前言

　　核查中心全年組織開展藥品注冊生產(chǎn)現(xiàn)場檢查、藥品GMP認(rèn)證檢查、GMP跟蹤檢查、飛行檢查、進(jìn)口藥品境外生產(chǎn)現(xiàn)場檢查、流通檢查以及觀察檢查共計434項。

第一節(jié) 藥品注冊生產(chǎn)現(xiàn)場檢查

　　一、檢查基本情況

　　2016年共收到29個檢查任務(wù)（包括多階段檢查），21個來自總局藥品審評中心（以下簡稱“藥審中心”），8個有因檢查任務(wù)。共派出43個檢查組178人次對34個品規(guī)進(jìn)行了現(xiàn)場檢查；完成現(xiàn)場檢查報告42個，其中通過34個，占81%；不通過及企業(yè)主動撤回注冊申請的8個，占19%。

　　二、發(fā)現(xiàn)主要問題

　　在2016年的現(xiàn)場檢查中，個別企業(yè)的數(shù)據(jù)無法溯源、申報資料不真實等數(shù)據(jù)可靠性問題仍然突出，同時發(fā)現(xiàn)工藝驗證不充分、生產(chǎn)工藝不穩(wěn)定、生產(chǎn)工藝或參數(shù)與核定的不一致等問題。
具體情況如下：

　　（一）數(shù)據(jù)可靠性問題
1.檢驗數(shù)據(jù)不能溯源。沒有按規(guī)定留樣并進(jìn)行穩(wěn)定性考察?，F(xiàn)場檢查未見檢查品種試制樣品的留樣和穩(wěn)定性試驗留樣，也不能提供相應(yīng)記錄。
2.批生產(chǎn)記錄不真實、不完整，與申報資料不符。

　　（二）工藝驗證不充分，生產(chǎn)工藝不穩(wěn)定
品種的工藝驗證不充分，企業(yè)在動態(tài)生產(chǎn)時，出現(xiàn)嚴(yán)重偏差、批量生產(chǎn)收率與驗證批次的偏離較大、生產(chǎn)設(shè)備控制系統(tǒng)不穩(wěn)定、生產(chǎn)線的部分設(shè)備不能完全滿足現(xiàn)有生產(chǎn)要求。

　?。ㄈ┥a(chǎn)工藝或關(guān)鍵工藝參數(shù)、內(nèi)包材與核定內(nèi)容不一致，未進(jìn)行研究評估
1.生產(chǎn)工藝與核定的/申報的生產(chǎn)工藝不一致。
2.關(guān)鍵工藝參數(shù)與核定的/申報的生產(chǎn)工藝不一致。
3.內(nèi)包材生產(chǎn)商與注冊申報不一致，企業(yè)未進(jìn)行對比研究。

　?。ㄋ模┪催M(jìn)行必要的偏差調(diào)查
動態(tài)生產(chǎn)中出現(xiàn)重大異常情況時，個別企業(yè)調(diào)查不充分，找不到根本原因。某化學(xué)原料藥工藝驗證三批和動態(tài)生產(chǎn)批結(jié)果顯示，4批成品收率差距較大，企業(yè)沒有分析查找原因。

第二節(jié) 藥品GMP認(rèn)證檢查

　　一、檢查基本情況

　　依據(jù)國家食品藥品監(jiān)督管理總局關(guān)于“未通過藥品生產(chǎn)質(zhì)量管理規(guī)范(2010年修訂)認(rèn)證企業(yè)停止生產(chǎn)和下放無菌藥品認(rèn)證有關(guān)事宜的公告（2015年第285號）”的精神，自2016年1月1日起，國家食品藥品監(jiān)督管理總局不再受理藥品GMP認(rèn)證申請。對于已經(jīng)受理的認(rèn)證申請，繼續(xù)組織完成現(xiàn)場檢查和審核發(fā)證。
鑒于上述情況，2016年全年共安排檢查16家，接收現(xiàn)場檢查報告16份，完成審核件14份，其中12家藥品生產(chǎn)企業(yè)通過藥品GMP認(rèn)證檢查，2家藥品生產(chǎn)企業(yè)未通過藥品GMP認(rèn)證檢查，發(fā)出告誡信的企業(yè)5家；另有兩家企業(yè)其GMP認(rèn)證檢查雖然結(jié)束，但因尚未拿到相關(guān)注冊批準(zhǔn)證明性文件，認(rèn)證程序暫停。
申請認(rèn)證的劑型包括大容量注射劑3家次、小容量注射劑3家次、凍干粉針劑3家次、粉針劑1家次、放射性藥品1家次、疫苗類產(chǎn)品2家次、其他類生物制品3家次。

　　二、發(fā)現(xiàn)主要問題

　　發(fā)現(xiàn)220條缺陷，包括主要缺陷23項，一般缺陷197項。其中質(zhì)量控制與質(zhì)量保證方面41項，文件管理方面缺陷32項，機(jī)構(gòu)與人員方面缺陷24項，設(shè)備方面缺陷23項，確認(rèn)與驗證方面缺陷21項。與2015年檢查發(fā)現(xiàn)缺陷的分布基本一致。
本年度認(rèn)證檢查的兩家體外診斷試劑生產(chǎn)企業(yè)，結(jié)果均為不通過，主要問題如下：
（一）質(zhì)量管理體系方面。質(zhì)量管理體系不能有效運行，無法保證產(chǎn)品的生產(chǎn)和質(zhì)量要求；人員流動性大，專業(yè)人員欠缺，培訓(xùn)不到位，無法滿足日常生產(chǎn)質(zhì)量管理要求；文件可操作性不強，數(shù)據(jù)記錄不完整；相關(guān)變更沒有按照變更程序進(jìn)行變更控制。

　　（二）確認(rèn)與驗證工作方面。未對所有申請GMP認(rèn)證的產(chǎn)品進(jìn)行工藝驗證，對公用設(shè)備設(shè)施的清潔驗證工作不到位；部分驗證記錄不完整；部分再驗證工作未按要求開展等。

第三節(jié) 藥品GMP跟蹤檢查

　　一、檢查基本情況

　　2016年核查中心公告跟蹤檢查計劃215家，共計228家次。其中停產(chǎn)、長期不生產(chǎn)等企業(yè)58家次，其余170家次全部進(jìn)行了檢查。另外，對省級認(rèn)證的無菌藥品生產(chǎn)企業(yè)21家進(jìn)行跟蹤檢查，雙隨機(jī)檢查13家。全年共完成跟蹤檢查204家次。

