Presentation on theme: "World Health Organization"— Presentation transcript:
1World Health Organization Pharmaceutical Development14 April, 2017Training Workshop on Pharmaceutical Development with focus on Paediatric FormulationsProtea HotelVictoria Junction, WaterfrontCape Town, South AfricaDate: 16 to 20 April 2007
2Pharmaceutical Development World Health OrganizationPharmaceutical Development14 April, 2017Stability testing of Finished Pharmaceutical Products (FPPs)Presenter: Susan WaltersFax: (61) ( is preferred)
3Stability testing of FPPs World Health OrganizationStability testing of FPPs14 April, 2017Outline of presentationWe will:Review relevant guidelinesDefine the objectives of stability testingOutline the design & conduct of stability studies for finished productsDetermine a shelf life based on study resultsDiscuss what to include in reports of stability studies
4Objectives of stability testing: What is the purpose? World Health Organization14 April, 2017Objectives of stability testing: What is the purpose?"…… to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity & light, & enables recommended storage conditions, re-test periods & shelf lives to be established”(ICH) 2003
5Variables that might affect the stability of a given API & dosage form World Health OrganizationVariables that might affect the stability of a given API & dosage form14 April, 2017FormulationPackagingSite and method of manufactureAPIFinished productBatch sizeBatch to batch variabilityThe importance of process validation & quality risk managementContainer labellingChanges to product
6World Health Organization 14 April, 2017Stability testingDevelopment studiesCharacterise compatibility with common excipientsCharacterise stability profile of APIEg susceptibility to acid, base, light, oxygen etc……Characterise stability profile of early formulationsEspecially susceptibility to heat, humidity & lightConfirmatory studiesLong term & accelerated studies on the product as it is to be registeredIn practice design is now largely dictated by ICH guidelines
7World Health Organization 14 April, 2017What does a regulator want to see demonstrated in the registration dataset?The product maintains relevant quality characteristics within the acceptable range:In proposed registration formulation & container/closure systemFor whole of shelf lifeAt permitted extremes of storageOver all batchesWhen manufactured at all registered sites (API & finished product)After any changes
8World Health Organization Relevant guidelines14 April, 2017Many countries have their own guidelines concerning stability testing & other registration topicsBut if a manufacturer wishes to market a product in several countries, it is simpler to use one of the international guidelines, such as those of WHO & ICHSo how widely are WHO & ICH guidelines accepted?Most countries will accept data generated according to ICH guidelinesMany countries will accept data generated according to WHO guidelines, & especially when the product in question has been prequalified by WHOBut possibly not ICH countriesWhilst ICH guidelines are more detailed than those of WHO, there are few ‘in-principle’ differences, except in relation to testing conditions for hot & humid climates
9ICH stability guidelines - 1 World Health OrganizationICH stability guidelines - 114 April, 2017Q1A(R2) Stability Testing of New Drug Substances & ProductsQ1B Stability Testing : Photostability Testing of New Drug Substances & ProductsQ1C Stability Testing for New Dosage FormsAvailable via html
10ICH stability guidelines - 2 World Health OrganizationICH stability guidelines - 214 April, 2017Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and ProductsQ1E Evaluation of Stability DataQ1F Stability Data Package for Registration Applications in Climatic Zones III and IV WithdrawnAlso available via html
11ICH stability guidelines - 3 World Health OrganizationICH stability guidelines - 314 April, 2017Remember that these have been adopted in the European Union, the United States, and JapanTechnically ICH guidelines apply only to new APIs & products made from them. But most regulators give ICH guidelines considerable weight when deciding requirements for non-new APIs.
