下载文档原格式
口服缓释制剂体内外相关性研究技术指导原则1997年9月 美国FDA发布2009年6月 药审中心组织翻译萌蒂制药有限公司翻译北核协会审核药审中心最终核准目录I. 前言 (1)II. 背景 (1)III. 体外/体内相关性分类 (2)A. A级 (2)B. B级 (3)C. C级 (3)D. 多重C级 (3)IV. 一般考虑 (3)V. A级体外/体内相关性的创建和评价 (5)A. 创建相关性 (5)B. 相关性的预测能力的评价 (6)VI. C级体外/体内相关性的创建和评价 (9)VII. IVIVC模型的应用 (9)A. 药品生产过程发生变更时的生物等效性豁免 (10)B. 制定溶出度质量标准 (14)有关名词定义口服缓释制剂体内外相关性研究技术指导原则I. 前言本指南的目的是为制药申请者提供有关建议，帮助他们更好地撰写注册文件以支持口服缓释（ER）制剂的体外/体内相关性（IVIVC）结论，此建议适用于新药申请（NDA）、仿制药申请（ANDA）或抗生素药物申请（AADA）。
本指导原则对以下方面进行了阐述：（1）IVIVC模型的创建及其可预测性的评价方法；（2）依据IVIVC模型制定溶出度质量标准；（3）在初期批准阶段或批准前后发生某些变更（如制剂、设备、工艺和生产场地变更）时，出现了必须要证明生物等效性的情况，此时如何将IVIVC模型作为体内生物等效性试验的替代指标。
II. 背景药学专家已对IVIVC模型概念（特别是针对缓控释制剂ER药品）进行了广泛的讨论，根据溶出特征精准预测ER产品生物利用度是一个探索良久的目标。
根据一些研讨会和文献，该领域研究工作已取得了一定成果，相关内容简述如下：•1987年由ASCPT/DIA/APS/FDA主办的研讨会上，一篇题为“CR制剂研讨会报告：问题与争议”（1987）的报告中指出，当时的科学技术水平还不能对ER制剂做出一致的、有效的IVIVC，只是鼓励将IVIVC模型作为将来的目标。
FDA检查员指导手册：原料药生产检查（药品质量保证）第I部分――背景至八十年代后期以来，美国食品与药品管理局以强化了其对原料药(API)生产企业的检查内容。
从部分方面来说，这归咎于对原料药质量在制剂的质量、效力、和安全方面所起的重要作用认识的提高。
例如，在配制成固体口服制剂，混悬剂和局部用药时原料药的化学特性会对制剂的溶出度/生物利用度产生不利影响。
另外，原料中的少量没有鉴别出的杂质或其特性未知的杂质会给病人造成的严重不良反应。
FDA长期以来一直认为，收载在制剂药品生产质量管理规范规定(21 CFR 210 and211)中的CGMP概念对原料药生产工艺同样有效。
这些概念包括，与其他一起，产品质量是生产出来的，雇佣能够胜任和经过培训的员工，建立适宜的书面程序和管理规定，建立一套在线测试和产品测试系统，工艺验证，和保证原料药在预期的使用期内质量稳定。
FDA在1991年出版的化学原料药检查指南，在1994年经过少量的编辑变化，包含有原料药生产的GMP/验证概念应用和范围方面的基本指南，并包含了FDA对杂质和杂质专论方面的要求。
在对国内和国外原料药进行检查时均必须使用该指南，以促进检查的一致性和均一性。
目前，FDA希望生产企业在API生产的全过程实施CGMP，即从起始原料的使用开始，到对原料药质量和纯度产生影响的关键工艺步骤的验证。
该方法认为所需的控制方法完全依赖于实际的生产工艺且随着合成步骤从早期的中间阶段向最终分离和纯化步骤的延伸控制水平也在不断加强。
该方法允许依据工艺本身（即，化学合成工艺和发酵工艺）及特殊工艺步骤的风险性和关键性采取适宜水平的控制方法。
该“控制所有步骤，验证关键工艺步骤”方法包含在FDA的《原料药制造，加工和储存指南》草案内，其在1996年9月20日公布供公众讨论。
后者可以从CDER的网站下载：/cder/api.htm.。
第II部分实施目的：该符合性程序的主要目的是为对国内和国外各类原料药生产企业的检查提供一份综合性的CGMP检查指南。
摘要鉴于美国药品市场在全球市场中的特殊地位，和美国监管法规FDA的cGMP 在全球法规监管政策中的指导性作用，学习和掌握该法规的要求是中国制药企业在实施国际化战略的必由之路。
批准前现场检查是美国药品审批的重要步骤之一，其目的是检查企业的现场GMP状态和检查现场原始数据是否真实及和申报资料一致，现场检查的意见对药品申请是否获得批准至关重要。
本文通过对美国FDA的药品申请批准前检查的政策要求的阐述，并分析总结若干国内企业在接受批准前检查过程中的经验教训，并将中美两国药品批准前检查政策进行了对比分析，希望藉此帮助国内企业更好地理解美国批准前检查政策的要求，在贯彻实施的过程中注意一些关键因素的把握，从而为企业顺利通过美国药品审批提供一些借鉴。
论文简要介绍了美国FDA药品申请批准前检查的政策发展历史和法规依据，并阐述了药品申请批准前检查的目的、范围、方式、实际执行流程、检查政策的基于体系的检查方式的特点，以及六大体系在检查过程中的关注重点等。
并通过国内三个企业通过FDA的批准前检查的案例分析，总结批准前检查流程中的关键环节和如何进行检查后的整改措施及检查成果和教训，强调在完成批准前检查后的维持GMP状态的重要性。
通过分析国际药品市场、中国药品市场、中国制药企业的现状及自身优缺点，论证国际认证特别是美国FDA认证是中国企业发展壮大的必由之路，及获得国际认证后的重要意义，鼓励国内企业坚定国际化战略思维。
鉴于国际法规政策的多样性，论文专门将中美两国的批准前政策的异同点进行了对比分析，并讨论了不同规定的优缺点，方便国内企业更好地理解美国政策。
国家新版的GMP即将推行，其宗旨和美国的cGMP要求更加接近，此对比分析对于国内企业理解和遵循新的中国法规也有积极意义。
关键词：药品申请批准前检查现行药品生产质量管理规范批准前检查政策基于体系的检查The Requirement and E nforcement of FDA’s Pre-approval Inspection（PAI）PolicyAbstractGiven the special position of American drug market in the global market, and the guiding function of American supervise regulations（FDA ‘s cGMP）in global regular policy, it is inevitable for Chinese drug companies to learn and master the requirements of this regulations in order to execute their globalization strategies. Pre-approval inspection is an important step of American drug approval, whose purpose is to ensure that the on-spot GMP and on-spot statistics of companies are true and the same as written in the application material. Therefore, the opinion from the on-spot check is vital to the approval of the application. This thesis, with an illustration of the checking policy requirements prior to FDA drug application approval in U.S.A. , through an analysis of some lessons and experience of some domestic companies during the checking, and a comparison of the checking policies between the two countries, aims to help domestic companies gain a better understanding of the American pre-approval inspection policy, and pay attention to some crucial factors during the execution process, thus to provide some guidance for the companies to get a smooth approval from the American drug approval.The thesis gives a brief introduction of the policy history and the regulation resources of American FDA pre-approval inspection, and an illustration of the purpose, the range, the method, and the actual execution procedure of the check. It lays emphasis on the features of the checking method and the checking policy, and the different focuses of the six systems.By analyzing the current situation and their own advantages and disadvantages of the international drug market, Chinese drug market, and Chinese drug companies, the author draws a conclusion that the international qualification, especial American approval is an inevitable path for Chinese companies to take for their development. Thesignificance of obtaining international 认证encourages domestic companies to become international.With an brief introduction of some necessary steps before the application check, and the sample analysis of the actual check of three domestic companies, the thesis illustrates the critical steps during the process and how to improve after the check. It emphasizes the importance to sustain the GMP state after the check by focusing on the check result, the lesson, and the staff training.Given the variety of international regulations and policies, the author gives a special comparison and analysis of the similarities and differences of the approval polices between China and U.S.A.. and discusses their merits and demerits, therefore hopes to give the domestic companies a better understanding of American policies.The thesis does not give too much pages to the methods and skills about how to cope with the check, with the hope that the companies can regard the basic requirements of GMP as their real target, and perfect and maintain their GMP system through the check. We found that the new Chinese GMP which is to be practice recently is highly similar with American’s cGMP, therefore this analysis is also helpful for Chinese pharmaceutical companies to understand and follow Chinese policy.Key Words: drug, application Pre-approval inspection cGMPChinese PAI policy System-based inspection目录第1章前言 (1)第2章美国FDA药品申请批准前GMP检查（PAI）的要求 (2)2.1 FDA的cGMP检查的目的、分类，检查范围和方式 (4)2.2 美国FDA的药品申请批准前GMP检查的执行流程 (6)2.3 美国FDA的药品申请批准前GMP检查的 (9)第3章中国企业通过FDA的cGMP检查的意义 (15)3.1全球市场情况分析 (15)3.2中国市场分析 (18)cGMP认证的意义分析 (19)第4章制药企业如何准备FDA药品申请批准前检查以及实施检查后的整改22 4.1制药企业如何准备FDA的批准前检查 (22)4.2迎接和陪同FDA的批准前检查 (23)第5章中国企业在准备和应对cGMP批准前检查过程中案例分析 (24)第6章中国企业通过FDA的cGMP现场检查后维持cGMP状态及应对批准后检查（Post- AI）的必要措施 (34)6．1维持良好的GMP状态的常规性条件 (34)6．2在职员工的cGMP培训 (37)第7章中美两国GMP批准前检查政策的异同点对比和先进性分析 (38)7.1中国GMP批准前检查政策的简要介绍 (38)7.2中美两国批准前检查政策的异同点对比和先进性分析 (43)7.3针对中国SFDA的批准前检查政策的建议 (49)结束语 (50)参考文献 (51)致谢 (53)第一章前言制药行业是一个非常特殊的行业，其产业应用的科学基础涵盖物理、化学、生物学、微生物学、医学、材料学、矿物学、机械、电子、光学、流体力学、计算机等多种学科；由于其产品的使用和人类健康息息相关，所以这也是一个被高度关注，关乎国家政治稳定性的特殊行业。
《美国FDA认证与申办指南》权威资讯系列《合成原料药DMF起草大纲》使用说明：1、本大纲是为了帮助我公司客户把握DMF的整体内容而准备的，由于DMF内容繁多，从整体上了解内容框架和组成部分，对于理解FDA对DMF的要求和意图非常有必要；2、根据FDA的要求，凡是本大纲提到的内容，原料药制造商均应该提供。
因此，客户务必依照规定提供尽可能详细的内容。
3、本大纲的内容和相关要求能够确保客户目前的运作达到FDA的cGMP标准，因此，准备DMF的过程，也使客户按照FDA的要求进行整改和提高的过程，这些都为FDA未来的现场检查打下良好基础；4、凡是本大纲中提到的非技术性具体内容要求，请参照本公司专有的与此大纲配套的相关DFM指导性文件，包括《FDA药物主文件指南》、《关于在药品递交中递交的有关原料药生产的支持文件的指南》、《药物申办中质量管理方面通用技术文件格式与内容要求》；5、凡是本大纲中提到的技术性具体内容要求，如杂质、稳定性、验证等具体技术要求，请参照本公司专有的FDA相关技术标准文件，包括《原料药认证指南》、《制剂认证指南》、《化学药物稳定性指南》、《化学药物杂质指南》、《化学药物化验与合格参数指南》、《化学药物验证指南》等；《合成原料药DMF起草大纲》一、公司和生产场地的基本描述1、第一类的DMF文件建议由位于美国之外的人提供，以帮助FDA对他们的生产设施进行现场检查。
DMF文件应描述生产场地、设备能力、生产流程图等。
A Type I DMF is recommended for a person outside of the United States to assist FDA in conducting on site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operational layout.2、第一类的DMF文件对美国国内设施通常不需要，除非该设施没有登记并定期接受检查。
FDA Inspections – Best and Worst Practices Bioresearch Monitoring InspectionsFDA Inspections •Intro•Before FDA arrives•While FDA is on-site•As the inspection closes•Common observations•Following the inspectionBefore FDA Arrives…•Be in compliance!–Have the appropriate staff–Provide training to staff on regulatory requirements, specific protocol requirements, any processes or procedures–Facilitate open communications–Not just the what, but the why compliance matters–Assume all studies conducted will be inspected•Be prepared for an inspection–Have procedures for how to handle an inspection–Mock inspection with staff; use sponsor audits as a toolWhile FDA is on-site•Opening meeting–Scope of inspection–Schedule–Explain roles and responsibilities, study conduct–Explain records, organization, access•Objective is to ensure investigator and site staff have clear communication and expectationsWhile FDA is on-site•During the inspection–Be accessible to answer questions, provide copies–Don’t delay unnecessarily, if time is needed to retrieve records/answer, explain why•Daily wrap up–Questions?–Concerns?–Progress?–Plan for following dayAs the inspection closes•Schedule close out meeting, ensure responsible/knowledgeable parties available•Is there an FDA 483?–Observations clear?–Do you have additional documentation not reviewed during inspection?