affecting drug stability, types of stability studies, and organizations that regulate stability guidelines such as the ICH.
Ich guidelines
- 1. Stability testing procedures for pharmaceuticals according to ICH guidelines UNDER THE GUIDENCE OF PROF.B JEEVANA JYOTHI
- 2. Contents Introduction ICH topics Stability protocol & report • Stability testing of new drug substances & products • Photo stability testing of new drug substances & products • Stability testing of dosage forms • Bracketing & matrixing design for stability testing of new drug substance & products • Evalution of stability data • Stability data package for the registration applications of the
- 3. Stability Stability of pharmaceutical product may be defined as the capability of a particular formulation in a specific container/closure system to remain with its physical, chemical, microbiological, therape utic and toxicological specification. Stability studies types Long term stability study Intermediate stability study Accelerated stability study
- 4. Factors Affecting Drug Stability D.E ratio D.E & D.D interactio n
- 5. Need for stability testing Provide evidence as - how the quality of drug product varies with time. Establish shelf life for the drug product Determine recommended storage conditions Determine container closure system suitability Safety point of view of patient Essential quality attribute
- 6. Organizations Regulating Stability Guidelines
- 7. The International Conference Of Harmonization of technical requirements for registration of pharmaceuticals for human use. It is unique in bringing together the regulatory authorities of Europe ,Japan ,US & experts from pharmaceutical industries to discuss the scientific and technical aspects of the product registration
- 8. ICH TOPICS QUALITY (Q) Related to mfg. QA SAFETY (S) EFFICACY (E) MULTIDISIPLINARY (M) Non clinical Medical terminolo pharmacology Clinical safety, electronic dose & toxicology studies response standards for studies, good transmission clinical practices regulatory of , clinical evaluation information etc.
- 9. ICH –Quality Quality topic of ICH consist of 6 sub follows: Q1: Stability testing Q2: Analytical method validation Q3: Impurity testing Q4: Pharmacopoeial harmonization Q5: Quality of bio technological products Q6: Specifications for the new drug substances &
- 10. Stability testing guidelines: They include six sub topics,they are • Stability testing of new drug substances & products • Photo stability testing of new drug substances & products • Stability testing of dosage forms • Bracketing & matrixing design for stability testing of new drug substance & products • Evalution of stability data • Stability data package for the registration applications of the climate zones III & IV
- 11. Where and Why? Stability Studies are preformed on ... Drug Substances (DS)/API: The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form. Drug Products (DP)/finished poduct: The dosage form in the final immediate packaging intended for Marketing.---(API & Excipients)
- 12. Zone concept Temperate zone KMT- 21⁰c RH-45% Mediterian zone KMT-25⁰c RH-60% Tropical zone KMT-30⁰c RH-35% Desert zone KMT-30⁰c RH-70%
- 14. Stability Protocol & Report
- 15. Q1A(R2) guidelines Q1A (R2) guide lines Stress testing Stress testing Selection of batches Container closure system specification Testing frequency Storage conditions Stability commitment Carried out on a single batch and it include the effect of tempratures, humidity where appropriate oxidation & photolysis on DS Scope: help to identify degradation products , degradation pathway & intrinsic stability of the molecule Evalution Statement&labelling Atleast 3 primary batches of the
- 16. Q1A(R2) guidelines Container closure system Stress testing Selection of batches Container closure system specification Testing frequency Storage conditions Stability commitment Stability study conducted on the drug substance Packed in a container closure system i.e, same or stimulate packaging proposed for Storage & distribution. Specification These guide lines states the list of test, Statement&labelling references to analytical procedure Evalution
- 17. Q1A(R2) guidelines Stress testing Testing frequency Type of study Testing frequency Long term studies For drug sub. With a proposed re test period of atleast 12 months. 1st year……….3month s 2nd……………..6mo nth There after……annualy Through the proposed re-test period Selection of batches Container closure system specification Testing frequency Storage conditions Stability commitment Evaluation Statement & labelling Accelerated Min. 3 time
- 18. Q1A(R2) guidelines Storage conditions Drug products - General case Stress testing Selection of batches Container closure system Study Long term specification Testing frequency Storage conditions Stability commitment Storage condition 25 C 2 C / 60% 5% R.H or 30 C 2 C / 65% 5% R.H. Intermediate 30 C 2 C / 65% Minimum time period covered by data at submission 12 months 6 months 5% R.H. Accelerated 40 C 2 C / 75% Evalution Statement&labelling 5% R.H. 6 months
- 19. Drug substances-intended for storage in refridgerator Study Storage condition Minimum time period covered by data at submission Long term 5 C 12 months Accelerated 25 C 3 C 2 C / 60% 5% R.H. 6 months Drug substances/Product- intended for storage in Freezer Study Storage condition Minimum time period covered by data at submission Long term -20 C 12 months 5C
- 20. Q1A(R2) guidelines Stress testing Section of batches Container closure system specification Testing frequency Storage conditions Stability commitment Evalution Statement&labelling
- 21. Q1A(R2) guidelines Evalution Evaluation The purpose of stability is to establish re-test period(DS) & shelf life (DP) for future batches based on evaluation of results obtained from chemical,physical,biological,microbio logical tests. A systemic approach should be adopted in the presentation & evaluation of the stability information which covers the physical ,chemical & biological parameter A minimum of 3 batches of drug product was tested.
