I CH

Guid eli nes And St a b i l i t y Pr oto cols Fo r D if f e r e n t if Pha ramc eu tica l D osa g e F o r m s

CONTENTS
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STABILITY

Stability of a pharmaceutical product may be defined as the capability of a particular formulation in a specific container/closure system to remain within its Physical Chemical Microbiological Therapeutic Toxicological Specifications.

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Type of stability studies conducted

Long

term stability studies Intermediate stability studies Accelerated stability studies

ADVERSEEFFECTSOFINSTABILITYINDRUG PRODUCTS
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Loss of potency of drug Change in concentration of active drug Alteration of bioavailability Loss of content uniformity Loss of pharmaceutical elegance and patient
acceptability Formation of toxic degradation products

The International Conference on Harmonization of Technical

Requirements for Registration of Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry v ICH's mission is to achieve greater harmonization to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner.

ICH Products:
Quality guidelines Efficacy guidelines
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Safety guidelines

Multi disciplinary guidelines

ualityguidelines
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Stability testing Guidelines vThe ICH Q1 topic on stability testing is covered by 5

separate guidelines vThe ICH Q1 series of guidelines are designed for stability programs
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Classification of climatic zones

Climatic Zone I II III IV Subtropical and Mediterranean climate Hot, dry climate Hot, humid climate Definition Temperate climate Storage conditions 21C / 45% r.h.
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25C / 60% r.h. 30C / 35% r.h 30C / 70% r.h.

Criteriausedtoclassifyasiteaccordingtoclimaticzone Meanannualtemperaturemeasuredintheopenair CalculatedmeanannualTemperature(<19C) MeanannualWatervapourpartialpressure

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Countries which come under different climate zones

I II III IV America: Europe: Barbados,Brazil, Costarica, Dominican Republic, EU,Belarus,Bulgaria,Estonia,Hungary,Latvia,Lithuania,Norway,Rumania, Equador, Salvador, Guatmela, Haiti, Handures, Russia,Switzerland,Ukraine Jamaica, Columbia, Cuba, Dutch, Antiles, America: Panama, Paragua. USA,Argentina,Bolivia,Chile,Canada,Mexico,Peru,Uruguay Africa: Angola, Ethiopia, Benin, Cameron, Kenya, Africa: Liberia, Congo, Madagascar, Mahwi, Egypt,Algeria,CanaryIslands,Libya,Morocco,Namibia,Rwanda,South Mali, Mayrtiania, Mozambique, Niger, Somalia, Africa,Tunisia,Zambia,Zimbabwe Sudan, Tanzania, Uganda, Zaire, Central African Asia: Republic. Japan,Afghanistan,Armenia,Azerbaijan,China,Georgia,Iran,Israel, Asia: Behrain, Bangladesh, Hongkong, India, Kazakhstan,Kirghizia,Korea,Lebanon,Nepal,Syria,Tadzhikistan,Turkey, Indonesia, Iraq, Jordan, Kambechev, Quatar, Turkmen,Uzbekistan, Kuwait, Malaysia, Maldives, Myanmar, UAE, Australia, Oman, Yemen. NewZealand. Australian oceanic: Fisi, Society Island, Marshal Island, Piping New Guinea.
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SELECTEDDEFINITIONS
Re-test date
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The date after which samples of an API should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given FPP.

Shelf life (expiration dating period, conformance period)

The time period during which an API or a FPP is expected to remain within the approved shelf-life specification, provided that it is stored under the conditions defined on the container label.

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Formalstabilitystudies

Long term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the re-test period of an API or the shelf life of a FPP. Studies undertaken to elucidate the intrinsic stability of the API. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing. Studies undertaken to assess the effect of severe conditions on the FPP. Such studies include photostability testing and compatibility testing on APIs with each other in FDCs and API(s) with excipients during formulation development.

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Stresstestingforceddegradation(API)

Stresstestingforceddegradation(FPP)

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STABILITYPROTOCOLANDREPORT
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
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Result sheets must bear date and responsible person signature / QA approval

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ILLUSTRATIVEDATAOFAPISTABILITY BATCHES
Batch number Date of manufacture Site of manufacture Batch size (kg) Primary packing materials Date of initial analysis
The batches should be representative of the manufacturing process and should be manufactured from different batches of key 13 intermediates.
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ILLUSTRATIVEDATAOF CAPSULE/TABLETSTABILITYBATCHES
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Batch number Date of manufacture Site of manufacture Batch size (kg) Batch size (number of units) Primary packing materials Date of initial analysis Batch number of the API

The batches should be representative of the manufacturing process 14 and should be manufactured from different batches of APIs.

