實施 PIC/S GMP 之藥廠應執行之相關作業 --- Product quality review system 與 持續性安定性試驗 等軟體差異介紹

1. 實施PIC/S GMP之藥廠應執行之相關作業---Product quality review system與持續性安定性試驗等軟體差異介紹 食品藥物管理局 呂理福科長 九十九年九月十五、二十七日

2. 大綱 • Product quality review system • 品質保證系統 • Product quality review • Corrective and Preventive Action（CAPA） • PIC/S 與我國現行GMP軟體標準差異介紹 • 持續性安定性試驗 • 文件 • 自我查核 • 確效作業 • 取樣方式、供應商稽查與法定留樣

3. Product quality review system • 品質保證系統 • Product quality review • Corrective and Preventive Action（CAPA）

4. 品質保證系統

5. 簡介 • Quality • 品質系統簡介 • 國際標準組織ISO • 世界衛生組織ＷＨＯ • 美國食品藥物管理局ＦＤＡ • 歐盟EC及國際醫藥品稽查協約組織ＰＩＣ/Ｓ • PIC/S中有關品質保證系統之介紹 • Quality System • CAPA • Product Quality review

6. Quality • The holder of a manufacturing authorization • must ensure their products: • Fit for their intended use, comply with the requirements of the marketing authorization • Do not place patients at risk due to inadequate safety, quality or efficacy

7. How to achieve the Quality Requirement To achieve the quality requirement: There must be a comprehensively designed and correctly implementedQuality system

8. Quality System Trend 2000 ISO 9001:2000 ”Quality Management System” 2002.8 FDA:「Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century」

9. Quality System Trend 2003.7 「ICH Q8 Pharmaceutical Development」 ( Status : Step 5, November 2005 ) 「ICH Q9 Quality Risk Management」 ( Status : Step 5, November 2005 ) 「ICH Q10 Pharmaceutical Quality System」 ( Status : Step 5, June 2008 )

10. Quality System Trend 2006.1 PIC/S,「Guide to GMP for Medicinal Products」/ Revision of 「Chapter 1 Quality Management」---1.5 Basic requirements of product quality review 2006.9 FDA,「Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations 」

11. 我國現行GMP • 第77條 ……藥廠得由其廠內各部門選派專業資深人員組成品質保證系統，定期執行廠內各項作業運作情形之確認，包括訂立廠內執行本編之自我審查作業程序，並製作紀錄、報告備查。

12. ISO 9000品質系統 • 品質系統是在建立與維持一個書面化的品質系統做為確保產品符合規定要求的手段ISO 10013 。品質保證是『一種依計畫進行，以便對實體將能達成品質要求提供信心的作業技術與活動』（ISO 8402:1994） • ISO 9000:2000提升到全面品質管理(TQM)層次，在內容上，主要依據下列八大原則作為建立的基礎： • 顧客導向的組織 (Customer focused organization) • 領導 (Leadership) • 全員參與 (Involvement of people) • 流程管理 (Process approach) • 系統著手的管理 (System approach to management) • 持續改善 (Continual improvement) • 依事實作決策 (Factual approach to decision making) • 互利的供應商關係 (Mutual beneficial supplier relationship)

13. Quality System (FDA) • This system assures overall compliance with cGMP and internal procedures and specifications. • The system includes the quality control unit and all of its review and approval duties (e.g., change control, reprocessing, batch release, annual record review, validation protocols, and reports, etc.) • It includes all product defect evaluations and evaluation of returned and salvage drug products.

14. Commission Directive 2003/94/EC • Pharmaceutical Quality assurance means the total sum of the organized arrangements made with the object of ensuring that medicinal products or the investigational medicinal products are the quality required for their intended use. • Good Manufacturing Practice means the part of quality assurance are consistently produced and controlled in accordance with the quality standards appropriate to their intended use.