–Verbal response? Will be included in Establishment Inspection Report –Plan to respond in writing?After the Inspection has Ended•If there was an FDA 483 – should respond in writing –Recap observation–Provide explanation if appropriate–Describe corrective actions considered and when they will beimplemented including any SOP revisions, staff training–Consider impact on any other on-going or future studies•No FDA 483, but discussion items?–Consider any impacts and corrective actions you may need to do –Consider a written response, the items will be reported in theEstablishment Inspection Report and reviewedWritten Responses•Will be reviewed by investigator and center•Will be considered if any regulatory/administrative action is contemplated•Thorough responses help!Common ObservationsWarning Letters and FDA 483s21 CFR 312.60 – General Responsibilities•Failure to Follow the Investigational Plan•Failure to Personally Conduct or Supervise •Failure to Protect Rights, Safety & Welfare of Human Subjects•Failure to Obtain ConsentCommon ObservationsWarning Letters and FDA 483s21 CFR 312.62 - RECORDKEEPINGAND RECORD RETENTION•Inadequate Case Histories•Record Retention•Drug DispositionHow do these Drug findings compare to MedicalDevice Research?•Failure to ensure that an investigation was conducted in accordance with the investigational plan [21 CFR 812.100 & 21 CFR 812.110(b)] was cited in 3 of 3 Warning Letters to Medical Device CIs.•Failure to maintain accurate, complete, and current records of each subject’s case history and exposure to the device [21 CFR 812.140(a)(3)] was included in 2 of 3 Warning Letters issued in 2014 & 2015.Failure to follow the Investigational Plan – WLsspecifically identified•Eligibility Violations - including unacceptable ECG results, a subject previously enrolled in a study and received a treatment that was disqualifying, out of range clinical labs (e.g., liver function, kidney function, hematology), disqualifying medical history, prohibited prior/ConMeds, (+) pregnancy test •Randomization prior to receipt/evaluation of Eligibility DataFailure to follow the Investigational Plan – WLsidentified•Dosing Errors – including overdosing, under-dosing, dispensing wrong drug, wrong sequence of dosing, & failing to follow titration or stopping rules•Missed Efficacy and/or Safety Assessments- blood, urine, and/or stool specimens, ECGs, scans•Out of Window Tests/AssessmentsViolations Can Be Avoided•As I mentioned previously, ensuring staff understand the protocol and regulatory requirements will aid in conducting research in compliance with the regulations•Training–make it effective for your staff–Most sites provide training and yet there are still violations–Not just standard GCP training, but training tailored to the studyrequirementsInvestigator Interaction•Most investigators are well trained professionals…•Each site and study are different, help the investigator understand how your site works and any specific study requirements that may be unique•What to do when there are disagreements between investigator and study staff•Should I fear retaliation?Contacts•FDA 482 will list the geographical district office and phone number•District/Program Division Director, HQ – Deputy Program Director, Program Director•OmbudsmanContacts•Program Director–Chrissy Cochran – Chrissy ***************.gov (301) 796-5663 •Deputy Program Director–David Glasgow –*********************.gov (301) 796-5403 •BIMO East Director–Anne Johnson –********************.gov (215) 717-3003 •BIMO West Director–Eric Pittman –********************.gov (312) 596-4259ORA Ombudsman•Jessica Zeller ********************.gov 240-535-6021•The ORA Ombudsman is dedicated to two primary objectives: –Informally address concerns, complaints, and other issues that arise between ORA and stakeholders outside of the Agency,including industry, governmental organizations (federal, state, territorial, and tribal), and other members of the public; and –Engage in outreach and education for these stakeholders and employees of ORA to enhance communication andtransparency with stakeholders.Questions? •Post Conference Follow-upDavid K. GlasgowDeputy Program Director*********************.gov301-796-5403FDA INSPECTIONSSPONSOR/MONITOR/CROPERSPECTIVE Cassandra KennedyGlobal Head, Regulatory Compliance & Quality AssuranceBest Approaches to InspectionsInspection Preparation begins at the time of study startPosted company policies on photography, internet, guestsCreation of Tried and True Inspection Management Procedures Official Management/Sponsor NotificationsClear Roles and Responsibilities•Inspection Lead•Dedicated Scribe•Document Assembly/Reviewers•Runner•Administrative AssistanceLog of all Document Requested and Provided – Reviewed at least daily Live display of scribe notes to the Prep RoomMaintenance of Duplicate Set of Documents TakenOfficial Daily UpdatesFinal ReportResponse Process including internal/external reviewersResolution and completion of findings (both written and verbal)ConfidentialInspection Lessons LearnedInspection Training – will need to be refreshed often!ReceptionistSecurity GuardsInspection RolesInspection ParticipationSenior Leaders – Not always a good ideaAffiliated representatives (sponsor, CRO, vendor, etc) – Good idea or more to manage??Training opportunity as an observerDon’t lose an inspector within your facility..“Typically”, “Usually”, “I think” – if this is the beginning of your inspection response –STOP The inspection isn’t over until the inspector is gone!ConfidentialFDA Inspections•Philip T. Leese MD•Board Certified in Internal Medicine (1980); I year ER Fellowship. •Investigator for Phase I/II Clinical Research studies (1979-2016) •VP Ph. I for Quintiles’ Phase I CRU in KC (1996-2013)•Retired from Quintiles in Spring of 2016•IRB Board Member for Midlands IRB (MLIRB)- 2016 to present •Consultant for Private Practice Research Initiatives 2016-2018 •Presently consulting with Dept. of Psychiatry Kansas University Medical Center•No Conflicts of Interest to disclose.1572 Investigator Commitments•I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects.•I agree to personally conduct or supervise the described investigation(s).•I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.1572 Investigator Commitments•I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64.•I have read and understand the information in the investigator’s brochure, including the potential risks and side effects of the drug.•I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.•I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those records available for inspection in accordance with 21 CFR 312.68.1572Investigator Commitments•I will ensure that an IRB that complies with the requirements of 21 CFR Part 56will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.•I agree to comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR Part 312.The FDA Inspector wants to ascertain•who performed various aspects of the protocol for the study (e.g., who verified inclusion and exclusion criteria, who obtained informed consent, who collected adverse event data);•whether the IRB approved the protocol, informed consent form, and any amendments to the protocol prior to implementation;•whether the clinical investigator and study staff adhered to the sponsor’s protocol and investigational plan and whether protocol deviations were documented and reported appropriately;•whether informed consent documents were signed by the subject or the subjects’ legally authorized representative prior to entry in the study (i.e., performance of any study related procedures);•whether authority to conduct aspects of the study was delegated, and if so, how the conduct of the study was supervised by the clinical investigator2 ; •where specific aspects of the investigation were performed;The FDA Inspector wants to ascertain •how the study data were obtained and where the study data were recorded;•accountability for the investigational product, including shipping records and disposition of unused investigational product; •whether the clinical investigator disclosed information regarding his financial interests to the sponsor and/or interests of any sub-investigator(s), spouse(s) and dependent children3 ;•the monitor’s communications with the clinical investigator;•the monitor’s evaluations of the progress of the investigation; and •corrective actions in response to previous FDA inspections, if any, regulatory, sponsor and/or monitor correspondence.Common Clinical Investigator Deficiencies*•Failure to follow the investigational plan/agreement &/or regulations. •Protocol deviations.•Inadequate recordkeeping.•Inadequate subject protection – informed consent issues, failure to report Aes.•Inadequate accountability for the investigational product. •Inadequate communication with the IRB.•Investigational product represented as safe/effective.