12WHO stability guidelines - 1 World Health OrganizationWHO stability guidelines - 114 April, 2017“Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms”WHO (1996)Available viaNote:Applies to ‘Well established drug substances’Applies to ‘Conventional dosage forms’These guidelines are under revision : See
13WHO stability guidelines - 2 World Health OrganizationWHO stability guidelines - 214 April, 2017So what are the types of product to which WHO guidelines (1996) do not apply?New chemical entities (NCEs)And possibly also new dosage forms of NCEsNew combinations of activesModified release dosage forms, includingSlow release productsTransdermal patchesModified release injections
14Stability guidelines for WHO’s Prequalification Program (PQP) - 1 World Health OrganizationStability guidelines for WHO’s Prequalification Program (PQP) - 114 April, 2017Stability testing: Section 3.11 of Guideline on Submission of Documentation for Prequalification of Multisource (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria & TuberculosisAvailable viaAre consistent with ICH guidelinesThere are extensive cross references to ICH guidelinesEffectively the PQP text is a practical interpretation of ICH guidelines
15Stability guidelines for WHO’s PQP - 2 World Health OrganizationStability guidelines for WHO’s PQP - 214 April, 2017“Extension of the WHO list of stable (not easily degradable ARV) APIs”WHO (2006)Also available viaRead this carefully. It describes circumstances in which a tentative 2-year shelf life may be allocated to certain APIs & FPPs, subject to a number of strict conditions.
16Stability report formats for WHO’s PQP World Health OrganizationStability report formats for WHO’s PQP14 April, 2017Annex 3: Model stability report of APIAnnex 4: Model stability report of capsules/tabletsAlso available via
17Terminology – adapted from ICH 2000 (1) World Health Organization14 April, 2017Terminology – adapted from ICH 2000 (1)Production batch:A batch manufactured at production scale using production equipment & in a production facility as specified in the registration applicationPilot scale batch:A batch manufactured by a procedure “fully representative of & simulating” full production scale. For tablets & capsules, this means 100,000 units or 1/10th of production scale, whichever is the larger
18Terminology – adapted from ICH 2000 (2) World Health OrganizationTerminology – adapted from ICH 2000 (2)14 April, 2017Re-test period: APIThe period of time for which the API remains within specification when stored under the recommended conditions in the proposed bulk storage container“After this period, the batch should be retested for compliance with specifications & then used immediately” [if in compliance]
19Terminology – adapted from ICH 2000 (3) World Health OrganizationTerminology – adapted from ICH 2000 (3)14 April, 2017Accelerated testingStudies designed to increase the rate of chemical degradation or physical change by means of exaggerated storage conditionsIntermediate testingStudies at 30degC/60%RH, intended for extrapolation to long term storage at 25degC [provided that 25degC is appropriate for the market in question]Stress testingAPI: Studies which elucidate intrinsic stab of API. Normally during development. Normally more stressful than ‘accelerated’ testing.Finished product: Studies of effect of ‘severe’ conditions. Eg freeze/thaw cycling for suspensions & emulsions, low humidity for aqueous liquids in moisture-permeable containers.Accelerated testing:Intended to allow extrapolation of conditions at max recd storage conditionsOr to “evaluate effect of short term excursions outside label storage conditions”Intermediate testing:Relevant if want to label product as “Store below 25degC”.Stress testing:For API, means devt studiesExamples of stress tests for finished product might be cycling temps (eg emulsions, creams), refrigeration for liquids which are or might be stored at low temp. Not sure what is referred to for mdis – FDA mentions possibility of testing at 25degC/75%RH for 1/3 of shelf life if moisture resistant packaging needed (?dpis).
20Terminology – adapted from ICH 2000 (4) World Health OrganizationTerminology – adapted from ICH 2000 (4)14 April, 2017In-use stability testing:Establishes the “period of time during which a multidose product can be used whilst retaining quality within an accepted specification once the container is opened”ICH 2000For example:liquids that are reconstituted prior to useeffervescent tablets in a moisture-proof container (eg Al screw-cap tube)ophthalmic products (especially with respect to preservative efficacy)
21Terminology – adapted from ICH 2000 (5) World Health Organization14 April, 2017Terminology – adapted from ICH 2000 (5)Climatic zones:Partition of the world into three temperature classes based on kinetic averaging of monthly temperatures, & subdivision of the hottest class into predominantly wet or predominantly dryZones (Futscher & Schumacher 1972):I Temperate (21oC/45%RH)II Subtropical (25oC/60%RH with possibly high RH)III Hot & dry (30oC/35%RH)IV Hot & wet (30oC/70%RH)The temperatures above are kinetic averagesZones originally proposed by Futscher & SchumacherGrimm subsequently elaborated mean annual %RH and kinetic temps for world regions based on meteorological data.