　　跟蹤檢查不通過的企業(yè)有12家，占6.1%，發(fā)告誡信的企業(yè)有59家，占29.6%。
在檢查不通過的12家企業(yè)中，2015年度抽驗不合格的企業(yè)有5家，雙隨機(jī)檢查的企業(yè)4家，胞磷膽堿鈉注射劑生產(chǎn)企業(yè)2家，骨肽注射劑生產(chǎn)企業(yè)1家。

　　（一）2015年度質(zhì)量公告品種抽查情況
共對10家企業(yè)進(jìn)行了跟蹤檢查，其中5家檢查不通過，占50%，另對4家企業(yè)發(fā)放告誡信。

　?。ǘ╇p隨機(jī)檢查
為落實國務(wù)院創(chuàng)新事中、事后監(jiān)管的要求，按照總局統(tǒng)一部署，藥品雙隨機(jī)檢查系統(tǒng)于2016年12月首次運行，采取分層雙隨機(jī)的方法對選出的13家企業(yè)開展了跟蹤檢查，包括化學(xué)制劑3個、原料藥2個、中藥8個，分布在9個省。共有4家企業(yè)檢查不通過，通過率僅69%，另對3家企業(yè)發(fā)告誡信。

　?。ㄈ┮呙缟a(chǎn)企業(yè)
對獲得藥品GMP證書的38家疫苗生產(chǎn)企業(yè)列入2016年跟蹤檢查計劃，除1家因藥品生產(chǎn)許可證和藥品GMP證書于2014年收回、1家因2015年申請變更生產(chǎn)地址藥品GMP證書未拿到?jīng)]有執(zhí)行檢查外，共對36家疫苗生產(chǎn)企業(yè)進(jìn)行了跟蹤檢查。檢查結(jié)果全部通過，共對7家企業(yè)發(fā)告誡信。其中一家企業(yè)因變更分析檢測器，檢查組現(xiàn)場初步認(rèn)為屬嚴(yán)重缺陷，后期專家研討認(rèn)為變更前后的檢測器方法原理一致，質(zhì)量風(fēng)險較低，要求企業(yè)開展進(jìn)一步的方法學(xué)對比驗證，降為主要缺陷?？傮w來說，疫苗生產(chǎn)質(zhì)量風(fēng)險可控，生產(chǎn)企業(yè)的生產(chǎn)和質(zhì)量管理較規(guī)范。

　?。ㄋ模┭褐破飞a(chǎn)企業(yè)
26家血液制品生產(chǎn)企業(yè)列入2016年跟蹤檢查計劃，共對25家血液制品企業(yè)開展跟蹤檢查，另有1家企業(yè)因停產(chǎn)整改未進(jìn)行檢查。檢查結(jié)果全部通過，共對4家企業(yè)發(fā)告誡信?？傮w來說，我國血液制品生產(chǎn)質(zhì)量風(fēng)險可控，生產(chǎn)企業(yè)的生產(chǎn)和質(zhì)量管理較規(guī)范，對個別企業(yè)仍需加強監(jiān)管力度。

　?。ㄎ澹?015年發(fā)告誡信的企業(yè)
共對2015年發(fā)告誡信的32家企業(yè)進(jìn)行了跟蹤檢查，盡管企業(yè)基本符合要求，但仍對14家企業(yè)再次發(fā)告誡信。

　?。┱J(rèn)證下放后，對省級認(rèn)證的無菌藥品生產(chǎn)企業(yè)抽查情況
共抽查省級認(rèn)證的無菌藥品生產(chǎn)企業(yè)21家，全部通過，對其中6家企業(yè)發(fā)告誡信。通過抽查，省局認(rèn)證檢查的尺度總體把握嚴(yán)格，各地平穩(wěn)承接了下放的認(rèn)證檢查職能。

　?。ㄆ撸└唢L(fēng)險品種的專項檢查
本年度重點對骨肽、果糖二磷酸鈉、胞磷膽堿鈉等三個產(chǎn)品的注射劑進(jìn)行了跟蹤檢查，計劃進(jìn)行114家次的高風(fēng)險品種專項檢查，其中有47家因企業(yè)未通過藥品GMP（2010年修訂）認(rèn)證、品種長期停產(chǎn)、批準(zhǔn)文號轉(zhuǎn)移等原因未進(jìn)行檢查，實際檢查67家次。1家骨肽注射劑生產(chǎn)企業(yè)和2家胞磷膽堿鈉注射劑生產(chǎn)企業(yè)不通過，對21家企業(yè)發(fā)告誡信。

　　二、發(fā)現(xiàn)的主要問題

　?。ㄒ唬┛傮w情況
204家次檢查共發(fā)現(xiàn)2260條缺陷項，其中嚴(yán)重缺陷22項，主要缺陷212項，一般缺陷2026項，與2015年GMP認(rèn)證、跟蹤檢查相比嚴(yán)重缺陷數(shù)目有所增加。
在高風(fēng)險品種專項檢查的企業(yè)中品種長期停產(chǎn)或未通過藥品GMP（2010年修訂）認(rèn)證的現(xiàn)象比較突出，檢查發(fā)現(xiàn)的一些共性問題如下：
1.個別存在生產(chǎn)工藝與注冊工藝不一致問題。
2.數(shù)據(jù)可靠性問題仍然存在，包括偽造生產(chǎn)記錄，檢驗記錄中套用圖譜、擅自修改數(shù)據(jù)問題，生產(chǎn)、設(shè)備、物料記錄中相關(guān)內(nèi)容不符等問題。
3.工藝驗證不充分，特別是變更生產(chǎn)批量后未進(jìn)行工藝驗證的問題較多。
4.數(shù)據(jù)管理的規(guī)范性問題突出，主要體現(xiàn)在系統(tǒng)權(quán)限設(shè)置、審計追蹤功能、文件和數(shù)據(jù)的修改及刪除權(quán)限等未進(jìn)行控制，以及對刪除數(shù)據(jù)和選擇使用的數(shù)據(jù)沒有合理控制和解釋。
5.計算機(jī)化系統(tǒng)、確認(rèn)和驗證兩個附錄的實施情況與法規(guī)要求存在一定差距，發(fā)現(xiàn)問題較多。
6.對偏差和變更的管理較薄弱，主要體現(xiàn)在對發(fā)生的偏差不能有效識別并記錄，對變更缺少必要的評估和驗證。

　　（二）2015年度抽驗不合格的企業(yè)
檢查10家企業(yè)共發(fā)現(xiàn)嚴(yán)重缺陷11項，主要缺陷27項，一般缺陷84項。

　　發(fā)現(xiàn)的主要問題包括：生產(chǎn)工藝與注冊工藝不一致，數(shù)據(jù)可靠性問題，工藝驗證問題。

　　（三）雙隨機(jī)檢查
發(fā)現(xiàn)嚴(yán)重缺陷5項，主要缺陷24項，一般缺陷123項。

　　發(fā)現(xiàn)的主要問題包括：偽造記錄，產(chǎn)品存在質(zhì)量安全隱患，數(shù)據(jù)可靠性問題，工藝驗證存在問題，物料管理不規(guī)范，存在污染、混淆和差錯風(fēng)險，清潔不徹底，不能有效防止污染和交叉污染。