15. Quality assurance (PIC/S GMP) • Quality assurance is the sum total of the organized arrangements made with the object of ensuring that medicinal products are the quality required for their intended use. • Quality assurance incorporates GMP plus other factors.

16. Quality System Model

17. An ICH vision： The future Pharmaceutical Quality Systems High Risk from Manufacturing Continual Improvement Quality Risk Management Q9 Q10 Pharm. Quality Systems Low Q8 Pharmaceutical Development Low Risk form Product / Process Development High

18. Quality Management --- PIC/S Quality Assurance System Product Development GMP (Facilities, Production,QC, Distribution,…) Product Quality Review (2006.1)

19. Quality ManagementSystem - ISO 9001:2000 Continuous improvement of the Quality Management System CLIENT CLIENT Management Responsibility Resource Management Measurement, Analysis and Improvement Satisfaction Product / Service Realization Requirement Product Input Output

20. Quality System Model --- FDA 「Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations」, FDA, 2006.9 Management Responsibilities Resources Evaluation Activities Manufacturing

21. PIC/S GMP Quality Management System • 要可靠地達成這個品質目標，應有經過全面設計和正確實施的品質保證系統，該系統涵蓋藥品優良製造準則與品質管制，它應完全文件化，且要監視其效果。品質保證系統的所有部門，應適當配置稱職人員，也要有合適且足夠的廠房、設備與設施。對於製造許可的持有者以及被授權的人員，須另負其他法律責任。

22. Quality Management System (Finished product) Senior Management Product R & D Quality Unit Supplier Production Storage Distribution QA QC 1.QA Policy, Regulation, Standard, MA 2.Validation/Revalidation 3.QA compliance 4.Documentation Control / Management 5.Corrective and Preventive Actions 6.Management Review Review and Approval of Documentation & Change Control. Ensuring Availability of Validation Resources Monitoring implementation of GMP Batch Review/Audit and release (Authorized person) Ensuring proper Storage, Distribution & Handling Complaint Handling & Product Recalls Contract Production & Analysis Monitoring Personnel Training Vender Qualification, Approval & Audit Self-Inspection, Quality audit, and Trend Evaluation Ensuring Proper Documentation Control & Management Product Review

23. API GMP • Quality management Quality should be the responsibility of all persons involved in manufacturing. Manufacturer should establish, document and implement an effective system for management quality. Active participation of management and appropriate manufacturing personnel. The system for management quality should encompass the organizational structure, procedures, processes and resources, as well as actives confidence that the API will meet its intended specifications for quality purity.

24. API GMP • Quality management There should be a quality unit (s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. Persons authorized to release intermediates and APIs should be specified. Responsibilities of the Quality Unit (s) should be specified. Responsibility for Production Activities should be specified. Internal Audits (Self inspection, Audit findings and related Corrective and Preventive actions) to verify GMP compliance. Product Quality Review, at least annually, to verify process consistency.

25. Quality Management System (API) Management Quality Unit Receipt Production Storage Distribution QA QC Organization, Procedures, Processes, & Resources. Validation of Manufacturing Resources & Change Control. Authorizes Persons to release intermediates & APIs. Documentation & Records Control/Management. Internal Audit. Product Quality Review. Complaint & Recall Handling. Contract Manufacturing & Analysis

26. Product Quality Review

27. 現行之品質評估系統 • 81條 本編所定有關製造、管制及運銷之所有記錄，均應保存於適當場所，俾供稽查，並供作至少每年1次評估產品品質之標準之依據；其保存期間，為該批產品或最終產品有效期間後1年。但免於標示有效期間者，應保存至該批產品或最終產品出廠3年。

28. Product Quality Review (PIC/S GMP1.5產品) 1.A review of staring materials and packaging materials used for the product, especially those from new sources. 相關原、物料審查(特別是新供應者) 2.A review of critical in-process controls and finished product results. 關鍵性管制及最終成品結果 3.A review of all batches that failed to meet established specification (s) and their investigation. 所有不合規格之批次及其調查 4.A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventive actions taken. 顯著性差異或不符合事項之相關調查及有效之預防校正措施 5.A review of all changes carried out to the processes or analytical methods. 製程或分析方法之變更