* Clinical Investigator (CP 7348.811) deficiencies identified in FDA Form 483 issued at close of inspections. 2017 BIMO DataPre-study Preparation•Review past Audits/Inspections: Recommendations and lessons learned?•Identify Study Specific tasks which are potential problem areas. •Are there nuances to the I/E criteria, screening, admission, dosing, safety monitoring procedures which could deep six your study? •Review Training files and update for study specific purposes. •Apply Failure Mode Effect Analysis (FMEA) tool to your study. •Use the SIV to clarify questions/issues which surfaced during the above steps.•Implement Checkoff sheets. Have verifiers for critical steps. •Communicate “knowledge” to your study team- not just by e-mail.During Study preparation •Evaluate FMEA risk mitigation action steps.•Document what is working, what is not working.•Make certain your CAPAs are clearly written.•Make certain you document follow-up on your CAPA action steps. •Document if your action steps worked, needed modifications. •Scrutinize amendments for important changes to I/E criteria, dose instructions or procedures, safety monitoring, stopping thresholds. •Communicate, Communicate, Communicate. (esp. Staff turnover). •Study specific sign off sheets for important delegation: PI and partner/s each sign off on a study specific delegation form.Post study Preparation•Have an internal post study “lessons learned session” and do the same with the CRO/Sponsor.•Use a checklist (e.g. UT Southwestern IRB FDA Inspection Preparation Guide) to scrutinize your study TMF and documents for FDA Inspection preparedness.•Go back to your study specific worksheets, your CAPA documents, your CRA memos, etc. to make certain you have documented follow-up on your action items.•Make your corrections and notes to file now, not months or years later when your are preparing for an audit.•Review page 4 of Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors FDA Inspections of Clinical InvestigatorsFDA Inspections•If you have SOPs- periodically review, revise, and update them and then read them and sign off that you have read them.•Have a “sign off” sheet for critical research documents: IB, Protocol, ICF, amendments, revised consents. Use a master checklist to track that Sub Investigators and other team members are updating their knowledge of the investigation. (Keep good team meeting minutes).•Use I/E exclusion checklists.•Dose escalation, Dose titration checklists- use them.•Subject is lost to follow-up- go the extra mile and find out why? •Train, Train, Train.•Communicate, Communicate, Communicate•Problem anticipate and expect errors. Promptly implement plan to address errors or omissions.•Document, Document, Document.FDA Inspection: “Do”•Have a Procedure for handling Audits/Inspections.a. Audit room, War room, scribes, document request process, etc. •Follow that procedure with the help of your team.•Concisely answer only the question asked.•It’s OK to say- I will get back to you.•Be prompt, accurate, honest, and courteous with your responses. •Ask questions to seek clarity around the Inspector’s observations orconcerns.•Update your team daily as to the flow of the “Inspection”.•Ask for recommendations on how to improve: “What have you seen at other sites that you would recommend for us”.FDA Inspection: “Do Not”•Don’t state you will do something and then fail to follow through.•Don’t try to recreate source documents.•Don’t Back date. Use Note to File.•Avoid saying “We usually do this procedure this way or most of the time”.•Don’t blame others for errors, omissions, protocol deviations.•Don’t fail to implement recommendations from an earlier inspection-esp. from the same inspector•Don’t treat the Inspector as an AdversarySome Relevant References•Howard Lee, Heechan Lee. Failure mode and effects analysis drastically reduced potential risks in clinical trial conduct. Drug Design, Development and Therapy 2017:11 3035-3043.•Robert J. Cody, M.D., M.B.A. Anticipating Risk for Human Subjects Participating in Clinical Research: Application of Failure Mode and Effects Analysis. Cancer Investigation, 24:209–214, 2006•/research/research-administration/irb/•1 U.S. FDA, Inspections, Compliance, Enforcement, and Criminal Investigations,/ICECI/EnforcementActions/Warninglett ers/defauIt.htm•Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors FDA Inspections of Clinical Investigators•/downloads/RegulatoryInformation/Guidances/UCM12 6553.pdfFDA Inspections •Questions?Reasons for Routine PI Federal Inspections•Top Recruiter•PI Reputation (Good or Bad)•Data are inconsistent with data from other sites•Importance of a particular study•Impact of site’s data•Just a chance occurrence•Scheduled pre-planned inspectionReasons for Directed (for cause) Inspection•Suspect false or fraudulent data; outlier data•PI appears to be “outside” his/her specialty•Sponsor appears to have rejected data from the site•Appearance of delay in reporting/submitting safety data (SAE and SUSAR reports are delayed)•Questionable sponsor or PI-sponsor monitoring•Questionable informed consent procedures•Questionable IRB approvals•Study carries significant influence on IP approval•Questionable compliance from the site’s IRBReasons for Direct (for cause) Inspection •Complaint filed by• a subject/patient/family member,• Research team staff, Institution, or• Sponsor•IRB•Concern for conflict of interest (COI) among the research team at the siteFDA Inspections from the IRB PerspectiveDavid BoraskyVice President, IRB ComplianceScope of IRB InspectionsFDA Regs21 CFR 11, 50, and 56Published guidance (not typically held to it)DocumentationIRB recordsRoster and related membership informationWritten procedures i.e., SOPs and controlled documentsProtocol-level documents, correspondence, etc.Inspection guided by BIMO manual Manual should guide the inspectionsCovers all areas of IRB work that fall under FDA regulationCan also be used to self-inspect an IRB or to audit vendorsTypical IRB Experience with BIMO InspectionAnnounced 1 to 3 business days in advance21 CFR 50 and 5621 CFR 11 has not been part of audits even when IRB is on Part 11 system Follow the manualRosters, SOPs, etc1 FDA person on site for2 –3 days2 –3 studies and a sample of approved sitesSite level records including ICFs, approval documentation, correspondenceQuestions for the Panel。
GUIDE(1) TO INSPECTIONSOF FOREIGN PHARMACEUTICAL MANUFACTURERS BACKGROUND背景There has been a significant increase in the number of foreign inspections of pharmaceutical manufacturing plants in the past few years. This trend is attributable mainly to the increase in the number of pre-approval inspections although the increase has been noted in other areas such as routine GMP inspections and compliance follow-up activities. Considering the resource-intensive nature of the foreign inspection program, it has become clear that effective and efficient inspectional coverage is crucial to the successful management of the program and that can be achieved only through maintenance of consistency and uniformity of inspection and enforcement activities.在最近几年医药制造厂外检查数量显著增加。
这一趋势主要是由增加的前置审批检查的次数虽然增加了在其他领域如日常GMP检查和合规性的后续活动记录。
美国食品药品治理局〔FDA〕〔一〕美国药政治理机构美国食品药品治理局〔FoodandDrugAdmistraton简称FDA〕，隶属于美国卫生教育福利部，负责全国药品、食品、生物制品、化装品、兽药、医疗器械以及诊断用品等的治理。
FDA下设药品局、食品局、兽药局、放射卫生局、生物制品局、医疗器械及诊断用品局和国家毒理研究中心、区域工作治理机构，即6个局〔有的刊物也称6个中心〕，一个中心和一个区域治理机构。
美国食品药品治理机构共有职工约7500人，FDA总部有1143人，其中药品局为350人。
药品局〔也称药品评价和研究中心〕负责人用药品审批工作，设有8个处和假设干科室。
1．药品治理处。
下设药品信息、信息系统设计、行政治理和预算、医学图书馆4个科室。
2．药品监督办公室。
下设有药品质量评价、药品标签监督、生产和产品质量、科研调查、法规等7个科室。
3．药品标准处。
设有常用药品评价、药品上市和广告2个科。
4．药品审评一处。
下设心血管——肾脏药、抗肿瘤药、营养药、医用造影外科和齿科药、肠胃药和凝血药5个科室。
5．药品审评二处。
下设抗感染药、代谢和内分泌药、抗病毒药3个科室。
6．流行病和生物统计处。
下设流行病及调查、生物统计2个科室。
7．研究处。
下设研究和测试、药物分析2个科室。
8．仿制药品处。
下设仿制药品、生物等效2个科室。
美国食品药品治理局设在华盛顿特区及马利兰州罗克威尔城，机构庞大，分支机构遍布全国各地。
为了加强药品质量治理，FDA将全国划分成6个大区，即太平洋区〔旧金山、西雅图、洛杉肌〕、西南区〔达拉斯、丹佛、堪萨斯〕、中西区〔芝加哥、明尼阿波利斯、底特律〕、东北区〔波士顿、纽约、布法罗〕、中大西洋区〔费城、辛辛那提、纽瓦克、巴尔的摩〕、东南区〔亚特兰大、纳什维尔、新奥尔良、奥兰多、波多利各的圣吉安〕。
每区设立一个大区所，大区所下又设假设干个地区所。
太平洋区的大区所所在地为旧金山，西南区的大区所所在地为达拉斯，中西区的大区所所在地为芝加哥，东北区的大区所所在地为波士顿，中大西洋区的大区所所在地为费城，东南区的大区所所在地为亚特兰大。
Dosage Form Drug Manufacturers cGMPs (10/93)FDA 制剂生产厂检查指南GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURER'S- CGMPR'SNote: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).注：此指南是FDA检查官和其工作人员的参考资料。
此文件不约束FDA，也不赋予任何人任何权利，特权，利益或豁免权。
I. 简介This document is intended to be a general guide to inspections of drug manufacturers to determine their compliance with the drug CGMPR's. This guide should be used with instructions in the IOM, other drug inspection guides, and compliance programs.A list of the inspection guides is referenced in Chapter 10 of the IOM. Some of these guides are:该文件旨在为检查药品生产厂家提供一个总体性的指导，以决定他们是否符合药物生产的cGMP法规。
该指南应该与IOM(Investigations Operations Manual，即检查操作手册)，其他的药品检查指南，及法规符合性程序中的指导一起使用。
