关键性制程确效作业资料

1、VALIDATION AND CRITICAL STEPS OF PROCESSING 關鍵性製程確效作業資料 林 邦德 VALIDATION AND CRITICAL STEPS OF PROCESSING製程確效（藥品優良製造確效作業基準88.04.13 4） 製 程 確 效: 確認產品之製造程序及其管制條件，具有良好的有效性與再現性。 確效計畫書:說明將如何進行確效之書面計畫書，內容包括予以測試之指標，產品特質，生產設備，以及測試合格之判定標準。 先期性確效先期性確效：為一種產品於上市前所進行之確效措施，適用於下列兩類品：(一一)新產品：新申請查驗登記新產品：新申請查驗登記 之產品。之產

2、品。(二二)既有產品於更改配方既有產品於更改配方(包括包括 成分及組成成分及組成)、製造場所、製造場所、 製造設備、製造設備、 製程等製造製程等製造 條件而可能會重大影響產條件而可能會重大影響產 品之品質特性者。品之品質特性者。VALIDATION AND CRITICAL STEPS OF PROCESSINGProcess Development 製程研發Commercial Production Process 量產3 batches validation 三批確效(Process Change another 3 batches validation) 製程更改則需另作三批Proces

3、s Scale Up 試製VALIDATION AND CRITICAL STEPS OF PROCESSING內容 一、計畫書之核准一、計畫書之核准 二、產品詳細處方一覽表二、產品詳細處方一覽表三、三、 批量批量四、製造流程圖四、製造流程圖五、各製程操作條件五、各製程操作條件六、關鍵製程步驟六、關鍵製程步驟七、機器設備七、機器設備3Q一覽表一覽表VALIDATION AND CRITICAL STEPS OF PROCESSING關鍵性製程確效作業查檢表 ( Courtesy of former BFDA-CDST) 品品 名名 :_ 主成分主成分 : _ 劑劑 型型 :_ 指標分析成分指標

4、分析成分 :_一、確效計畫書與執行一、確效計畫書與執行 執行確效方法執行確效方法 : : 先期性先期性 併行性併行性回溯性回溯性 計畫書之核准計畫書之核准 制訂人制訂人 核定人核定人 制訂日期制訂日期 核定日期核定日期VALIDATION AND CRITICAL STEPS OF PROCESSING確效計畫書（藥品優良製造確效作業基準7） 確效或驗證之項目。 確效或驗證之目的及整體目標。 預定實施頻率。 該項確效或驗證之計畫書制訂及各次改訂日期，以及改訂事項。 確效或驗證方法。 合格標準範圍。 數據或資料處理方法。 確效或驗證書面資料之改訂程序及保管相關事項。 執行確效或驗證之責任單位及負

5、責人員。VALIDATION AND CRITICAL STEPS OF PROCESSING產品詳細處方一覽表產品詳細處方一覽表 主成分主成分(Active substance) 賦形劑賦形劑(Excipients) 增量增量 (Overages)Ref: ICH Q8 Pharmaceutical DevelopmentVALIDATION AND CRITICAL STEPS OF PROCESSING 批量批量 Pilot Batch: Batch size should correspond to at least 10% of the future industrial-scale

6、 batch. For oral solid dosage forms this size should be at least 10% or 100,000 units whichever is greater unless otherwise justified. Production Batch: Drug product manufactured at production scale by using production equipment in a production facility as specified in the application.VALIDATION AND

7、 CRITICAL STEPS OF PROCESSING A short description of the manufacturing process in a schematic drawing or flow chart 製造流程圖製造流程圖VALIDATION AND CRITICAL STEPS OF PROCESSINGRef: 關鍵性製程及其指標（88.10.21公告）含量均一性含量均一性固形製劑固形製劑混合工程混合工程造粒工程造粒工程打錠工程打錠工程充填工程充填工程液劑液劑溶解工程溶解工程混合、溶解工程混合、溶解工程充填工程充填工程膏劑膏劑栓劑栓劑貼片劑貼片劑練合工程練合工