29. Product Quality Review 6.A review of Marketing Authorization variations submitted/granted/refused, including those for third country (export only) dossiers. 許可證之核准、預備申請或拒絕 7.A review of the results of the stability monitoring programmed and any adverse trends. 安定性試驗及任何不良趨勢 8. A review of all quality-related returns, complaints and recalls and the investigations performed at the time. 與品質相關之事項(怨訴、回收即時的調查報告) 9. A review of adequacy of any other previous product process or equipment corrective action 製藥設備及分析儀器之校正 10.For new marketing authorizations and variations to marketing authorizations, a review of post-marketing commitments. 新產品及產品許可差異，上市後之承諾保證

30. Product Quality Review 11. The qualification status of relevant equipment and utilities, e.g. HVAC, Water, compressed gases etc.相 關設施及儀器之驗證狀態 12. A review of Technical agreements to ensure that they are up to date. 技術協議確保已更新

31. Product Quality Review

32. Corrective and Preventive Action CAPA

33. 矯正與預防措施(ISO 9000) • 任何矯正和預防措施被執行以消除現存或潛在不符合事項的原因時，其實施程度應依問題大小及相對風險考量而定。因應矯正與預防措施所引起的任何書面程序變更，供應商應加以執行與記錄。 • 矯正措施矯正措施程序應包括： • a)有效的處理顧客抱怨和產品不合格報告； • b)調查有關產品、製程與品質系統之不符合原因並記錄其調查結果； • c)確定必要的矯正措施以消除不合格原因； • d)應用各種管制以確保矯正措施被執行並具成效。

34. 矯正與預防措施(ISO 9000) • 預防措施預防措施程序應包括： • a)應用適切的資訊來源，例如影響產品品質的製程與操作、特准允收、稽核結果、品質記錄、服務報告與顧客抱怨等，以發覺、分析及消除不合格事項的潛在原因； • b)決定必要的步驟以處理任何需採行預防措施的問題； • c)發起預防措施及應用各種管制以確保其有效執行； • d)確保採行措施的相關資訊送交管理審查之用

35. Quality System Requirements for Pharmaceutical Inspectorates (PIC/S) • 14.2 Corrective/ Preventive action • 14.2.1 The Pharmaceutical Inspectorate should establish and maintain a procedure for investigation of non-compliances with the quality system which are identified through internal or externalaudit of its activities. The procedure should include the prescribing, implementation and verification of corrective action. The procedure should cover also corrective actions arising from the investigation of complaints and other observations relating to the activities of the inspectorate. • 14.2.2 The system should include a description of the steps to be taken in assessing the need for quality improvement and preventive action. • 14.2.3 Corrective and preventive actions should be documented and records should be retained for a defined period.

36. Corrective and Preventive Actions Any of the Quality Related Complaints and/or Recalls, the deficiencies observed in internal audits and quality audits, and problems noted in trendanalysis, must lead to an investigation of the root causes, corrective actions and preventions actions, and followed by monitoring of the effectiveness of the corrective action, and possibly an additional internal audit to assure that the change have remained effective. There must have policies and procedures, and designated staff to implement corrective and preventive actions when necessary. Root cause analysis can be the most difficult part of the corrective and preventive procedures. All possible causes must be investigated,. Deeper analysis is needed to determine whether the root cause was inadequate training, confusing forms, or other type of mistakes.

