關(guān)鍵性制程確效作業(yè)資料.ppt

關(guān)鍵性製程確效作業(yè)資料,林 邦德,製程確效（藥品優(yōu)良製造確效作業(yè)基準(zhǔn)88.04.13 4）,製 程 確 效: 確認(rèn)產(chǎn)品之製造程序及其管制條件，具有良好的有效性與再現(xiàn)性。 確效計(jì)畫書:說明將如何進(jìn)行確效之書面計(jì)畫書，內(nèi)容包括予以測試之指標(biāo)，產(chǎn)品特質(zhì)，生產(chǎn)設(shè)備，以及測試合格之判定標(biāo)準(zhǔn)。,內(nèi)容,關(guān)鍵性製程確效作業(yè)查檢表 ( Courtesy of former BFDA-CDST),品 名 :_ 主成分 : _,劑 型 :_ 指標(biāo)分析成分 :_,一、確效計(jì)畫書與執(zhí)行 執(zhí)行確效方法 : 先期性 併行性回溯性 計(jì)畫書之核準(zhǔn) 制訂人 核定人 制訂日期 核定日期,確效計(jì)畫書（藥品優(yōu)良製造確效作業(yè)基準(zhǔn)7）,確效或驗(yàn)證之項(xiàng)目。 確效或驗(yàn)證之目的及整體目標(biāo)。 預(yù)定實(shí)施頻率。 該項(xiàng)確效或驗(yàn)證之計(jì)畫書制訂及各次改訂日期，以及改訂事項(xiàng)。 確效或驗(yàn)證方法。 合格標(biāo)準(zhǔn)範(fàn)圍。 數(shù)據(jù)或資料處理方法。 確效或驗(yàn)證書面資料之改訂程序及保管相關(guān)事項(xiàng)。 執(zhí)行確效或驗(yàn)證之責(zé)任單位及負(fù)責(zé)人員。,產(chǎn)品詳細(xì)處方一覽表,主成分(Active substance) 賦形劑(Excipients) 增量 (Overages) Ref: ICH Q8 Pharmaceutical Development, 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. Production Batch: Drug product manufactured at production scale by using production equipment in a production facility as specified in the application.,A short description of the manufacturing process in a schematic drawing or flow chart, 製造流程圖,Ref: 關(guān)鍵性製程及其指標(biāo)（88.10.21公告）, 各製程操作條件,Acceptance Criteria 合格範(fàn)圍,Product Specifications 產(chǎn)品既定規(guī)格 Pharmacopoeia Specifications 產(chǎn)品藥典規(guī)格 Product In-process Specifications 產(chǎn)品製程規(guī)格,設(shè)定合格範(fàn)圍,Setting Limits 藥品查驗(yàn)登記的規(guī)格 安定性規(guī)格 成品檢驗(yàn)放行規(guī)格 確效規(guī)格,成品放行規(guī)格,產(chǎn)品查驗(yàn)登記的規(guī)格 依據(jù)安定性規(guī)格,製程規(guī)格(Limits),固型製劑之分類,散、粉劑 顆粒、錠劑、丸劑 加衣錠 膠囊、軟膠囊,散劑、粉劑之製造程序,稱量 顆粒粉碎 過篩 混合,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 Roll Compaction / Slugging 乾製粒 Direct Mixing 直混,固型製劑之製造程序（II）,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,固型製劑之製造程序（IV）,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 polishing,製程參數(shù),Mixing 混合 Kneading 鍊合 Fluid Bed Granulation 流動床造粒,Time / RPM Time / RPM Liquid addition rate 添加率 Inlet air temp. 進(jìn)氣溫度 Fluidizing air vol. 空氣量 Process air humidity 濕度 Atomization air Pressure 空壓,製程參數(shù),Extrusion 擠出 Roll Compaction 滾壓 Drying 乾燥 Milling / Sizing 整粒 Final Blending 最終混合 Lubrication 潤滑,Time / Pressure Time / Pressure Time / Temp. Mesh / Blade RPM 網(wǎng)徑 / 切刀轉(zhuǎn)速 Time / RPM Time / RPM,固型製劑之規(guī)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(shí)間 efficiency,固型製劑之規(guī)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(chǎn)物 purity,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,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 Hardness Disintegration / Dissolution Weight and content uniformity Hardness Capping / Lamination Friction / Adhesion Hardness Disintegration / Dissolution Poor Physical / Chemical Stability,半固型製劑之處方組成,Active Ingredients Bases Other excipients Antimicrobial Preservatives Antioxidants Stabilizers Emulsifiers Thickeners Penetration Enhancers,半固型製劑之規(guī)格,potency content uniformity drug release Particle size viscosity pH Pathogen Microbial Preservative efficacy Appearance Package compatibility Crystal form,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,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(dāng)溶劑，或相互混合溶劑之混合物。 酏劑 - 為一種供內(nèi)服用之澄明、甜味、含乙醇水溶液。 醑劑 - 為一種含是揮發(fā)性物質(zhì)之乙醇溶液，或含水乙醇溶液。 酊劑 - 為生藥或化學(xué)藥品，經(jīng)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(tǒng)之液體製劑，其中一種液體呈小球狀分散於另一種液體中。,液劑的製造程序,液劑之規(guī)格,Appearance pH Specific gravity Viscosity Alcohol, v/v (%) Assay of active ingredients,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, Sampling 取樣,Sampling timing 取樣時(shí)機(jī) Sampling points 取樣點(diǎn) Sample size 取樣數(shù),Sampling timing 取樣時(shí)機(jī),during the process at the time of blender discharge or directly from drums,Sampling points 取樣點(diǎn),不同Blender 可能發(fā)生 Segregation (Pony Pan Type) Poor mixing Dead spot (Ribbon Blender) Lumps (Tumbler Blender) Re-crystallization (High Shear Mixer),Sampling points 取樣點(diǎn),Sampling points 取樣點(diǎn),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,*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(guān)之查檢表 無菌充填過程確效 環(huán)氧乙烯滅菌確效 放射線滅菌確效 _ 製程確效三批結(jié)果彙整報(bào)告 是 否 批號及批量：_,關(guān)鍵性製程確效作業(yè)查檢表(cont.),關(guān)鍵性製程及其指標(biāo)（88.10.21公告）,Introduction,Sterilization,Thermal,Moist heat Sterilization,Dry heat Sterilization,Non thermal,Gamma irradiation,Chemicals: Ethylene Oxide,Moist Heat,Saturated steam Common cycles: 121C for 15 minutes 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 processing,PNSU - Probability of a Non-Sterile Unit The 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 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 121.1C,Validation - Cycle Development,Concept of Fo Lethality 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 phases Typical temperature profile of a heat sterilization process What would be the Fo of a cycle at 121C for 15 minutes?,Other Sterilization Processes,Sterilization 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 control,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 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,無菌作業(yè),Drug Product,Sterilization Process,Container,Closure,Excipient,Ster