8、程充填工程充填工程塗布工程塗布工程 各製程操作條件各製程操作條件VALIDATION AND CRITICAL STEPS OF PROCESSINGAcceptance Criteria 合格範圍 Product Specifications 產品既定規格 Pharmacopoeia Specifications 產品藥典規格 Product In-process Specifications 產品製程規格VALIDATION AND CRITICAL STEPS OF PROCESSING設定合格範圍Setting Limits 藥品查驗登記的規格 安定性規格 成品檢驗放行規格 確效規格成

9、品放行規格產品查驗登記的規格依據安定性規格依據安定性規格製程規格(Limits)VALIDATION AND CRITICAL STEPS OF PROCESSING固型製劑之分類 散、粉劑 顆粒、錠劑、丸劑 加衣錠 膠囊、軟膠囊VALIDATION AND CRITICAL STEPS OF PROCESSING散劑、粉劑之製造程序 稱量 顆粒粉碎 過篩 混合VALIDATION AND CRITICAL STEPS OF PROCESSING固型製劑之製造程序（I） 混合與造粒Mixing & Granulation Granulation 造粒 Wet Granulation 濕製粒 R

10、oll Compaction / Slugging 乾製粒 Direct Mixing 直混VALIDATION AND CRITICAL STEPS OF PROCESSING固型製劑之製造程序（II）Granulation 製粒Wet GranulationSlugging /Roll CompactionDirect MixingWeighing 稱量Sieving 過篩 Mixing 混合Kneading 煉合Extrusion 擠出Drying 乾燥Milling / Sizing 整粒Final Blending 最終混合Lubrication 潤滑Weighing 稱量Sievi

11、ng 過篩 Mixing 混合Roll Compaction 滾壓Milling 整粒Lubrication 潤滑Weighing 稱量Sieving 過篩 Mixing 混合Lubrication 潤滑VALIDATION AND CRITICAL STEPS OF PROCESSING固型製劑之製造程序（III） 壓錠與膠充Compressing & Encapsulation Compression 打錠 單層錠 雙層錠 子母錠 Encapsulation 充填 硬膠囊 軟膠囊VALIDATION AND CRITICAL STEPS OF PROCESSING固型製劑之製造程序（IV）

12、 加衣Coating Film Coating 膜衣 Sugar Coating 糖衣 Enteric Coating腸溶錠 shellac coating sub coating color coating polishing enteric coating sub coating color coating polishingVALIDATION AND CRITICAL STEPS OF PROCESSING製程參數 Mixing 混合 Kneading 鍊合 Fluid Bed Granulation 流動床造粒Time / RPMTime / RPMLiquid addition r

13、ate 添加率Inlet air temp. 進氣溫度Fluidizing air vol. 空氣量Process air humidity 濕度Atomization air Pressure 空壓VALIDATION AND CRITICAL STEPS OF PROCESSING製程參數 Extrusion 擠出 Roll Compaction 滾壓 Drying 乾燥 Milling / Sizing 整粒 Final Blending 最終混合 Lubrication 潤滑Time / PressureTime / Pressure Time / Temp.Mesh / Blade

14、RPM網徑 / 切刀轉速Time / RPMTime / RPMVALIDATION AND CRITICAL STEPS OF PROCESSING固型製劑之規格（I） Physical Analysis Appearance 外觀AQ-UP Diameters 大小strength Hardness 硬度stability Friability 脆度stability Weight Variation 重量偏差strength Moisture Content 水份含量stability Disintegration 崩散時間efficiencyVALIDATION AND CRITICA

15、L STEPS OF PROCESSING固型製劑之規格（II） Chemical Analysis Identity 鑑定safety Dissolution 溶離度efficiency Content Uniformity 含量均一度strength Content 含量strength Impurity Content 不純物含量purity Stability Analysis 安定性分析stability Decomposition Products 分解產物 purityVALIDATION AND CRITICAL STEPS OF PROCESSING固型製劑之製程管制 混合工

