本文包含研發不同階段的GMP和質量體系要求，包括以下質量體系項目在不同階段如何實施：

 

Quality management/ oversight

質量管理/監督

 

Personnel training

人員培訓

 

Documentation & records

文件記錄

 

Product release

產品放行

 

Change management

變更管理

 

Deviations/ investigations

偏差/調查

 

CAPA (Corrective Action Preventive Action)

CAPA

 

Auditing

審計

 

Quality agreements

質量協議      

 

研發不同階段的GMP和質量體系要求

 

R&D階段

 

Personnel have science background & aretrained in routine laboratory practices but should also be made aware of GMPprinciples.

人員有科學背景并接受日常實驗室操作的培訓且應使其了解GMP原則

 

Signed notebook records are kept ofproduction and testing activities. If batches fail, they are studied toincrease product and process knowledge.

應保存生產和檢驗活動的簽字記錄。如果批次失敗，對其進行研究以增加產品和工藝知識。

 

R&D activities are well documented inthe note books, as well as in periodic development reports.

研發活動在記錄本和定期開發報告中都有很好的記錄。

 

There is a need to document source/pedigree/chain of custody of biological starting materials – cell ancestor andany animal materials used to create the initial cell line to the extentfeasible (Reference Section 6.0 and Section 3.3.2 of this technical report formore information). 

有必要記錄生物起始物料（用于創建初始細胞系的細胞供體和任何動物材料）的來源/譜系/保管鏈。

 

Toxicity Studies

毒性研究階段

 

GLP practices are implemented as perregulations in specific global regions

GLP實踐是按照全球特定地區的法規實施的

 

EU and FDA GLP Requirements cover the areasof:

歐盟和FDA GLP要求涵蓋以下領域：

 

Organization and Personnel

組織和人員

 

Facilities

設施

 

Equipment

設備

 

Facility Operation

設施操作

 

Articles

物品

 

Protocol and Conduct

方案和執行

 

Records and Reports

記錄和報告

 

Disqualification

不合格

 

There is a need to document the Tox lot andreference standard material with sufficient diligence to allow comparability toclinical/GMP lots later

有必要對毒理學批次和參考標準進行充分的記錄，以便日后與臨床/GMP批次進行比較   

 

Phase 1

一期階段

 

It is expected that a laboratory directorwith a science background is in charge of the Quality Unit (or equivalentfunction) and reviews all procedures and documents.

要求有科學背景的實驗室負責人負責質量部門(或同等職能)并審查所有程序和文件。

 

Use of batch records are highly recommendedbut could be generic.

強烈建議使用批記錄，但可以是通用的。

 

The Bulk Drug Substance is released byQA/QP after satisfactory review of the manufacturing and analytical records anddata (e.g., Completed batch record, analytical results, COA, environmental andwater monitoring data, deviations and changes), as well as compliance to theinvestigational new drug registration (e.g., IND, IMPD).

在對生產和檢驗記錄和數據(如完整的批記錄、檢驗結果、COA、環境和水監測數據、偏差和變更)以及臨床試驗新藥注冊(如IND、IMPD)的符合性進行滿意審查后，散裝藥用物質由QA/QP放行。

 

Manufacturing or testing deviations orunexpected events that do not impact product quality or patient safety shouldbe documented, but could be appended to the executed batch records. Formaldeviation and CAPA systems are recommended, albeit a simple and uncomplicatedsystem, with the level of investigation dictated by the severity of theincident.

應記錄不影響產品質量或患者安全的生產或檢驗偏差或意外事件，但可添加在已執行的批記錄中。建議使用正式的偏差和CAPA系統，即便是一個簡單和不復雜的系統，調查級別由事件的嚴重程度決定。

 

Change management is important duringdevelopment of a product and the process to catalogues changes and facilitatesproduct /process understanding. A system should be in place at all GMPmanufacturing facilities.

變更管理在產品開發和對變更進行分類并促進產品/工藝理解的過程中非常重要。在所有GMP生產設施都應有一個系統。

 

Auditing/self-assessment is recommended,even though it is not mandated.

建議進行審計/自檢，盡管這不是強制性的。

 

Testing or manufacturing conducted by athird party should be subject to a written agreement that might outline criticalquality expectations but a separate quality agreement may not be required.

由第三方進行的檢驗或生產應遵守一份書面協議，說明關鍵的質量期望，但單獨的質量協議則可能不需要。

 

Phase 2 →Phase 3

二期→三期階段

 

Responsibilities are governed by CGMP(e.g., ICH Q7 Eudralex - Volume 4 Good Manufacturing Practice Guidelines, andits Annex 13 by phase of development for some items (e.g., as methods are fullyvalidated or transferred, as master batch records are created). QA/QPresponsibilities must not be delegated to another functional area (unlessallowable by local law), but may be contracted to a qualified external serviceprovider.

