ICH Purpose, participants, process of harmonization, Brief overview of QSEM, with special - PowerPoint Presentation

1. ICHPurpose, participants, process of harmonization, Brief overview of QSEM, with special emphasis on Q-series guidelines, ICH stability testing guidelinesINTERNATIONAL COUNCIL FOR HARMONIZATION

2. Q1B- Photostability (PS) testing of NDSPTo collect the inform. about PS of new molecular entity and associated drug productsNo information about the PS of drug after administrationOn Exposure to light – no unacceptable changesCarried out on single batch of materialSystematic approach:Tests on drug substanceTest on exposed drug product outside of the immediate packTest on drug product in immediate packTest on drug product in marketing pack

3. Q1B- Photostability (PS) testing of NDSPSource of lightDuring testing- control of temp. & maintain dark env. Option 1: D65/ID 65 emission standard- artificial day light fluorescent lamp combined with visible , UV, xenon or metal halide lamp. ISO 10977 (1993)- D65- internationally recognized standard for outdoor daylightOption 2: same sample to be exposed to cool white fluorescent lamp in ISO 10977 and near UV lamp.Procedure: expose samples to light of 1.2million lux hrs & emits near UV energy of 200 watt hr/sqmtCompare drug subst. & drug productFor confirmation- samples exposed to validated chemical actinometric system/ calibrated radiometers/lux meters to monitor duration of exposureDark control samples wrapped in aluminium foil kept beside authentic sample

4. Decision on resultsFor drug substances: Results of confirmatory studies to indicate precautionary measures to be taken during manufacturing so that the degradation of dosage form is avoided during mfg.To ensure that drg remains within limits at the time of its useFor dosage forms:Special labeling or packaging depending on degradation of dosage form. Ensure that formulation should comply with the specifications for its quality/safety and therapeutic efficacy during shelf life

5. Q1C- Stability testing for new dosage formsIssued on October 27th 1993It is annexure to ICH parent stability guidelineTells what is to be submitted in support of stability of new dosage forms by the owner of original application after original submission of NDSPNew dosage form? It is the drug product which is different from existing drug product but contains same drug substances as in its existing product approved by Regulatory AuthoritiesEx: Product of different routes of administration eg. Oral to parenteralNew specific functionality/delivery systems eg. Immediate release tablet to modified release tabletDifferent dosage forms of same administration routes eg. Capsule, tablet, solution to suspension

6. Q1D Bracketing and matrixing designs for stability testing of NDSPFull study design : samples for every combination of all design factors are tested at all time pointsBracketing : design of a stability schedule so that only samples on extremes of certain design factors eg. Strength, container size or fill are tested at all time points as in full design (ex: 15ml-500ml containers extreme)Design assumes that the stability of any intermediate levels is represented by the stability of the extremes testedDesign factors are variables: strength, container size/fill to be evaluated in a study design for their effect on product stabilityMatrixing: is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combination would be tested at a specified time point At a subsequent time point another subset for all factor combination would be testedDesign assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point

7. Q1E Evaluation of stability dataTells how to use the stability data generated during stability testingHow to use Stability Data to be submitted in registration application for new drug entityGuideline Recommends on establishing retest periods, shelf lives of drug storage at or below RTCovers stability studies using single/multi factor designs and full or reduced designsPurpose of Stability study: To establish retest period or shelf life and label storage instructionsStability information should include data on physical, chemical, biological and microbiological tests and also special to dosage forms like dissolution rate for solid dosage forms

8. Q1F : Stability Data package for registration applications in climatic zones III and IVIt is annexure to parent guideline Q1A (R): Stability testing of NDSPRecommends long term storage condition for stability testing of NDSP for registering application in climatic zones III and IVFollowing common guidelines are considered to any territory in world Stress testingSelection of batchesContainer closure systemSpecificationTesting frequency Storage conditions for drug substance or product in a refrigeratorStorage conditions for drug subs or product in a freezerStability commitmentEvaluationStatements/labelling

9. General case as per parent guideline: long term and accelerated storage conditions for climatic zone III and IVNo intermediate storage conditions are recommended in Zone III and IVFor aqueous based drug products packaged in semi permeable containers as per parent guidelinesStudyStorage ConditionMinimum time period covered by data at submissionLong term 30°C±2°C/65%RH±5%RH12 monthsAccelerated40°C±2°C/75%RH±5%RH6 monthsStudyStorage ConditionMinimum time period covered by data at submissionLong term 30°C±2°C/35%RH±5%RH12 monthsAccelerated40°C±2°C/25%RH±5%RH6 months

10. Q2 ANALYTICAL VALIDATIONDone to demonstrate that NS, DP are suitable for intended purposeShould describe each step important to perform each analytical testSample, reference standard, reagent preparation, use of apparatus, calibration curve, formula for calculationsCommon analytical procedures: Identification tests, Quantitative tests for impurities, Limit test, Quantitative tests of the active moiety in samples Typical validation characteristics are:Accuracy, Precision, Repeatability, Intermediate precision, specificity, detection limit, quantitation limit, linearity, range

11. Q3A-Q3D impuritiesImpurities in New drug substances have 02 aspectsChemistry aspects: classification and identification of impurities, report generation, listing of impurities in specifications, brief discussion of analytical proceduresSafety aspects: specific guidelines for those impurities which were not present or in low levels in batches of NDS used in safety and clinical studies