　　（四）疫苗生產(chǎn)企業(yè)
發(fā)現(xiàn)主要缺陷38項，一般缺陷383項。

　　發(fā)現(xiàn)的主要問題包括：
1設(shè)備方面。注射用水制備系統(tǒng)進(jìn)入注射水儲罐的不銹鋼管路閥門到制水機(jī)之間過長。
2.物料與產(chǎn)品方面。成品不合格品銷毀記錄有待細(xì)化；個別貨位卡缺失；未建立生產(chǎn)用的菌毒種主種子全基因序列的背景資料。
3.文件管理方面。個別文件規(guī)定不夠具體、操作性不強，文件規(guī)定的內(nèi)容與實際稍有出入；個別記錄內(nèi)容不全面；批生產(chǎn)記錄設(shè)計內(nèi)容不合理，實際操作時填寫容易造成不及時。
4.質(zhì)量控制與質(zhì)量保證方面
（1）質(zhì)量實驗室管理：未向接受委托檢驗的機(jī)構(gòu)索取必要的檢驗數(shù)據(jù)和圖譜。
（2）偏差處理：企業(yè)偏差處理相關(guān)文件的培訓(xùn)、執(zhí)行不到位；個別偏差未能及時啟動調(diào)查；少數(shù)偏差原因分析和糾正預(yù)防措施不到位，對偏差可能引起的對產(chǎn)品質(zhì)量的潛在影響沒有充分評估。
（3）變更控制：變更未按變更流程處理并申報注冊補充申請。對某些變更沒有進(jìn)行評估或評估不充分。
（4）供應(yīng)商管理：對關(guān)鍵物料供應(yīng)商的審計內(nèi)容有待細(xì)化，供應(yīng)商審計內(nèi)容針對性有待提高。
（5）產(chǎn)品質(zhì)量回顧：應(yīng)按品種分別進(jìn)行年度質(zhì)量回顧，且回顧中對CAPA有效性分析不足；年度產(chǎn)品質(zhì)量回顧分析報告分析內(nèi)容可進(jìn)一步細(xì)化。
5.計算機(jī)化系統(tǒng)。企業(yè)制定了計算機(jī)化系統(tǒng)管理的文件制度，但并未完全按照制度分類進(jìn)行管理，對現(xiàn)有條件不符合文件的情形，未采取有效措施降低風(fēng)險；質(zhì)量檢驗室HPLC檢測設(shè)備登錄界面權(quán)限設(shè)置要求需細(xì)化。

　?。ㄎ澹┭褐破飞a(chǎn)企業(yè)
共檢查25家企業(yè)，發(fā)現(xiàn)嚴(yán)重缺陷0項，主要缺陷13項，一般缺陷241項。

　　發(fā)現(xiàn)的主要問題：
1.機(jī)構(gòu)與人員方面，對部分崗位操作人員培訓(xùn)欠缺。
2.廠房與設(shè)施方面，存在不能有效控制污染和交叉污染的可能。
3.設(shè)備方面。部分設(shè)備校準(zhǔn)未覆蓋實際使用范圍；部分檢驗用儀器設(shè)備未定期校準(zhǔn)或校準(zhǔn)不充分，記錄不完善；部分設(shè)備標(biāo)識不全。
4.物料與產(chǎn)品方面。價撥冷沉淀標(biāo)簽中信息不充分，標(biāo)簽未固定。
5.確認(rèn)與驗證方面。培養(yǎng)基模擬灌裝實驗未明確干預(yù)要求、剔除標(biāo)準(zhǔn)等具體要求。
6.文件管理方面。工藝規(guī)程、操作程序等文件內(nèi)容不具體，規(guī)定不規(guī)范。記錄存在不及時填寫、填寫不全面等不規(guī)范行為。
7.生產(chǎn)管理方面。滅活前加入的辛酸鈉溶液，缺少微生物的控制措施；未對沉降碟在A級層流下的放置時間進(jìn)行確認(rèn)。
8.質(zhì)量控制與質(zhì)量保證方面
（1）質(zhì)控實驗室管理：檢品收發(fā)臺賬記錄內(nèi)容不完整，未記錄中間品、半成品檢驗樣品的接收信息；未對外購的用于環(huán)境監(jiān)測的平皿培養(yǎng)基進(jìn)行檢測；無菌試驗未按藥典設(shè)置陰性對照；
（2）產(chǎn)品穩(wěn)定性考察：中間產(chǎn)品制定了效期，但缺少持續(xù)穩(wěn)定性考察或驗證數(shù)據(jù)支持；
（3）變更控制：變更控制管理不到位。對部分變更沒有進(jìn)行評估或評估不充分；
（4）偏差處理：個別偏差未能及時啟動調(diào)查；部分偏差調(diào)查及糾正和預(yù)防措施不充分；
（5）供應(yīng)商管理：冷沉淀價撥供應(yīng)商未納入企業(yè)合格供應(yīng)商目錄；
（6）產(chǎn)品質(zhì)量回顧：某些信息未納入年度產(chǎn)品質(zhì)量回顧中；
（7）產(chǎn)品發(fā)運與召回：對批簽發(fā)樣品的發(fā)運方式未進(jìn)行規(guī)定；
（8）計算機(jī)化系統(tǒng)：計算機(jī)化系統(tǒng)的管理文件不完善。QC實驗室部分儀器設(shè)備無審計追蹤功能；某些電子數(shù)據(jù)導(dǎo)入電腦打印后均沒有保存和備份；系統(tǒng)未設(shè)置不同層級訪問權(quán)限，存在數(shù)據(jù)和系統(tǒng)被修改風(fēng)險。

　　（六）2015年發(fā)告誡信的企業(yè)
檢查32家企業(yè)共發(fā)現(xiàn)嚴(yán)重缺陷2項，主要缺陷32項，一般缺陷328項。

　　發(fā)現(xiàn)的主要問題包括：數(shù)據(jù)可靠性問題，未對偏差進(jìn)行記錄和調(diào)查，無菌保障存在不足，相關(guān)確認(rèn)與驗證工作不夠充分。

　　（七）省級認(rèn)證的無菌藥品生產(chǎn)企業(yè)
檢查21家企業(yè)共發(fā)現(xiàn)嚴(yán)重缺陷0項，主要缺陷15項，一般缺陷209項。

