Stability analysis of long term data can be useful attribute to establish retest period
Ich guidelines for stability studies 2
PRESENTED BY:O.PRIYANKAM-PHARMDEPARTMENT OF PHARMACEUTICS
Drug Stability refers to the capacity of a drugsubstance or product to remain withinestablished specifications of identity, strength,quality, and purity in a specified period of time. Stability is officially defined as the time lapseduring which the drug product retains the sameproperties and characteristics that it possessedat the time of manufacture. The stability of a product is expressed as theexpiry period or technically as shelf life.
STAGE 1-Early stage stress-and acceleratedtesting with drug substancesSTAGE 2-Stability on pre-formulation batchesSTAGE 3-Stress testing on scale-up batchesSTAGE 4-Accelerated and long term testing forregistration purposesSTAGE 5-On-going Stability TestingSTAGE 6-Follow-up Stabilities
To gather information during preformulationstage to produce a stable product. To determine maximum expiration date. To get an idea of storage condition.To determine the packaging components. To establish retest period of pharmaceuticals.To establish Transport conditions.
Chemical degradation of active drug may reduce thequality of therapeutic indices like 5-flurouracil, carbamazepine etc have very smalltherapeutic range, slight degradation of drug mayproduce sub therapeutic concentration. After degradation a drug may produce more toxicproduct(s) which may be more toxic than the parentproduct. Instability of drug product reduce bioavailability. Thismay be caused by physical or chemical instability. Instability of a product may change the physicalappearance of the product.
DRUG AND EXCIPIENT: - Physical form -particle size -surface areaFORMULATION: -drug excipient ratio -Processing method -pH -solvent -chelating agentENVIRONMENT: -Temperature -Relative humidity -Packaging-Light-oxygen
Chemical : Each active ingredient retains its chemicalintegrity and labeled potency within the specified limit Physical : The original Physical properties includingappearance, palatability, uniformity, dissolution andsuspendability are retained . Microbiological : Sterility or resistance to microbialgrowth is retained according to specified requirement . Therapeutic : Therapeutic effect remains unchanged Toxicological : No significant increase in toxicity occurs
Accelerated stability testingLong term testing Stress testingPhoto stability study
The ICH (International Conference onHarmonization) Guidelines Q1A(R2) “Stabilitytesting of new drug substances and products” isthe “gold standard” for conducting stabilitystudies. This is valid for “new drug substances ordrug products” that are sufficient for aregistration application.
Q1A(R2)- Stability Testing of New Drug Substances andProductsQ1B- Stability Testing : Photostability Testing of NewDrug Substances and ProductsQ1C- Stability Testing for New Dosage FormsQ1D- Bracketing and Matrixing Designs for StabilityTesting of New Drug Substances and ProductsQ1E- Evaluation of Stability DataQ1F- Stability Data Package for RegistrationApplications in Climatic Zones III and IVQ5 C-Stability testing of biotechnological /biologicalproducts
OBJECTIVE OF THE GUIDELINE:It defines stability of drug substance and drug product for registration of application of NCE or associated drug, within three regions of ICH i.e; EU, Japan, USA .NOTE: It does not cover testing for registration of drug substance or product intended for import or export to other areas of the world.
1. Purpose of stability testing is to provide evidence how quality varies with time under influence of - temperature - humidity - light2. establish re-test period for drug substances RETEST PERIOD: the period after which samples of the drug substance should be examined to ensure that the material is still in compliance with the specification, and thus suitable for use in manufacturing.A retest period should be proposed on the basis of stability results and may be extended to five years (e.g., Ethambutol 2HCl, or Isoniazid)3. establish shelf life for drug products SHELF LIFE: (EXPIRY DATE/EXPIRATION DATING PERIOD) The period of time during which a pharmaceutical product, if stored correctly, is expected to comply with the specification as determined by stability studies on a number of batches of the product. The shelf-life is used to establish the expiry date of DRUG PRODUCT.
