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
stability study of ICH
光照试验-Photostability Testing
Under forcing conditions, decomposition products may be observed that are unlikely to be formed under the conditions used for confirmatory studies. 在强制条件下，可以观察到在确认研究条件下不易生成的分解产 物。 Confirmatory studies should then be undertaken to provide the information necessary for handling, packaging, and labeling. 确认研究提供处理、包装、标签等所需要的信息。
LБайду номын сангаасght Sources
Option 1 Any light source that is designed to produce an
output similar to the D65/ID65 emission standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp. 采用任何输出相似D65/ID65发射标准的光源，如具有紫外输出的 人造日光荧光灯、氙灯或金属卤化物灯。
固体样品应分散在容器中，厚度不超过3mm，液体样品应存放在 化学惰性的透明容器中
11
光照试验-Photostability Testing
CGMP文件_稳定性试验研究程序SOP
4.1 QC 负责进行稳定性研究样品的分析。 The responsibility of performing the analysis of stability samples lies with Quality control.
4.2 QA 负责监督稳定性计划的执行，负责稳定性数据的审核和评估。
3.2 复验日期 Retest Date:
签名/日期 Sign / Date
名字 Name 职务 Designation
制定人 Prepared by
审核人 Reviewed by
批准人 Approved by
文件编码 Doc. No.: 标题：稳定性研究程序 TITLE: PROCEDURE FOR STABILITY STUDIES
制定人 Prepared by
审核人 Reviewed by
批准人 Approved by
文件编码 Doc. No.: 标题：稳定性研究程序 TITLE: PROCEDURE FOR STABILITY STUDIES
Page No.: 4 of 13
5.1.2.5 返工/重新加工的批次 Reprocessed/Reworked batches
标准操作程 序
Standard Operating Procedure
文件编码 Doc. No.: 颁发日期： Issue Date:
替代： Supersedes:
标题：稳定性研究程序 TITLE: PROCEDURE FOR STABILITY STUDIES
生效日期： Effective Date: 复审日期： Review Date: 页码：第 1 页共 13 页 Page No.: 1 of 13
2010 Stability Studies of Fucoxanthin From Sargassum Binderi=FX稳定性
Australian Journal of Basic and Applied Sciences, 4(10): 4580-4584, 2010ISSN 1991-8178Stability Studies of Fucoxanthin From Sargassum Binderi1Siew-Ling Hii, 2Pooi-Yi Choong, 1Kwan-Kit Woo, 2Ching-Lee Wong 1Department of Chemical Engineering, 2Department of Science, Faculty of Engineering and Science, Universiti Tunku Abdul Rahman, Jalan Genting Kelang, Setapak,53300 Kuala Lumpur, Malaysia.Abstract:F ucoxanthin is an important carotenoid component available in all brown algae. In this study, Sargassum binderi was used as the source of fucoxanthin and the main purpose of the study was to evaluate the stability of fucoxanthin extract against the different storage conditions. Stabilities of the extracted fucoxanthin were tested with different pH and with supplementation of antioxidant(i.e., ascorbic acid) in light and dark condition over a storage period of 4 weeks. Colour changes ofthe fucoxanthin extract were monitored using colour software CIE LAB system. The results revealed that fucoxanthin pigment exhibited the greatest stability when stored in dark condition. The pigments were more stable at alkaline pH region as compared to neutral and acidic condition. In dark condition, the addition of ascorbic acid greatly delayed fucoxanthin degradation and concentration ascorbic acid at 1.0% w/v displayed greatest pigment retention. In conclusion, fucoxanthin pigments were sensitive to light exposure and acidic pH condition and could be stabilised by higher concentration of ascorbic acid.Key words: F ucoxanthin, S. binderi, Stability, Colour softwareINTRODUCTIONPigments, as a form of nutrient found in seaweeds, have important nutraceutical properties, including antioxidant, besides providing anti-obesity, anticancer and anti-inflammation effect (Miyashita and Hosokawa, 2007; Maeda et al., 2008). Apart from that, seaweeds have been used for many medical purposes in several traditional medical systems, including