22World Health Organization Extract of WHO Technical Report Series Expert committee on specifications for pharmaceutical preparations (2006): Quality assurance: Stability testing conditions14 April, 2017“The Secretariat reminded the Committee that the WHO guidelines had been revised in the light of harmonization efforts in collaboration with ICH. Subsequently focus had been placed within regional harmonization initiatives on the recommendations for hot and humid conditions (referred to as Zone IV). After extensive discussion the Committee reached consensus that the WHO stability guidelines be amended to reflect conditions for Zone IV as follows:— Zone IVa (30 degrees Celsius and 65% relative humidity); and— Zone IVb (30 degrees Celsius and 75% relative humidity).It was agreed that each individual Member State within the former Zone IV would need to indicate whether its territory should be classified as Zone IVa or IVb.”
23World Health Organization Consequently…14 April, 2017Each nation within zone IV must now decide whether to adopt a stability test condition of30oC & 65%RH, or30oC & 75%RHASEAN nations & Brazil have adopted 30oC & 75%RH
24Terminology – adapted from ICH 2000 (6) World Health Organization14 April, 2017Terminology – adapted from ICH 2000 (6)Reduced study designs:BracketingA design in which only the extremes are tested at all time points, eg strength, pack size, container fillMatrixingDesigns in which a selected subset of samples is tested, eg different strengths, container/closure systems, batchesReduced study designs:ICH emphasises:Bracketing not applicable to APIsMatrixing has “limited utility”Are risks involved in conducting reduced study designs, and must justify use in each caseIn general, I suspect that ICH is implying (but not actually stating) that bracketing and matrixing is appropriate when there is a reasonable expectation that there will be no significant change.Bracketing:Assumes that intermediate conditions (ie those not tested) are intermediate in all respects.Eg if test different cap strengths, that all strengths are made from same granulation with different compression weights.Matrixing:I would add that can matrix temps, but ICH does not specifically mention that so might not get through TGAFff
25Example of a bracketing design World Health Organization14 April, 2017This is an example of a bracketing design. The table was taken from the current ICH draft entitled “Bracketing and matrixing designs for stability testing of new drug substances and products”.In this design, 12 sets of tests are conducted at each time point instead of 15.Intermediate strength does not have to be same formulation, so long as is all ingredients in the intermediate strength are intermediate in proportion between upper and lower strengths.As we said earlier today, these designs do carry a risk in that if one element of the design shows instability, may be left with a very incomplete dataset. For example if the 50mg strength showed instability, have no acceptable data on the 75mg strength either.I have seen cases of instability of a strength at one end of a range, even with tablets. So prudence would suggest would not undertake this design unless already have some data on these or related formulations.T = Sample is tested
26Example of a matrixing design “One half reduction” World Health Organization14 April, 2017A number of matrix designs are tabulated in the ICH guideline, of which this is one.ICH describes this as a “Matrixing design on time points for a product with two strengths; One-half reduction”.Describes a product for which three batches of each strength have been put on test.Samples of every strength and batch are tested at the beginning and at the end of the study, and at the 12 months time point.At the intermediate time points, only half of the samples are tested.T = Sample is tested
27World Health Organization When might bracketing & matrixing be appropriate? (NB The following is not from ICH ! You must argue the case!)World Health Organization14 April, 2017Container size?Batch size?Formulation of coating?With varying amounts of an excipient (eg starch, Mg stearate)?EXERCISEWhat are some other situations in which bracketing and matrixing may be appropriate?