職責由CGMP(例如，ICH Q7Eudralex - Volume 4 Good Manufacturing Practice Guidelines，及其附件13)管理，按某些項目的開發階段(例如，方法完全驗證或轉移時，主批記錄創建時)。QA) / QP的職責不能委托給其他職能部門(除非當地法律允許)，但可以委托給有資質的外部服務提供商。

 

QA/QP takes a more active role in directinginvestigations and approving findings and CAPAs.

QA/ QP在管理調查、審批結果和CAPA方面發揮更積極的作用。

 

The reporting structure and hierarchy ofthe Quality Unit should ensure its ability to be independent from production.(From ICH Q7: There should be a quality unit(s) that is independent ofproduction and that fulfills both quality assurance (QA) and quality control(QC) responsibilities).

質量部門的報告結構和等級應確保其可以獨立于生產。(來自ICH Q7:應該有一個獨立于生產并同時履行質量保證(QA)和質量控制(QC)職責的質量部門)。

 

Quality standards (e.g., policies, SOPs)must be reviewed and approved by QA. Even when these standards and procedureshave not been formally changed, they should be subject to periodic review inorder to ensure that they are still valid and up to date with actual practices.It is recommended that for each phase of clinical development, the relevantsummary development reports should be completed to review process

development activities and results. Thereports should include an evaluation of deviations and unexpected results thatare encountered during clinical production, scale up, tech transfer, characterizationstudies, etc.

質量標準(如方針、標準操作規程)必須由質量保證部門(QA)審核和批準。即使這些標準和程序沒有正式變化，也應定期審查，以確保它們仍然有效，并與實際做法保持一致。建議對于臨床開發的每個階段，都應完成相關的總結開發報告，以審查工藝開發活動和結果。報告應包括在臨床生產、放大、技術轉移、特征研究等過程中遇到的偏差和意外結果的評估。

 

The Bulk Drug Substance is released by QA/QPafter review of the completed batch record, COA, environmental and watermonitoring data, deviations and changes, the investigational new drugregistration (e.g., IND, IMPD), and any other relevant information available inthe product specification file as specified in the procedures for batchrelease. QA/QP can delegate the release of manufactured intermediates to otherqualified personnel upon formalized agreements and acceptance.

散裝藥物物質在完成對完整批記錄、COA，環境和水的監測數據，偏差和變更，臨床試驗新藥注冊(例如,IND,IMPD)，以及批放行程序中指定的產品標準文件中規定的其他任何相關信息的審核后，由QA / QP放行。在正式協議和任命后，QA/QP可以將所生產中間體的放行委托給其他有資質的人員。

 

As clinical development proceeds, moredetailed batch records with acceptance criteria or target values should bedeveloped. Master batch records should be used prior to conducting processvalidation. Deviations should be recorded in the batch records as well asrequire formal investigations and CAPA. Deviation and investigations areincreasingly thorough as clinical development proceeds. By Phase 3 a formaldeviation tracking system and a CAPA system should be in place.

隨著臨床開發的進行，應該指定更為詳細的帶有接受標準或目標值的批記錄。主批記錄應在進行工藝驗證之前使用。偏差應在批記錄中記錄，并要求正式調查和CAPA。隨著臨床開發的進行，偏差和調查越來越徹底。在第三階段，正式的偏差跟蹤系統和CAPA系統應到位。

 

Clinical materials should not bedistributed to external partners of the clinical supply chain until all opendeviations, test results, or other documentation are closed and approved byQA/QP.

在所有偏差、檢測結果或其他文件關閉并經QA/QP批準之前，不應將臨床物料分發給臨床供應鏈的外部合作伙伴。

 

Changes during the initial phases ofclinical development should be documented and justified based on the magnitudeof the change. Significant changes to the process should be conducted inaccordance with a written change management procedure and the IND should beupdated accordingly. As clinical development progresses a formal change controlprogram should be developed for Phase 3. Any potential impact of the change onon-going trials should be considered. Changes made during production operationsmust be reviewed by QA/QP during batch disposition.

在臨床開發開始階段的變更應進行記錄，并根據變更的大小進行論證。工藝的重大變更應按照書面變更管理程序進行，IND也應相應更新。隨著臨床開發的進展，應該為第三階段制定一個正式的變更控制程序。變更對正在進行的試驗的任何潛在影響都應予以考慮。在生產操作過程中所做的變更必須在批處理過程中由QA/QP進行審核。

 

QA/QP audits should be conducted based upona risk assessment. Typically, fewer audits are conducted for early phasedevelopment operations and compounds.

應基于風險評估進行QA/QP 審計。通常，對開發早期階段的操作和合成進行的審計較少。