nutritional support, immune stimulation and body detoxification (Maeda et al., 2008).F ucoxanthin, a yellowish brown pigment belonging to the xanthophylls of carotenoid pigments is found abundantly in brown algae. The pigment fucoxanthin has attracted much attention as a thermogenic agent, besides contains several other functional components that could benefit an individual with obesity (Maeda et al., 2005). A study proved that the anti-obesity effect of fucoxanthin, through protein and gene expressions mitochondrial uncoupling protein 1 (UCP1) in white adipose tissue (WAT). The results revealed that fucoxanthin up-regulated the expression of UCP1 in WAT and hence contributed to reduction of WAT weight. It is an ideal therapy of obesity as most of the fat is stored in WAT (Maeda et al., 2005, Maeda et al., 2008). Efficiency of fucoxanthin in reducing the viability of prostate cancer cells was also reported (Kotake-Nara et al., 2001). Another beneficial effect of fucoxanthin is the chemoprevention of cancer in which fucoxanthin possesses the inhibitory effect on cancer cells by inhibiting the growth of human neuroblastoma cells and intestinal carcinogenesis (Mori et al., 2004). In poultry breeding and aquaculture, fucoxanthin were excellent feed additive as it increases the yellow color of egg yolk when fed to poultry and the metabolic fate of fucoxanthin in laying hens (Strand et al., 1998).As a type of carotenoids, fucoxanthin are highly susceptible to degradation by external agents, such as heat, low pH, and light exposure, promoting changes of colour due to several conjugated double bonds (Mercadante, 2008). The degradation process would lead to the rearrangement or formation of degradation compounds such as cis-isomers which are thermodynamically less stable and hence resulted in different colours properties and in some cases, volatile compounds (Mercadante, 2008).The present study was undertaken to extract the pigment of fucoxanthin from Sargassum binderi and subsequently, to evaluate the stability of fucoxanthin that subjected to different treatment methods and storage conditions.Corresponding Author:Siew-Ling Hii, Department of Chemical Engineering,E-mail: hiisl@.my; phone: +603-41079802; fax: +603-41079803MATERIALS AND METHODSSpecimen collection:The seaweeds (Sargassum binderi) were collected from Cape Rachado, Port Dickson, Malaysia. The freshly collected were rinsed successively with distilled water to remove sand, epiphytes and saline ions. The seaweeds were left for air-dried in the laboratory for few days. The dried seaweeds were ground into powder form. Extraction of fucoxanthin:The powderised seaweeds were treated with acetone solution for 2 h in the dark condition. Following that, absolute methanol was added and the mixture was stirred for 15 min in room temperature. The supernatant were then vacuum-filtered to remove the seaweed solid particles. The resulting acetone filtrate was concentrated at 40 C, at 556 mbar in a rotary evaporator. The concentrated extract was stored at -20 C for further analysis on its stability.Stability studies of fucoxanthin:For pH stability test, the initial pH of fucoxanthin pigment extract were adjusted to desired pH (pH 3, pH 5, pH 7 and pH 9) by using 1 M HCl or 1 M NaOH, prior to storage. Sample with pH 7 was used as control. For the investigation of antioxidant effect on fucoxanthin stability, L-ascorbic acid were added to the aliquots containing fucoxanthin