28The risk associated with bracketing & matrixing World Health Organization14 April, 2017If the results are not what you expected, you may have insufficient to propose an intermediate shelf lifeWould be risky to use bracketing & matrixing if you did not have a good idea as to what the product’s stability will beConsequently: Bracketing & matrixing designs are used mainly for confirmatory studiesEXERCISEWhat are some other situations in which bracketing and matrixing may be appropriate?
29World Health Organization 14 April, 2017ICH minimum dataset at submission - 1If you think you have seen this table before, you have. It is identical to the one for APIs.
30World Health Organization 14 April, 2017ICH minimum dataset at submission - 2FPPs packaged in impermeable containers need not be stored under controlled humidity conditionsThere are different minimum conditions for:Liquid products packaged in semi-permeable containers [relating to potential loss of solvent]Products intended for storage in a refrigerator, freezer or deep-freezeIf you think you have seen this table before, you have. It is identical to the one for APIs.
31Classes of degradation World Health OrganizationClasses of degradation14 April, 2017ChemicalPhysicalMicrobiological
32World Health Organization Chemical degradation14 April, 2017Has been dealt with by Dr Elder
33Physical degradation (≡ physicochemical degradation) World Health OrganizationPhysical degradation (≡ physicochemical degradation)14 April, 2017Physical properties can change too!Important attributes vary with dosage formBottom line is relevance to quality, safety & efficacyExamples for liquid formulations:Appearance, colour, odour, pH, clarity (solutions) and freedom from visible particulate contamination, size range of particulate contamination (large volume parenterals), particle size distribution (suspensions), micelle size distribution (micellar solutions), resuspendability (suspensions), viscosity, moisture content (powders for reconstitution), phase separation (emulsions)See other examples at
34Other forms of physical deterioration may include: World Health OrganizationOther forms of physical deterioration may include:14 April, 2017LeachingAbsorption (into container walls)Adsorption (on to container walls)Volatilisation (eg sertraline base, glyceryl trinitrate)Altered particle size distributionLoss of higher order molecular structure (normally only for biological medicines)DenaturationAggregation
35Minimising physical deterioration World Health Organization14 April, 2017Minimising physical deteriorationSome examples:When prone to adsorption on to, or absorption into, packaging materials, use resistant packaging materials, such as good quality glassWhen prone to volatilisation:Use a non-volatile salt (if possible)Use packaging materials that are resistant to vapour transferWhen prone to altered particle size in suspensions:Formulate a continuous phase in which the active is less soluble
36Microbiological deterioration World Health Organization14 April, 2017Microbiological deteriorationProliferation of microbes in non-sterile productsConsequences may include:Infection of the patientFormation of endotoxins (≡ pyrogens)Foul odourFormation of gasChange in colourCloudinessHydrolysis
37Minimising microbiological deterioration of non-sterile products World Health Organization14 April, 2017Minimising microbiological deterioration of non-sterile productsControl the microbial load of API & excipientsValidate & monitor manufacturing conditionsInclude antimicrobial preservatives in formulationsNB Normally only bacteriostatic & not bactericidal
38Appropriate tests for stability studies - 1 World Health OrganizationAppropriate tests for stability studies - 114 April, 2017Normally test same attributes as for routine QCMay use other methodology for stability testing (avoid for dissolution rate) but must be validatedAvoid changing methodology mid-study (unless correcting a clear deficiency)
39Appropriate tests for stability studies - 2 World Health OrganizationAppropriate tests for stability studies - 214 April, 2017Quantitate degradation products if possible, even if the assay is specific for the APIBut can be difficult to quantitate impurities if there are no reference standards & relative response factors are unknown → semiquantitative estimatesRegulatory authorities usually expect an approximate mass balanceAppropriate physical tests vary with dosage form.Remember to conduct preservative efficacy tests too, in addition to assay of any antimicrobial preservative
40For all stability studies World Health OrganizationFor all stability studies14 April, 2017Validate the analytical methodology!See relevant guidelines, especially:Validation of analytical procedures: TerminologyICH Q2B 1994Validation of analytical procedures: MethodologyICH Q2B 1996Use stability-indicating assays
41World Health Organization Dissolution rateWorld Health Organization14 April, 2017Avoid using a method different to that in routine QCMost regulatory authorities, including PQP, prefer dissolution profiles rather than single time points during stability testing. Better ability to detect trends.Avoid using a method different to that in routine QC (less critical for assay during dissolution test)Very difficult to interpret results in terms of compliance with specifications over time, if for example the rotation speed is different to that in routine QCTGA has preference for dissolution profiles rather than single time points, even for IR productsCertainly provides more information than single point testsIs a requirement for prolonged release products
