Stability Studies
欧盟药品贮运声明指南
欧盟药品贮运声明指南1. BACKGROUND 背景Suitable storage conditions, consistent with those defined in the SPC should be included in the package leaflet and on the product labelling, if appropriate, as stated in Directive 2001/83/EC. The storage conditions for medicinal products should be based on evaluation of the stability studies undertaken on the finished product. Details of the conditions recommended for these stability studies are included in the relevant CHMP/ICH Guidelines where storage conditions for real time studies were chosen as 25°C/60% RH supported by accelerated or, where applicable, intermediate conditions and based on the mean kinetic temperature of climatic zone I/II, the relevant zone for the EU. The mean kinetic temperature includes the annual variations, i.e. lower and higher temperatures during winter and summer seasons. Thus, storage at a continuous temperature of 25°C during real time stability studies covers the actual temperature exposure likely to be encountered under ambient conditions throughout Europe, including real time excursions from 25°C.与其在SPC中定义相一致的适当的存贮条件，应包括在包装说明书里以及在药品标签上。
仿制药晶型研究的技术指导原则英文
仿制药晶型研究的技术指导原则英文Technical Guidance Principles for the Study of Generic Drug Polymorphs1. Comprehensive Literature Review:Conduct a thorough review of existing literature on the polymorphic forms of the reference drug substance. Identify the different polymorphs reported and their characterization methods, including X-ray diffraction, thermal analysis, and spectroscopic techniques.2. Sample Preparation:Ensure that the sample preparation technique maintains the integrity and purity of the reference drug substance. Use appropriate methods such as crystallization, recrystallization, or solvent evaporation to obtain the desired polymorphs for characterization.3. Controlled Crystallization Conditions:Conduct crystallization experiments under controlled conditions to promote the formation of specific polymorphs. Factors such as temperature, solvent selection, cooling rate, and agitation should be considered and optimized to achieve reproducible results.4. Polymorph Characterization:Employ a combination of analytical techniques to characterize the obtained polymorphs. X-ray diffraction is essential to confirm the crystalline nature and determine the crystal structure. Use thermal analysis techniques such as differential scanning calorimetry and thermogravimetric analysis to investigate thermal behavior. Complement these techniques with spectroscopic tools like infrared spectroscopy and solid-state nuclear magnetic resonance to confirm structural differences.5. Physical Property Comparison:Compare the physical properties (e.g., melting point, solubility, density) of the newly formed polymorphs with those of the reference drug substance. Any significant differences may indicate a new polymorphic form.6. Stability Studies:Conduct stability studies to evaluate the stability of the polymorphs under different environmental conditions, including temperature, humidity, and light exposure. Monitor changes in physical properties and assess any potential degradation or transformation.7. Bioavailability Studies:Perform bioavailability studies to determine if the newly formedpolymorphs exhibit similar or improved bioavailability compared to the reference drug substance. In vitro dissolution testing and in vivo pharmacokinetic studies can provide valuable insights into the drug's performance.8. Regulatory Compliance:Ensure that the research and development of generic drug polymorphs adhere to applicable regulatory guidelines, such as those set by the Food and Drug Administration (FDA) or European Medicines Agency (EMA). Demonstrate the equivalence or superiority of the polymorphs through rigorous scientific evidence.9. Documentation and Reporting:Maintain detailed records of all experimental procedures, data, and observations. Prepare comprehensive reports that summarize the research findings and provide sufficient evidence to support the conclusions drawn.10. Intellectual Property Considerations:Respect existing patents and intellectual property rights when conducting research on generic drug polymorphs. Ensure compliance with applicable legal requirements and consider seeking legal advicewhen necessary.Note: It is important to consult specific guidelines and requirements from regulatory authorities or professional organizations when conducting research on generic drug polymorphs.。
Lecture7_Statistical Designs for Stability Studies
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四类地区稳定性试验要求
The stability of finished pharmaceutical products depends on environmental and product-related factors ICH and WHO started discussions in 2000 to harmonise the number of stability tests and conditions employed worldwide……but there was little agreement from interested parties on an ICH proposal regarding long-term storage conditions in zone IV (hot and humid countries)Stability Testing of Pharmaceutical Products in a Global EnvironmentDr Sabine Kopp reports on the development of World Health Organization policy on stability testing.Following lengthy discussions, the World Health Organization (WHO) has revised its guidelines on stability testing conditions for climatic zone IV , ie hot and humid countries. The guidelines are expected to be made available shortly. This article summarises the key events that have marked the WHO’s work on developing