BRACKETIN G vStability studies should be performed on each individual strength, dosage form and container size of the pharmaceutical product. If dosage form is the same, then bracketing can be applied to: vDifferent strengths (including FDC products)
have identical formulations (including FDC products) are made with closely related formulations

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vContainer-closure system is the same and either the

container size or the fill size varies vEven when the container-closure system varies bracketing is possible with some justification. Such justification might be the demonstration that the product is not water sensitive, or the discussion of the relative permeation rates of the closure systems.
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EXAMPLEOFBRACKETINGDESIGN
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MATRIXING
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Matrixing Each At

schedule.

is the statistical design of a stability

storage condition should be treated separately under its own matrixing design a given time point (other than the initial or final ones) not every batch on stability needs to be tested testing must be performed at the maximum storage period at the time of submission
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Full

EXAMPLEOFMATRIXDESIGN
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Guidelines are laid for both API(drug substance) and FPP( drug product)
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(Finished (Active pharmaceutical ingredient) pharmaceutical product )

API

FPP

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STABILITYPROTOCOLAPI
Protocol Parameter Storage conditions (including tolerances) and testing frequency Batch number and size Container closure system(s) Tests and acceptance criteria Other(s) Description
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25C/60% RH 0, 3, 6, 9, 12, (18, 24, oC/75% RH 30 0, 3, 6, 9,12, (18, 24, 36) months 40C/75% 0,3,6 months 36) monthsRH L40438 (Jan. 2005), 80.50 kg L50041 (Feb.2005), 69.00 kg L50054 (March 2005), 73.00 kg Simulated: double PE bags in black PE bag kept in one-kg fiberboard drums wellAssay by(98.0-102.0%), ImpA (NMT closed 0.15%), ImpB (NMT0.3%), and so on Stress testing, including photostability testing according to ICH Q1B

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STABILITYPROTOCOLFORORAL SUSPENSION(FPP)
Protocol Parameter Storage conditions (including tolerances) and testing frequency Batch number and size Container closure system(s) Tests and acceptance criteria Other(s) Description
25C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months 30oC/75% RH 0, 3, 6, 9,12, (18, 24, 36) months 40C/75% RH 0,3,6 months L40438 (Jan. 2005), 80.50 kg L50041 (Feb.2005), 69.00 kg L50054 (March 2005), 73.00 kg Simulated: double PE bags in black PE bag kept in one-kg fiberboard drums wellclosed Assay by(98.0-102.0%), ImpA (NMT 0.15%), ImpB (NMT0.3%), and so on Stress testing, including photostability testing according to ICH Q1B
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Guidelines for drug substance (API) and drug product(FPP)

Drug Substance Stress testing Selection of batches Container Closure system Testing frequency Storage conditions Stability commitment Evaluation Statements/Labeling Drug Product Photo stability testing Selection of batches Container Closure system Testing frequency Storage conditions Stability commitment Evaluation Statements/Labeling In use stability Variations Ongoing stability studies
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Ongoing stability studies

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GUIDELNESONSTRESS TESTING Standard ICH Q1A(R2) ICH Q1B ICH Q2B ICH Q3A(R) ICH Q3B(R) Title and reference
Stability Testing of New Drug Substances and Products (the parent guideline) Photostability Testing of New Drug Substances and Products Validation of Analytical Procedures: Methodology Impurities in New Drug Substances Impurities in New Drug Products
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STRESS TESTING IN API

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ess testing of the API can help identify the likely degradation products, ch, in turn, can help establish the degradation pathways ss testing may be carried out on a single batch of the API. It should lude the effect of temperature, humidity.
Storage conditions pH 2, room temperature pH 7, room temperature pH 10-12, room temperature H2O2, 0.1-2% at neutral pH, room temperature Testing period* 2 weeks 2 weeks 2 weeks 2 weeks
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FORMALSTABILITYSTUDIES
In general an API should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its 91 sensitivity to moisture. The storage conditions and the lengths of studies chosen should be suf1 cient to cover storage and shipment.
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Type of study Storage condition Long term

25C 2C/60% RH 5% RH or 30C 2C/65% RH 5% RH 30C 2C/65% RH 5% RH

Minimum time period covered by data at submission

12 Months 6 Months 6 Months

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Intermediate Accelerated
40C 2C/75% RH 5% RH

STABILITYRESUL TS
A

storage statement should be proposed for the labeling (if applicable), which should be based on the stability evaluation of the API. re-test period should be derived from the stability information, and the approved retest date should be displayed on the container label. API is considered as stable if it is within the defined/regulatory specifications when stored at 302oC and 655% RH for 2 years and at 402oC and 755%RH for 6 months.