42Frequency of testing during a stability study - ICH World Health Organization14 April, 2017Frequency of testing during a stability study - ICH“For long term studies, frequency of testing should be sufficient to establish the stability profile of the pharmaceutical product”“For products with a proposed shelf life of at least 12 months, the frequency of testing in the long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, & annually thereafter throughout the proposed shelf life.Other frequencies are suggested for accelerated & intermediate storage conditions.ICH 2003ICH requirements are the minimum.More frequent testing, especially in early stages, allows earlier detection of a problem.See the sensible TGA comment (from 1970s and in 1994 AGRD)
43Some notes concerning reporting (1) World Health OrganizationSome notes concerning reporting (1)14 April, 2017It is rarely appropriate to cite only average resultsFor the benefit of the manufacturer & the DRADissolution results on individual tablets (not only mean results)It’s certainly OK to cite mean & derived results as wellAssay results should be reported as absolute valuesAnd not only as values normalised for initial results, ie % of initialTest methods must be recorded with the study reportBy the time that stability studies are conducted on finished product, is possible that more than one method has been usedIs rarely appropriate to cite only average resultshides informationFor benefit of your company & the DRAEg dissolution results on 6 tabletsBy all means cite mean & derived results too (eg std dev)Assay results should be reported as absolute values (and not only as values normalised for initial results, ie % of initial)By all means provide percent of initial as wellRecord test methodsBy the time that stability studies ar conducted on finished product, likely to be > one method that could have been used
44Some notes concerning reporting (2) World Health OrganizationSome notes concerning reporting (2)14 April, 2017Numerical results should be provided wherever possibleNot just ‘complies’If results are below the limit of quantitation, they should be reported as ‘below LQC’ or similar wording‘Not detectable’ is acceptable provided it is defined & reasonableResults that are out of the ordinary should be discussedProduct labelling should be consistent with stability data. For example:Solvents for reconstitutionRecommendations for mixing of injections with other injectionsGive numerical results wherever possibleie not just ‘complies’If results are below limit of quantitation, report as ‘below LQC’ or similar wordingResults that are out of the ordinary:Eg discolouration of a tabletMay need further investigationPre-empt questions from regulatorAvoid embarrassing qns years after the eventCheck product labelling for statements relevant to stability results, & ensure data have been provided - EgSolvents for dilution (example of soluble hydrochloride that was recommended for dilution in 0.9% NaCl). On conducting the study, drug precipitated out of solution. HClde was not as soluble as manufacturer had thought – had not done calculations.Recommendations for mixing with other injections
45Evaluation / Interpretation of the results World Health OrganizationEvaluation / Interpretation of the results14 April, 2017So what’s the shelf life?Give numerical results wherever possibleie not just ‘complies’If results are below limit of quantitation, report as ‘below LQC’ or similar wordingResults that are out of the ordinary:Eg discolouration of a tabletMay need further investigationPre-empt questions from regulatorAvoid embarrassing qns years after the eventCheck product labelling for statements relevant to stability results, & ensure data have been provided - EgSolvents for dilution (example of soluble hydrochloride that was recommended for dilution in 0.9% NaCl). On conducting the study, drug precipitated out of solution. HClde was not as soluble as manufacturer had thought – had not done calculations.Recommendations for mixing with other injections
46World Health Organization 14 April, 2017First pointThe validity of an assigned shelf life depends upon:The results of stability studies, &Whether the batches used in the stability studies accurately model those to be marketed, &Whether analytical methodology was adequately validated
47World Health Organization 14 April, 2017Assigning a shelf lifeAssigning a shelf life is easier if results are available:For the full duration of the proposed shelf lifeAt the maximum recommended storage conditionsFor all formulations & manufacturing methodsIn exactly the packaging to be registeredAt all sites of manufacture of finished product & APIIf these conditions are not met, that’s when shelf life assignment becomes difficult.There will be arguments between manufacturers & registration/prequalification authoritiesThere will be delays in approving the productUnfortunately manufacturers are not always in the position of having exactly this informationEspecially generic manufacturers who may have decided to develop and register the product in the last year.
