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UNDER THE GUIDENCE OF PROF.B JEEVANA JYOTHI PRESENTED BY B.N.S.SAI LAKSHMI Stability testing procedures for pharmaceuticals according to ICH guidelines

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Contents Introduction Organizations regulating stability guidelines ICH topics Stability protocol & report ICH stability guidelines 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 Evaluation of stability data Stability data package for the registration applications of the climate zones III & IV Guideline for Residual Solvents Conclusion References

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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, therapeutic and toxicological specification. Stability studies types Long term stability study Intermediate stability study Accelerated stability study

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Factors Affecting Drug Stability Physical form Particle size Surface area D.E ratio D.E & D.D interaction Temperature RH Light oxygen Drug & Excipients Formulation Environment

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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

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Organizations Regulating Stability Guidelines

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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

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Related to mfg. QA Non clinical pharmacology & toxicology studies Clinical safety, dose response studies, good clinical practices , clinical evaluation Medical terminology, electronic standards for transmission of regulatory information etc.

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ICH –Quality Quality topic of ICH consist of 6 sub topics as 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 & products

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Stability testing guidelines: T hey include six sub topics, they are

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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 product: The dosage form in the final immediate packaging intended for Marketing.---(API & Excipients) Where and Why?

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Zone concept Temperate zone KMT- 21 ⁰ c RH-45% Mediterian zone KMT-25 ⁰ c RH-60% Tropical zone KMT-30 ⁰ c RH-35% Desert zone KMT-30 ⁰ c RH-70%

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Batches tested General information Container/closure system Literature and supporting data Stability-indicating analytical methods Testing plan Test parameters Test results Other requirements (post-approval commitments) Conclusions Result sheets must bear date and responsible person signature / QA approval Stability Protocol & Report

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Q1A(R2) guidelines Stress testing Selection of batches Container closure system specification Testing frequency Storage conditions Stability commitment Evaluation Q1A (R2) guide lines Stress testing Carried out on a single batch and it include the effect of temperatures, humidity where appropriate oxidation & photolysis on DS Scope: help to identify degradation products , degradation pathway & intrinsic stability of the molecule Selection of batches Atleast 3 primary batches of the drug substance should be representative to quality of material used for production scale. Statement&labelling

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Q1A(R2) guidelines Stress testing Selection of batches Container closure system specification Testing frequency Storage conditions Stability commitment Evaluation Container closure system 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, references to analytical procedure acceptance criteria. Statement&labelling

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Q1A(R2) guidelines Stress testing Selection of batches Container closure system specification Testing frequency Storage conditions Stability commitment Evaluation Testing frequency Type of study Testing frequency Long term studies For drug sub. With a proposed re test period of at least 12 months. 1 st year……….3months 2 nd ……………..6month There after……annually Through the proposed re-test period Accelerated studies Min. 3 time points(0,3,6 months),from a 6-month study Intermediate studies Min. 4 time points (0,6,9,12 months),for a 12month study. Statement&labelling

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Q1A(R2) guidelines Stress testing Selection of batches Container closure system specification Testing frequency Storage conditions Stability commitment Evaluation Study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C / 60% ± 5% R.H or 30°C ± 2°C / 65% ± 5% R.H. 12 months Intermediate 30°C ± 2°C / 65% ± 5% R.H. 6 months Accelerated 40°C ± 2°C / 75% ± 5% R.H. 6 months Storage conditions Statement&labelling Drug products - General case

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Study Storage condition Minimum time period covered by data at submission Long term 5°C ± 3°C 12 months Accelerated 25°C ± 2°C / 60% ± 5% R.H. 6 months Drug substances-intended for storage in refrigerator Study Storage condition Minimum time period covered by data at submission Long term -20°C ± 5°C 12 months Drug substances/Product- intended for storage in Freezer

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Q1A(R2) guidelines Stress testing Section of batches Container closure system specification Testing frequency Storage conditions Stability commitment Evaluation Statement&labelling Stability commitment In case where data submitted for registration do not cover the proposed shelf life, it is necessary to give commitment to continue the stability studies post approval in order to firmly the shelf life. In addition to long term studies on at first three production batches covering the proposed shelf life, commitment of six month accelerated stability study also is a mostly for new product.

