OUTSOURCING: NEEDS OF THE SUPPLIER AND PURCHASER 外包：供应商和采购商的需求 Steven S. Kuwahara, Ph.D. GXP BioTechnology LLC E-Mail: stevekuwahara@yahoo.com Website: www.gxpbiotech.org SRIBEI11300506 copyright 2006 S.Kuwahara

Common Needs and Goals 普遍需求和目标 The purchaser is planning to produce a marketable final product, and the supplier is providing needed raw material or intermediates. 采购商计划生产适销的最终产品，而供应商提供所需的原材料/中间体。 The supplier needs to provide the purchaser with needed information. 供应商需要向采购商提供所需的信息。 The information is needed because of regulatory requirements imposed on the purchaser. 需要提供这些信息是因为法规方面对采购商的要求。 SRIBEI11300506 copyright 2006 S.Kuwahara

Model for Discussion 讨论模式 We will assume that the purchaser is a U.S. – based pharmaceutical company. 我们假定采购商是一家美国制药公司。 The supplier is an independent Chinese company. 供应商是一家独立的中国公司。 The material is a raw material that will become an ingredient of a final pharmaceutical product that will, initially, be marketed in the U.S. 材料是一种原料，并且将用作首先在美国销售的一种药品的成分。 SRIBEI11300506 copyright 2006 S.Kuwahara

U.S. REGISTRATION 美国方面的登记问题 A company that supplies any component of a U.S. made drug, must register with the FDA. 向在美国制造的药物供应任何成分的公司均必须在美国食品及药品管理局登记。 This company should also designate (appoint) a U.S. agent. This is separate from the Agent for the DMF. 这家公司还应该指定（任命）一家美国代理商。这个代理商与DMF代理商相区分。 SRIBEI11300506 copyright 2006 S.Kuwahara

Purchaser’s Needs Will Become Supplier’s Needs 采购商的需求将成为供应商的需求 The purchaser will need to move toward a marketing license as quickly as possible. 采购商需要尽快拿到营销许可证。 Someone will need to make the first product. 某些人会需要制造第一例产品。 Early product will be tested for toxicity and pharmacokinetics (Also known as Tox, PK &ADME) 早期产品会做毒性和药物动力学测试（也就是毒性、药代动力学及吸收、分布、代谢、排泄测试) This work is done in animals and is covered by the Good Laboratory Practices (GLP) regulations. 这需要先做动物试验并且遵守良好实验室管理规范(GLP) SRIBEI11300506 copyright 2006 S.Kuwahara

MATERIAL SAFETY DATA SHEET (MSDS) 材料安全数据清单(MSDS) Under U.S. rules, before doing ANY work with a new chemical entity (NCE), the workers must receive and read the MSDS for the compound. 根据美国的规定, 在对新化学实体(NCE)做任何工作之前，工作人员必须收到和阅读该化合物的MSDS。 Some people have used copies of other MSDS, but it is best if the MSDS is generated by the manufacturer of the NCE, because each company’s product is different. 某些人使用了其它MSDS的复印件, 但最好是使用这种新化学实体制造者撰写的MSDS, 因为每个公司的产品都是不一样的。 SRIBEI11300506 copyright 2006 S.Kuwahara

MSDS Contents: I MSDS内容： I Company Identification 公司标识 Chemical name, family, CAS No., Product name. 化学名、族、CAS号码、产品名。 Hazards: Health effects, Effects of over exposure. 危险性：健康效应, 过量接触的影响。 First Aid Needs in case of Exposure or Ingestion. 接触或摄入情况下所需的急救措施。 SRIBEI11300506 copyright 2006 S.Kuwahara

MSDS Contents: II MSDS内容： II Fire fighting needs, potential for explosion, flashpoint, hazardous combustion products. 消防需要, 爆炸的可能性, 闪点, 燃烧后产生的有害物质。 Accidental release: Spills, Leaks, Clean up. 事故性排放：泄露, 渗漏, 清理。 Handling and Storage. Stability and Reactivity. 处理与贮藏, 稳定性和反应性。 Personal protection in case of exposure. 接触情况下的个人防护。 SRIBEI11300506 copyright 2006 S.Kuwahara