　　發(fā)現(xiàn)的主要問題表現(xiàn)在：小容量注射劑共線生產(chǎn)風(fēng)險評估不充分；僅對單品種進(jìn)行清潔驗證，未對企業(yè)所有品種進(jìn)行清潔風(fēng)險評估；部分檢驗記錄內(nèi)容不完整；尚未開展計算機(jī)化系統(tǒng)的驗證和審計工作；物料管理不當(dāng)，存在混淆、差錯風(fēng)險等。

　　（八）高風(fēng)險品種的專項檢查
檢查61家企業(yè)共發(fā)現(xiàn)嚴(yán)重缺陷3項，主要缺陷64項，一般缺陷658項。

　　發(fā)現(xiàn)的主要問題如下：
1.骨肽注射液
（1）從肉制品公司購入的前腿骨，未按規(guī)定采購、驗收。物料到貨后，未按SOP索取、核對供應(yīng)商出具的檢驗報告；驗收時，未索取豬四肢骨冷鏈運輸溫度監(jiān)測記錄。
（2）復(fù)方骨肽原溶液的病毒滅活未經(jīng)驗證；對豬四肢骨提取后存放時間、復(fù)方骨肽注射液從灌封到滅菌開始的時間沒有驗證數(shù)據(jù)支持。
（3）持續(xù)穩(wěn)定性考察方案未對活性指標(biāo)及相關(guān)的安全性指標(biāo)加以規(guī)定及檢驗，如：過敏實驗、熱原、異常毒性等。
2.果糖二磷酸鈉注射液
果糖二磷酸鈉企業(yè)內(nèi)控標(biāo)準(zhǔn)中微生物限度標(biāo)準(zhǔn)未按中國藥典2015年版相應(yīng)規(guī)定進(jìn)行修訂；用于果糖二磷酸鈉原料藥含量測定用的復(fù)合酶試劑超過保質(zhì)期后，仍用于原料藥的含量測定。
3.胞磷膽堿鈉注射液
某企業(yè)胞磷膽堿鈉原料藥內(nèi)控標(biāo)準(zhǔn)制定不合理，未參照原料藥生產(chǎn)企業(yè)質(zhì)量標(biāo)準(zhǔn)增加甲苯殘留的項目。某企業(yè)胞磷膽堿鈉注射液未分別對不同廠家的原料進(jìn)行分開工藝驗證；未提供胞磷膽堿鈉注射液除菌過濾器相容性試驗的相容性試驗資料。

第四節(jié) 藥品飛行檢查

　　一、基本情況

　　2016年共接收總局飛檢任務(wù)45次，完成并上報結(jié)果的藥品GMP飛行檢查39家次，其他于2017年開展。已上報結(jié)果的39家次中，涉及北京、江蘇、廣東等20個?。ㄊ校?，共包括9家生化藥品生產(chǎn)企業(yè)、20家中藥生產(chǎn)企業(yè)、9家普通化學(xué)藥品生產(chǎn)企業(yè)及1家血液制品生產(chǎn)企業(yè)。
2016年的飛行檢查任務(wù)中來自總局藥化監(jiān)管司的任務(wù)33件，來自總局藥化注冊司等司局的任務(wù)共計6件。總局藥化監(jiān)管司的任務(wù)占比約85%，是飛行檢查任務(wù)的主要來源。39次飛行檢查中中藥占全部飛行檢查工作的51%，普通化學(xué)藥品和生化藥品各占23%。2016年飛行檢查共有21家藥品生產(chǎn)檢查不通過，占比約54%。其中有14家企業(yè)被建議收回藥品GMP證書，10家企業(yè)被建議立案調(diào)查，7家企業(yè)的問題產(chǎn)品被責(zé)令召回。在藥品GMP飛行檢查中，中藥和生化藥品發(fā)現(xiàn)的問題較多。總局已經(jīng)依法依規(guī)對飛行檢查中發(fā)現(xiàn)的問題進(jìn)行了處理。

　　二、發(fā)現(xiàn)的主要問題

　?。ㄒ唬┲兴庮惼髽I(yè)發(fā)現(xiàn)的主要問題
2016年針對中藥類生產(chǎn)企業(yè)，共派出18個檢查組66人次對20家企業(yè)進(jìn)行了飛行檢查，其中涉及信訪舉報的7家企業(yè)，人工牛黃生產(chǎn)企業(yè)3家企業(yè)，含牛黃類產(chǎn)品7家企業(yè)，探索性研究檢驗發(fā)現(xiàn)問題3家企業(yè)，中藥飲片1家企業(yè)。
20家中藥類生產(chǎn)企業(yè)的飛行檢查，其中12家企業(yè)不符合藥品GMP要求，對3家企業(yè)的有關(guān)問題移交省局處理，對1家企業(yè)發(fā)出了告誡信，1家企業(yè)無相關(guān)生產(chǎn)，符合要求的有3家企業(yè)。
1.中成藥生產(chǎn)企業(yè)
（1）擅自改變工藝問題較為突出。
中成藥口服制劑為降低生產(chǎn)成本，擅自改變前處理、提取工藝的現(xiàn)象還是一個比較突出的問題。本年度因探索性檢驗發(fā)現(xiàn)問題開展飛行檢查的，均是企業(yè)將處方中部分應(yīng)提取的中藥材不按工藝規(guī)程進(jìn)行提取，而是粉碎后直接投料。
（2）中藥材、中藥飲片物料管理混亂。
個別中成藥生產(chǎn)企業(yè)，為應(yīng)對各級藥品監(jiān)督管理部門的監(jiān)督檢查，編造倉庫物料臺賬和出入庫記錄，根據(jù)中成藥的生產(chǎn)量倒推出中藥材的使用量，并按需用量編造物料臺賬。
（3）對購入的中藥材、中藥飲片不能嚴(yán)格全檢，且數(shù)據(jù)可靠性存在問題。
傳統(tǒng)中成藥生產(chǎn)企業(yè)產(chǎn)品品種多，涉及的中藥材、中藥飲片品種也多，由于配置的精密分析儀器和QC人員與生產(chǎn)規(guī)模不相適應(yīng)，不能保證購入的中藥材和中藥飲片批批全檢，造成對部分批次中藥材、中藥飲片不進(jìn)行全檢，或者采用一圖多用的行為應(yīng)對檢查。
2.人工牛黃
部分企業(yè)不能按照藥品GMP要求組織生產(chǎn)，尤其是對人工牛黃上游產(chǎn)業(yè)鏈供應(yīng)商審計和管理要求嚴(yán)重不足，供應(yīng)商的加工場所衛(wèi)生環(huán)境惡劣，原材料來源無法溯源，加工過程不可控。主要問題包括：（1）供應(yīng)商管理環(huán)節(jié)薄弱；（2）微生物限度檢查結(jié)果真實性存疑；（3）未納入質(zhì)量保證體系。
3.中藥飲片
購進(jìn)中藥材或炮制后產(chǎn)品的含量檢測問題突出，染色、增重問題時有發(fā)生，批生產(chǎn)記錄真實性存疑。主要問題包括：（1）批生產(chǎn)記錄不真實；（2）涉嫌外購飲片進(jìn)行分裝、銷售；（3）數(shù)據(jù)可靠性問題。