pigment extract to achieve the desired concentration (% w/v) of 0.1%, 0.5% and 1.0%. Control was also prepared with no addition of L-ascorbic acid. All samples were prepared in triplicates.A total of two sets of triplicate were prepared as the stability of pigment was studied for both light and dark condition. The samples were then subjected to 4 consecutive weeks of observation. Spectrophotometric Analysis of Fucoxanthin Concentration:Concentrations of fucoxanthin were measured at the lof 425 nm by using a single-beam visiblemaxspectrophotometer (Genesys 20, Thermo Scientific).Color characteristics including lightness (L*) and chroma value (colour intensity) were measured using a double-beam UV-Visible spectrophotometer (Lambda 35 UV/Vis Spectrum, Perkin-Elmer) equipped with UVWinLab Version 2.85.04 and a colour software, Wincol Version 2.05 Perkin-Elmer Advanced Spectroscopy Colour Application Software.Statistical analysis:The data obtained in this study were statistically analysed by using the SPSS 11.5 software (SPSS 11.5 for Windows® software, SPSS Incorporation). Statistical analysis was performed to determine and compare the relationship between different sample treatments in different storage conditions by one-way analysis of variance (ANOVA) and Post Hoc Duncan test. Significance of difference was defined at p < 0.05.RESULTS AND DISCUSSIONEffect of Antioxidant Additives on Fucoxanthin Stability:As shown in F igure 1, despite the addition of ascorbic acid, fucoxanthin pigment degraded drastically immediate after one week of storage, in all samples which were exposed to the artificial light source. In contrast, with the addition of ascorbic acid, fucoxanthin pigment exhibited the greatest stability with approximately 50% of pigment retained when stored in dark condition (Table 1). F rom statistical analysis, samples without the addition of ascorbic acid exhibited the least pigment retention while with the addition of 1% w/v of ascorbic acid, the fucoxanthin pigment possessed greater stability as compared to others. This phenomenon suggested that fucoxanthin is at its most stable state with higher concentration of ascorbic acid supplementation.Ascorbic acid is a powerful antioxidant owing to the ability to donate a hydrogen atom and form a relatively stable ascorbyl free radical (Weber et al., 1996). Being a scavenger of reactive oxygen and nitrogen oxide species, ascorbic acid showed effectiveness in combating superoxide radical ion, hydrogen peroxide, the hydroxyl radical and singlet oxygen (Yan et al., 1999). F rom Table 1, the degradation rate of pigment was slower with the aid of ascorbic acid and ascorbic acid at 1% w/v proved to be a good treatment for preservation of the colour. In addition, antioxidant such as ascorbic acid is a molecule capable of slowing and preventing the oxidation of other molecules. Fucoxanthin is a major carotenoid in brown algae and it has the property of easily oxidized (Sinninghe Damsté & Koopmans, 1997). Hence, addition of ascorbic acid might be favourable and thus contributing to the stability of fucoxanthin.Fi g. 1: Stability of fucoxanthin treated with ascorbic acid and exposed to lightEffect of pH:The stabilities of fucoxanthin in different pH condition (pH 3, pH 5, pH 7 and pH 9) were studied over a storage period of four weeks in light and dark condition. The extracted fucoxanthin exhibited greater stability in dark condition when pH of solution was adjusted to pH 9 (Table 2). According to Hui (2006), carotenoids are relatively stable at alkaline pH and it was suggested that the pigment could retain pigment better in alkaline condition as compared to acidic condition. Furthermore, acid is known to initiate degradation of carotenoids in food and beverages by a largely unknown mechanism (Chen et al., 1995). Factors such as acids could also promote trans–cis isomerization reactions and lead to the degradation of pigment (Gliemmo et al., 2009).The stability of fucoxanthin was the least in the pH 3 which suggested that fucoxanthin was relatively unstable in acidic condition (Table 2). Carotenoids have been found to be protonated by nitric acid and moderately strong acids such as trichloroacetic acid and trifluoroacetic acid, except for carotenoids bearing the hydroxyl group (Mortensen and Skibsted, 2000). However, the protonation site varies where carotenoids containing carbonyl groups are preferentially protonated on this group and not on a carbon atom of the conjugated system. F or carotenoids containing hydroxy groups, there was only a slight alteration of the carotenoid recativity (Mortensen and Skibsted, 2000). Thus, this contributed to the higher stability of carotenoids with carbonyl groups compared to that of other xanthophylls and carotenes.According to a study conducted by Chen et al. (1995), at high pH (pH 10 and pH 8), the rate of degradation of carotene and xanthophylls contents of lucerne juice was significantly slower than at acidic pH (pH 6.5 and pH 5.4). Hence, it could possible be verified that acidity increased degradation of carotenoids, with the presence of other degradation mechanisms of carotenoids such as heat and light.Effect of light:Carotenoids are sensitive towards light and hence easily degraded by light (Mortensen & Skibsted, 2000). In the present study, accelerated degradation of pigment was highly observed in the presence of light under the various condition of pH and antioxidant addition (Table 1 and Table 2). F actor such as light promotes trans-cis isomerisation reactions and eventually explained the fading colour of the pigment (Gliemmo et al., 2009). Besides that, it might also be accompanied by the formation of new compounds due to oxidation which would give rise to loss of color (Arita et al., 2005) and in some cases, formation of aroma compounds as well (Mortensen and Skibsted, 2000). According to Arita et al. (2005), light is a potential reason for degradation of carotenoids during storage as the photostability of pigment is very much affected by its carotenoids’structure.Colour properties analysis:The fucoxanthin extract were evaluated with respect to lightness and chroma weekly during the four week storage period. Luminosity (L) is a measure of lightness or brightness of the colour. A positive ǻL value is lighter and a negative value is darker. Chroma, on the other hand, is a measure of colour intensity where the higher the value the higher is the intensity it represents (Diaz et al., 2006). For instance, the higher luminosity value of sample indicated that the lower amount of pigment retained in the sample while the higher content of pigment was represented by higher chroma values.In the present study, despite the method of treatments, all the samples stored in dark condition exhibited higher chroma values and smaller increase in lightness values when compared to the samples exposed to light (data not shown), indicating better stability of