MSDS Contents: III MSDS内容： III Physical and Chemical Properties. 物理和化学性状。 Toxicity, Ecological problems, Disposal needs. 毒性, 生态问题, 处理需要。 Conditions for Transportation. 运输条件。 Regulatory Considerations and Disclaimer 法规方面的考虑和放弃声明 SRIBEI11300506 copyright 2006 S.Kuwahara

DRUG MASTER FILE (DMF) 药物主文件(DMF) When the purchaser submits the application for permission to begin clinical trials and, later, when the application for a marketing license is submitted, they will need to describe the raw material. 采购商申请开始临床试验的许可，以及后来提交营销许可证的申请时，均需要对原材料进行描述。 The description must include all of the details about the manufacturing procedure. 这种描述必须包括制造过程的所有细节。 SRIBEI11300506 copyright 2006 S.Kuwahara

WHY A DMF? 为什么要有DMF？ Many manufacturers use special procedures in their manufacturing processes, and they consider them to be company trade secrets. 许多制造商在制造过程中采用特殊的工序, 并且视这些工序为公司的商业秘密。 These secrets are protected by using a DMF. 这些秘密会通过使用DMF而得到保护。 IF THE COMPANY HAS NO TRADE SECRETS, THERE IS NO POINT TO A DMF ! 如果公司没有商业秘密的话, 就不需要DMF！ SRIBEI11300506 copyright 2006 S.Kuwahara

DO YOU NEED A DMF? 你需要DMF吗？ THERE IS NO LEGAL NEED FOR A DMF. 法律方面没有对DMF提出要求。 Just because FDA accepts a DMF, this does not mean that the DMF is approved for anything. FDA仅仅是接受DMF，但这并不意味着DMF在任何方面得到了批准。 DMFs have open and closed sections. The closed section protects confidential information. Not everything can be “closed.” DMF有公开和保密部分。保密部分保护机密信息。不是所有信息都能“保密”。 SRIBEI11300506 copyright 2006 S.Kuwahara

TYPES OF DMFs DMF的类型 FDA had five types of DMFs which will be discussed. 我们会讨论FDA五个类型的DMF。 There are also DMFs for Bulk Antibiotics, Blood and Plasma for Processing, etc., if you go to Europe. 如果你的产品销往欧洲的话, 还有散装抗生素DMF, 血液和血浆加工的DMF, 等等。 It is important to know how the product will be used so the correct type of DMF can be chosen. 知道产品是如何使用的是非常重要的。只有知道产品的用途，才能正确地选择DMF的类型。 The DMF contains the Product Specifications and an example of the Certificate of Analysis. DMF 包括产品说明书，以及一份分析证书的样板。 SRIBEI11300506 copyright 2006 S.Kuwahara

DMF Types I - III. DMF类型I - III There are four different types of DMFs. 有四种不同类型的DMF。 Type I covers manufacturing sites, facilities, operating procedures and personnel. It does not exist 类型I包括生产场地、设施、操作程序和人员。（这种类型现在已废除。） Type II covers drug substance (API), intermediates, products and material used in their preparation. 类型II包括原料药(API), 中间体，以及制备过程中使用的产品和材料。 Type III covers packaging material. 类型III包括包装材料。 SRIBEI11300506 copyright 2006 S.Kuwahara

DMF Types IV & V. DMF类型IV 和类型 V Type IV covers Excipients, colorings, flavors, essences (odorants) and material used in their preparation. 类型IV包括赋形剂、着色剂、调味剂、香精（添香剂), 以及制备过程中使用的材料。 Type V covers FDA accepted reference information. You need FDA approval before submitting a Type V except for DMFs for sterile manufacturing facilities and biotechnology product manufacturing. 类型V包括FDA接受的参考信息。你需要先得到FDA的批准, 然后才能提交类型V，除非是无菌制造设施和生物技术产品制造。 SRIBEI11300506 copyright 2006 S.Kuwahara