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Q1A(R2) guidelines Stress testing Section of batches Container closure system specification Testing frequency Storage conditions Stability commitment Evaluation Statement&labelling 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,microbiological 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. The analyst must found the batch to batch variability & if it is small then only it is accepted & can be done by different statistical tests

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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

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Q1A(R2) guidelines Stress testing Section of batches Container closure system specification Testing frequency Storage conditions Stability commitment Evaluation Statement&labelling Statement & labeling A storage statement should be established for labeling in relevant national or regional requirements Should be established based on the stability evaluation of drug substance Terms such as “Ambient conditions "or “Room temperature” should be avoided Retest date for DS & expiry date for DP should be displayed on the container label if appropriate

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Photo stability 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 fluorescence lamp combining visible & UV out put , xenon or metal halide lamp D65 is for out door day light ID65 is for indoor indirect day light

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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 (e.g.., wrapped in aluminium foil)are used as dark controls to evaluate the contribution of thermally induced change to the total observed change.

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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 parameters for various types of dosage forms Dosage form Parameter Appearance, colour ,odour, assay,disintigration /dissolution, moisture & friability Appearance, colour ,odour, assay,disintigration /dissolution, moisture &microbial limits Soft gelatin capsules Appearance, colour ,odour,assay,disintigration /dissolution,moisture ,microbial limits ,pH,leakage & pellicle formation Tablets Hard gelatin capsules

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Emulsions Appearance including phase seperation ,colour ,odour,assay,pH,viscosity,preservative content ,weight loss & microbial limits Suppositories Appearance,colour ,assay ,particle size ,softening range , dissolution& microbial limits Small volume Small volume parentrals Appearance ,colour,assay,pH, preservative content ,particulate matter , sterlity & pyrogenicity Large volume Parentrals Appearance ,colour,assay,pH, preservative content ,particulate matter , sterlity & pyrogenicity Transdermals Appearance, assay , leakage,sterility, peel & adhesive forces , drug release rate

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Bracketing & matrixing design for stability testing of new drug substance & products Study design Full study design Reduced study design Samples of all designed factors for every combination are tested at all time points Not Samples of all designed factors for every combination are tested at all time points Bracketing Matrixing

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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 the stability of the extremes tested. Example of a Bracketing Design

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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 point.

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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 of 0.25. This guideline is intended to provide recommendations on how to use stability data generated in accordance with the principles detailed in the ICH guideline ―Q1A(R) Stability Testing of New Drug Substances and Products Extrapolation 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 . Evaluation Of The Stability Data

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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 considered during drug development phase. So the world has been divided into four climatic zones based on prevalent annual climatic conditions .

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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 crystal form, purity, and solubility. .

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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 .

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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 Class 1 solvents: Solvents to be avoided Solvent Conc.limit(ppm) Concern Benzene 2 Carcinogen Ccl 4 4 Toxic and environmental hazard 1,2-Dichloro ethane 5 Toxic 1,1-Dichloro ethane 8 Toxic

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Class 2 solvents: Solvents to be limited 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-Dichloro ethane 1870 18.7 Hexane 290 2.9

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Class 3 solvents: Solvents with low toxic potential 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 long term toxicity or carcinogenicity Eg : Acetic acid Acetone 1-butanol 2-butanol Heptane

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Class 4 solvents: Solvents for which no adequate toxicological data was found Eg : Isooctane Petroleum ether 1,1diethoxy propane Trichloro acetic acid Methyl tetra hydro furan

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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 propose a retest date or expiry date . Conclusion

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Remington the science and practice of pharmacy ICH recommended evaluation Pg no:1032. Oxford journal of toxicological sciences ICH Guidelines – Inspection ,revision and implementation for drug development vol.108. Physical pharmaceutics by manavalan .Ramasamy Pg no:288-301. ICH official web site www.ich.org . http//www.ich.org/products/guidelines/quality/articl e/quality-guidelines .html. References

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