fucoxanthin with the absence of light source.Table 1: Effect of ascorbic acid supplementation on retention of fucoxanthinAscorbic acid concentration (% w/v)Pigment retention (%)----------------------------------------------------------------------------------------------Light condition Dark conditionControl 2.949.10.1 5.655.90.510.166.41.07.871.0Table 2: Effect of pH on retention of fucoxanthinpH Pigment retention (%)-----------------------------------------------------------------------------------------Light condition Dark condition3 1.729.35 1.937.37 2.048.79 2.162.1Conclusion:Fucoxanthin extracted from Sargassum binderi exhibited sensitivity towards different factors such as light, pH and addition of antioxidant. Overall, the fucoxanthin pigments were more resistant to degradation in dark condition as compared to pigment exposed to light which had accelerated rate of colour degradation. Addition of antioxidant further protects the fucoxanthin pigments from degradation. The fucoxanthin extract supplemented with 1.0% w/v of ascorbic acid displayed greatest pigment retention in both dark and light condition. The most favourable pH condition in providing the greatest stability for the pigment was pH 9, especially in dark condition. Therefore, it could be concluded that the fucoxanthin pigments were sensitive to light exposure, the least stable in acidic pH condition and higher concentration of ascorbic acid supplementation exerted stabilisation role on fucoxanthin.ACKNOWLEDGEMENTSThe authors gratefully acknowledge Department of Science, Faculty of Engineering and Science, Universiti Tunku Abdul Rahman (UTAR), Malaysia for the research facilities.REFERENCESArita, S., S. Ando, H. Hosoda, K. Sakaue, T. Nagata, Y. Murata, Y. Shimoishi and M. Tada, 2005. Acceleration effect of sulfides on photodegradation of carotenoids by UVA irradiation.Biosci. Biotech. Bioch., 69: 1786-1789.Chen, B.H., H.Y. Peng and H.E. Chen, 1995. Changes of carotenoids, color, and vitamin A contents during processing of carrot juice. J. Agr. F ood Chem., 43: 1912-1919.Diaz, F.S., E.M.S. Lopez, S.F. Kerstupp, R.V. Ibarra and L. Scheinvar, 2006. Colorant extraction from red prickly pear (Opuntia Lasiacantha) for food application. Electron. J. Env. Agr. Food Chem., 5: 1330-1337.Gliemmo, M.F., M.E., Latorre, L.N. Gerschenson and C.A. Campos, 2009. Color stability of pumpkin (Cucurbita moschata, Duchesne ex Poiret) puree during storage at room temperature: Effect of pH, potassium sorbate, ascorbic acid and packaging material. LWT - F ood Sci. Tech., 42: 196-201.Hui, Y.H., 2006. Handbook of food science, technology, and engineering. United States of America: CRC Press.Kotake-Nara, E., M. Kushiro, H. Zhang, T. Sugawara, K. Miyashita and A. Nagao, 2001. Carotenoids affect proliferation of human prostate cancer cells. J. Nutr., 131: 3303-3306.Maeda, H., M. Hosokawa, T. Sashima, K. F unayama and K. Myashita, 2005. F ucoxanthin from edible seaweed, Undaria pinnatifida, shows antiobesity effect through UCP 1 expression in white adipose tissues. Biochem. Bioph. Res. Co., 332: 392-397.Maeda, H., T. Tsukui, T. Sashima, M. Hosokawa and K. Miyashita, 2008. Seaweed carotenoid, fucoxanthin, as a multi-functionals nutrient. Asia Pac. J. Clin. Nutr., 17:196-199.Mercadante, A.Z., 2008. Carotenoids in foods: sources and stability during processing and storage. In: Carmen S (ed.) F ood colorants: chemical and functional properties. Boca Raton, CRC Press., pp: 