【正文】 ? 附件 3,應(yīng)用的 GMP應(yīng)符合 ICH Q7A,如果有 ,GMP證書的復(fù)印件 ? 如果涉及第三方 ,詳細(xì)的牽涉內(nèi)容 ,地址 ? 如果制造商僅是由純化得到最終物質(zhì)的 ,那么 GMP的聲明和愿意接受檢查的聲明應(yīng)由合同制造商提供 Content of the Dossier ? Nomenclature ? General properties : ? Physical characteristics , in case more than one grade .. special particle size, pacted, particular polymorphic form one CEP only possible in case general specification is identical , otherwise different CEP with sub title ? Mixtures ( as explained in Substances for pharmaceutical ) API plus excipient only accapetable if this is defined in the monograph ? Claims regarding sterility etc. with reference to the monograph, freedom of pyrogens only if monograph foresees this 文件目錄 ? 化學(xué)名 ? 常規(guī)屬性 : ? 物理屬性 ,當(dāng)不只一種級別時 ,如 ,特殊的顆粒度 ,壓縮的 ,如果一般的規(guī)格是確定的 ,一個多態(tài)形式只能有一個 CEP ,否則 ,有副標(biāo)題的不同 CEP ? 混合物 ( 見藥物物質(zhì)的解釋 )原料藥加賦形劑只有在藥典專論中有確認(rèn)才是可接受的 . ? 關(guān)于無菌等的聲明 ,參考專論 ,如果專論預(yù)見到焦精 ,而焦精的免用的聲明 Content of the Dossier ? Manufacturer . ? If different sites are involved for asingle defined process for manufacture or testing , this should be explained ? Make clear which production step is conducted at which sites ? Names and addresses of each site should be given 文件的目錄 ? 制造商 . ? 如果一個單獨(dú)的已確定的制造工藝或檢測涉及不同的現(xiàn)場 ,這需要解釋 . ? 明確哪個生產(chǎn)步驟是在哪個現(xiàn)場進(jìn)行的 . ? 須給出每個現(xiàn)場的名稱和地址 ARED E. TIEFENBACHER (GmbH amp。 Co) VanderSmissenStr. 1 22767 Hamburg Germany Tel.: +49404418090 Fax.: +494044180926 Mail.: Content of the dossier for chemical purity and microbiological quality 文件內(nèi)容 化學(xué)純度和微生物 質(zhì)量 Description of the manufacturing process and Process controls ? Flow Chart incl. Structural formula for starting material and all intermediates ? Include all steps of the process, from starting material to the isolated intermediates to the drug substance ? Detailed description: solvents , reagents ,catalysts , reaction conditions, inf. on intermediates, quantities of all materials for a batch of mercial batch size, yields for isolated intermediates ? Specific emphasis on purification ? Max. batch size with experience acquired , reference to batches in the dossier ? In case of pilot scale batches yet, CEP can be granted providing scale up is immediately reported to the EDQM. 制造工藝和工藝控制的描述 ? 流程圖包括起始物料和全部中間體結(jié)構(gòu)式 ? 包括從起始物料到分離中間體再到得到藥物物質(zhì)的所有工藝步驟 ? 詳細(xì)描述：溶劑，試劑，催化劑，反應(yīng)條件，中間體的信息，一個商業(yè)生產(chǎn)批次的所有材料的數(shù)量，分離出的中間體的產(chǎn)量 ? 尤其強(qiáng)調(diào)純度 ? 經(jīng)驗(yàn)中所獲得的最大批量，參考文件中的批次 ? 仍處在中試批次中，如果批放大后立即報告 EDQM，也可以獲得 CEP Description of the manfacturing process and Process controls ? For sterile products , variable or alternative batch sizes to be justified ? Isemisynthetically manufactured API , fermented starting material well characterised, possible carrying impurities ? Declaration of use/non use of material of animal origin ? Different manufacturing sites and methods or alternatives could be described in one dossier , in case proof is given for each case sepcification and imp. Profile is exactly the same ? Responsibilities of different sites ? In case of alternative processes, batch analysis results to be presented to demonstrate no significant diff. in impurity profiles ? Reprocessing , if reapplication of a step already used 制造工藝和工藝控制的描述 ? 對于無菌產(chǎn)品，可變的或交替的批量要被評估 ? 半合成制造的原料藥，已經(jīng)完全定性的發(fā)酵起始物料，可能的運(yùn)載雜質(zhì)。概況是完全相同的。 ? 再加工，再申請，如果一個工藝步驟已經(jīng)使用 Description of the manfacturing process and Process controls ? Reworking –application of steps different from the described process not acceptable ? Recovery ( mother liquors or filtrates ) of reactants, intermediates or final substance , acceptable in case of approved procedures ? Recovery of the substance without further purification is reworking, not acceptable ? Blending of production batches to obtain larger size is acceptable, providing each incorporated batch is individually tested and meets specification, prior to blending 制造工藝和工藝控制的描述 ? 與所描述的工藝不同的步驟的返工申請不可接受 ? 如果規(guī)程經(jīng)過批準(zhǔn)，回收的（母液或?yàn)V液）反應(yīng)物，中間體或最終物質(zhì)可接受， ? 沒有進(jìn)一步純化的回收物質(zhì)進(jìn)行返工，不可接受 ? 如果每個混合前的小批都是被獨(dú)立檢測過的，并且符合標(biāo)準(zhǔn)，混合小批以獲得大批是可接受的， Schematic description SM 1 SM 2 catalyst Solvent AS 圖解 SM 1 SM 2 催化劑 溶劑 AS Control of materials ?Specification of raw materials and solvents , appropriate ?In case a class I solvent could be present in a solvent , specification and test method。 Control of Critical steps and intermediates : ?Critical steps definition: where process conditions , test requirements or other relevant parameters must be controlled within the predetermined limits to ensure that AS meets specification ?Description of In Process controls ?Intermediates : ?Information on the quality and control of intermediates 關(guān)鍵步驟和中間體的控制： ?關(guān)鍵步驟的定義 ：工藝條件，檢測要求或其他相關(guān)參數(shù)必須控制在預(yù)先確定的限度內(nèi)的以確保 AS符合標(biāo)準(zhǔn) ?過程控制的定義 ?中間體 : ?質(zhì)量信息和中間體的控制 Process validation and/or evaluation ? Process Validation should be provided as appropriate: ? Sterilisation process, including filtration and aseptic processing ? In case the monograph indicates specific additional requirements pliance should be demonstraeted ? For biological substances , specific microbial grade, suitable inactivation should be demonstrated ? Manufacturing process development ? Description and discussion 工藝驗(yàn)證和 /或評估 ? 應(yīng)提供適當(dāng)?shù)墓に囼?yàn)證： ? 消毒工藝，包括過濾和無菌工藝 ? 如果藥典專論中指出專門附加的要求，準(zhǔn)則應(yīng)該被證明 ? 對于生物物質(zhì)，專門的微生物指標(biāo)，適當(dāng)?shù)氖Щ顟?yīng)當(dāng)被證明 ? 制造工藝開發(fā) ? 描述和討論 Characterisation ? Elucidication of Structure and other Characteristics : ? Evidence of chemical structure : ? Elemental analysis, IR spectra, NMR, MS, UV spectra ? Evidence of structure of key intermediates, XRay christallography, optical rotation ? Physicochemical Characteristics : ? Polymorphism, Melting point, DSC ? Solubility ? pKa and pH values 性狀 ?