12. Classification of ImpuritiesOrganic impuritiesInorganicResidual solventsStarting materialsBy productsDegradation productsReagents, ligands, catalystsDuring storage, Mfg., volatile non-vol. identified/non Reagents, ligands, catalystsHeavy metals/residual metalsInorganic saltsFilter aids/charcoal/ othersResults from Mfg. process/ usually known & identifiedInorganic/organicOf known toxicityQ3C guidelines

13. Other impurity guidelines

14. Q4-Q4B PHARMACOPOEIASQ4 PharmacopoeiasQ4 A Pharmacopoeial HarmonizationQ4 B- Evaluation of recommendation of pharmacopoeial texts for use in the ICH regionsQ4B- Annex. 1R1 Residue on ignition/sulphated ash Q4B- Annex. 2R1- Test for extractable volume of parenteral preparations Q4 B Annex. 3R1- Test for particulate contamination: Sub visible particlesQ4B Annex. 4AR1: microbiological examination of non sterile products: Microbial enumeration tests Q4B Annex. 4BR1: microbiological examination of non sterile products: Tests for specified micro organisms

15. Q4-Q4B PHARMACOPOEIASQ4B- Annex. 4CR1 microbiological examination of non sterile products: Acceptance criterion for pharmaceutical preparations & substances for pharmaceutical use Q4B- Annex. 5R1-Disintegration testQ4 B Annex. 6- Uniformity of dosage unitsQ4B Annex. 7R2:Dissolution testQ4B Annex. 8R1: Sterility TestQ4B Annex. 9R1: Tablet friabilityQ4B Annex. 10R1: Polyacrylamide Gel electrophoresis Q4B Annex. 11: Capillary electrophoresis Q4B Annex. 12: Analytical sieving Q4B Annex. 13: Bulk density & tapped density of powdersQ4B Annex. 14: Bacterial endotoxins testQ4B FAQs Frequently asked questions

16. Q5 A-Q5E: Quality of Biotechnological ProductsQ5A (R1): Viral safety evaluation of Biotechnological products derived from cell lines of human of animal origin Q5B Analysis of the expression construct in cells used for production of r-DNA derived protein productsQ5C Stability testing of biotechnological / Biological productsQ5 D Derivation & characterization of cell substrates used for production of biotechnological / biological productsQ5E Comparability of biotechnological / biological products subject to changes in their manufacturing process

17. Q6 A-Q6B: SpecificationsQ6A Specifications: Test procedures & acceptance criteria for NDSP, Chemical substancesQ6B Specifications: Test procedures and acceptance criteria for biotechnological / biological productsQ7: GMP: Outlines the manufacturing of API Q8: Pharmaceutical DevelopmentAim is to design a quality product & its mfg. processQuality should be built in by designInformation & knowledge gained from pharmaceutical development studies & mfg. experience provides scientific understanding to support establishment of the design space.

18. Q9: Quality Risk ManagementProcess for assessment, control, communication, review of risks to quality of drug across life cycle of productPrinciples: Based on scientific knowledge & links to patientLevel of effort, formality and documentation of QRMCoordinate, facilitate and improve sciences based decision making with respect to riskSteps to initiate and plan QRM:Define problem, risk Assemble background information or data on potential hazard, harm, human health impact Identify a leader and resourcesSpecify timeline, deliverables and appropriate level of decision making for risk management process

19. Q9: Quality Risk ManagementRisk AssessmentConsists of identification of hazards & analysis & evaluation risksQuality Risk Management:Systemic use of information to identify hazards Information includes historic data, theoretical analysis, informed opinions, concerns to stakeholdersRisk controlIncludes decision making to reduce or accept risksPurpose is to reduce risk to an acceptable level

20. Q10: Pharmaceutical Quality SystemManagement system to direct and control Pharm. company related to qualityICH Q10 based on ISO 9000:2005Regional GMP requirements, ISO standards & ICH Q7 regional GMP req., ICH Q7 guideline GMP guide for API, ISO quality management system guideliness form foundation of ICH Q10Continuous improvement across entire product lifecycle

21. Q11: Development and manufacture of drug substances Addresses the aspects of Development and manufacture including steps designed to reduce the impuritiesAlso provides clarification on ICH on Q8, Q9, Q10.Traditional approach: set points & operating ranges for process parameters. Process reproducibility & testing to meet standard goalEnhanced approach: Risk management & scientific knowledge to identify process parameters, unit operations impacting the critical quality attributes (CQAs)

22. Q13: Continuous manufacturing (CM) of Drug substances and Drug productCM improves efficiency, expedition, flexibility But lack of regulatory guidelines can make implementation, regulatory approval, lifecycle management challenging, particularly for products for commercialization on International basisICH guideline facilitate International harmonizationReduces barrier to adoption of CM technology Revised ICH Q2 R1New guidelines for harmonizing the scientific approaches of analytical procedure developmentImproves regulatory communication b/w Industry & regulatorsFacilitates efficiency, sound scientific and risk based approval. Include validation principles covering use of spectroscopic or spectrometry data (NMR, Raman, MS) Q14: Analytical Procedure Development