　?。ǘ┥幤?br /> 1.“單唾液酸四已糖神經(jīng)節(jié)苷酯鈉”的檢查
2016年共檢查4家“單唾液酸四已糖神經(jīng)節(jié)苷酯鈉”生產(chǎn)企業(yè)，發(fā)現(xiàn)其在原料質(zhì)量和供應(yīng)商管理方面存在一定的風(fēng)險。主要問題包括：
（1）供應(yīng)商管理有待提高，企業(yè)對供應(yīng)商的管理不能保證有效的追溯性。
（2）對原料冷鏈運輸監(jiān)控的電子數(shù)據(jù)管理不夠。
2.“注射用促肝細(xì)胞生長素”的檢查
2016年共檢查4家“注射用促肝細(xì)胞生長素”生產(chǎn)企業(yè)，其中2家企業(yè)被收回《藥品GMP證書》，對另外2家企業(yè)發(fā)出了告誡信。主要問題包括：（1）編造記錄文件；（2）數(shù)據(jù)可靠性問題；（3）與注冊生產(chǎn)工藝不一致；（4）無法有效保證肝臟原料的質(zhì)量。

第五節(jié) 進(jìn)口藥品境外檢查

　　一、檢查基本情況

　?。ㄒ唬┠甓葯z查任務(wù)概況
按照總局《關(guān)于執(zhí)行2016年度進(jìn)口藥品境外生產(chǎn)現(xiàn)場檢查計劃的函》等文件要求。2016年度境外任務(wù)共計49個。

　　1.2016年檢查任務(wù)涉及19個國家。其中歐洲、北美等地區(qū)品種數(shù)量居多，藥品質(zhì)量地域性風(fēng)險高的印度、越南等國家的檢查品種也占一定比例，同時增加對南美地區(qū)和澳洲地區(qū)檢查力度。

　　2.遵循檢查服務(wù)于審評審批的原則，兼顧已上市產(chǎn)品安全要求，在審品種檢查比例增大，申報臨床、申報生產(chǎn)、再注冊和補充申請階段產(chǎn)品均納入檢查范圍，已上市產(chǎn)品檢查的原因主要為口岸質(zhì)量檢驗問題，增加不良反應(yīng)監(jiān)測風(fēng)險較高品種。

　　3.檢查任務(wù)顯現(xiàn)品種全面、劑型廣泛等特點，并加大對化學(xué)藥品制劑的延伸檢查力度。涉及化學(xué)藥品40個，含注射劑、固體制劑、植入劑、鼻噴劑等，其中生化藥3個，延伸檢查原料藥6個；疫苗、血液制品、治療用生物制品11個；植物藥4個。

　?。ǘ?016年檢查執(zhí)行情況
由于年中總局工作安排，重新調(diào)整了2016年境外檢查計劃時間，生產(chǎn)企業(yè)排產(chǎn)變化導(dǎo)致2016年共完成15個品種檢查任務(wù)，其中赴現(xiàn)場檢查7個品種，3個品種不通過，占檢查數(shù)量的42%；8個品種在檢查組織期間，企業(yè)主動撤銷品種進(jìn)口注冊證，或被退審等，占年度總計劃的17%。另21個品種由于企業(yè)排產(chǎn)原因，于2017年第一季度完成檢查，剩余12個品種，因企業(yè)無法在2017年第一季度接受檢查，已納入2017年境外檢查計劃。

　　二、境外檢查發(fā)現(xiàn)的主要問題

　　已檢查的7個品種中，3個品種不通過，不通過率較往年有所提高。檢查共發(fā)現(xiàn)缺陷117項，其中嚴(yán)重缺陷3項，主要缺陷18項。問題主要集中在質(zhì)量控制與質(zhì)量保證、物料系統(tǒng)、變更管理等方面；嚴(yán)重缺陷主要為生產(chǎn)工藝一致性以及數(shù)據(jù)可靠性問題。對境外發(fā)現(xiàn)的問題都依法依規(guī)進(jìn)行處理。

　　主要及嚴(yán)重問題如下：
1.實際生產(chǎn)工藝、生產(chǎn)場地等與注冊申報不一致，重大變更等情況未向我國進(jìn)行申報卻已執(zhí)行。
2.數(shù)據(jù)可靠性存在重大問題，嚴(yán)重影響產(chǎn)品質(zhì)量。
3.非現(xiàn)場檢查處理品種數(shù)量增多。

第六節(jié) 藥品流通檢查

　　一、檢查基本情況

　　2016年度，國家食品藥品監(jiān)督管理總局對藥品流通領(lǐng)域違法經(jīng)營行為開展了集中整治，通過企業(yè)自查整改，省局監(jiān)督檢查，總局實施飛檢等方式進(jìn)一步整頓和規(guī)范藥品流通秩序，嚴(yán)厲打擊違法經(jīng)營行為。全年共組織3批，對50家藥品批發(fā)企業(yè)進(jìn)行了檢查。飛行檢查結(jié)果由總局對外進(jìn)行公告。

　　檢查組依據(jù)《總局關(guān)于整治藥品流通領(lǐng)域違法經(jīng)營行為的公告》（2016年第94號）以及《藥品經(jīng)營質(zhì)量管理規(guī)范》對相關(guān)企業(yè)進(jìn)行了飛行檢查。結(jié)果發(fā)現(xiàn)，藥品流通企業(yè)存在的違法違規(guī)行為較為普遍，情況如下。

　　二、發(fā)現(xiàn)主要問題

　　（一）企業(yè)違反總局94號公告情況。

　　存在主要問題：
1.未按規(guī)定對藥品儲存、運輸、進(jìn)行溫濕度監(jiān)測。
2.購銷藥品時，證（許可證書）、票（發(fā)票、隨貨同行票據(jù)）、賬（實物賬、財務(wù)賬）、貨（藥品實物）、款（貨款）不能相互對應(yīng)一致；藥品未入庫，設(shè)立賬外賬，藥品未納入企業(yè)質(zhì)量體系管理，使用銀行個人賬戶進(jìn)行業(yè)務(wù)往來等情形。
3.偽造藥品采購來源，虛構(gòu)藥品銷售流向，篡改計算機(jī)系統(tǒng)、溫濕度監(jiān)測系統(tǒng)數(shù)據(jù)，隱瞞真實藥品購銷存記錄、票據(jù)、憑證、數(shù)據(jù)等，藥品購銷存記錄不完整、不真實，經(jīng)營行為無法追溯。