international stability testing guidelines.The stability of finished pharmaceutical products depends on several factors. On the one hand, it depends on environmental factors such as ambient temperature, humidity and light. On the other, it depends on product-related factors such as the chemical and physical properties of the active substance and pharmaceutical excipients, the dosage form and its composition, the manufacturing process, the nature of the container-closure system and the properties of the packaging materials.For established drug substances in conventional dosage forms, literature data on the decomposition process and degradability of the active substance are generally available together with adequate analytical methods. Thus, the stability studies may be restricted to the dosage forms.The actual stability of a dosage form will depend to a large extent on the formulation and packaging-closure system selected by the manufacturer. Stability considerations, for example selection of excipients, determination of their level and process development, should therefore be given high priority in the developmental stage of the product. The possible interaction of the drug product with the packaging material in which it will be delivered, transported and stored throughout its shelf-life must also be investigated.The shelf-life should be established with due regard to the climatic zone(s) in which the product is to be marketed. For certain preparations, specific storage instructions must be complied with if the shelf-life is to be guaranteed.The storage conditions recommended by manufacturers on the basis of stability studies should guarantee the maintenance of quality, safety and efficacy throughout the shelf-life of a product. The effect on products of the extremely adverse climatic conditions in certain countries to which they may be exported calls for special consideration.T o ensure both patient safety and the rational management of drug supplies, it is important that the expiry date and, where necessary, the storage conditions are indicated on the label.The beginningWork on stability of pharmaceutical products was initiated by the WHO in 1988 and the WHO Guidelines on Stability Testing for Well Established Drug Substances in Conventional Dosage Forms were adopted in 1996 by the WHO Expert Committee on Specifications for Pharmaceutical Preparations following extensive consultation 1.In 2000, discussions began between the International Conference on Harmonization (ICH)expert working group Q1 (stability) and the WHO to harmonise the number of stability tests and conditions employed worldwide.The working group, when developing guidance Q1F Stability Data Package for Registration Applications in Climatic Zones II and IV , proposed a modification to the WHO guidelines. The proposal concerned the long-term storage conditions for climatic zone IV (hot and humid countries). The group suggested that the WHO change its conditions from 30°C and 70% relative humidity (RH) to 30°C and 60% RH. A detailed paper including the rationale for the change was widely circulated for comment. Non-governmental organisations, international professionals’bodies and specialists, and members of the WHO expert advisory panel on the international pharmacopoeia and pharmaceutical preparations were among those consulted.Responses to the proposal varied. A number of experts agreed that the proposal constituted a sound scientific approach. It was recognised that packaging was very important and common testing conditions should be agreed upon for WHO and ICH guidelines. Others criticised the approach as being too scientific and impractical while pointing out that actual meteorological and physical storage conditions in these countries would not allow simulation of long-term storage conditions as defined by the new proposal. Arguments were also put forward against the application of some parameters used in the calculations.In 2001, in a further round of discussions, it was proposed to change the real-time storage conditions for zone IV from 30°C and 70% RH to 30°C and 65% RH. This suggestion was again circulated widely for comments and the results discussed in July 2001.In October 2001, the WHO expert committee modified the storage conditions and these were subsequently published in the WHO guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms, to read 30°C (±2°C) and 65% (±5%) RH for real-time stability studies defined for climatic zone IV . It was also agreed that where special transportation and storage conditions did not comply with these criteria, additional study data supporting these conditions might be needed 2,3.ASEAN stability testing guidelinesThe Association of South East Asian Nations (ASEAN) comprises Brunei Darussalam, Cambodia,Indonesia, Lao PDR (Laos), Malaysia, Myanmar, Philippines, Singapore, Thailand and Vietnam.These countries are all situated in a hot and humid climatic zone (zone IV). ASEAN regulatory authorities have defined harmonised requirements for marketing authorisation forpharmaceuticals with a view to establishing a common market for their pharmaceutical products.This process includes harmonisation of requirements for stability testing.Regulators and experts from ASEAN countries have met regularly with the WHO and experts from the International Federation of Pharmaceutical Manufacturers & Associations to discuss whether the conditions outlined