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Guidelines And Stability Protocols For Different Pharamceutical Dosage Forms :

Guidelines And Stability Protocols For Different Pharamceutical Dosage Forms Presented by P.KRANTHI KUMAR Pharmaceutics M.Pharmacy -I Semester St.john college of pharmacy Yellapur - warangal ICH


CONTENTS 8/10/2011 2

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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 . 8/10/2011 3 Long term stability studies Intermediate stability studies Accelerated stability studies Type of stability studies conducted

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Adverse Effects Of Instability In Drug Products 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 8/10/2011 4

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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 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: 5 Quality guidelines Efficacy guidelines Safety guidelines Multi disciplinary guidelines

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uality guidelines 8/10/2011 6

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The ICH Q1 topic on stability testing is covered by 5 separate guidelines The ICH Q1 series of guidelines are designed for stability programs 8/10/2011 7 Stability testing Guidelines

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Climatic Zone Definition Storage conditions I Temperate climate 21°C / 45% r.h . II Subtropical and Mediterranean climate 25°C / 60% r.h . III Hot, dry climate 30°C / 35% r.h IV Hot, humid climate 30°C / 70% r.h . Classification of climatic zones Criteria used to classify a site according to climatic zone Mean annual temperature measured in the open air Calculated mean annual Temperature (< 19°C) Mean annual Water vapour partial pressure 8/10/2011 8

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I II III IV Europe: EU, Belarus, Bulgaria, Estonia, Hungary, Latvia, Lithuania, Norway, Rumania, Russia, Switzerland, Ukraine America: USA, Argentina, Bolivia, Chile, Canada, Mexico, Peru, Uruguay Africa: Egypt, Algeria, Canary Islands, Libya, Morocco, Namibia, Rwanda, South Africa, Tunisia, Zambia, Zimbabwe Asia: Japan, Afghanistan, Armenia, Azerbaijan, China, Georgia, Iran, Israel, Kazakhstan, Kirghizia, Korea, Lebanon, Nepal, Syria, Tadzhikistan, Turkey, Turkmen, Uzbekistan, Australia, New Zealand. America : Barbados,Brazil , Costarica , Dominican Republic, Equador , Salvador, Guatmela , Haiti, Handures , Jamaica, Columbia, Cuba, Dutch, Antiles , Panama, Paragua . Africa: Angola, Ethiopia, Benin, Cameron, Kenya, Liberia, Congo, Madagascar, Mahwi , Mali, Mayrtiania , Mozambique, Niger, Somalia, Sudan, Tanzania, Uganda, Zaire, Central African Republic. Asia: Behrain , Bangladesh, Hongkong , India, Indonesia, Iraq, Jordan, Kambechev , Quatar , Kuwait, Malaysia, Maldives, Myanmar, UAE, Oman, Yemen. Australian oceanic: Fisi , Society Island, Marshal Island, Piping New Guinea. Countries which come under different climate zones 8/10/2011 9

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Selected definitions Re-test date 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. 8/10/2011 10

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Formal stability studies 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 a n API or the shelf life of a FPP. Stress testing – forced degradation ( API ) 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 . Stress testing – forced degradation ( FPP ) 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 . 8/10/2011 11

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Stability protocol AND REPORT 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 8/10/2011 12

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8/10/2011 13 Illustrative data of API stability batches Batch number Date of manufacture Site of manufacture Batch size (kg) Primary packing materials Date of initial analysis T he batches should be representative of the manufacturing process and should be manufactured from different batches of key intermediates.

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8/10/2011 14 Illustrative data of capsule/tablet stability batches 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 T he batches should be representative of the manufacturing process and should be manufactured from different batches of APIs .

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Stability studies should be performed on each individual strength, dosage form and container size of the pharmaceutical product . If dosage form is the same, then b racketing can be applied to: Different strength s (including FDC products) have identical formulations (including FDC products) are made with closely related formulations Container- closure system is the same and either the container size or the fill size varies Even 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. BRACKETING 8/10/2011 15

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Matrixing is t he statistical design of a stability schedule. Each storage condition should be treated separately under its own matrixing design A t a given time point (other than the initial or final ones) not every batch on stability needs to be tested Full testing must be performed at the maximum storage period at the time of submission MATRIXING 8/10/2011 17

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Guidelines are laid for both API(drug substance) and FPP( drug product) 19 3/10/2011 19 API ( Active pharmaceutical ingredient ) FPP (Finished pharmaceutical product)

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STABILITY PROTOCOL - API Protocol Parameter Description Storage conditions (including tolerances) and testing frequency 25°C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months 30 o C/75% RH 0, 3, 6, 9,12, (18, 24, 36) months 40°C/75% RH 0,3,6 months Batch number and size L40438 ( Jan. 2005 ), 80.50 k g L50041 ( Feb.2005 ), 69.00 k g L50054 (March 2005 ), 73.00 kg Container closure system(s) Simulated: double PE bags in black PE bag kept in one-kg fib er board drums well-closed Tests and acceptance criteria Assay by(98.0-102.0%), ImpA (NMT 0.15%), ImpB (NMT0.3%), and so on Other (s) Stress testing, including photostability testing according to ICH Q1B 8/10/2011 20