口服速释制剂依据BCS 分类系统的生物利用度与生物等效性争论及生物等效性豁免〔草案〕Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a BiopharmaceuticsClassification System Guidance for Industry2023 年5 月一、介绍本指南为 IND、NDA、ANDA、口服固体速释制剂的补充申请以及申请体内生物利用度或生物等效性争论的申请人供给建议。
这些生物等效豁免包括：〔1〕subsequent in vivo BA or BE studies of formulations after the initial establishment of the in vivo BA of IR dosage forms during the IND period；〔2〕in vivo BE studies of IR dosage forms in ANDAs.美国食品及药物治理局颁发的“联邦法规 21 章”〔21CFR〕第 320 局部描述了药品申请和补充申请对生物利用度和生物等效性数据的要求。
同时在 21CFR 320.22 局部有关于体内生物利用度或生物等效性豁免的有关条款。
本指南是在2023 年8 月份公布的“Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System”根底上的更，指南中说明的关于口服固体制剂生物等效的豁免是基于BCS 分类系统的方法。
GUIDE TO INSPECTIONS ORAL SOLUTIONS AND SUSPENSIONSNote: This document is reference material for investigators and other FDApersonnel. The document does not bind FDA, and does no confer any rights,privileges, benefits, or immunities for or on any person(s).I. INTRODUCTIONThe manufacture and control of oral solutions and oral suspensions haspresented some problems to the industry. While bioequivalency concerns areminimal (except for the antiseptic products such as phenytoin suspension),there are other issues which have led to recalls. These includemicrobiological, potency and stability problems. Additionally, because thepopulation using these oral dosage forms includes newborns, pediatrics andgeriatrics who may not be able to take oral solid dosage forms and may becompromised, defective dosage forms can pose a greater risk because of thepopulation being dosed. Thus, this guide will review some of the significantpotential problem areas and provide direction to the investigator whengiving inspectional coverage.II. FACILITIESThe design of the facilities are largely dependent upon the type of productsmanufactured and the potential for cross-contamination and microbiologicalcontamination. For example, the facilities used for the manufacture of OTCoral products might not require the isolation that a steroid or sulfaproduct would require.Review the products manufactured and the procedures used by the firm for theisolation of processes to minimize contamination. Observe the addition ofdrug substance and powdered excipients to manufacturing vessels to determineif operations generate dust. Observe the systems and the efficiency of thedust removal system.The firm's HVAC (Heating Ventilation and Air Conditioning) system may alsowarrant coverage particularly where potent or highly sensitizing drugs areprocessed. Some manufacturers recirculate air without adequate filtration.Where air is recirculated, review the firm's data which demonstrates theefficiency of air filtration such should include surface and/or airsampling.III. EQUIPMENTEquipment should be of sanitary design. This includes sanitary pumps,valves, flow meters and other equipment which can be easily sanitized. Ballvalves, packing in pumps and pockets in flow meters have been identified assources of contamination.In order to facilitate cleaning and sanitization, manufacturing and filling lines should be identified and detailed in drawings and SOPs. In some cases, long delivery lines between manufacturing areas and filling areas have been a source of contamination. Also, SOPs, particularly with regard to timelimitations between batches and for cleaning have been found deficient inmany manufacturers. Review cleaning SOPs, including drawings and validation data with regard to cleaning and sanitization.Equipment used for batching and mixing of oral solutions and suspensions is relatively basic. Generally, these products are formulated on a weight basis with the batching tank on load cells so that a final Q.S. can be made byweight. Volumetric means, such as using a dip stick or line on a tank, have been found to be inaccurate.In most cases, manufacturers will assay samples of the bulk solution orsuspension prior to filling. A much greater variability has been found with batches that have been manufactured volumetrically rather than by weight.For example, one manufacturer had to adjust approximately 8% of the batches manufactured after the final Q.S. because of failure to comply with potency specifications. Unfortunately, the manufacturer relied solely on the bulkassay. After readjustment of the potency based on the assay, batchesoccasionally were found out of specification because of analytical errors.The design of the batching tank with regard to the location of the bottomdischarge valve has also presented problems. Ideally, the bottom discharge valve is flush with the bottom of the tank. In some cases valves, including undesirable ball valves, have been found to be several inches to a footbelow the bottom of the tank. In others, drug or preservative was notcompletely dissolved and was lying in the "dead leg" below the tank withinitial samples being found to be subpotent. For the manufacture ofsuspensions, valves should be flush. Review and observe the batchingequipment and transfer lines.With regard to transfer lines, they are generally hard piped and easilycleaned and sanitized. In some cases manufacturers have used flexible hoses to transfer product. It is not unusual to see flexible hoses lying on thefloor, thus significantly increasing the potential for contamination. Such contamination can occur by operators picking up or handling hoses, andpossibly even placing them in transfer or batching tanks after they had been lying on the floor. It is also a good practice to store hoses in a way that allows them to drain rather than be coiled which may allow moisture tocollect and be a potential source of microbial contamination. Observemanufacturing areas and operator practices, particularly when flexible hose connection are employed.Another common problem occurs when a manifold or common connections areused, especially in water supply, premix or raw material supply tanks. Such common connections have been shown to be a source of contamination.IV. RAW MATERIALSThe physical characteristics, particularly the particle size of the drugsubstance, are very important for suspensions. As with topical products in which the drug is suspended, particles are usually very fine to micronized(less than 25 microns). For syrups, elixir or solution dosage forms in which there is nothing suspended, particle size and physical characteristics ofraw materials are not that important. However, they can affect the rate of dissolution of such raw materials in the manufacturing process. Rawmaterials of a finer particle size may dissolve faster than those of alarger particle size when the product is compounded.Examples of a few of the oral suspensions in which a specific and welldefined particle size specification for the drug substance is importantinclude phenytoin suspension, carbamazepine suspension, trimethoprim andsulfamethoxazole suspension, and hydrocortisone suspension. Review thephysical specifications for any drug substance which is suspended in thedosage form.V. COMPOUNDINGIn addition to a determination of the final volume (Q.S.) as previouslydiscussed, there are microbiological concerns. For oral suspensions, there is the additional concern with uniformity, particularly because of thepotential for segregation during manufacture and storage of the bulksuspension, during transfer to the filling line and during filling. Review the firm's data that support storage times and transfer operations. Thereshould be established procedures and time limits for such operations toaddress the potential for segregation or settling as well as otherunexpected effects that may be caused by extended holding or stirring.For oral solutions and suspensions, the amount and control of temperature is important from a microbiological as well as a potency aspect. For thoseproducts in which temperature is identified as a critical part of theoperation, the firm's documentation of temperature, such as by controlcharts, should be reviewed.There are some manufacturers that rely on heat during compounding to control the microbiological levels in product. For such products, the addition ofpurified water to final Q.S., the batch, and the temperatures duringprocessing should be reviewed.In addition to drug substances, some additives, such as the parabens aredifficult to dissolve and require heat. The control and assurance of their dissolution during the compounding stage should be reviewed. From a potency aspect, the storage of product at high temperatures may increase the level of degradants. Storage limitations (time and temperature) should bejustified by the firm and evaluated during your inspection.There are also some oral liquids which are sensitive to oxygen and have been known to undergo degradation. This is particularly true of the phenothiazine class of drugs, such as perphenazine and chlorpromazine. The manufacture of such products might require the removal of oxygen such as by