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1、VALIDATION AND CRITICAL STEPS OF PROCESSING 關鍵性製程確效作業資料 林 邦德 1VALIDATION 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
2、產品。(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。2VALIDATION 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Proc
3、ess Scale Up 試製3VALIDATION AND CRITICAL STEPS OF PROCESSING內容 一、計畫書之核准 二、產品詳細處方一覽表三、 批量四、製造流程圖五、各製程操作條件六、關鍵製程步驟七、機器設備3Q一覽表4VALIDATION AND CRITICAL STEPS OF PROCESSING關鍵性製程確效作業查檢表 ( Courtesy of former BFDA-CDST) 品 名 :_主成分 : _劑 型 :_指標分析成分 :_一、確效計畫書與執行 執行確效方法 : 先期性 併行性回溯性 計畫書之核准 制訂人 核定人 制訂日期 核定日期5VALID
4、ATION 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責人員。6VALIDATION AND CRITICAL STEPS OF PROCESSING產品詳細處方一覽表主成分(Active substance)賦形劑(Excipients)增量 (Overages)Ref: ICH Q8 Pha
5、rmaceutical Development7VALIDATION AND CRITICAL STEPS OF PROCESSING 批量Pilot Batch: Batch size should correspond to at least 10% of the future industrial-scale batch. For oral solid dosage forms this size should be at least 10% or 100,000 units whichever is greater unless otherwise justified.Producti
6、on Batch: Drug product manufactured at production scale by using production equipment in a production facility as specified in the application.8VALIDATION AND CRITICAL STEPS OF PROCESSING A short description of the manufacturing process in a schematic drawing or flow chart 製造流程圖9VALIDATION AND CRITI
7、CAL STEPS OF PROCESSINGRef: 關鍵性製程及其指標（88.10.21公告）含量均一性固形製劑混合工程造粒工程打錠工程充填工程液劑溶解工程混合、溶解工程充填工程膏劑栓劑貼片劑練合工程充填工程塗布工程 各製程操作條件10VALIDATION 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11VALIDAT
8、ION 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)12VALIDATION 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13VALIDATION AND CRITICAL STEPS OF PROCESSING散劑、粉劑之製造程序稱量顆粒粉碎過篩混合14VALIDATION AND CRITICAL STEPS OF PROC
9、ESSING固型製劑之製造程序（I）混合與造粒Mixing & GranulationGranulation 造粒Wet Granulation 濕製粒Roll Compaction / Slugging 乾製粒Direct Mixing 直混15VALIDATION 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
10、出Drying 乾燥Milling / Sizing 整粒Final Blending 最終混合Lubrication 潤滑Weighing 稱量Sieving 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16VALIDATION AND CRITICAL STEPS OF PROCESSING固型製劑之製造程序（III）壓錠與膠充Compressing & EncapsulationCompression 打錠單層錠雙層錠子母錠Encaps
11、ulation 充填硬膠囊軟膠囊17VALIDATION AND CRITICAL STEPS OF PROCESSING固型製劑之製造程序（IV）加衣CoatingFilm Coating 膜衣Sugar Coating 糖衣Enteric Coating腸溶錠shellac coatingsub coatingcolor coatingpolishingenteric coatingsub coatingcolor coatingpolishing18VALIDATION AND CRITICAL STEPS OF PROCESSING製程參數Mixing 混合Kneading 鍊合Flu
12、id Bed Granulation 流動床造粒Time / RPMTime / RPMLiquid addition rate 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19VALIDATION 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
13、滑Time / PressureTime / Pressure Time / Temp.Mesh / Blade RPM網徑 / 切刀轉速Time / RPMTime / RPM20VALIDATION AND CRITICAL STEPS OF PROCESSING固型製劑之規格（I）Physical AnalysisAppearance 外觀AQ-UPDiameters 大小strengthHardness 硬度stabilityFriability 脆度stabilityWeight Variation 重量偏差strengthMoisture Content 水份含量stability
14、Disintegration 崩散時間efficiency21VALIDATION AND CRITICAL STEPS OF PROCESSING固型製劑之規格（II）Chemical AnalysisIdentity 鑑定safetyDissolution 溶離度efficiencyContent Uniformity 含量均一度strengthContent 含量strengthImpurity Content 不純物含量purityStability Analysis 安定性分析stabilityDecomposition Products 分解產物 purity22VALIDATIO
15、N AND CRITICAL STEPS OF PROCESSING固型製劑之製程管制混合工程造粒工程乾燥工程整粒工程壓錠工程加衣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23VALIDATION AND CRITICAL STEPS OF PROCESSING顆粒特性對錠劑之影響Bulk density Flow abilityParticle size distribution 粒度分佈Moisture Content 水份含量Weight and content unif
16、ormity Hardness Disintegration / Dissolution Weight and content uniformityHardness Capping / Lamination Friction / Adhesion Hardness Disintegration / DissolutionPoor Physical / Chemical Stability24VALIDATION AND CRITICAL STEPS OF PROCESSING半固型製劑之處方組成Active IngredientsBasesOther excipientsAntimicrobi
17、al PreservativesAntioxidantsStabilizersEmulsifiersThickenersPenetrationEnhancers25VALIDATION AND CRITICAL STEPS OF PROCESSING半固型製劑之規格potencycontent uniformitydrug releaseParticle sizeviscositypHPathogenMicrobialPreservative efficacyAppearancePackage compatibilityCrystal form26VALIDATION AND CRITICAL
18、 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27VALIDATION 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，其中一種液體呈小球狀分散於另