213-240.Miyashit, K. and M. Hosokawa, 2007. Beneficial health effect of seaweed carotenoid, fucoxanthin. In: Marine nutraceuticals and functional foods. United States of America, CRC Press.Mori, K., T. Ooi, M. Hiraoka, N. Oka, H. Hamada, M. Tamura and T. Kusumi, 2004. F ucoxanthin and its metabolites in edible brown algae cultivated in deep seawater. Mar. Drugs, 2: 63-72.Mortensen, A. and L. H. Skibsted, 2000. Kinetics and mechanism of the primary steps of degradation of carotenoids by acid in homogeneous solution. J. Agr. F ood Chem., 48: 279-286.Sinninghe Damsté, J.S. and M.P. Koopmans, 1997. The fate of carotenoids in sediments: An overview. Pure Appl. Chem., 69: 2067-2074.Strand, A., O. Herstad and S. Liaaen-Jensen, 1998. Fucoxanthin metabolites in egg yolks of laying hens. Comp. Biochem. Physiol. A, 119: 963–974.Weber, P., A. Bendich and Schalch, 1996. Ascorbic acid and human health – a review of recent data relevant to human requirements. Int. J. Vitam. Nutr. Res., 66: 19-30.Yan, X., Y. Chuda, M. Suzuki and T. Nagata, 1999. F ucoxanthin as the major antioxidant in Hijikia fusiformis, a common edible seaweed. Biosci. Biotech. Bioch., 63: 605-607.。
Q1A(R2) 新原料药和制剂的稳定性试验 中英文对照版_2020.4.16
STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTSQ1A(R2)新原料药和制剂的稳定性试验Current Step4version现第四版Dated6February20032003年2月6日制定目录1.INTRODUCTION导言 (3)1.1.Objectives of the Guideline目的 (3)1.2.Scope of the Guideline范围 (3)1.3.General Principles通则 (4)2.GUIDELINES指导 (5)2.1.Drug Substance原料药 (5)2.1.1.General概述 (5)2.1.2.Stress Testing影响因素试验 (5)2.1.3.Selection of Batches批次选择 (6)2.1.4.Container Closure System包装容器系统 (6)2.1.5.Specification质量标准 (7)2.1.6.Testing Frequency检验频次 (7)2.1.7.Storage Conditions贮藏条件 (8)2.1.8.Stability Commitment稳定性承诺 (11)2.1.9.Evaluation评估 (12)2.1.10.Statements/Labeling说明书/标签 (14)2.2.Drug Product制剂 (14)2.2.1.General通则 (15)2.2.2.Photostability Testing光稳定性试验 (15)2.2.3.Selection of Batches批次选择 (15)2.2.4.Container Closure System包装容器系统 (16)2.2.5.Specification质量标准 (16)2.2.6.Testing Frequency检验频次 (17)2.2.7.Storage Conditions贮藏条件 (18)2.2.8.Stability Commitment稳定性承诺 (26)2.2.9.Evaluation评估 (27)2.2.10.Statements/Labeling说明书/标签 (29)3.GLOSSARY术语 (29)4.REFERENCES参考文献 (38)1.INTRODUCTION导言1.1.Objectives of the Guideline目的The following guideline is a revised version of the ICH Q1A guideline and defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the three regions of the EC,Japan,and the United States.It does not seek necessarily to cover the testing for registration in or export to other areas of the world.以下指导原则是ICH Q1A的修订版，定义了新原料药和制剂在欧洲、日本、美国三个地区注册所需要的稳定性资料要求。
2013.8-FDA指南：ANDA：原料药和制剂稳定性试验问答(中英文)
201308 FDA指南：ANDA：原料药和制剂稳定性试验问答（中英文）Guidance for Industry 行业指南ANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料药和制剂稳定性试验问答DRAFT GUIDANCE指南草案This guidance document is being distributed for comment purposes only.本指南文件发布仅供讨论。
Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic commentsto . Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document contact (CDER) Radhika Rajagopalan 240-276-8546.U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)August 2013GenericsGuidance for IndustryANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料药和制剂稳定性试验问答Additional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 2201Center for Drug Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave., Silver Spring, MD 20993Phone: 301-796-3400; Fax: 301-847-8714druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)August 2013Generics Contains