in the WHO and ICH guidelines as described above are appropriate for countries which have vast areas with climatic conditions that are above the average RH and temperature used to characterise zone IV 4.After consultation and several meetings, a meeting held in Jakarta on 12-13 January 2004concluded that the conditions described in the WHO and ICH guidelines cited above did not adequately address the climatic conditions prevalent in the majority of ASEAN countries. The conditions shown in T able 1 were then adopted for stability studies in ASEAN countries.Arguments supporting this conclusion have been set out 5.Table 1. Conditions for stability testing in ASEAN countriesType Conditions Products in primary containers permeable to30°C ±2°C/75% ±5% RH water vapourProducts in primary containers impermeable to30°C ±2°C/RH not specified water vapourAccelerated studies40°C ±2°C/75% ±5% RH Stress studies Unnecessary if accelerated studies at aboveconditions are availableASEAN based its considerations on the principle that testing should be biased towards more stressful rather than less stressful conditions so as to provide a margin of error in favour of the patients and to increase the likelihood of identifying substances or formulations that pose particular stability problems. ASEAN also concluded that stability is obviously affected to a large extent by the permeability of primary packaging materials. Products packed in primary containers demonstrated to be impermeable to water vapour do not require testing at any specific RH, storage at constanttemperature of 30°C throughout real-time testing being sufficient. However, guidelines will be needed to specify parameters, such as a thickness and permeability coefficient, which indicates demonstrated impermeability of packaging materials.Implementation of the above decision will be preceded by a transition period during which existing national guidelines will still be applicable. In addition, a science-based approach will be taken to ensure correct evaluation when submitted data is based on conditions that are less stressful than those required (eg 30°C/65% RH). Factors to be taken into consideration include:•complementary data provided to enable proper scientific evaluation;•detected instability;•data obtained under accelerated conditions;•when more protective packaging is provided; and •commitment to generate data under the new guideline conditions (30°C/75% RH, or 40°C/75% RH, or both) within a specified period. A suitable label recommendation such as “Store below 30°C and protect from moisture” may also be applied.ASEAN bloc countriesrejected the conditionsdescribed in revised ICHand WHO guidelines……saying they were not appropriate for the climatic conditions in their countries…different conditions forstability testing wereadopted……and these will be implemented after a transition periodThe ASEAN developments meant a decision would have to be made on whether to amend the WHO guidanceA decision was eventually taken to split zone IV into two zones,with zone IVb being hot and very humid areas and zone IVa being hot and humid areas The official revised guideline could be available by the end of May 2006Next steps in WHO’s harmonisation effortsIn view of the decisions taken by ASEAN as described above, the WHO responded with the following action plan. First, a WHO document was circulated in early 2004, in accordance with the WHO consultative procedure, to interested parties for consultation. The document requested comments on whether the WHO guidance on stability testing should be modified for long-term stability testing conditions (hot and humid climatic zone) and sought suggestions on how modifications should be implemented. Thereafter an informal consultation discussed comments received, in preparation for the meeting of the WHO expert committee on specifications which met in October 2004.As the ASEAN guidance was confirmed and adopted, the WHO organised a meeting including ASEAN, WHO and ICH experts and other interested parties in December 20046. The following recommendations were agreed during the meeting:•the existing WHO guideline on stability testing should be reviewed in the light of new information on climatic conditions in zone IV as raised by the ASEAN countries; and•all concerned parties represented at the meeting should return to their constituencies,consider the options that were discussed, and provide feedback and recommendations to the WHO, indicating preferences and giving reasons. Those parties will be invited to be involved in the continuation of the consultative process. The options are:–revert to 30°C/70% RH as the long-term stability testing condition for zone IV as it is likely that considerable data are already available. This might serve as a potential platform for future harmonisation between ICH and the WHO;–change to 30°C/75% RH as the long-term stability testing condition for zone IV in the interest of patient safety worldwide; or–add a new climatic zone IVb to accommodate hot and very humid areas (30°C/75% RH).The present zone IV (30°C/65% RH) would become zone IV a.Feedback was requested by the end of March 2005. WHO member states not represented at the meeting were also invited to give their feedback.Answers were received from the following member states and partners: Amazonian Countries (Bolivia, Brazil, Colombia, Cuba, Equator, Peru, Suriname and V enezuela), ASEAN (Brunei