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Protocol Parameter Description Storage conditions (including tolerances) and testing frequency 25°C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months 30 o C/75% RH 0, 3, 6, 9,12, (18, 24, 36) months 40°C/75% RH 0,3,6 months Batch number and size L40438 ( Jan. 2005 ), 80.50 k g L50041 ( Feb.2005 ), 69.00 k g L50054 (March 2005 ), 73.00 kg Container closure system(s) Simulated: double PE bags in black PE bag kept in one-kg fib er board drums well-closed Tests and acceptance criteria Assay by(98.0-102.0%), ImpA (NMT 0.15%), ImpB (NMT0.3%), and so on Other (s) Stress testing, including photostability testing according to ICH Q1B STABILITY PROTOCOL FOR ORAL SUSPENSION(FPP) 8/10/2011 21

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8/10/2011 22 Drug Substance Drug Product Stress testing Photo stability testing Selection of batches Selection of batches Container Closure system Container Closure system Testing frequency Testing frequency Storage conditions Storage conditions Stability commitment Stability commitment Evaluation Evaluation Statements/Labeling Statements/Labeling In use stability Variations Ongoing stability studies Ongoing stability studies Guidelines for drug substance (API) and drug product(FPP)

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Standard Title and reference ICH Q1A(R2) Stability Testing of New Drug Substances and Products (the p arent guideline) ICH Q1B Photostability Testing of New Drug Substances and Products ICH Q2B Validation of Analytical Procedures: Methodology ICH Q3A(R) Impurities in New Drug Substances ICH Q3B(R) Impurities in New Drug Products GUIDELNES ON STRESS TESTING 8/10/2011 23


STRESS TESTING IN API 8/10/2011 24 Stress testing of the API can help identify the likely degradation products, which, in turn, can help establish the degradation pathways tress testing may be carried out on a single batch of the API. It should include the effect of temperature, humidity. Storage conditions Testing period* pH ± 2, room temperature 2 weeks pH ± 7, room temperature 2 weeks pH ± 10-12, room temperature 2 weeks H 2 O 2 , 0.1-2% at neutral pH, room temperature 2 weeks

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FORMAL STABILITY STUDIES 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 sufficient to cover storage and shipment. Type of study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 12 Months Intermediate 30°C ± 2°C/65% RH ± 5% RH 6 Months Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 Months 8/10/2011 25

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8/10/2011 26 Stability results A storage statement should be proposed for the labeling (if applicable), which should be based on the stability evaluation of the API. A re-test period should be derived from the stability information, and the approved retest date should be displayed on the container label. An API is considered as stable if it is within the defined/regulatory specifications when stored at 30 ±2 o C and 6 5 ±5% RH for 2 years and at 40±2 o C and 75±5%RH for 6 months.

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8/10/2011 27 Potential instability issues of FPPs Loss/increase in concentration of API F ormation of ( toxic ) degradation products M odification of any attribute of functional relevance A lteration of dissolution time/profile or bioavailability D ecline of microbiological status L oss of package integrity R eduction of label quality L oss of pharmaceutical elegance and patient acceptability

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8/10/2011 28 Stability-indicating quality 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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8/10/2011 29 S tress testing of FPPs Storage conditions Testing 40°C, 75 % RH; open storage** 3 months 50-60 °C, ambient RH; open storage 3 months Photostability according to ICH * 3 months or 5-15% degradation, whatever comes first ** For API1-API2 , or API-excipient , or FPP without packing material , typically a thin layer of material is spread in a Petri dish. Open storage is recommended , if possible.

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8/10/2011 30 Selection of Batches 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. Where possible, batches of the FPP should be manufactured by using different batches of the API.

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8/10/2011 31 TESTS AT ELEVATED TEMPERATURE AND/OR EXTREMES OF HUMIDITY (ICH-Q1F) 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 50°C/ambient humidity to cover extremely hot and dry conditions and at 25°C/80% RH to cover extremely high humidity conditions. Stability testing at a high humidity condition, e.g., 25°C/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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8/10/2011 32 Evaluation A systematic approach should be adopted in the presentation and evaluation of the stability information . Where 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 . An 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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8/10/2011 33 No significant change at accelerated conditions within six (6) months. Long-term data show little or no variability and little or no change over time. Accelerated data show little or no variability and little or no change over time. Statistical analysis is normally unnecessary. Proposed retest period or shelf life = double of period covered by long-tem data A retest period or shelf life granted on the basis of extrapolation should always be verified by additional long-term stability data Evaluation – Best Case

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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. 8/10/2011 34

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8/10/2011 35 ONGOING STABILITY STUDIES 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 specifications under 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 suffi cient data to allow for trend analysis. Unless otherwise justifi 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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8/10/2011 36 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


REFERENCES ICH official web site. www.ich .org World Health Organization 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 ) 8/10/2011 37

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8/10/2011 38 Thank you…

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