DMF After Submission 提交DMF后的事项 If FDA accepts a DMF and assigns a number, this is not approval. That depends on the submission 如果FDA接受了DMF, 并且给出了一个接受号, 这并不意味着批准。批准取决于提交的文件。 DMFs need annual updates, especially authorizations DMF需要每年更新一次, 尤其是授权问题。 No requirements, but a U.S. DMF agent can be helpful. (Different from marketing agent.) 这并不是要求, 但如果有美国DMF代理商, 会对事情有帮助。（这个代理与营销代理商不同）。 SRIBEI11300506 copyright 2006 S.Kuwahara

DMF Consequences 提交DMF后的结果 FDA communicates with the DMF owner or agent in case of deficiencies for a submission. 如果提交的文件不全，FDA会与DMF的所有者或代理联系沟通。 When inspected, the DMF owner will be held to everything in the DMF, including GMPs. 检查的时候，DMF的所有者要负责DMF中的所有事宜，包括GMP在内。 Type II and IV DMFs should follow the ICH Common Technical Document (CTD) format. DMF的类型II和类型IV应遵从ICH（人用药物注册技术要求国际协调会议 ）的通用技术文件(CTD)格式。 SRIBEI11300506 copyright 2006 S.Kuwahara

DMF Commitments and Consequences. DMF义务和后果 If the purchaser submits a license application that involves the DMF, the DMF holder can be inspected. 如果采购商提交的授权申请涉及到DMF，DMF的持有者也要接受检查。 The inspection will be a GMP inspection against the contents of the DMF. 这种检查是针对DMF内容的GMP检查。 If the DMF holder fails the inspection, the purchaser’s submission will go on hold. 如果DMF持有者没有通过检查，那么采购商的申请就不能继续下去。 SRIBEI11300506 copyright 2006 S.Kuwahara

THERE ARE MANY GMPs FOR THE U.S. 美国有许多种GMP They are found in Title 21 of the Code of Federal Regulations (21CFR). 这些GMP包含在《美国联邦政府行政法规汇编》第21章 (21CFR)中。 21CFR part 110 (21CFR110) contains the Food GMPs. 21CFR中的第110部分包括食品ＧＭＰ。 21CFR210 and 21CFR211 are the drug GMPs. 21CFR中的第210和第211部分是药物ＧＭＰ。 21CFR210, 211 and 21CFR600, 610 are for biologics. 21CFR中的第210、211、600和610部分是生物制品方面的内容。 21CFR603 has GMPs for blood and blood products. 21CFR中的第603部分包括血液和血液产品方面的内容。 SRIBEI11300506 copyright 2006 S.Kuwahara

U.S. and E.U. GMPs 美国和欧盟的GMP 21CFR 609 and 809 have GMPs for in vitro diagnostics. 21CFR中的第609和809部分包括体外检测试剂的GMP。 21CFR820 contains the GMPs for medical devices. 21CFR中的第820部分包括医疗器械的GMP。 21CFR1241 has the GTPs (Good Tissue Practices). 21CFR中的第1241部分包括良好组织规范（GTP）方面的内容。 21CFR58 has the GLPs (Good Laboratory Practices). 21CFR中的第58部分包括良好实验室管理规范 （GLP）。 E.U. Medical Devices are regulated separately. 欧盟医疗器械区别监管。 Pharmaceutical Inspection Convention 《药品生产检查互相承认公约》 Pharmaceutical Inspection Co-Operation Scheme. (PIC/S) 医药品稽查协约组织 SRIBEI11300506 copyright 2006 S.Kuwahara

THE E.U. ALSO HAS MANY GMPs 欧盟也有许多种GMP Guide To Good Manufacturing Practice For Medicinal Products. 《药品生产质量管理规范准则 》 Vol. 4 of the rules governing medicinal products 该准则第4卷包括医药产品的监管。 in the European Union. 欧盟范围内 Annex 1: Manufacture of Sterile Medicinal Products. 附件1：无菌医药产品的制造 Annex 16: Certification by a Qualified person and Batch Release. 附件16：批签发人的资质证明 SRIBEI11300506 copyright 2006 S.Kuwahara