nitrogenpurging. Additionally, such products might also require storage in sealedtanks, rather than those with loose lids. Manufacturing directions for these products should be reviewed.VI. MICROBIOLOGICALQUALITYThere are some oral liquids in which microbiological contamination canpresent significant health hazards. For example, some oral liquids, such as nystatin suspension are used in infants and immuno-compromised patients, and microbiological contamination with organisms, such as Gram-negativeorganisms, is objectionable. There are other oral liquid preparations such as antacids in which Pseudomonas sp. contamination is also objectionable.For other oral liquids such as cough preparations, the contamination withPseudomonas sp. might not present the same health hazard. Obviously, thecontamination of any preparation with Gram-negative organisms is notdesirable.In addition to the specific contaminant being objectionable, suchcontamination would be indicative of a deficient process as well as aninadequate preservative system. The presence of a specific Pseudomonas sp. may also indicate that other plant or raw material contaminants couldsurvive the process. For example, the fact that a Pseudomonas putidacontaminant is present could also indicate that Pseudomonas aeruginosa, asimilar source organism, could also be present.Both the topical and microbiological inspection guides discuss the methods and limitations of microbiological testing. Similar microbiological testing concepts discussed apply to the testing of oral liquids for microbiological contamination. Review the microbiological testing of raw materials,including purified water, as well as the microbiological testing of finished products. Since FDA laboratories typically utilize more sensitive testmethods than industry, consider sampling any oral liquids in whichmanufacturers have found microbiological counts, no matter how low. Submit samples for testing for objectionable microorganisms.VII. ORAL SUSPENSIONSUNIFORMITYThose liquid products in which the drug is suspended (and not in solution) present manufacturer and control problems.Those liquid products in which the drug is suspended (and not in solution) present manufacture and control problems. Depending upon the viscosity, many suspensions require continuous or periodic agitation during the fillingprocess. If delivery lines are used between the bulk storage tank and thefilling equipment, some segregation may occur, particularly if the product is not viscous. Review the firm's procedures for filling and diagrams forline set-up prior to the filling equipment.Good manufacturing practice would warrant testing bottles from thebeginning, middle and end to assure that segregation has not occurred. Such samples should not be composited.In-process testing for suspensions might also include an assay of a sample from the bulk tank. More important, however, may be testing for viscosity.VIII. PRODUCTSPECIFICATIONSImportant specifications for the manufacture of all solutions include assay and microbial limits. Additional important specifications for suspensionsinclude particle size of the suspended drug, viscosity, pH, and in somecases dissolution. Viscosity can be important from a processing aspect tominimize segregation. Additionally, viscosity has also been shown to beassociated with bioequivalency. pH may also have some meaning regardingeffectiveness of preservative systems and may even have an effect on theamount of drug in solution. With regard to dissolution, there are at least three products which have dissolution specifications. These products include phenytoin suspension, carbamazepine suspension, and sulfamethoxazole andtrimethoprim suspension. Particle size is also important and at this point it would seem that any suspension should have some type of particle sizespecification. As with other dosage forms, the underlying data to supportspecifications should be reviewed.IX. PROCESS VALIDATIONAs with other products, the amount of data needed to support themanufacturing process will vary from product to product. Development (data) should have identified critical phases of the operation, including thepredetermined specifications, that should be monitored during processvalidation.For example, for solutions the key aspects that should be addressed during validation include assurance that the drug substance and preservatives are dissolved. Parameters, such as heat and time should be measured. Also,in-process assay of the bulk solution during and/or after compoundingaccording to predetermined limits are also an important aspects of process validation. For solutions that are sensitive to oxygen and/or light,dissolved oxygen levels would also be an important test. Again, thedevelopment data and the protocol should provide limits. Review firm'sdevelopment data and/or documentation for their justification of theprocess.As discussed, the manufacture of suspensions presents additional problems, particularly in the area of uniformity. Again, development data should have addressed the key compounding and filling steps that assure uniformity. The protocol should provide for the key in-process and finished product tests, along with their specifications. For oral solutions, bioequivalency studies<<< Continued to next message >>><<< This message is part 2 of a previous message >>>may not always be needed. However, oral suspensions, with the possibleexception of some of the antacids, OTC products, usually require abioequivalency or clinical study to demonstrate effectiveness. As with oral solid dosage forms, comparison to the biobatch is an important part ofvalidation of the process.Review the firm's protocol and process validation report and, ifappropriate, compare data for full scale batches to biobatch, data andmanufacturing processes.X. STABILITYOne area that has presented a number of problems includes the assurance of stability of oral liquid products throughout their expiry period. Forexample, there have been a number of recalls of the vitamins with fluoride oral liquid products because of vitamin degradation. Drugs in thephenothiazine class, such as perphenazine, chlorpromazine and promethazine have also shown evidence of instability. Good practice for this class ofdrug products would include quantitation of both the active and primarydegradant. Dosage form manufacturers should know and have specifications for the primary degradant. Review the firm's data and validation data formethods used to quantitate both the active drug and degradant.Because interactions of products with closure systems are possible, liquids and suspensions undergoing stability studies should be stored on their side or inverted in order to determine whether contact of the drug product with the closure system affects product integrity.Moisture loss which can cause the remaining contents to become superpotent and microbiological contamination are other problems associated withinadequate closure systems.XI. PACKAGINGProblems in the packaging of oral liquids have included potency (fill) ofunit dose products, accurate calibration of measuring devices such asdroppers that are often provided. The USP does not provide for doseuniformity testing for oral solutions. Thus, for unit dose solutionproducts, they should deliver the label claim within the limits described in the USP. Review the firm's data to assure uniformity of fill and testprocedures to assure that unit dose samples are being tested.Another problem in the packaging of Oral Liquids is the lack of cleanliness of containers prior to filling. Fibers and even insects have been identified as debris in containers, and particularly plastic containers used for these products. Many manufacturers receive containers shrink-wrapped in plastic to minimize contamination from fiberboard cartons. Many manufacturers utilize compressed air to clean containers. Vapors, such as oil vapors, from thecompressed air have occasionally been found to present problems. Review the firm's systems for the cleaning of containers.There are no references from this document.。
GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT AND VALIDATIONJanuary, 1994Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).I INTRODUCTIONThis inspection guide provides information regarding the inspection and evaluation of the manufacturing and control processes used to manufacture solid oral dosage form pharmaceutical products. This document provides guidance for the FDA investigator and promotes uniformity and consistency during the inspection and evaluation of the validation of the solid oral dosage form manufacturing and control processes. It covers three phases of the validation process; product development, design of the validation protocol, and demonstration runs (validation) of the equipment and process in the manufacture of full scale commercial production batches.Although this document it is not all inclusive, it addresses many of the issues and examples of validation problems of oral solid dosage forms which investigators and analysts may encounter. The inspection team is expected to review other agency documents in preparation for these inspectionsThe Validation Guideline issued by the agency in 1987 defines processvalidation as establishing documented evidence which provides a high degreeof assurance that a specific process will consistently produce a productmeeting its predetermined specifications and quality attributes.The three components of this definition include documented evidence,consistency, and predetermined specifications. Documented evidence includesthe experiments, data and analytical results that support the masterformula, the in-process and finished product specifications, and the filed manufacturing process.With regard to consistency, several batches would have to be manufactured,using the full scale batch size, to demonstrate that a process meets the consistency test. At least three batches are needed to demonstrateconsistency.The development of a product and its manufacturing process andspecifications, the design of the validation protocol, and the demonstration (validation) runs of the full scale manufacturing process requiresscientific judgement based on good scientific data. We expect thatin-process control and product specifications will be established during theproduct development process, with the test batch serving as the critical batch used for the establishment of specifications.Specifications, such as hardness and particle size, should be established prior to validation of the process; these specifications should be included in the validation protocol. The use of product development runs of the process to establish both specifications and demonstrate that the system is validated often causes problems. In these cases, more in-depth inspection and evaluation will be required; some of these process runs often produce failing product because the product specifications have not been fully established and tested.The inspection team should observe facilities, equipment and processes to put data review in proper context. It is also important that raw data, including validation and laboratory logbooks be audited or reviewed toverify accuracy and authenticity.II BACKGROUNDTwo common complaints regarding validation issues frequently have been raised. The first concerns the misconception that the 1987 validation guide represents a new requirement. The second concerns the lack of specificity in the agency's guides. In 1978, the Current Good Manufacturing Practice Regulations were revised and provided for process validation. Therefore this guideline does not represent a new requirement. The regulation is nearly 15 years old.Both the agency and the industry have recognized the need to establish general guidance for the validation of manufacturing processes, and the agency published a draft guideline in March, 1983. However this draft guideline was a very general document addressing general principles and was applicable to sterile and non-sterile drugs and devices. In March, 1984, it was reissued as a draft guideline, and was finalized in May, 1987.The 1987 validation guideline merely points out the need to adequately develop and control manufacturing processes. It discusses microbiological issues and provides few specific an practical applications for thevalidation of manufacturing processes for a marketed solid oral dosage form.The issue of retrospective validation, and its application to marketed products, is frequently encountered. This concept of using historical data (test results), along with process control and process specificity was of value until more scientific methods for demonstrating process validation evolved. It should be pointed out that retrospective validation is not merely the review of test results. It also requires that the manufacturing process be specific and the same each time a batch is manufactured. Thus, specific raw material specifications (including particle size when necessary), in-process specifications (tablet hardness, etc.), and specific manufacturing directions are required. Obviously, any failing batches attributed to the process would necessitate the conclusion that the process is not validated and is inadequate.Prospective process validation is required, particularly for those products introduced in the last 7 to 8 years, or those for which manufacturingchanges have been made. However, in some cases where older products have been on the market without sufficient pre-market process validation, it may be possible to validate, in some measure, the adequacy of the process by examination of accumulated test data on the product and records of the manufacturing procedures used.III PRODUCT DEVELOPMENTA. PRODUCT DEVELOPMENT REPORTSThere is no statute or regulation that specifically requires a product development report, although companies are required to produce scientific data which justifies the formulation and the manufacturing and control processes. Most companies have used product development reports, technology transfer reports, and others to summarize the scientific data that justifies the product and process. The product development report should satisfy the needs of the company. Therefore, there is no specific format for the contents of the report.It is suggested that the company develop a product development SOP which describes the development process, the documentation requirements, and the individuals responsible for approving the filed process. This SOP can be brief and again there is no legal requirement that companies produce such an SOP.Investigators must not list the absence and or the poor quality of a product development report on the FDA 483. The investigators should list or include the inadequacy of data to support the filed process and specific Master Formula filed. It is not a GMP deficiency nor is it a filing requirement to have a formal Development Report. Investigators should review product development reports since they will reduce the time required to inspect the process.The development data found in these reports should include the following:1. Drug Substance CharacterizationCharacterization of the chemical and physical properties of the drug substance is one of the most important steps in the development of a solid dosage form. Chemical properties especially the identification of impurities are very important. In addition, the physical properties of the BPC such as solubility, polymorphism, hygroscopicity, particle size, density, etc. must be addressed.The literature, and actual experience demonstrates, that the physical quality, e.g., particle size of raw materials, can sometimes produce a significant impact on the availability and clinical effect of a dosage form drug. Therefore, it is appropriate that the physical characteristics of a drug substance be characterized, that the impact of the physical characteristics be determined and that a specification for the bulk drug product be established if necessary.Development data will vary between new drugs and generics. Characterization and establishment of specifications for the drug substance is one example.In most cases the manufacturing process for a new drug substance (newchemical entity) is developed and scaled-up before the dosage form. In early development stages very little information is available regardingpolymorphic forms, solubility, etc. Consequently, changes to themanufacturing process for the drug substance may change the purity profileor physical characteristics and thus cause problems with the finished dosage form. Although these types of problems are expected, the firm mustinvestigate and document batch failures for the BPC and dosage form product.On the other hand the generic manufacturer usually purchases the drugsubstance from a BPC manufacturer who may not be willing to supplyinformation regarding the synthesis or analysis of the drug substance.Therefore, the finished dosage form manufacturer must perform theappropriate test to characterize the drug substance chemically andphysically and establish appropriate specifications. This may requiredeveloping analytical methods to identify impurities. In some cases this information can be obtained from literature searches.In either case it is important that the firm compare the drug substance usedto manufacturer the bio-batch or clinical batch(es) and the drug substanceused for the commercial batches. Therefore, review the specifications,analytical methods, and test results for the lots of the drug substance usedto manufacture these batches. Remember that the safety of the drug may bebased upon