Darussalam, Indonesia, Malaysia and Thailand), ICH parties (the EU on behalf of European,Japanese and US regulators, as well as their respective industry associations), the South African Development Community (South Africa on behalf of SADC), the International Generic Pharmaceutical Alliance and the World Self-Medication Industry. There was no consensus among the various parties. Each option was favoured by at least one party. Current statusBased on the above outcome, the experts who met during the 40th WHO expert committee meeting at the end of October 2005 had to take a decision about the WHO position for future stability testing. They were faced with a difficult situation . The WHO secretariat reminded the expert committee members that the WHO guideline had been revised in the light of harmonisation efforts in collaboration with ICH. After extensive discussion, the committee reached consensus that the WHO stability guidelines should be amended to reflect conditions for zone IV as follows:•zone IV a – 30°C and 65% RH; and•zone IVb – 30°C and 75% RH.It was agreed that each individual member state within the former zone IV would need to indicate which of these conditions (zones IV a or IVb), would be applicable in its territory. This was intended to accommodate the two conditions currently in use.The report and its outcomes, including annexes, ie the new guidelines adopted during the WHO expert committee meeting, are now with editors. It is expected that the recommendations and the report will be presented to the WHO executive board in May 2006 (final step). The report will be available thereafter on the web and in printed form 7. International Conference of Drug Regulatory AuthoritiesA discussion on stability conditions was held during the International Conference of Drug Regulatory Authorities (ICDRA) in Seoul in April 2006 ( ). During this session, entitled “Stability: Global challenges for harmonisation”, the following topics were addressed:•news from Asia: how to deal with real humid and hot storage conditions in ASEAN countries;•what’s new in the Americas? Stability testing for varying climatic conditions; and•challenges for the ICH stability guidelines outside the ICH regions.Recommendations from this meeting will be available on the WHO medicines website (www.who.int/medicines ).Future implementationIt remains to be seen how these new conditions will be implemented in the WHO member states.The WHO would be very interested to receive information from its individual member states as to which of the above described conditions (zones IV a or IVb) would be applicable in their territory.The intention is to make this information easily accessible to third parties on an international basisand to see which of the two conditions is most commonly applied.References1.World Health Organization, Expert Committee on Specifications for Pharmaceutical Preparations, 34th Report, T echnical Report series, No 863 Annex 5 (1996) (www.who.int/medicines/strategy/quality_safety/annex5_trs863.doc)2.World Health Organization, Expert Committee on Specifications for Pharmaceutical Preparations, 37th Report, T echnical Report Series, No 908, page 13 (2003), http://whqlibdoc.who.int/trs/WHO_TRS_908.pdf3.World Health Organization, WHO guidelines on stability testing, WHO Drug Information, 16(1): 35,(2002), www.who.int/druginformation/vol16num1_2002/16-1table_of_contents.shtml4.International Conference on Harmonization, guidelines Q1A and Q1F , /5.Stability testing for hot and humid climates,WHO Drug Information V ol 18, No 2, 2004, page 113ff,www.who.int/druginformation/vol18num2_2004/DI18-2.pdf6.Consultation of stability studies in a global environment,www.who.int/medicines/areas/quality_safety/quality_assurance/ConsultStabstudies/en/index.html7.World Health Organization, Expert Committee on Specifications for Pharmaceutical Preparations, 40th Report, T echnical Report Series, No 937, 2006The WHO now wantsmember countries to tellit whether zone IVa orIVb would apply in theirterritory。
稳定评估会议流程步骤及内容分析
稳定评估会议流程步骤及内容分析The process of a stability review committee meeting typically involves the following steps:1. Opening remarks: The meeting begins with a welcome address and introduction of the committee members.2. Review of previous meeting minutes: The minutes from the previous meeting are reviewed and approved.3. Presentation of stability data: The data collected from stability studies are presented by the responsible team or individual. This includes information on the product's stability profile, any observed changes, and any potential impact on product quality.4. Discussion and analysis: The committee members discuss the presented data, analyze the findings, and raise any questions or concerns.5. Decision-making: Based on the data and discussions, the committee makes decisions regarding the product's stability and anynecessary actions or recommendations.6. Action plan: If any issues or concerns are identified, an action plan is developed to address them. This may include additional stability testing, formulation adjustments, or process improvements.7. Documentation: The decisions, action plan, and any other important discussions or recommendations are documented in the meeting minutes.8. Closing remarks: The meeting concludes with a summary of the decisions made and any next steps to be taken.中文回答：稳评会议的流程通常包括以下步骤：1. 开场致辞：会议开始时，会进行欢迎辞并介绍与会人员。
Good_manufacturing_practice_lecture_7