4. recommends storage conditions5.Gives Test conditions based on analysis of effects of climatic conditions in the three regions of the EU, Japan, USA.6. Gives mean kinetic temperature which is derived from climatic data7.divided world into four climatic zone I-IV- This guideline addresses climatic zones I and II8. And the Stability information generated in one of the three regions is mutually acceptable to the other two provided: - information is consistent with this guideline, - labelling is in accord with national/ regional requirements.
CLIMATIC ZONE DEFINITION STORAGE CONDITIONS TEMPERATE CLIMATE 210C/45 % R.H I SUBTROPICAL AND 250C/60 % R.H II MEDITERRANEAN CLIMATE HOT , DRY CLIMATE 300C/35 % R.H III HOT , HUMID CLIMATE 300C / 70% R.H IV
Stress Testing These guidelines help toQ1 A (R2)guidelines identify the likely degradation products , to Stress testing establish the degradation pathway and intrinsic stability of the molecule.Selection of batches Container closure system specifications Testing frequency Selection of batches At least 3 primary Storage condition batches of the drug substance should be selected. The quality should beStability commitment representative to quality of material used evaluation for production scale.Statements/labelling
Container Closure system: Should simulate packaging proposed forQ1 A (R2)guidelines storage and distribution. Stress testingSelection of batches Specification:Container closure specification: system • list of tests, Specifications • reference to analytical procedure, • proposed acceptance criteria Testing frequency Storage condition Test Attributes • attributes that are susceptible to changedStability commitment storage, evaluation • influence quality, safety and/or efficacyStatements/labelling • Should cover physical, chemical, biological and microbiological attributes
TESTING FREQUENCY: TestingfrequencyFor productswitha proposed shelflifeof at least 12 months:Q1 A (R2)guidelines First year------------------3 month Stress testing Second --------------------6 monthSelection of batches Thereafter------------------annually Container closure through out the proposed re-test system period specifications At accelerated storage condition Testing frequency minimum of three time points (0, 3 and 6 months), from a 6- month study. Storage conditionStability commitment At Intermediate storage condition minimum of four time points (0, 6, 9 and 12 months), from a 12- evaluation month study.Statements/labelling
STORAGE CONDITIONS: Long term testing should cover a minimum of 12 months duration on at least three primary batches at time of submission and shouldQ1 A (R2)guidelines be continued sufficient to cover the proposed re-test period. Stress testing GENERAL:Selection of batches STUDY STORAGE CONDITION DURATION Container closure system Long term* 25°C ± 2°C/60% ± 12 months 5% specifications or 30°C ± 2°C/65% ± Testing frequency 5% Storage conditions Intermediate** 30°C ± 2°C/65% ± 6 months 5%Stability commitment Accelerated 40°C ± 2°C/75% ± 6 months evaluation 5%Statements/labelling
STUDY STORAGE CONDITION DURATIONLong term 5°C ± 3°C 12 monthsAccelerated 25°C ± 2°C/60% ± 5% 6 monthsIf significant change between 3 and 6 months at acceleratedtesting propose re-test data based on real time data. (LONG TERM STUDY)If significant change within 3 months discussion should address excursions outside labelstorage. Single batch shorter than 3 months with more frequent testing.
STUDY STORAGE DURATION CONDITIONS Long term - 20 °C ± 5°C 12 monthsRe-test period based on real time data at long term storagecondition.In absence of accelerated storage condition testing on a singlebatch at an elevated temperature e.g. 5°C ± 3°C address shortterm excursions
Stability Commitment: When Re-test period not covered or not mentionedQ1 A (R2)guidelines long term stability data do not cover proposed re-test period granted at Stress testing time of approval, commitment should be made to continue post approval to establish re-test periodSelection of batches Container closure Not required for Submission which includes data from 3 production system batches, commitment to continue through proposed re-test period. specifications Fewer than three production batches commitment continue with Testing frequency these studies through proposed re-test period and place additional production batches to a total of three on long term stability through Storage condition proposed re-test periodStability commitment No Production batches commitment to place first three production batches on long term stability studies through proposed re-test period. evaluationStatements/labelling
A systematic approach should be adopted in the presentation and 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 than only it is accepted & it can be done by different statistical tests ( P value for level of significance for rejection). Where the data shows so little degradation & so little variability that is apparent from looking the data that the requested shelf life will be granted. & it is normally unnecessary to go through the formal statistical analysis. Any evaluation also consider the not only the assay but also consider the other parameter testing & also the different stability and degradation performance. The stability of the drug product after reconstitution or diluting according to labeling ,should be addressed to provide appropriate and supportive information.