　?。ǘ┢髽I(yè)違反總局藥品經(jīng)營質(zhì)量管理規(guī)范（GSP）情況。

　　藥品流通企業(yè)GSP缺陷主要集中于總則、儲存與養(yǎng)護(hù)、銷售等方面。主要存在問題：
1.未依法經(jīng)營，存在虛假、欺騙行為。
企業(yè)擅自變更經(jīng)營注冊地址；在經(jīng)營許可范圍外設(shè)倉庫儲存藥品；為他人違法經(jīng)營藥品提供條件；虛構(gòu)藥品采購來源及銷售流向；藏匿票據(jù)、提供虛假資料；自查報告不真實；納稅申報表造假；篡改溫濕度監(jiān)測數(shù)據(jù)等。
2.未按規(guī)定儲存藥品，未對庫房溫濕度進(jìn)行有效監(jiān)測、調(diào)控。
3.購銷藥品時，票、帳、貨、款不一致，特藥銷售未執(zhí)行國家規(guī)定。

第七節(jié) 國外機(jī)構(gòu)GMP觀察檢查

　　一、檢查基本情況

　　2016年核查中心共組織完成藥品生產(chǎn)企業(yè)的觀察檢查81家次，涉及企業(yè)76家，涵蓋浙江、山東等20個省（市），其中浙江、山東、江蘇、廣東、湖北、海南、河北占80%，與上年度相比基本一致，但各省之間比例略有變化。

　　2016年檢查觀察涉及的檢查機(jī)構(gòu)包括世界衛(wèi)生組織（WHO）、歐洲藥品質(zhì)量理事會（EDQM）、美國食品藥品監(jiān)督管理局（US FDA）、德國漢堡健康及消費者保護(hù)部（BGV）、巴西衛(wèi)生監(jiān)督局（ANVISA）、法國國家醫(yī)藥健康安全管理局（ANSM）等12個國際組織或國外藥品監(jiān)管部門。其中發(fā)現(xiàn)9家制藥企業(yè)出現(xiàn)嚴(yán)重缺陷，未通過國外監(jiān)管/檢查機(jī)構(gòu)的現(xiàn)場檢查（占比約11%）。

　　與2015年相比，不通過比率有所上升。在9家未通過檢查的企業(yè)中，多數(shù)嚴(yán)重缺陷項均涉及數(shù)據(jù)可靠性問題（包括重復(fù)測試至合格、修改系統(tǒng)時間后檢測、刪除數(shù)據(jù)、刪除審計追蹤記錄、選擇性使用數(shù)據(jù)、修改電子數(shù)據(jù)名稱、試進(jìn)樣、記錄不及時、記錄不真實、數(shù)據(jù)和記錄缺失、文件記錄控制不足等），部分企業(yè)涉及到物料標(biāo)準(zhǔn)制定不合理、避免交叉污染的措施不足等方面。總體上，數(shù)據(jù)可靠性問題較為突出，這也是2016年國內(nèi)企業(yè)接受國外檢查不通過率上升的主要原因，也體現(xiàn)出目前藥品檢查的變化趨勢。
本年度觀察檢查共涉及172個藥品，包括119個原料藥、23個口服固體制劑、19個注射劑、5個生物制品。在81家次檢查中涉及原料藥的檢查共62次，約占全部檢查次數(shù)的69%，涉及口服固體制劑的檢查12次，約占全部檢查次數(shù)13%。其中原料藥占比最大，其次是口服固體制劑，其他劑型出口相對較少。與2015年相比，其他劑型（包括無菌制劑、生物制品等）接受檢查的比例有了一定的提升，占比由2015年的10%上升至18%，

　　二、發(fā)現(xiàn)的主要問題

　　2016年觀察檢查工作中共記錄發(fā)現(xiàn)的缺陷項1108項，依據(jù)我國2010版GMP正文章節(jié)對缺陷項進(jìn)行分類分析發(fā)現(xiàn)：質(zhì)量控制與質(zhì)量保證、文件管理、設(shè)備、物料與產(chǎn)品、確認(rèn)與驗證、廠房與設(shè)施六個類別的缺陷占了全部缺陷的88%。與2015年相比，文件管理部分缺陷由第4位上升至第2位，在目前企業(yè)逐漸加強數(shù)據(jù)可靠性管理的環(huán)境下仍增長了約7%（由10.5%增加至17.3%），充分體現(xiàn)出當(dāng)前國外檢查對數(shù)據(jù)可靠性的關(guān)注程度與嚴(yán)格要求。
在國外藥品GMP檢查中，“質(zhì)量控制與質(zhì)量保證”部分提出的缺陷占總?cè)毕輸?shù)的27.3%，位居首位。主要問題集中在實驗室計算機(jī)化分析儀器的管理、偏差處理與CAPA、產(chǎn)品質(zhì)量回顧分析、變更控制、OOS/OOT結(jié)果處理、實驗室未遵循控制程序的規(guī)定、微生物檢驗管理、質(zhì)量風(fēng)險管理、穩(wěn)定性試驗等方面。“文件管理”部分出現(xiàn)的缺陷居于第二位，缺陷主要集中在記錄完整性和可追溯性、文件的生命周期管理、文件完整性、記錄操作四個方面。“設(shè)備”部分出現(xiàn)的缺陷居于第三位，其中設(shè)備的使用與清潔、校準(zhǔn)、維護(hù)與維修、制水系統(tǒng)管理四個方面的缺陷占該部分全部缺陷項的83.6%。“物料與產(chǎn)品”部分的缺陷項集中在供應(yīng)商管理、物料與產(chǎn)品標(biāo)識、物料流程管理、物料與產(chǎn)品標(biāo)準(zhǔn)的合規(guī)性、放行管理方面。“確認(rèn)與驗證”方面的缺陷主要包括驗證的科學(xué)性、驗證管理、驗證文件與記錄三類。“廠房與設(shè)施”部分的缺陷主要包括環(huán)境控制、倉儲區(qū)管理、降低污染和交叉污染的措施、廠房設(shè)施的生命周期管理等四個方面。