U. S. GOOD MANUFACTURING PRACTICES (GMP) 美国的GMP ICH Q7A covers GMPs for Active Pharmaceutical Ingredients (APIs). 人用药物注册技术要求国际协调会议 Q7A文件包含了原料药的GMP。 FDA considers Q7A to be a Guideline not a regulation, but Q7A overlaps 21 CFR 210 and 211. FDA将Q7A视为指导方针，而不是规定。Q7A与21 CFR 的第210和第211部分重叠。 FDA says API must meet 21 CFR 210 and 211. FDA称原料药必须满足21 CFR 的第210和第211部分的要求。 SRIBEI11300506 copyright 2006 S.Kuwahara

European Union GMP for APIs 欧盟的原料药GMP The E.U. has adopted Q7A as Annex 18 to the GMPs in Vol. 4 of the Rules Governing Med. Products. 欧盟已经在医药产品监管规则的第四卷GMP部分采纳了Q7A，将其作为附录18。 Directive 2004/27/EC amends Directive 2001/83/EC; requires all APIs to meet Q7A as of Oct. 10, 2005. 《 2004/27/EC指针》是对《 2001/83/EC 指针》进行修改后的版本；新的指针要求, 在2005年10月10日前, 所有的原料药必须达到Q7A的要求。　 SRIBEI11300506 copyright 2006 S.Kuwahara

GMP CONSEQUENCES GMP的后果 Under all GMPs the company making the final drug product must verify the quality of raw materials that it purchases. 所有的GMP均要求，生产最终医药产品的企业必须检验所采购原材料的质量。 This is normally done by auditing the API manufacturer for GMP compliance, and periodically testing the product to verify the information in the Certificate of Analysis. 这一般是通过以下方式达到的：审查原料药制造商是否符合GMP要求；定期对产品进行测试, 以确认《分析证书》中的信息。 SRIBEI11300506 copyright 2006 S.Kuwahara

GUIDANCE FOR INDUSTRY 行业指南 FDA and EMEA (CPMP/CHMP) have issued many guidance documents to tell companies how to meet GMP requirements. FDA和欧洲药品管理局 （专利医药产品委员会/人用医药产品委员会）已经颁布了许多指南性文件, 告知企业如何达到GMP要求。 Guidance documents are not regulations, but if a company follows them, their compliance will not be challenged. 指南性文件不是规定, 但如果一个企业遵从这些文件的话, 企业对规定的符合性就不会受到质疑。 SRIBEI11300506 copyright 2006 S.Kuwahara

QUALITY AGREEMENTS 质量协议 They are normally made between the supplier and purchaser, but a distributor may come between them 质量协议通常是由供应商和采购商签订的，但分销商也可能参与其中。 The agreement is usually between the API and final product manufacturers. 协议通常发生在原料药和最终产品制造商之间。 These have come to be real contracts in the legal sense. 这些协议已经成为法律意义上的真正合同。 SRIBEI11300506 copyright 2006 S.Kuwahara

Requirements of Quality Agreements I. 质量协议的要求I The agreement relates to the quality of the product and commitments from the supplier to the purchaser on how the quality will be maintained. 协议与产品质量相关，与供应商对采购商在如何保持产品质量方面的承诺相关。 Normally, it contains a commitment from the API supplier that the manufacturing method will not be changed without notifying the purchaser BEFORE the change is made. 通常情况下，协议包括原料药供应商的承诺，即不会在不事先通知采购商的情况下改变制造方法。 SRIBEI11300506 copyright 2006 S.Kuwahara

Requirements of Quality Agreements II. 质量协议的要求II There will be agreements on how notifications regarding change control of documents, test methods, and non-conforming product will be handled. 会有协议涉及到如何处理文件、测试方法，以及不合格产品控制方面变动的通知问题。 The basic commitments will be that GMPs will be followed and no major changes may be made without the approval of the purchaser. 基本的承诺是，遵从GMP要求，不在未获得采购方批准的情况下作出大的变动。 SRIBEI11300506 copyright 2006 S.Kuwahara