48Statistical estimation of shelf life - 1 World Health Organization14 April, 2017Statistical estimation of shelf life - 1“Where the data show so little degradation & so little variability that it is apparent from looking at the data that the requested shelf life will be granted, it is normally unnecessary to go through the formal statistical analysis but only to provide a justification for the omission”ICH 2003 & PQP 2005In other words: If it is blindingly obvious that there is minimal change in the parameter in question, is unnecessary to conduct the numerical/statistical analysis.
49Statistical estimation of shelf life - 2 World Health Organization14 April, 2017Statistical estimation of shelf life - 2“An approach for analyzing data of a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided confidence interval for the mean curve intersects the acceptance criterion”ICH 2000Most pharmaceuticals are complex systems in which kinetic equations do not apply.FDA (and now ICH) addressed this by suggesting a numerical estimation of trends, ie not predicated on kinetic equations.
50Statistical estimation of shelf life - 3 World Health Organization14 April, 2017Statistical estimation of shelf life - 3Is there any degradation of any relevant product characteristic?If no, then shelf life assignment is straightforward based on the labelled storage conditions & the time for which testing has been conductedIf yes (that is there is at least some degradation/change):Conduct a statistical analysis using a suitable software packageConsider:Statistical pooling of results for multiple batchesEstimation of time to degrade to expiry limits using a 95% confidence intervalSee the file concerning software packagesNB I am not recommending any of these software packages!Conduct your own Internet search! Then evaluate cost against usefulness to your company.Most pharmaceuticals are complex systems in which kinetic equations do not apply.FDA (and now ICH) addressed this by suggesting a numerical estimation of trends, ie not predicated on kinetic equations.
51Statistical estimation of shelf life - 4 World Health Organization14 April, 2017Statistical estimation of shelf life - 4Superimposition of a 95% confidence interval on to the regression line for stability data from Bolton 1984NB This is an old graph & it describes a very unstable productThis is a graph of assay of a product against time at a given storage condition.- Taken from FDA guideline of 1987Shows 95% confidence interval for loss of active after least squares regressionProgram for calculation is on FDA website:Less reliable for deterioration of physicochemical properties, which can show non-linear changes, eg sudden deterioration such as formation of a precipitate.
52What are the limitations of this statistical algorithm? World Health Organization14 April, 2017What are the limitations of this statistical algorithm?It applies only to quantitative attributesDoes not apply for example to colour tests, or to semiquantitative comparisons such as TLC limit testsIt may be unreliable for physical attributesSuch as dissolution tests & discolorationUse your judgement! Look at the slope of the curve. Does the change accelerate with time?Most pharmaceuticals are complex systems in which kinetic equations do not apply.FDA (and now ICH) addressed this by suggesting a numerical estimation of trends, ie not predicated on kinetic equations.
53Estimation of shelf life World Health Organization14 April, 2017Estimation of shelf life“Any evaluation should consider not only the assay but also the degradation products & other appropriate attributes”ICH 2003In other words: If evaluation of different (but relevant) attributes leads to different conclusions as to shelf life, the shortest of these shelf lives should be chosen.
54Estimation of shelf life World Health Organization14 April, 2017Estimation of shelf life“Where appropriate, attention should be paid to reviewing the adequacy of the mass balance & different stability & degradation performance”ICH 2003In other words: If the loss of active is not of the same order (=approximately the same) as formation of degradation products, more investigation is needed.Note however that mass balance will always be approximate; it is rarely exact.