Good ManufacturingPracticeLaboratory controlDrug stabilityIt refers to the capacity of a drug substance or product to remain within established specifications of identity, strength, quality and purity in a specified period of time.Stability is officially defined as the time lapse during which the drug product retains the same properties and characteristics that it possessed at the time of manufacture.The stability of a product is expressed as the expiry period or technically as shelf-life.Why Stability?Provide a 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,• and lightEstablish a• re-test period for the drug substance or a• shelf life for the drug product and• recommended storage conditionsObjectives of stability study-To gather information during preformulation stage to produce a stable product. -To determine maximum expiration date.-To gate on idea of storage conditions.-To determine the packaging components.-The retest period of pharmaceuticals.-Transport conditions.The purposes of stability studies are to predict and confirm productshelf-life under the climatic conditions expected during trade storage,shipping, house storage, and use.●Chemical degradation of active drug may reduce the quality of therapeutic indices like 5-fluorouracil, carbamazepine etc have very small therapeutic range, slight degradation of drug may produce sub-therapeutic concentration.●After degradation, a drug may produce more toxic product (s) which may be more toxic than the parent product.●Instability of drug product reduce bioavailability. This may be caused by physical or chemical instability.●Instability of a product may change the physical appearance of the product.Factors affecting drug stabilityStorage timeStorage conditionsType of dosage formContainer and closure system1-Environmental factorsTemperature --Light-TemperatureOxygen --Moisture-Oxygen-Carbon dioxide2-Drugs or excipients in the dosage formParticle size of drugpH of the vehicle3-Microbial contamination4-Trace metal Contamination5-Leaching from containersTypes of stability studies:Physical stabilityChemical stabilityMicrobiological stabilityPhysical stability implies that:-The formulation is totally unchanged throughout its shelf life and has not suffered any changes by way of appearance, organoleptic properties, hardness, brittleness, particle size etc.It is significant as it affects:-pharmaceutical elegance-drug content uniformity-drug release rate.Chemical stability implies:-The lack of any decomposition in the chemical moiety that isincorporated in the formulation as the drug, preservatives or anyother excipients.-This decomposition may influence the physical and chemicalstability of the drugMicrobiological stability implies that:-The formulation has not suffered from any microbiological attack and is meeting the standards with respect to lack of contamination/sterility.Physical changes• Appearance• Melting point• Clarity and color of solution• Water• Crystal modification (Polymorphism)• Particle sizeChemical changes• Increase in Degradation products • Decrease of AssayMicrobial changes• Growth of microorganismPackaging And Stability :The immediate container and closure are particularly important in affectingproduct stability. They play an important role in the product shelf-life.They may accelerate degradation reactions, be an additive to or an absorbentof the drug substance, or be ineffective in protecting the contents from environmental conditions.Packaging And Stability:Glass-Glass is resistant to chemical and physical change and is the most commonly used material.Limitations Overcome1. Its alkaline surface may raise the use of Borosilicate glass whichpH of the pharmaceutical andinduce chemical reaction.contains fewer reactive alkali ionsthan the other 3 types of USP-recognized glass.2. Ionic radicals in the drug mayprecipitate insoluble crystals fromthe glass such as barium sulfate.Treatment the glass with heat aswell as the use of buffers.3-Permits the transmission of lightwhich may accelerate physical andchemical reactions in the drug.Amber coloured glass reducinglight-induced reactions.Packaging And Stability :PlasticsThe problems with plastic are:1. Migration of the drug through the plastic into the environment.2. Transfer of environmental moisture, oxygen, and other elements into the pharmaceutical product.3. Leaching of container ingredients into the drug.4.Adsorption or absorption of the active drug or excipients by the plastic.Packaging And Stability : MetalsVarious alloys and aluminium tubes may be utilized as containers for-emulsions, ointments, creams and pastes.They may cause corrosion and precipitation in the drug Limitation:-product especially with products at extreme pH values or those containing metallic ions.Overcome:Coating the tubes with polymers may reduce these-tendencies.Packaging And Stability :RubberRubber also has the problems of extraction of drug ingredients and leaching-of container ingredients.The use of neoprene, butyl or natural rubber, in combination with certain epoxy, Teflon, or vanish coating, substantially reduces drug-container interaction.The pretreatment of rubber vial stoppers and closures with water and steam-removes surface blooms and also reduces potential leaching that might affect chemical analysis, toxicity, or pyrogenicity of the drug formulation.Stability studies at different stages1. Stress-and accelerated Testing with drug substances2. Stability