19、一種液體中。28VALIDATION AND CRITICAL STEPS OF PROCESSING液劑的製造程序29VALIDATION AND CRITICAL STEPS OF PROCESSING液劑之規格AppearancepHSpecific gravity ViscosityAlcohol, v/v (%)Assay of active ingredients 30VALIDATION 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31VALIDATION AND CRITICA
20、L 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 processat the time of blender discharge or directly from drums32VALIDATION AND CRITICAL STEPS OF PROCESSINGSampling points 取樣點不同Blender 可能發生Segregation (Pony Pan Type)Poor mixingDead
21、 spot (Ribbon Blender)Lumps (Tumbler Blender)Re-crystallization (High Shear Mixer)33VALIDATION AND CRITICAL STEPS OF PROCESSINGSampling points 取樣點34VALIDATION AND CRITICAL STEPS OF PROCESSING35VALIDATION AND CRITICAL STEPS OF PROCESSINGSampling points 取樣點36VALIDATION AND CRITICAL STEPS OF PROCESSING
22、Sampling 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37VALIDATION AND CRITICAL STEPS OF PROCESSING*滅菌工程 是 否（無菌製劑）無菌充填/ 最終滅菌 冷凍乾燥另附相關之查檢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 是 否 批號及批量：_關
23、鍵性製程確效作業查檢表(cont.)38VALIDATION AND CRITICAL STEPS OF PROCESSING關鍵性製程及其指標（88.10.21公告）指標製程階段劑型無菌性含量均一性無菌製劑最終滅菌製劑滅菌工程溶解工程混合、溶解工程充填工程無菌操作製劑無菌操作工程過濾滅菌工程無菌充填工程凍晶乾燥工程溶解工程混合、溶解工程充填工程39VALIDATION AND CRITICAL STEPS OF PROCESSINGIntroductionSterilizationThermalMoist heat SterilizationDry heat SterilizationNon
24、 thermalGammairradiationChemicals: Ethylene Oxide40VALIDATION AND CRITICAL STEPS OF PROCESSINGMoist HeatSaturated steamCommon cycles:121C for 15 minutes134C for 3 minutesOther cycles of lower temperature and longer time may be used (e.g. 115C for 30 minutes)Used for sterilization of:terminal sterili
25、zation of aqueous injections, ophthalmic preparations, irrigation & haemodialysis solutions, equipment used in aseptic processing41VALIDATION AND CRITICAL STEPS OF PROCESSING PNSU - Probability of a Non-Sterile UnitThe probability of a unit (product container) being non-sterile after the application
26、 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 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 equiva
27、lent to 8 minutes at 121.1C42VALIDATION AND CRITICAL STEPS OF PROCESSINGValidation - Cycle DevelopmentConcept of FoLethality factor equivalent to 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
28、sterilization processWhat would be the Fo of a cycle at 121C for 15 minutes?43VALIDATION AND CRITICAL STEPS OF PROCESSINGOther Sterilization ProcessesSterilization using other processes should follow a similar approach as that described for moist heatValidation protocolEquipment calibrationDetermini
29、ng the process that will deliver the desired SAL (10-6)IQ, OQ, PQRequirements for routine monitoring and control44VALIDATION AND CRITICAL STEPS OF PROCESSING無菌充填無菌充填test filling processperform filling process with nutrient media run at full scale for at least one fill sizeworst case; large volume an
30、d number of vialsfilled vials incubated, observed and test for contamination by validated sterility testmust be sterile for 3 consecutive runs media fill performed twice a yearsize of run must be large enough to detect low levels of contamination e.g. contamination rate of 1/1000, 3000 units are nee
31、ded to provide 95% confidence 45VALIDATION AND CRITICAL STEPS OF PROCESSING無菌作業 Drug ProductSterilization ProcessContainerClosureExcipientSterilization ProcessSterilization ProcessSterilization ProcessSterile ClosureSterile ExcipientAseptic ProcessingSterile DrugProductSterileContainerCan use multip
32、le sterilization processes each optimized for the individual componentSterile Final Product46VALIDATION AND CRITICAL STEPS OF PROCESSING凍晶乾燥 DoorSterile roomwallVacuum gauge Upper compensating shelf Defrose water inlet Pump isolation valve Icecondenser Vacuum Pumpinggroup Drain Refrigeration groupHe
33、ating system 47VALIDATION AND CRITICAL STEPS OF PROCESSING清潔確效 主 成 分：_ 指標分析成分：_ 確效批號：_ 合格標準：_ 結果：_組群組 Grouping 個別產品Rinse Swab 關鍵性製程確效計畫書查檢表(cont.)48VALIDATION AND CRITICAL STEPS OF PROCESSING清潔確效取樣方法直接表面取樣法（擦拭法） 取樣方式規範 取樣物材質規範、取樣媒介質（溶媒） Blank test、取樣之回收檢品能力間接取樣法（洗滌液取樣法） 大面積或不能不能拆解的設備 （篩網、除粉機、流動床濾袋）
34、標的物之溶解度（取樣） 於適當溶媒中直接測量（檢品配製）49VALIDATION AND CRITICAL STEPS OF PROCESSING77.5.6. 優良藥品製造標準 (GMP)88.4.29. 現行優良藥品製造標準 (cGMP)90.10. 清潔確效指導手冊 美國 FDA Guide to inspections validation of cleaning processes 加拿大 Cleaning validation guidelines-Therapeutic products programme (May, 2000.)清潔確效50VALIDATION AND CRITICAL STEPS OF PROCESSINGThank You!51