A 5% change in assay from its initial value.Any degradation product exceeding itsacceptance criterion.Failure to meet the acceptance criteria forappearance, physical attributes, andfunctionality test (e.g., colour, phase separation,hardness).As appropriate for the dosage form, e.g., failureto meet the acceptance criteria for dissolutionfor 12 dosage units.
STATEMENTS /LABELLING:Q1 A (R2)guidelines Stress testing A storage statement should beSelection of batches established based on the stability Container closure evaluation of the drug substance. system specifications Terms such as “ambient conditions” or Testing frequency “room temperature” should be avoided. Storage conditionStability commitment Retest date should be displayed on the container label if appropriate. evaluationStatements /labelling
Light can affect drugs, causing chemical changes so… To Evaluate that light exposure does not result in unacceptable change. Provides means of screening drug early in the development process & allows identification of particular photo labile drug. gives idea about how to store drug For generation of photo stability information for submission in Registration Applications for new molecular entities and associated drug products.
A systematic approach to photostability testing is recommended covering, as appropriate, studies such as :i) Tests on the active substance;ii) Tests on the exposed product outside of the immediate pack, and if necessary ;iii) Tests on the product in the immediate pack; and if necessary ;iv) Tests on the product in the marketing pack.
Combination of visible and UV light. D65/ID65 emission standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp. D65 is the internationally recognised standard for outdoor daylight as defined in ISO 10977 (1993). ID65 is the equivalent indoor indirect daylight standard. For a light source emitting significant radiation below 320 nm, an appropriate filter(s) may be fitted to eliminate such radiation.
Samples should be exposed to light providing anoverall illumination of not less than 1.2 millionlux hours and an integrated near ultravioletenergy of not less than 200 watt hours/squaremeter. Protected samples (e.g., wrapped in aluminumfoil) are used as dark controls to evaluate thecontribution of thermally induced change to thetotal observed change[ LUX = Is the unit which indicates the intensityor the brightness of the light]
definition: A new dosage form is defined as a medicinal product which is a different pharmaceutical product type, but containing the same active substance as included in an existing product approved by the pertinent regulatory authority.Include: products of a different route of administration (e.g., oral to parenteral), new specific functionality/delivery systems (e.g., immediate release tablet to modified release tablet) and different dosage forms of the same route of administration (e.g., capsule to tablet, solution to suspension). Stability protocols for new dosage forms should follow the guidance in the parent stability guideline in principle. However, a reduced stability database at submission time may be acceptable with proper justification. e.g.,6 months accelerated and 6 months long term data from ongoing studies may be acceptable in certain justified cases.
Tablets – Appearance, colour, odour, assay, disintegration/dissol ution, moisture and friability or hardness testing. Hard gelatin capsules - Appearance, colour, odour of contents, assay, disintegration/dissolution, moisture and microbial limits Soft gelatin capsules - Appearance, colour, odour of contents, assay, disintegration/dissolution, moisture, m icrobial limits, ph , leakage and pellicle formation. Emulsions – Appearance including phase separation, colour, odour, assay, pH, viscosity, preserva tive content, weight loss and microbial limits.
Suppositories – Appearance, colour, assay, particle size, softening range, appearance, dissolution and microbial limits. Small volume parenteral: Drug injection – Appearance, colour, assay, ph, preservative, content, particulate matter, sterility and pyrogenicity. Large volume parenteral - Appearance, colour, assay, ph, preservative content, particulate matter, sterility and pyrogenicity Transdermals – Appearance, assay, leakage, microbial limit/sterility, peel and adhesive forces, drug release rate.
Outlines recommendations, principles, and considerations for reduced designs.Terms: Full Study Design: samples for every combination of all design factors are tested at all time points Reduced Study Design: not all samples for every factor combination are tested at all time points ex: bracketing, matrixing.