the type and level of impurities and different physicalcharacteristics may affect dissolution or content uniformity.Inspectional coverage should be given to the physical characteristics of raw materials, especially bulk drug substances, since they frequently affect the performance of the dosage form in which they are incorporated. This isparticularly important for those drug substances that are poorly soluble in water.For those products on which biostudies were conducted, the physicalcharacteristics of the drug substance used for the study should serve as thebasis for the physical specifications.It is widely recognized that when discussing in-vivo release rates and drug absorption rates, fast, immediate release is not always best. For some "immediate" release drug products, such as carbamazepine tablets, a slowerrelease is desired. Therefore, it is frequently desirable to have minimumand maximum particle size specifications to control the release rate. For example, micronizing or milling a drug substance and providing greatersurface area of the substance may also result in faster dissolution andpossibly faster absorption and higher blood levels. Such changes to"improve" the dissolution may not always be desired.In addition to release or dissolution, variation in particle size, particle shape, and/or bulk density can also have an effect on the uniformity ofdosage forms, particularly those manufactured by direct compression ordirect encapsulation.Particulate solids, once mixed, have a tendency to segregate by virtue of differences in the shape, size and density (other variables are also important) of the particles of which they are composed. This process of separation occurs during mixing, as wellas during subsequent handling of the completed mix. Generally, large differences in particle size, density or shape within the mixture result in instability in the mixture. The segregation process normally requires energy input and can be reduced following mixing by careful handling.Some manufacturers have established wide ranges for specifications.Investigators should review these specifications from a GMP and validation perspective. Even though a wide range for a physical specification, such asparticle size or surface area may be established in a filing, it is expectedthat such ranges be verified in the validation of the process. In a recentcourt decision the judge ruled that companies cannot hide behind theapproval of processes listed in an application when these processes do notwork. In other words the approval of the filing has no impact on processesthat do not perform consistently.For example, in a filed process it was determined that particle size wouldhave no effect on drug absorption and dissolution and a wide range particlesize specification was established. However, in the GMP review, it was foundthat variation in particle size had a major effect on content uniformity. Therefore, a tighter particle size specification had to be established.Control of the physical characteristics of the excipient is also important because variations in such characteristics may also affect the performanceof the dosage form. Changes in particle size of some excipients, forexample, may affect content uniformity. In other cases, a change in thesupplier of an excipient or lubricant may affect dissolution orbioavailability. In fact, the release of the active ingredients in someproducts is "timed" by varying lubricant blending time and concentration.The literature contains many examples of lubricant processing causing major changes. Such changes in excipients illustrate the deficiencies with theutilization of retrospective validation because, for such validation to beContinued to next message >>>This message is part 2 of a previous message >>>satisfactory, control of all parameters and key steps in the process are necessary.The control of mixing times and physical characteristics of all ingredientsis critical to successful validation of all formulations and processes. Amajor question that must be addressed is the need for testing physical characteristics (particle size) for each batch of excipient. For many single source excipients, particle size is a supplier specification and is usuallytightly controlled. Having established a specification and not testing eachlot of excipient upon receipt may be satisfactory in such cases. However,for some multi-source excipients and where the dosage formulator expects toshift sources of supply, there may be differences in physicalcharacteristics (particle size) that may have an effect on dose uniformityand dissolution. Examine the practices with respect to the source of supplyof the key excipients and determine if there is justification for the lackof testing lots of excipient for physical characteristics.2. Manufacturing ProceduresProcedures used to manufacture development batches must be specific and well documented. This is necessary for scale-up and subsequent comparison to the commercial process.This is another area where you will see differences between NDA/NADA and ANDA/ANADA products. In the case of the NDA/NADA you will see severalclinical and/or test batches manufactured over a period of time and you would expect to see changes in the process as more is learned about the drug and the process. The level of documentation should increase as the process becomes more defined and the firm begins phase II and III studies.The generic product focus is on the biobatch. Again the process used to manufacturer the biobatch must be well defined and well documented. Also the firm should have worked with the process by means of test batches so they can reproduce the biobatch. Therefore you would expect to see more than one batch made at this stage of the development process.3. In-process TestingSpecific specifications required to control the manufacturing process must be established and justified. This will require granulation studies which would include blend uniformity, sieve analysis, and moisture. Read the section under, "Demonstration Runs of the Process (Validation of Process)" for more information.4. Finished Product TestingTesting for the monograph standards such as content uniformity (when a specification applies), assay, hardness, friability, dissolution, and others are essential.5. Dissolution ProfileThe dissolution profiles for the biobatch or pivotal clinical batches should be evaluated in the product development report. There should be good correlation to the dissolution specifications and test results for the biobatch/clinical test batches and the full scale commercial process.6. StabilityThe Center for Drugs conducts an evaluation of the stability data and approves the expiration date. The product development report should contain an evaluation of the stability data that has been obtained.During post-approval inspections stability data is reviewed by the field. Therefore, the investigator must audit underlying raw data and analytical worksheets to assure the accuracy and authenticity of stability data contained in summary reports.B. PRE-APPROVAL INSPECTIONSValidation of three full size commercial lots is not required for approval of the application, however the firm must have data that justifies the full scale commercial process filed in the NDA/ANDA or NADA/ANADA application. Inother words, the firm should have sufficient research on the test batches to establish specifications for the manufacturing and control procedures listed in the application. These data and specifications form the basis for the validation protocol which may be developed following approval of the application. The final step in the process is the demonstration (validation) runs proving that the process will perform consistently. Firms should validate the process using the specifications listed in the filing.To evaluate the proposed manufacturing process the following areas must be covered during the pre-approval inspection:1. Master FormulaThis document must include specific manufacturing directions for the full scale commercial process including in-process and finished product specifications.Compare the process filed in the application to the process used to manufacturer the bio/clinical batch. In some cases the process may be different after scale-up. This is acceptable if the firm has data showing the product produced by this process will be equivalent. Data such as granulation studies, finished product test results, and dissolution profiles are used to document that the two processes are equivalent.2. History Section of the ApplicationThis section of the application is used to identify the biobatch or batches used for pivotal clinical studies. It is also useful for review of the correspondence between the firm and CDER/CVM. One of the basic objectives of our review is to identify