Nonbinding Recommendations Draft — Not for ImplementationTABLE OF CONTENTSI. INTRODUCTION 介绍II. QUESTIONS AND ANSWERS 问与答A. General 一般问题B. Drug Master File 药物主文件.C. Drug Product Manufacturing and Packaging 药品生产和包装D. Amendments to Pending ANDA Application 未批准ANDA申请的增补E. Stability Studies 稳定性试验.Guidance for Industry[1]ANDAs: Stability Testing of Drug Substances andProductsQuestions and AnswersANDA：原料药和制剂稳定性试验问答This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any right s for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.本指南草案，如果最终定稿，代表的是FDA目前对这一专题的态度。
FDA指南设计：ANDA原料药和制剂稳定性试验问答201805
201405 FDA指南：ANDA：原料药和制剂稳定性试验问答Guidance for Industry 行业指南ANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料药和制剂稳定性试验问答Final GUIDANCE最终稿指南U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)May 2014GenericsGuidance for IndustryANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料药和制剂稳定性试验问答Additional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 2201 Center for Drug Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave., Silver Spring, MD 20993 Phone: 301-796-3400; Fax: 301-847-8714druginfo@U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)May 2014GenericsTABLE OF CONTENTS 目录I. INTRODUCTION介绍II. QUESTIONS AND ANSWERS提问和回答A. General一般问题B. Drug Master File药物主文件.C. Drug Product Manufacturing and Packaging药品生产和包装D. Amendments to Pending ANDA Application未批准ANDA申请的增补E. Stability Studies稳定性试验.Guidance for IndustryANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料药和制剂稳定性试验问答This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.本指南代表的是FDA目前对这一专题的态度。
in use stability专题研究
In use stability专题研究Zhulikou431 内部培训2012 中国谨记纸上得来终觉浅，绝知此事要躬行！---陆游1.本培训资料参考文献更新至20121101.2.本专题资料主要针对药品in use stability研究。
3.任何宝贵建议，请联系zhulikou431@.目录（contents）第01章：概念解析第02章：中国药典对药品使用期间稳定性要求第03章：cde指导原则对药品使用期间稳定性要求第04章：EMA指南对药品使用期间稳定性要求第05章：WHO对药品使用期间稳定性要求第06章：cde电子刊物对药品使用期间稳定性要求第07章：其他法规文献阐述In use stability专题研究第01章：in use stability概念解析In use stability，顾名思义，指的是药品使用期间稳定性研究项目。
对于如下使用条件的药品，需要考察in use stability 项目：---药品使用前，需要重新配置或者稀释；---药品标签声明，和其他药品混合仍然具有稳定性；---药品包装多次打开以后，药品需要继续保持质量稳定性。
In use stability专题研究第02章：中国药典对药品使用期间稳定性要求中国药典2010版附录XIX C《原料药与药物制剂稳定性试验指导原则》也要求：此外，有些药物制剂还应考察临用时配制和使用过程中的稳定性。
In use stability专题研究第03章：cde指导原则对药品使用期间稳定性要求中国cde2005年发布了《化学药物稳定性研究技术指导原则》，其中对于in use stability，进行了明确规定：稳定性试验要求在一定的温度、湿度、光照条件下进行，这些放置条件的设置应充分考虑到药品在贮存、运输及使用过程中可能遇到的环境因素。
对于需要溶解或者稀释后使用的药品，如注射用无菌粉末、溶液片剂等，还应考察临床使用条件下的稳定性。
In use stability专题研究第04章：EMA指南对药品使用期间稳定性要求2001年3月，EMA发布了《NOTE FOR GUIDANCE ON IN-USE STABILITY TESTING OF HUMAN MEDICINAL PRODUCTS》，专门对此问题进行法规阐述。
大分子药物cmc流程
大分子药物cmc流程大分子药物指的是分子量较大的药物，例如蛋白质药物和多肽药物。
和小分子药物相比，大分子药物具有更复杂的结构和药理作用，因此其研发和制造具有独特的挑战和流程。
以下是大分子药物的药物制剂CMC（化学-制造-控制）流程的一个概览。
1. 药物研发和筛选阶段（Discovery and Lead Optimization）在这个阶段，研究人员通过生物工程技术或合成方法，产生和筛选出具有潜在药理活性的大分子药物候选物（例如蛋白质药物或多肽药物）。
这些候选物需要经过初步的理化性质和生物活性评估。
2. 药物候选物开发阶段（Drug Candidate Development）在这个阶段，候选药物会进一步进行优化和开发。
首先，需要详细了解候选物的结构和功能特性，包括药物的抗原性、稳定性、免疫原性和生理药理学等。
这些信息将在后续的制造和控制过程中起到指导作用。
3. 制备药物原料（Starting Materials）大分子药物的制备过程通常包括大量的蛋白表达和精细分离纯化步骤。
制备药物原料涉及到选择适合的表达系统和培养条件，以及利用蛋白分离技术将目标蛋白纯化出来。
纯化的目的是去除杂质，确保制备出纯度高的蛋白质药物。
4. 药物制造（Drug Manufacturing）大分子药物的制造通常涉及到复杂的生产过程。
其中一个关键步骤是蛋白药物的表达和培养。
这包括将蛋白质基因导入表达宿主细胞，并通过适合的培养条件使其表达和产生目标蛋白质。
接下来，需要对蛋白质进行纯化、结构调节和去除杂质。
5. 药物质量控制（Quality Control）药物质量控制是确保生产出的药物符合规定质量标准的关键步骤。
这包括对药物进行识别、浓度测定、杂质检测、活性测定、稳定性评估等一系列的物理化学和生物学测试。
药物质量控制旨在确保药物的纯度、活性和稳定性。
6. 药物配方开发（Formulation Development）药物配方开发是将纯化得到的蛋白质药物转化为适合使用的制剂的过程。
稳定性考察SOP