Applicability of Reduced Designs Applicable to formal stability studies of most types of drug products Drug substances: matrixing limited, bracketing generally not applicable Whether bracketing or matrixing depends on circumstances Any reduced design should be justified. Type and level of justification depends on avaiable supporting data. Careful consideration and scientific justification, if bracketing and matrixing in one design.
Bracketing is the design of a stability schedule such that only the extremes of certain design factors are tested at all time points.- different strengths- different container size and/or fill Stability of intermediate levels represented by stability or tested extremes. Bracketing design not appropriate, if tested samples are not the extremes.
BRACKETING - Strengths: Applicable: strengths of identical or closely related formulations Applicable with additional justification (e.g., supporting data): strengths where the relative amounts of the drug substance and excipients vary within the product line Not applicable: different excipients among strengthsBracketing – Container Size, Fill: Applicable: same container closure system where either the container size or fill varies while the other remains constant Applicable with additional justification (e.g., supporting data): same container closure system but both the container size and fill vary Not applicable: different container closure systems
Three strengths and three container sizes:Container size Dosage strength 50 mg 75 mg 100mg 1 2 3 1 2 3 1 2 315 ml T T T T T T100 ml500 ml T T T T T T
MATRIXING:Def: testing a selected subset of the total number of possible samples for all factor combinations at a specified time point, while testing another subset of samples at a subsequent time point applicable: strengths with identical or closely related formulations container sizes or fills of the same C/C system different batches made with the same equipment and process applicable with additional justification: where the relative amounts of excipients change or different excipients are used not applicable: different storage conditions different test attributes
Design should be balanced as far as possible sothat each combination is tested to the sameextent over the intended duration of the studyand through the last time point prior tosubmission Where time points are matrixed, all selectedfactor combinations should be tested at theinitial and final time points (and the last timepoint prior to submission)
It describes: How to propose a retest period for drug substances and a shelf life for drug products in the registration application When and how a extrapolation beyond available data can be considered. EXTRAPOLATION:extrapolation is the practice of using a known data set to infer the information about a future data.
CASE 1: NO SIGNIFICANT CHANGE AT ACCELERATED CONDITION:Long term and accelerated Long term/accelerated datadata showing a little or no showing change overchange over time and time/variabilitylittle /no variabilityDrug substance/product will remain within the Stability analysis of long term data canacceptance criteria during the proposed retest be useful attribute to establish retestperiod/shelf life periodStatistical analysis is not required
CASE 2: SIGNIFICANT CHANGE AT ACCELERATED CONDITION: No significant change at intermediate Significant change at intermediate The extent of extrapolation wpould depend on whether LT data for attributes are amenable to The proposed retest period or shelf statistical analysis life should not exceed the period covered by long term data Data not amenable to data amenable to statistical analysis statistical analysisThe proposed retest The proposed retest period orperiod/shelf life can be shelf life can be upto one &halfupto 3 months beyond the times but should not be more thanperiod covered by LT data 6 months beyond the period covered by LT data
REGRESSION ANALYSIS: appropriate approachfor evaluation of stability dataUpper and lower confidence limit(95%) shouldbe calculated and compared to acceptancecriterionAPPENDICES:APPENDIX –A:decision tree for data evaluationfor retest period or shelf life estimation of drugsubstance and drug productAPPENDIX –B:examples of statistical approachesto stability data analysis.
Q1F- Stability Data Package for Registration Applicationsin Climatic Zones III and IVClimatic conditions in the countries where the product is to be marketed should be carefully considered during the development phase . So the world has been divided into four climatic zones based on the prevalent annual climatic conditions.Temperature and humidity determine the storage conditions and so they greatly affect the stability of the product.
Tests at elevated temperatures and/or extremes of humidity Special transportation and climatic conditions outside the storage conditions recommended in this guideline should be supported by the additional data. Stability testing at a high humidity condition, e.g. 25°C/80%RH, is recommended for solid dosage forms in water- vapour permeable packaging viz., tablets in PVC/ aluminium blisters, intended to be marketed in territories with extremely high humidity conditions in Zone IV.
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