- 22. Significant change of drug substance or product A 5% change in assay from its initial value Any degradation product exceeding its acceptance criteria Failure to meet acceptance criteria for appearance ,physical attributes (colour,phase separation ,hardness), pH Failure to meet acceptance criteria for dissolution for 12 dosage forms
- 23. Q1A(R2) guidelines Stress testing Section of batches Container closure system specification Testing frequency Storage conditions Stability commitment Evalution Statement&labelling Statement & labelling A storage statement should be established for labeling in relevant national or regional requirements Should be established based on the stability evalution of drug substance Terms such as “Ambient conditions "or “Room temperature” should be avoided Retest date for DS & expiry
- 24. Photostability testing Light can effect drugs ,causing chemical changes so evolution of drugs after exposing to light must be carried on single batch of material selected Gives idea about how to store drug Testing carried out on: Tests on active substance Exposed drug product out side of the immediate pack Drug product in the immediate pack Drug product in the marketing pack Light sources Artificial daylight flourosence lamp combining visible & UV out put , xenon or
- 25. Procedure Sample should be exposed to light providing an over all illumination of not less than 1.2 million lux hours & an integrated near UV energy of not less than 200 watt hours /sq.meter Protected samples (eg., wrapped in aluminium foil)are used as dark controls to evaluate the contribution of thermally induced change to the total observed change.
- 27. Stability test for New dosage forms new dosage forms …… • Same active substance • Different administration route • New specific functionality or delivery systems • Different dosage forms of same administration route Stability test parameteres for various types of dosage forms Dosage form Parameter Appearance,colour Tablet ,odour,assay,disintigration s /dissolution,moisture & Hard gelatin friability capsules Appearance,colour ,odour,assay,disintigration /dissolution,moisture µbial limits Soft Appearance,colour ,odour,assay,disintigration
- 28. Emulsions Suppositories Small volume Small Appearance including phase seperation ,colour ,odour,assay,pH,viscosity,preserv ative content ,weight loss & microbial limits Appearance,colour ,assay ,particle size ,softening range ,dissolution& microbial limits Appearance ,colour,assay,pH, preservative content ,particulate matter , sterlity & pyrogenicity volume parentrals Large volume Parentrals Appearance ,colour,assay,pH, preservative content ,particulate
- 29. Bracketing & matrixing design for stability testing of new drug substance & products Study design Full study design Reduced study design Not Samples of all designed factors for every combination are tested at all time points Samples of all designed factors for every combination are tested at all time points Bracketing Matrixing
- 30. Bracketing Bracketing is the design of a Stability schedule such that only samples on the extremes of certain design factors (e.g., strength,container size and/or fill) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by Example of a the stability Designextremes tested. Bracketing of the
- 31. Matrixing Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested. The Design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time
- 33. Evaluation Of The Stability Data The parent guideline states that regression analysis is an appropriate approach to analyzing quantitative stability data for retest period or shelf life estimation and recommends that a statistical test for batch poolability be performed using a level of significance This guideline is intended to provide of 0.25. recommendations on how to use stability data generated in accordance with the principles detailed in the ICH guideline ―Q1A(R) Stability Testing of New Extrapolation and Products Drug Substances Extrapolation is the practice of using a known data set to infer information about future data. Extrapolation to extend the retest period or shelf life beyond the period covered by long-term data can be proposed in the application, particularly if no significant change is observed at the accelerated condition.
- 34. Stability Data Package For Registration In Climatic Zones III and IV A product’s shelf life should be established according to climatic conditions in which the product is to be marketed. Storage conditions recommended by manufacturers on the basis of stability studies are meant to guarantee the maintenance of quality, safety and efficacy throughout the shelf-life of product. Temperature and humidity determine the storage conditions and so they greatly affect the stability of drug product. Climatic conditions in countries where the product is to be marketed should be carefully
- 36. ICH Topic Q3C (R4) Guideline for Residual Solvents Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the . preparation of drug products. The solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as
- 37. Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements. Drug products should contain no higher levels of residual solvents than can be supported by safety data.
- 38. Known human carcinogens, strongly suspected human carcinogens, and environmental hazards. Not be employed in manufacturing bcoz of their unacceptable toxicity or their deleterious environmental effect If their use is unavoidable – levels should be restricted Solvent Conc.limit(ppm) Concern Benzene 2 Carcinogen Ccl4 4 Toxic and environmental hazard 1,2-Dichloroethane 5 Toxic 1,1-Dichloroethane 8 Toxic
- 39. Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Limited use bcoz of their inherent toxicity. Solvent Conc. limit(ppm) PDE(mg/day) Chlorobenzene 360 3.6 Chloroform 60 0.6 1,2-Dichloroethane 1870 18.7 Hexane 290 2.9
- 40. Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDEs of 50 mg or more per day. Less toxic. No longterm toxicity or carcinogenicity Eg : Acetic acid Acetone 1-butanol 2-butanol Heptane
- 41. Eg : Isooctane Petroleum ether 1,1diethoxy propane Trichloro acetic acid Methyl tetra hydro furan
- 43. Conclusion Stability studies should be planned on the basis of pharmaceutical R+D and regulatory requirements. Forced degradation studies reveal the intrinsic chemical properties of the API, while formal stability studies establish the retest date. The shelf life (expiry date) of FPPs is derived from formal stability studies. Variability and time trends of stability data must be evaluated by the manufacturer in order to
- 44. References 2. ICH official web site. www.ich .org http://www.ich.org/products/guidelines /quality/article/quality-guidelines.html