55World Health Organization 14 April, 2017Factors to be taken into account when assigning a shelf life based on statistical analysis - 1Release limitsExpiry limitsResults of stability studiesIs there any desired safety margin?This is largely a matter for the manufacturer/supplierSafety margin?Bracketed because not a regulatory requirementA prudent manufacturer may wish to incorporate a safety margin intothe estimate of shelf life.Minimise possibility of recalls, with attendant publicity
56World Health Organization Factors to be taken into account when assigning a shelf life based on statistical analysis - 214 April, 2017A batch may be released with a result anywhere in range of release limitsConsequently a prudent manufacturer will take into account the lower limit of release when estimating shelf lifeA batch may be released with a result anywhere in range of release limits.So starting point for that calculation is lower limit of releaseApplies to all testsEg impurities, content of preservative
57World Health Organization 14 April, 2017Combining results for several batchesPoolabilityMost pharmaceuticals are complex systems in which kinetic equations do not apply.FDA (and now ICH) addressed this by suggesting a numerical estimation of trends, ie not predicated on kinetic equations.
58Poolability of multiple batches World Health Organization14 April, 2017Poolability of multiple batchesA statistical concept that allows the results for several batches to be combinedIf we estimated stability based on results for individual batches, we would have to select the shortest estimate of shelf lifePooling usually leads to a longer shelf life as compared with the results for one batch onlyBut we must first test whether the batches can legitimately be pooledAre the batches statistically homogenous?Most pharmaceuticals are complex systems in which kinetic equations do not apply.FDA (and now ICH) addressed this by suggesting a numerical estimation of trends, ie not predicated on kinetic equations.
59World Health Organization 14 April, 2017Testing for poolability as described by Bolton 1997Perform statistical test for common slopeNot significantlydifferentSignificantlydifferentUse separate slope & intercept for each batchPerform statistical test for common interceptSignificantlydifferentNot significantlydifferentUse common slope but separate interceptsUse common slope & common interceptSignificance is on the basis of F tests (p>0.25) as modelled by Bolton 1997
60Extrapolation beyond real-time data - 1 World Health Organization14 April, 2017Extrapolation beyond real-time data - 1“Limited extrapolation of the real time data from the long term storage condition beyond the observed range to extend the shelf life can be undertaken at approval time, if justified. This justification should be based on what is known about the mechanisms of degradation, the results of testing under accelerated conditions, the goodness of fit of any mathematical model, batch size, existence of supporting stability data, etc. However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the observed data.”ICH 2000
61Extrapolation beyond real-time data - 2 World Health Organization14 April, 2017Extrapolation beyond real-time data - 2“If long term data are supported by results from accelerated studies the retest period/shelf life may be extended beyond the end of the long- term studies. The proposed retest period or shelf life can be up to twice, but should not be more than 12 months beyond, the period covered by long-term data”. ”PQP 2005
62World Health Organization References14 April, 2017References in your CD may be useful:Regulatory guidelinesSources of climate-controlled cabinetsSoftware for processing stability dataMost include laboratory information management for the dataDefined “In-use” stability earlier today.EXERCISE:What other examples might there be of in-use stability that should be addressed in stability studies?[Possible answers:- Pdr for injn reconstituted before use- Mixing of injectable with LVPs- Heating of injectable with solid particles before use (see fluorouracil injection DBL “If a ppt has formed as a result of exposure to low temperature, redissolve by heating to 60degC accompanied by vigorous shaking. Allow to cool to body temperature prior to use”. )Antibiotics po lqds for reconstitution by a pharmacist prior to useIssue of separate labelling after reconstitution]
63Pharmaceutical Development World Health OrganizationPharmaceutical Development14 April, 2017Summary and conclusionStability data submitted during the registration process should confirm that all batches of the FPP will remain of acceptable quality when stored in the marketing container, at the most extreme storage conditions permitted by container labelling & prescribing information, for the duration of the shelf lifeAny subsequent variations (for example to site or method of manufacture of the API or FPP) should be shown not to reduce the shelf life as defined above