16、程混合工程 造粒工程造粒工程 乾燥工程乾燥工程 整粒工程整粒工程 壓錠工程壓錠工程 加衣工程加衣工程 膠囊充填工程膠囊充填工程含量均一度殘餘量水分含量粒徑分布、安息角、粗密度與輕擊密度外觀、厚度、硬度、脆度、重量均一度、崩散度或溶離度外觀、包覆百分率、釋離行為重量均一度VALIDATION AND CRITICAL STEPS OF PROCESSING顆粒特性對錠劑之影響 Bulk density Flow ability Particle size distribution 粒度分佈 Moisture Content 水份含量Weight and content uniformity Ha

17、rdness Disintegration / Dissolution Weight and content uniformityHardness Capping / Lamination Friction / Adhesion Hardness Disintegration / DissolutionPoor Physical / Chemical StabilityVALIDATION AND CRITICAL STEPS OF PROCESSING半固型製劑之處方組成 Active Ingredients Bases Other excipients Antimicrobial Pres

18、ervatives Antioxidants Stabilizers Emulsifiers Thickeners Penetration EnhancersVALIDATION AND CRITICAL STEPS OF PROCESSING半固型製劑之規格 potency content uniformity drug release Particle size viscosity pH Pathogen Microbial Preservative efficacy Appearance Package compatibility Crystal formVALIDATION AND C

19、RITICAL STEPS OF PROCESSING半固型製劑之製程管制 真空乳化工程 充填工程pH值、含量均一度、比重、黏度含量均一度、重量偏差VALIDATION AND CRITICAL STEPS OF PROCESSING液劑之分類（中華藥典）Example: 溶液劑 - 係含是一種或多種藥品溶解或分散於一適當溶劑，或相互混合溶劑之混合物。 酏劑 - 為一種供內服用之澄明、甜味、含乙醇水溶液。 醑劑 - 為一種含是揮發性物質之乙醇溶液，或含水乙醇溶液。 酊劑 - 為生藥或化學藥品，經滲漉法、浸漬法或溶液法製成之一種乙醇溶液，或含水乙醇溶液。 乳劑 - 為一種二相系統之液體製劑，其中

20、一種液體呈小球狀分散於另一種液體中。VALIDATION AND CRITICAL STEPS OF PROCESSING液劑的製造程序VALIDATION AND CRITICAL STEPS OF PROCESSING液劑之規格 Appearance pH Specific gravity Viscosity Alcohol, v/v (%) Assay of active ingredients VALIDATION AND CRITICAL STEPS OF PROCESSING液劑劑之製程管制 溶解工程 充填工程pH值、含量均一度、比重、黏度含量均一度、重量偏差VALIDATION

21、AND CRITICAL STEPS OF PROCESSING Sampling 取樣 Sampling timing 取樣時機 Sampling points 取樣點 Sample size 取樣數Sampling timing 取樣時機 during the process at the time of blender discharge or directly from drumsVALIDATION AND CRITICAL STEPS OF PROCESSINGSampling points 取樣點 不同Blender 可能發生 Segregation (Pony Pan Type

22、) Poor mixing Dead spot (Ribbon Blender) Lumps (Tumbler Blender) Re-crystallization (High Shear Mixer)VALIDATION AND CRITICAL STEPS OF PROCESSINGSampling points 取樣點VALIDATION AND CRITICAL STEPS OF PROCESSINGVALIDATION AND CRITICAL STEPS OF PROCESSINGSampling points 取樣點VALIDATION AND CRITICAL STEPS O