　　三、不同機(jī)構(gòu)藥品GMP檢查分析

　　檢查內(nèi)容方面，盡管不同藥品GMP檢查機(jī)構(gòu)檢查的重點存在一定的差異，但通過對2016年觀察檢查中的缺陷情況分析發(fā)現(xiàn)：質(zhì)量控制與質(zhì)量保證、文件管理、設(shè)備、物料與產(chǎn)品、確認(rèn)與驗證、廠房與設(shè)施等六個部分出現(xiàn)的缺陷相對較多。在檢查最終報告中提出的缺陷條數(shù)方面，EDQM、WHO檢查出具的缺陷數(shù)據(jù)相對較多，平均每次檢查約20條缺陷，缺陷項目中對檢查過程中發(fā)現(xiàn)的問題都進(jìn)行描述，檢查結(jié)束后整理編寫最終檢查報告（通常一個月左右）。US FDA在檢查中提出的缺陷條數(shù)相對較少，平均每次檢查約7條缺陷，并不將檢查過程中發(fā)現(xiàn)的所有問題均作為最終缺陷項，檢查員根據(jù)發(fā)現(xiàn)的問題結(jié)合對產(chǎn)品的風(fēng)險進(jìn)行判斷后形成最終缺陷項，并在召開檢查末次會時書面（483表）告知企業(yè)。

 

Foreword

　　The Center for Food and Drug Inspection (CFDI) organized to conduct a total of 431 inspections throughout the year, including pre-approval inspection, GMP certification inspection, GMP follow-up inspection, unannounced inspection, overseas inspection ,GSP unannounced inspection and inspection observation.

Part I Pre-approval Inspection

　　I. Overview of Inspections

　　A total of 29 inspection tasks were received in 2016, of which 21 tasks were from the Center for Drug evaluation of CFDA (hereinafter referred to as CDE), 8 tasks were from the Department of Drug and Cosmetics Registration of CFDA and discipline inspection and supervision departments (for-cause inspection tasks). A total of 178 person-times, 43 inspection teams have been sent out to conduct pre-approval inspection on 34 varieties; 42 on-site inspection reports have been completed, of which 34 passed the inspection, accounting for 81%; and 8 failed or proactively withdrew registration applications, accounting for 19%.

　　II. Main findings

　　In the pre-approval inspections in 2016, such problems in data integrity as untraceable data and untruthful application dossier were still prominent while insufficient process validation and instable production process and inconsistency between production process or parameters with approved ones were also identified, which were specifically as follows: (All issues found in inspection have been dealt in accordance with the law.)
(I) Problems in data integrity
1. Testing data were untraceable. A few enterprises failed to retain samples as required and conduct stability investigation. No retained preproduction samples and retained samples for stability test of the inspected varieties were found in pre-approval inspection, and enterprises also failed to provide both the requisition and destruction records of corresponding retained samples and the samples for stability test and use records of the equipment for stability test.
2. Batch production records were untruthful and incomplete and inconsistent with application dossier.
(II) The process validation was insufficient and production process was instable
The process validation for the variety was insufficient. During the dynamic production of the enterprises, some procedure had serious deviation or batch product yield had a greater deviation from the validated batch.
(III) The production process or key process parameters and inner packaging materials were inconsistent with the approved ones and no study and assessment was conducted
1. The production process was inconsistent with that approved / under application.
2. Key process parameters were inconsistent with the production process approved / under application.
3. The manufacturer of inner packing materials was inconsistent with that under registration application, and the enterprise did not conduct comparison study.
(IV) Necessary deviation investigation was not conducted
There was significant abnormality in dynamic production, but the investigation was insufficient and the primary cause was not identified. The results of the process validation of three batches and dynamic production batch of the chemical APIs under application by an enterprise showed that there was significant difference in the rate of finished products among four batches, but the enterprise did not analyze and identify the reasons.

Part II Pharmaceutical GMP Certification Inspection

　　I. Overview of Inspections

　　based on the spirit in the Announcement of China Food and Drug Administration on Relevant Issues of Halting the Production by the Enterprises Failing to Pass the Pharmaceutical GMP (revised in 2010) Certification and Decentralizing the Certification of Sterile Pharmaceuticals (2015 No.285), China Food and Drug Administration no longer accepted the application for pharmaceutical GMP certification as of January 1st, 2016. For the certification applications that have been accepted, on-site inspection as well as review and certificate-issuing continued to be completed.
In view of above situation, the inspections on 16 pharmaceutical manufacturers have been arranged, 16 copies of on-site inspection reports have been received and 14 copies have been reviewed throughout the year of 2016. Among them, 12 pharmaceutical manufacturers passed pharmaceutical GMP certification inspection, 2 pharmaceutical manufacturers failed to pass pharmaceutical GMP certification inspection and 5 pharmaceutical manufacturers were issued with Warning Letter; and another two pharmaceutical manufacturers have not yet received approval document for registration so the GMP certification process is suspended.
The dosage forms under application for certification included large volume injection of three enterprises, small volume injection of three enterprises, c of three enterprises, powder injection of one enterprise, radiopharmaceutical of one enterprise, vaccine of two enterprises and other biologics of three enterprises.

　　II. Main findings

　　A total of 220 deficiencies were identified, including 23 major deficiencies and 197 general deficiencies. There were 41 deficiencies in Quality Control and Quality Assurance, 32 deficiencies in documentation Management, 24 deficiencies in Institutions and Personnel, 23 deficiencies in Equipment and 21 deficiencies in Verification and Qualification. The distribution was basically consistent with that in 2015.
The two manufacturers of in vitro diagnostic reagents receiving certification inspection all failed this year. The main problems were as follows:
(I) Quality Management System. Quality management system could not be effective operated and failed to meet the production and quality requirements of the products; The personnel mobility was frequent, there lacked professionals and the training was not conducted, which could not meet the quality management requirements in routine production; The operability of the documents were poor and data were incompletely recorded; relevant changes were not subject to change control in accordance with change procedure.
(II) Verification and Qualification. The enterprises failed to conduct process validation for all the products under application for GMP certification, and the cleaning validation for public equipment and facilities was not in place; part of validation records was incomplete; and some re-validation work was not conducted as required.

Part III Pharmaceutical GMP Follow-up Inspection

　　I. Overview of Inspections

　　In 2016, it was planned in the Announcement to conduct follow-up inspection on 215 enterprises, a total of 228 inspections. Among them, 58 inspections were conducted on the enterprises out of production or having no production for a long time, and other 170 inspections have all been conducted.
In addition, follow-up inspection was conducted on 21 sterile drug manufacturers passing provincial certification, and double random inspection was conducted on 13 enterprises. A total of 204 follow-up inspections were completed.