on pre-formulation batches3. Stress testing on scale-up Batches4. Accelerated and long term testing for registration5. On-going Stability testing6. Follow-up StabilitiesStability testingThere shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability shall be used in determining appropriate storage conditions and expiration dates.The written program shall be followed and shall include:1) Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability.2) Storage conditions for samples retained for testing.3) Reliable, meaningful, and specific test methods.4) Testing of the drug product in the same container-closure system as that in which the drug product is marketed.5) Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted.An adequate number of batches of each drug product shall be testedto determine an appropriate expiration date and a record of such datashall be maintained.(c) For homeopathic drug products, the requirements of this section are as follows:(1) There shall be a written assessment of stability based at least on testing or examination of the drug product for compatibility of the ingredients,and based on marketing experience with the drug product to indicate that there is no degradation of the product for the normal or expected period of use.(2) Evaluation of stability shall be based on the same container-closuresystem in which the drug product is being marketed.The purposes of stability studies are to predict and confirm productshelf life under the climatic conditions expected during trade storage,shipping, house storage, and use.●Before commencement of a stability evaluation the stability protocolshould be written and approved—usually by technical services andQA.●The key elements of a stability protocol include1. Product name and packaging details. The information should besufficiently detailed to clearly identify the specific formulation(s) to beevaluated, the specific container/closure types (and sources), the batchsize(s).2. Storage conditions.3. Number of batches to be evaluated. Normally a minimum of three batches is required to provide a sufficient basis for shelf-life prediction. Developmentand stability batches may be used provided they are of the same formulationsas the commercial product and they were processed in an equivalent manner.ICH, which used the climatic zoneconceptThe key points included:• Stability storage conditions will normally involve long-term studies at 25°±2°C with 60% RH ±5% with at least 12 months of data before filing; accelerated studies at 40°±2°C and 75% RH ±5% with at least 6 months of data.• Where ‘‘significant change’’ occurs during the 40°C accelerated study an additional intermediate station should be used, such as 30°±2°C/ 60% RH ±5%. ‘‘Significant change’’ was defined as a 5% loss of potency, any degradant exceeding its specification limit, exceeding pH limits, dissolution failures using 12 units, failures of physical specifications (hardness, color, etc.).In general, “significant change” for a drug product is defined as:1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures;2. Any degradation product’s exceeding its acceptance criterion;3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation); however, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions; and, as appropriate for the dosage form:4. Failure to meet the acceptance criterion for pH; or5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.• For less stable products the storage (and labeling) conditions maybe reduced but the accelerated conditions should still be at least 15°Cabove those used for long-term evaluation.• For products where water loss may be important, such as liquids orsemisolids in plastic containers, it may be more appropriate toreplace the high-RH conditions by lower RH such as 10–20%.• The same storage conditions are to be applied for the evaluation ofbulk drug substances. However, retest dates may be used instead ofexpiration dates.4. Test methodology.The stability testing monograph need not include all of the criteria defined in the product release monograph. Only those parameters that are potentially susceptible to change during storage and that may impact on quality, safety, or efficacy needto be evaluated.5. Test frequency should be adequate to demonstrate any degradationand to provide enough data points for statistical evaluation. For thescale-up batches and the first three commercial batches testing isexpected initially, at 3-month intervals during the first year, 6-monthlyin the second year, and yearly thereafter.For long term studies, frequency of testing should be sufficient to establish the stability profile of the drug product. For products with a proposed shelf life of at least 12 months, the frequency of testing at the long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed shelf life.At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study isrecommended.6. Name and/or titles of those responsible for assessing the data. Where possible, and appropriate, the data should be evaluated statistically to obtain the shelf-life.When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended .Stability studies can be classified into three types:1. Studies, usually under accelerated conditions to predict a tentativeshelf-life for a new or modified product or process. For a new drugsubstance these studies usually commence with a preformulationevaluation.The effect of stress conditions such