the biobatch. Also, any batches in which in-vivo studies were carried out, and particularly those which in-vivo studies showed inequivalency should be reviewed.3. Development Data (Product Development Report)The firm cannot logically proceed to the validation step without some prior evaluation of the process. During the development phase the critical process parameters must be identified and specifications established. These predetermined specifications must be established during the development of the process, with the biobatch or pivotal clinical batch serving as the reference batch.Development of a solid dosage form will vary from firm to firm and will be dependent upon the specific product and process. However, the formula ranges, physical and chemical specifications of the drug substance and excipients, in-process variables, interaction effects of the dosage form ingredients under normal and stress aging conditions, should be confirmed by limited challenge in pilot-scale and production-size batches.This development data serves as the foundation for the manufacturing procedures, specifications and validation of the commercial process. In some cases, manufacturers have attempted to establish specifications such as hardness and particle size during validation. However, as the validation definition states, specifications must be determined prior to validation ofthe process.When a manufacturer files a manufacturing process in an application, we expect that the process will yield a product which is equivalent to the product on which the biostudy or pivotal clinical study was conducted. Therefore, it is important that the development and scale-up of the process be well documented so that a link between the bio/clinical batches and the commercial process can be established. The firm should have data such as granulation studies, finished product test results, and dissolution profiles which may be used to document that the two processes are equivalent.In most cases in vitro data alone will not be sufficient to document equivalency. Determine if an equivalency evaluation has been made. This bioequivalency evaluation must be made by qualified individuals, and thefirm should have a signed statement documenting that the processes are equivalent. Therefore, in many cases you may see an in-vivo bioequivalency study performed. Obviously, the firm cannot provide this type of data if the have not manufactured pilot or test batches using the types of equipment an controls specified in the proposed master formula.4. Inspection of the FacilitiesIt is important that you physically inspect the facility to assure that the area and the ancillary equipment such as air handling and water systems are suitable for the proposed manufacturing process. Construction of new walls, installation of new equipment, and other significant changes must be evaluated for their impact on the overall compliance with GMP requirements. This includes facilities used for development batches and to be used forfull-scale production batches.5. Raw MaterialsReview the information contained in the Raw Material section under Product Development Report above. Inventory records are a good source for the identification of batches used for product development and biostudies.6. LaboratoryThe inspection of a laboratory requires the use of observations of the laboratory in operation and of the raw laboratory data to evaluate compliance with GMP's and to specifically carry out the commitments in an application or DMF.Evaluate raw laboratory data, laboratory procedures and methods, laboratory equipment, and methods validation data to determine the overall quality of the laboratory operation and the ability to comply with GMP regulations. (Refer to the Laboratory Inspection Guide for additional discussion).Many of our inspection have identified foreign peaks and impurities notfiled or discussed in applications. Also, many of our inspections have shown laboratory test methods not to be validated. The transfer of laboratory methods and technology from the Research and Development Department to the Quality Control Department should be reviewed.7. EquipmentAt the time of the pre-approval inspection we expect that the equipment isin place and qualified. New products, particularly potent drug products, can present cleaning problems in existing equipment. Manufacturers must validate their cleaning processes for the new drug/dosage form. (Refer to the Cleaning Validation Inspection Guide for additional discussion).IV VALIDATION PROTOCOLSValidation protocols are developed from the information obtained during product development research. These protocols list the specific manufacturing process and specifications that will be tested during the demonstration runs. Validation protocols are not required for thePre-Approval Inspection but are required for Post-Approval Inspections.Key processes and control specifications should have been established during product development research and should be carefully listed in thevalidation protocol.V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS)A. TEST BATCH RELATIONSHIPSA "validated" process should produce a dosage form that is directly related to the dosage form on which equivalency and/or efficacy an safety were determined. This is usually the test batch. Therefore, compare the process used to make the test batch with the process that is used for routine full scale production batches. These processes and specifications must be equivalent. Therefore, the importance and the need for good control of the manufacturing process used to produce the test and clinical batches cannot be overemphasized. Typically the control of test batches includes, among others, drug substance characterization, granulation analyses, and dose uniformity and dissolution profiles.The validation report should compare the manufacturing processes and specifications for the test batches to the full scale batches. However, such a finding may be contained in other documents. Request any evaluation that has been conducted on the equivalency of these batches and processes and review any tabulated data that shows the processing equivalency between the biobatch and validation batches.B. Post-Approval Prospective Validation InspectionsInspection team members must reread the sections under Part I Product Development which will not be restated under this section. Those sections contain information that is key to the evaluation of the validation process.In the post-approval, pre-marketing phase, we review the Validation Protocol and the Validation Report. Obviously, a Validation Protocol that lists all of the variables and parameters that should be controlled when the processis validated cannot be written until the variables are identified in the development phase.In many of our post-approval, pre-marketing inspections, validation (and consistency) could not be established. Failures of production size batches included dissolution, content uniformity and potency. Validation reports on batch scale-ups may also reflect selective reporting of data. Only through inspection and review of the facilities and raw data were the problems identified.Several parameters must be considered when evaluating the validation of an oral solid dosage form manufacturing process. For example there are at least eight major areas that must be included:o Biobatch Relationshipo Raw Materialso Manufacturing Procedures and Equipmento Granulation/Mix Analysiso In-Process Controlso Test Results with Validated Methodso Investigations/Product Failureso Site Review1. Raw MaterialsPhysical characteristics of raw materials can vary among manufacturers of drug substances and, on occasion, have varied from lot to lot from the same manufacturer. Upon examination of retain samples of the lots of raw material, obvious physical differences between the two lots may be observed.Review the raw material inventory records to evaluate the use of the drug substance in biobatch, clinical, and/or test batches. Pay attention to the quantities and source of materials used and the testing performed.Inspections should cover the firm's data for the establishment of their physical specifications for drug substances. If the firm has no specification, or a very vague specification, they should be able to provide data to demonstrate that dissolution profiles and content uniformity will be satisfactory over a wide range of particle sizes. For example, a manufacturer may establish a specification of 90% of the particles must be less than 300 microns. For validation of this process, one would expect the use of micronized as well as material with particles close to 300 microns in size.Continued to next message >>>This message is part 3 of a previous message >>>2. Manufacturing Procedures and Equipment。