23、F PROCESSINGSampling method 取樣方法 Simple sampling 簡易取樣法 Samples taken from the discharged blend 出料中取樣 Thief sampling 取樣器法 Samples taken from the blender 使用取樣器取樣VALIDATION AND CRITICAL STEPS OF PROCESSING*滅菌工程滅菌工程 是是 否（無菌製劑）否（無菌製劑）無菌充填無菌充填/ 最終滅菌最終滅菌 冷凍乾燥冷凍乾燥另附相關之另附相關之查檢查檢表表無菌充填過程確效無菌充填過程確效環氧乙烯滅菌確效環氧乙烯

24、滅菌確效放射線滅菌確效放射線滅菌確效 _ 製程確效三批結果彙整報告製程確效三批結果彙整報告 是是 否否 批號及批量：批號及批量：_關鍵性製程確效作業查檢表(cont.)VALIDATION AND CRITICAL STEPS OF PROCESSING關鍵性製程及其指標（88.10.21公告）指標指標製程階段製程階段劑型劑型無菌性無菌性含量均一性含量均一性無菌製劑無菌製劑最終滅菌製劑最終滅菌製劑 滅菌工程滅菌工程溶解工程溶解工程混合、溶解工程混合、溶解工程充填工程充填工程無菌操作製劑無菌操作製劑無菌操作工程無菌操作工程過濾滅菌工程過濾滅菌工程無菌充填工程無菌充填工程凍晶乾燥工程凍晶乾燥工程溶

25、解工程溶解工程混合、溶解工程混合、溶解工程充填工程充填工程VALIDATION AND CRITICAL STEPS OF PROCESSINGIntroductionSterilizationThermalMoist heat SterilizationDry heat SterilizationNon thermalGammairradiationChemicals: Ethylene OxideVALIDATION AND CRITICAL STEPS OF PROCESSINGMoist Heat Saturated steam Common cycles: 121C for 15 m

26、inutes 134C for 3 minutes Other cycles of lower temperature and longer time may be used (e.g. 115C for 30 minutes) Used for sterilization of: terminal sterilization of aqueous injections, ophthalmic preparations, irrigation & haemodialysis solutions, equipment used in aseptic processingVALIDATION AN

27、D CRITICAL STEPS OF PROCESSING PNSU - Probability of a Non-Sterile UnitThe probability of a unit (product container) being non-sterile after the application of a lethal agent. PNSU of 1 in 106 - the probability that a unit is non-sterile is one in a million FO - Sterilization Process Equivalent Time

28、 The equivalent number of minutes at 121.1C delivered to a unit by a sterilization process.FO = 8 minutes - the cycle delivered a microbial lethality equivalent to 8 minutes at 121.1CVALIDATION AND CRITICAL STEPS OF PROCESSINGValidation - Cycle Development Concept of Fo Lethality factor equivalent t

29、o time at 121C 1 minute at 121C is equivalent to Fo of 1. Lethality can accumulate during heat up and cool down phasesTypical temperature profile of a heat sterilization processWhat would be the Fo of a cycle at 121 C for 15 minutes?VALIDATION AND CRITICAL STEPS OF PROCESSINGOther Sterilization Proc

30、essesSterilization using other processes should follow a similar approach as that described for moist heat Validation protocol Equipment calibration Determining the process that will deliver the desired SAL (10-6) IQ, OQ, PQ Requirements for routine monitoring and controlVALIDATION AND CRITICAL STEP

31、S OF PROCESSING無菌充填無菌充填 test filling process perform filling process with nutrient media run at full scale for at least one fill size worst case; large volume and number of vials filled vials incubated, observed and test for contamination by validated sterility test must be sterile for 3 consecutive

32、 runs media fill performed twice a year size of run must be large enough to detect low levels of contamination e.g. contamination rate of 1/1000, 3000 units are needed to provide 95% confidence VALIDATION AND CRITICAL STEPS OF PROCESSING無菌作業 Drug ProductSterilization ProcessContainerClosureExcipientSterilization ProcessSterilization ProcessSterilization Pr