as temperature, humidity, light,acidity, and oxygen, can provide much useful information to theformulator.The potential interactive effects of the bulk drug and the anticipateddosage form excipients may also be evaluated.The accelerated studies at elevated temperature on the dosage form should allow some extrapolation to provide a tentative shelf-life.The ICH guidelines allow extrapolation of 6 months data under accelerated conditions with 12 months data at 25°C/60% RH to predict a shelf-life of up to 24 months. Shelf-life in excess of 24 months should rarely be extrapolated from accelerated data.Where there is a change of manufacturing facility for the dosageform, but using the same process and similar equipment, 3 monthsaccelerated data may suffice, again with the commitment to monitorthe first three commercial batches.2. Studies under conditions appropriate to the market, or those defined in the product labeling, are used to provide real-time data for confirmation of the predicted tentative shelf-life. These studies are usually performed using controlled environmental cabinets.A typical warehouse may be an acceptable alternative provided temperature and humidity are recorded. For certain physical parameters such as dissolution, tablet fragility, and parenteral sterility, accelerated conditions may not provideuseful data for extrapolation.Where such studies demonstrate that the predicted tentative shelf-life was too optimistic it would be necessary to consider recall of released batches.Real-time studies are also used to extend the defined shelf-life where the predicted value is found to be too pessimistic.3. Stability studies on current production.Once the shelf-life is established it is necessary to evaluate someongoing batches to confirm that current production is behaving in asimilar manner. This is to detect the possible impact of any subtle orunknown changes to the components or process. In the event that achange is observed, it will be necessary to perform a root causeanalysis.At this stage there should be a considerable amount of availablestability data that identify the shelf-life limiting factors.The stability requirements for homeopathic products are less demanding than for other drug products. The levels of ‘‘active ingredients’’ are frequently so low that determination of degradation products, or even assay of the active itself, may not be practicable. The requirements allow examination for compatibility as an alternative to testing.Climatic zones●Climatic zonesThe four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions.●Expiration dateThe date placed on the container label of a drug product designating the time prior to which a batch of the product is expected to remain within the approved shelf life specification if stored under defined conditions, and after which it must not be used.●Shelf life (also referred to as expiration dating period)The time period during which a drug product is expected to remain within the approved shelf-life specification, provided that it is stored under the conditions defined on the container label.。
ICH指导原则
Q8 Pharmaceutical Development 药物开发
Q8(R2) Pharmaceutical Development 药物开发
Q8/9/10 Q&AsR4Q8/Q9/Q10 Implementation
Q9 Quality Risk Management 质量风险管理
Q9 Quality Risk Management Q8/9/10 Q&AsR4Q8/Q9/Q10 Implementation
Changes in their Manufacturing Process 基于不同生产工艺的生物技术产品/生物产品的可比较性
Q6A- Q6B Specifications规格
Q6A Specifications : Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances质量规格：新原料 药和新制剂的检验程序和可接收标准：化学物质( 包括决定过程)
Q1C Stability Testing for New Dosage Forms新剂型的稳定性试验 Q1D Bracketing and Matrixing Designs for Stability Testing of New
Drug Substances and Products 原料药和制剂稳定性试验的交叉和矩阵设计
Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients活性药 物成份的GMP指南
Q7 Q&As Questions and Answers: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
WHO稳定性试验指南
introductionintroductionintroductionintroductionfinishedpharmaceuticalfinishedpharmaceuticalproductsfppsproductsfppsfinishedpharmaceuticalfinishedpharmaceuticalproductsfppsproductsfppsactivepharmaceuticalactivepharmaceuticalingredientsingredientsapisapisactivepharmaceuticalactivepharmaceuticalingredientsingredientsapisapisactivepharmaceuticalingredient31general降解产物degradationproduct其他易发生变化的api参数otherapiparameterschange32stresstesting影响因素试验强力破坏试验api的stresstesting可以进而确定降解途径和分子固有的稳定性并验证所使用的分析方法的稳定性指示能力可以提供科技文献中支持确定的降解产物和降解途径的相关数据若没有相关支持性数据则进行stresstesting使用一批api进行stresstesting试验内容取决于api的性质及相关fpp的类型
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Technical Details: P-values
Consider the following three models:
• Model 1 – Time, Batch, Batch * Time • Model 2 – Time, Batch • Model 3 – Time
P-value = 0.5 x P-value using the difference and chisquare distribution with 1 df + 0.5 x P-value using the difference and chi-square distribution with 2 df. If the P-value from model 1 vs model 2 > 0.25, then fit model 3 and compare it to model 2 (to test Batch term).
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Stability Study Analysis
按照ICH指南，你可以假设三批溶液具有相同的截距（如果p-值批
>0.25）。换句话说，你可以假设三批开始时间= 0相同的杂质水平，
并可以合并三批的截距。
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Using Minitab
立足保质期的平均无故障时间（回归线）并不保证大多数产品将保持
In our example, both differences are 0. P(X>0) is equal to 2 2 1 for both 1 and 2 , so
• P-value for Interaction is .5*1 + .5*1 = 1 • P-value for Batch is .5*1 = .5
药物的稳定性评估和药物的成分分析是由全球范围内的食品药品监督
管理局FDA
稳定性研究分为几个批次，随着时间的推移进行一系列测试，以获得
药物产品的稳定性的保证
主要工具是回归分析.