●稳定性考察SOP stability study SOP1. 目的Objective/Purpose (3)2. 适用范围Scope (3)3. 责任部门（人）及权限Responsible department (person) (3)3.1 处于临床和注册阶段的研发产品development products in clinical and registration phase (3)3. 2 对于商业化产品commercial products (4)4. 定义、符号和缩略语Definition，signal and abbreviation (4)4.1 定义 (4)4.1.1 加速试验Accelerated testing (4)4.1.2 强力破坏试验Stress testing (Drug Substance) (4)4.1.3 强力破坏试验(制剂) Stress testing (Drug Product) (5)4.2 简写abbreviations (5)5. 物料和设备Materials and equipment (5)6. 规程Procedure (5)6.1 稳定性方案stability protocol (5)6.2 成品稳定性研究Drug Product stability (6)6.2.1 批次和数量Number and Size of Batches (6)6.2.2 加速稳定性accelerated stability (7)6.2.3贮存条件Storage Conditions (7)6.2.4检测方法和标准Test methods and specifications (7)6.2.5 容器密封系统Container-Closure System (8)6.2.6 防腐剂Preservatives (8)6.2.7 变更引起的稳定性研究Stability study for change control (8)6.3原液和中间体Bulk Drug Substances and Intermediates (9)6.3.1 考察批次和样品量Number and Size of Batches (9)6.3.2 加速稳定性研究Accelerated Studies (9)6.3.3 贮存条件Storage Conditions (9)6.3.4 检测方法和标准Test methods and specifications (10)6.3.5 容器密封系统Container-Closure System (10)6.3.6 防腐剂检测Preservatives (11)6.3.7 变更引起的稳定性研究Stability study for change control (11)6.4 实际贮存条件下长期稳定性稳定性试验计划real storage conditions long term stability plan (12)6.5 加速和强力稳定性试验研究Accelerated and stress study (12)6.6取样检测时间点和检测窗Timepoints for sampling and testing window (13)6.7 可接收标准Acceptance criteria (13)6.8 偏差管理和它们在稳定性报告中的追朔Deviations Management and their traceability in the stabilityreport (13)6.9稳定性数据趋势分析和统计分析Stability Data trending and Statistical Analysis (14)6.10 上市产品的稳定性研究后续产品的稳定性研究Time point frequency for Follow-up Stability Studies 156.11 和药政部门沟通Communication with Health Authorities (15)6.12 稳定性试验箱/稳定性试验房间管理stability chamber or stability room (16)6.13 稳定性样品留样stability samples retention (16)6.14 稳定性样品送检stability samples delivery (16)6.15 稳定性结果汇总 (16)6.16 稳定性报告stability report (17)6.17 稳定性中期报告Interim Study Report (17)6.18 稳定性方案和报告的编号stability protocol and report number (17)7．记录报告Reporting (17)8．参考文献Reference documents (17)9．附件attachment (18)10．注意事项Notes (18)1. 目的Objective/Purpose本文的主要目的是按照WHO，ICH,《中国药典》和GMP要求，管理研发和上市疫苗产品稳定性研究，确定产品的复验期/有效期，贮存和运输条件。
stability词根
stability词根Stability是一个常用的词根，它来自于拉丁语的“stabilitas”，意为坚定、稳定、持久。
在现代英语中，它被广泛用于描述事物的保持不变、固定性和稳定性。
今天，我们就来探讨一下围绕“stability词根”这个主题。
一、相关词汇1. Stable：稳定的，牢固的2. Instability：不稳定性，动荡3. Unstable：不稳定的，不安定的4. Stability control：稳定控制，车辆稳定性控制系统5. Stability test：稳定性测试，评估某物的稳定性和可靠性的测试二、在日常生活中的应用1. 经济稳定：在经济领域，稳定经济是政府的首要任务之一。
为了实现经济稳定，政府通过财政和货币政策等手段，保持住通货膨胀率、失业率和财政收支平衡等指标，使经济保持平稳发展。
2. 婚姻稳定：在家庭生活中，稳定婚姻关系对人们的幸福和家庭和睦至关重要。
夫妻可以通过相互尊重、理解和支持来保持稳定的婚姻关系，避免因种种问题导致婚姻破裂。
3. 交通稳定：在交通领域，车辆稳定性控制系统能够帮助驾驶员在潮湿、不平、弯曲或紧急情况下，避免失控。
通过保持相关部分的合理布局，提高车辆的稳定性，减少发生交通事故的风险。
三、在科学中的应用1. 化学反应稳定性：化学反应的稳定性是最基本的化学性质之一。
化学反应稳定性的高低能够直接影响着其应用效能，因此研究化学反应稳定性是化学领域的一个重要研究方向。
2. 生态系统稳定性：生态系统的稳定性能够反映生态系统中的物种多样性和生态连通性等生态因素的综合作用。
研究生态系统稳定性的高低，有助于了解生态系统的结构、功能和演化等生态学问题，从而为制定生态保护策略提供科学依据。
在总体上说，“stability词根”无疑是一个具有广泛应用场景的学术术语。
无论在生活中还是科学中，这个词根经常出现且被人们广泛使用。
词根的含义在某种程度上是我们了解这个词汇的基础，有助于对知识的准确掌握和深入了解。
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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)
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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。
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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 .
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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.
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