37. Guidance for IndustryQuality Systems Approach to Pharmaceutical CGMP Regulations (FDA) • CAPA (Corrective and Preventive Action) CAPA is a well-known CGMP regulatory concept that focuses on investigating, understanding, and correctingdiscrepancies while attempting to prevent their recurrence.  Quality system models discuss CAPA as three separate concepts, all of which are used in this guidance. • Remedial corrections of an identified problem • Root cause analysis with corrective action to help understand the cause of the deviation and potentially prevent recurrence of a similar problem • Preventive action to avert recurrence of a similar potential problem

38. Root cause analysis(藥品生產魚骨圖) 製造管制標準書 設施及設備 水系統 空調系統 處方 分析儀器 批次製造紀錄 容器包裝 製藥設備 電腦化 系統 檢驗規格 成品 品質 對照標準品 標籤仿單 製程管制 紀錄簿 中間產品 製程確效 分析方法 確效 微生物 檢驗 原物料管制 清潔確效 製造管理 分析檢驗

39. Corrective Action • 調查偏差/不符合事項 • 決定根本原因 • 決定預防之校正措施 • 即時性作為 • 評估校正作為之有效性

40. Preventive Action • 從數據之審視預期和避免問題之發生 • 系統性分析產品品質 • 即時監控及評估系統 • 適當使用風險評估

41. CAPA（FDA） investigating, understanding, and correcting

42. Investigating • 收集相關資料 • 是否單一個案？亦或全面性？ • 製造管制標準書（處方、製程、製藥設備） • 批次製造紀錄： • 除該批號產品外、前後3批情形，相關資料趨勢分析 • 去年度成品品質評估趨勢分析情形） • 原物料供應商、生產條件、分析條件是否改變 • 運銷紀錄 • 運銷系統是否改變 • 運銷商是否改變 • 留樣品檢視

43. Understanding • 決定根本原因 • 製藥設備更新？未校正或接近校正期？供貨商改變？運銷商改變？製程改變？不良趨勢分析圖？新進人員？ • 決定預防之校正措施 • 再確效？儀器校正？供(運貨)商重新評估？

44. Correcting • 即時性作為 • 產品回收？庫存及法定留樣品檢測？ • 評估校正作為之有效性 • 是否陸續有其他不良品出現？批次製造紀錄情形評估？ • 從數據之審視預期和避免問題之發生、系統性分析產品品質、即時監控及評估系統、適當使用風險評估 • 數據分析、趨勢分析圖製作及討論

45. Monitoring System 鑑別品質數據來源 執行預防校正措施 並紀錄之 Implement/ Perform/ Record 品質數據之路徑及趨勢 確認效用 調查、鑑別問題 Change Management System 異常報告完整紀錄 調查根本原因及風險 訂定預防校正措施 品質數據之路徑及趨勢 核定異常報告 及預防校正措施 管理者審閱 Review Management System Corrective and Preventive Action (CAPA) Process Intra/Inter Data Trend of Data Identify/ Evaluate Investigate Action Plans

46. CAPA case I • 某XXX抗組織胺藥錠，接獲怨訴為顏色異常(變色) 調查報告：QC lab實際含量(Assay)降低!! CAPA：包裹糖衣??

47. CAPA case II • 某XXX降血壓糖衣錠，接獲怨訴為錠劑碎裂、龜裂(通報數為2次，可能持續再有？) 調查報告： 1st: 客戶保存時忽略防潮措施導致。 2nd: 研判係造粒時水分含量規格過高，經 coating後，水分不平衡釋出造成。 CAPA：加強防潮之宣導? 更改水分規格? 調查程度足夠?有無風險相當?

48. PIC/S 與我國現行GMP軟體標準差異介紹 持續性安定性試驗(On going stability testing) 文件 自我查核 確效作業 取樣方式、供應商稽查與法定留樣

49. 持續性安定性試驗(On going stability testing)

50. PIC/S Part 1 ( 2003.09.01 ) • 第一章 品質管理 • 第二章 人事 • 第三章 廠房設施與設備 • 第四章 文件 • 第五章 生產 • 第六章 品質管制(6.1~6.22 On going stability programme) • 第七章 委/受託製造與委/受託檢驗 • 第八章 怨速和產品回收 • 第九章 自我查核