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组成部分
该功能包含什么?
创建稳定性分析工作表，类似于创建GageR&R工作表，以便用于建
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Technical Details: P-values
P-Value for model 1 vs model 2 (Batch*Time) uses the following theory: Under the null hypothesis that the variance of the interaction term is zero, the difference follows a mixture distribution of 12 and 22 with weights 0.5.
Since Batch is random, Batch*Time is also random.
Fit model 1 using REML. If converge, get the -2 LogLikelihood value. Repeat the process with model 2. Difference = -2LogLikelihood for model 2 – (-2 Log Likelihood for model 1)
© 2013 Minitab, Inc.
Technical Details: P-values
Essentially do the same thing with models 2 and 3. Difference = -2LogLikelihood for model 3 – (-2 Log Likelihood for model 2) No we have a mixture of Chi-Square 1 and 0, so the P2 value = 0.5 x P-value using only the difference with 1
24月后分别测量
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Stability Study Analysis
按照ICH指南，你可以假设三批有相同的斜率（如果交互作用的p-值
>0.25）。换句话说，你可以假设三批溶液随着时间的推移以相同的
速度在降低，你可以合并他们的斜率。
© 2013 Minitab, Inc.
ICH has the following minimum guideline for submission 人用药物注册技术遵循以下最小建议值
Minimum time period covered for submission 12 months 6 months 6 months
Study Long-term Intermediate Accelerated
可能也取决于储藏条件.
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Using Minitab
一个常见的稳定性研究涉及原料药的3批存放2年，从每批采取每3个月
测量
另一种常见情况的稳定性研究涉及原料药的3批存放4年，从每批的第
一年采取每3个月测量的，每6个月，第二年，第三年和第四年每12个
月。 Default in Minitab.
Technical Details: Stability Study
Fixed batch: regression analysis. Random batch, mixed effect model analysis by REML.
Stability Study: Impurity Level versus Month, Batch Factor Information Factor Type Number of Levels Levels Batch Random 3 AC-228, HX-476, LP-392 Model Selection with α = 0.25 Model -2 LogLikelihood Difference P-Value Month Batch Month*Batch -59.0624 Month Batch -59.0624 0.0000000 1.000 Month -59.0624 -0.0000000 0.500
Terms in selected model: Month, Batch Cumulative Distribution Function Chi-Square with 1 DF x P( X ≤ x ) 1.49946 0.779246
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Technical Details: Stability Study
立收据收集计划 .
对数据的分析，包括分批汇集在适当的时候，简单的图形的结果
预测不同批次之间是否有差异.
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Introduction
案例介绍 稳定性研究往往涉及
• 活性度成分的降解 • 增加一些杂质的含量
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Introduction
Shelf life plot by default always shows a combined graph for all of the batches (regardless of p-values)
Shelf life plot shows graphs for individual batches if Month*Batch or Batch is significant. If not, only get combined graph.
总体而言，这两个收集总数据相同量的
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Using Minitab
一家制药公司希望以评估他们的产品性能相对于一个为期两年的有效
期限 .
特别是，该公司希望以确定产品是否符合ICH指导原则进行稳定性分
析（其中的边界，对平均值的95％可信区间的一个符合规范的地步）。 有两个响应变量:
• 杂志百分比 (<1.5%) • 有效成分 (> 0.90 mg/mL).
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Using Minitab
从当前的生产线中随机抽取三批Байду номын сангаас本溶液进行分析，每批样本溶液装进
27个容量瓶密封并在室温下存储，然后分别测量0, 3, 6, 9, 12, 15, 18, 21，
在规格的产品的使用寿命。
我们可以用百分位数来确定货架寿命，结果在至少95％的产品在规格
以95％的置信度（可靠性的方法）是的。
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Technical Details: Stability Study
可以把批次设置为随机因子.
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那些行业会用到稳定性分析?
该模块主要指针对制药行业的客户
尽管如此，像化工，食品、饮料及其它消费品行业可能会用到该工具，
用于判断在保质期内，随着时间的推移，产品的稳定性 .
© 2013 Minitab, Inc.
Introduction
Minitab 17新增的功能?
以前的很多客户都是基于Macro来进行分析，在Minitab17中，已经有正式 的工具
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Stability Study: Prediction
Prediction works just like other linear models.
© 2013 Minitab, Inc.