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An

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POTENTIALINSTABILITYISSUESOF FPPS
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Loss/increase

in concentration of API Formation of (toxic) degradation products Modification of any attribute of functional relevance Alteration of dissolution time/profile or bioavailability Decline of microbiological status Loss of package integrity Reduction of label quality Loss of pharmaceutical elegance and patient acceptability
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STABILITYINDICATINGQUALITY PARAMETERS

Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. For instance, in case of tablets:
appearance hardness friability moisture content dissolution time degradants assay microbial purity

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STRESSTESTINGOFFPPS
Storage conditions Testing
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40C, 75 % RH; open storage**

3 months

50-60 C, ambient RH; open storage Photostability

3 months

according to ICH

*3monthsor515%degradation,whatevercomesfirst **ForAPI1API2,orAPIexcipient,orFPPwithoutpackingmaterial, typicallyathinlayerofmaterialisspreadinaPetridish. Openstorageisrecommended,ifpossible.

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SELECTIONOFBATCHES
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At

the time of submission data from stability studies should be provided for batches of the same formulation and dosage form in the container closure system proposed for marketing.

Stability

data on three primary batches are to be provided. The composition, batch size, batch number and manufacturing date of each of the stability batches should be documented and the certificate of analysis at batch release should be attached. possible, batches of the FPPshould be manufactured by using different batches of the API.
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Where

TESTSATELEVATEDTEMPERATUREAND/OREXTREMESOF HUMIDITY(ICHQ1F) Special transportation and climatic conditions outside the storage conditions recommended in this guideline should be supported by additional data. For example, these data can be obtained from studies on one batch of drug product conducted for up to 3 months at 50C/ambient humidity to cover extremely hot and dry conditions and at 25C/80% RH to cover extremely high humidity conditions.
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Stability testing at a high humidity condition, e.g., 25C/80% RH, is recommended for solid dosage forms in water-vapour permeable packaging, e.g., tablets in PVC/aluminum blisters, intended to be marketed in territories with extremely high humidity conditions in Zone IV. However, for solid dosage forms in primary containers designed to provide a barrier to water vapour, e.g. aluminum/aluminum blisters, stability testing at a storage condition of extremely high humidity is not considered necessary.
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EVALUATION
A

systematic approach should be adopted in the presentation and evaluation of the stability information. the data show so little degradation and 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; providing a justification for the omission should be sufficient. approach for analysing data on a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided confidence limit for the mean curve intersects the (lower) acceptance criterion (95% assay).

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Where

An

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EVALUATIONBESTCASE
4.

2.No significant change at accelerated conditions within six (6) months. 3.Long-term data show little or no variability and little or no change over time. 4.Accelerated data show little or no variability and little or no change over time. 5.Statistical analysis is normally unnecessary. 6.Proposed retest period or shelf life = double of period covered by long-tem data 7.A retest period or shelf life granted on the basis of extrapolation should always be verified by additional long-term stability data

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VARIATIONS
Once the FPP has been registered, additional stability studies are required whenever variations that may affect the stability of the API or FPP are made, such as major variations The following are examples of such changes: change in the manufacturing process; change in the composition of the FPP; change of the immediate packaging; change in the manufacturing process of an API.

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ONGOINGSTABILITYSTUDIES
The purpose of the ongoing stability programme is to monitor the API and to determine that the API /FPP remains, and can be expected to remain, within specicationsunder the storage conditions indicated on the label, within the re-test period in all future batches. This mainly applies to the FPP in the container closure system in which it is supplied, but consideration should also be given to inclusion in the programme of bulk products. The number of batches and frequency of testing should provide suf cient data to allow for trend analysis. Unless otherwise justi1 ed, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability programme (unless none is produced during that year).
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CONCLUSION
Stability Forced

studies should be planned on the basis of pharmaceutical R+D and regulatory requirements. degradation studies reveal the intrinsic chemical properties of the API, while formal stability studies establish the retest date. shelf life (expiry date) of FPPs is derived from formal stability studies. and time trends of stability data must be evaluated by the manufacturer in order to propose a retest date or expiry date.

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The Variability

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REFERENCES
ICH official web site. www.ich .org World Health Organization

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WHO Technical Report Series, No. 953, 2009 Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C. T. Rhodes Statistical Evaluation of Stability Data: Criteria for Change-over-time and Data Variability (PDA Journal of Pharmaceutical Science and Technology, Vol. 57. No.5, Sept./Oct. 2003, pp. 369-377)

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Thank

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