　　12 enterprises failed in follow-up inspection, accounting for 5.9%, and 58 enterprises were issued with Warning Letter, accounting for 28.9%.
Among 12 enterprises failing in the inspection, there were 5 enterprises unqualified in casual inspection in 2015, 4 enterprises subject to double random inspection, 2 manufacturers of citicoline sodium injection and 1 manufacturer of ossotide injection. (All issues found in inspection have been dealt in accordance with the law.)
(I) The situation of casual inspection of the varieties in quality report in 2015
10 enterprises accepted the follow-up inspection on such dosage forms and varieties as eye drops, bendazol tablets and APIs of sodium benzoate, of which 5 enterprises failed, accounting for 50%, and 4 enterprises were issued with Warning Letter.
(II) Double random inspection
In order to implement the requirements of innovating the supervision inwards and afterwards by the State Council, in accordance with the unified arrangement by CFDA, double random inspection system for pharmaceuticals was initially operated in December 2016, follow-up inspection was conducted on the 13 seleced enterprises. The inspections distributed in 9 provinces and involved 3 chemicals, 2 APIs and 8 TCMs. 4 enterprises failed in the inspection, and the pass rate was only 69%. In addition, 3 enterprises were issued with Warning Letter.
(III) Vaccine manufacturers
38 vaccine manufacturers that have obtained GMP certificate were marketed in the follow-up inspection plan in 2016. Except for 1 enterprise having production license and GMP certificate revoked in 2014 and 1 enterprise failing to get GMP certification in 2015 due to the application for the change of production address, the follow-up inspection was conducted on other 36 vaccine manufacturers. All 36 enterprises passed the inspection, and 7 enterprises which found general risks and can be improved by rectification were issued with Warning Letter. According to experts assessment that one critical deficiency that was evaluated by inspectors on site should be decreased to major deficiency, being low risk. On the whole, the quality risks in vaccine production are controllable and the manufacturers have a standardized production and quality management.
(IV) Blood product manufacturers
26 blood product manufacturers were marketed in the follow-up inspection plan in 2016. Except for 1 enterprise in production suspension and rectification, the follow-up inspection was conducted on other 25 blood product manufacturers. All 25 enterprises passed the inspection, and 4 enterprises which found general risks and can be improved by rectification were issued with Warning Letter. On the whole, the quality risks in blood product production are controllable, the manufacturers have a standardized production and quality management, but the supervision shall be intensified for individual enterprises.
(V) The manufacturers issued with warning letter in 2015
Follow-up inspection has been conducted on 32 manufacturers issued with warning letter in 2015. The manufacturers were basically met the requirements, but 14 manufacturers were issued with warning letter again.
(VI) The situation of casual inspections on the sterile drug manufacturers passing provincial certification after the decentralization of certification
21 sterile drug manufacturers passing provincial certification received casual inspection. All of them passed the inspection and 6 enterprises were issued with Warning Letter. According to the inspection result, the Provincial Bureau can undertake the GMP certification inspection functions smoothly down.
(VII) Special inspection on high-risk varieties
This year, follow-up inspection was mainly conducted on the injection of three products including ossotide, fructose diphosphate and citicoline sodium. It was planned to conduct 114 special inspections on high-risk varieties. 47 enterprises were not inspected because of failing in GMP (2010 version) certification, out of production for a long time and transfer of approval number, and 67 inspections were actually conducted. In the inspections, 1 ossotide injection manufacturer and 2 citicoline sodium injection manufacturers failed, and 21 manufacturers were issued with Warning Letter.

　　II. Main findings

　　(I) Overall situation
A total of 2271 deficiencies were identified in 204 inspections, of which there were 22 critical deficiencies, 210 major deficiencies and 2039 general deficiencies. Compared with GMP certification and follow-up inspections in 2015, the number of critical deficiencies was increased.
Among the manufacturers of high-risk varieties subject to special inspection, out of production for a long time or failing in pharmaceutical GMP (2010 version) certification were prominent. The common problems identified in the inspections were as follows:
1. Individual enterprise had inconsistency between its production process and registered process.
2. The problems in data integrity and authenticity still existed, including falsification of production records, indiscriminate use of maps and arbitrary modification of data in inspection records and inconsistency in relevant content in production, equipment and material records.
3. The process validation was insufficient, and the enterprises failing to conduct process validation after changing production lot size had more problems.
4. The problems in the standardization of data management were prominent, mainly manifesting as failing to control the permission setting of the system, audit tracking function and the permission for the modification and deletion of documents and data, and having no reasonable control and explanation for deleting, selecting and using data.
5. There was certain gap between the implementation of the Appendix of Computer System and Appendix of Qualification and Validation and regulatory requirements, and many problems were identified.
6. There was a weak management of deviations and changes, mainly manifesting as failing to effectively identify and record the deviations that occurred, and lacking necessary assessment and validation for the changes.

　(II) The enterprises unqualified in casual inspections in 2015
A total of 11 critical deficiencies, 27 major deficiencies and 84 general deficiencies were identified in the inspections on 11 enterprises.

　　Main findings were as follows:
1. Production process was inconsistent with registered process
2. Problems in data integrity
3. Problems in process validation
(III) Double random inspection
A total of 5 critical deficiencies, 24 major deficiencies and 123 general deficiencies were identified.

　　Main findings were as follows:
1. Record falsification
2. Potential hazards in product quality and safety
3. Problems in data integrity
4. Problems in process validation
5. Non-standardized material management with the risks in pollution, confusion and error.
6. Incomplete cleaning, which cannot effectively prevent contamination and cross-contamination.
(IV) Vaccine manufacturers
38 major deficiencies and 383 general deficiencies were identified.

　　Main findings:
1. Equipment. There was a too long stagnant water section between the stainless steel pipe valve through which water for injection preparation system enters into injection water storage tank and water generator; Individual device had rust.
2. Materials and Products. The quantity of the destructed items was not recorded in the destruction records of the non-conforming finished products; the enterprise failed to establish the background information of whole-genome sequence of main bacterial and viral seeds for production.
3. documentation Management. Individual document was not specifically specified and was poor in its operability. The content specified in the document was inconsistent with the actual situation; individual record had incomplete content; the batch production records were unreasonably designed and were not timely filled in actual operation.
4. Quality Control and Quality Assurance
(1) Quality management of laboratories: the enterprise failed to request necessary test data and maps from the institutions conducting entrusted test; some material was subject to infrared test after sample mixing.
(2) the Deviation handling: The training and implementation of the documents related to deviation handling was not conducted; the enterprise failed to timely initiate the investigation for individual deviation; the reason analysis and corrective and preventive measures for a few deviations were not in place, and there was in adequate assessment on the potential impact of the deviations on the quality of products.
(3) Change control: The enterprise failed to handle the changes in accordance with change process and submit supplementary application for registration. There was no or inadequate assessment on some changes;
(4) Supplier management: There was incomplete auditing content for the suppliers of some materials, and the enterprise failed to determine the auditing content for suppliers based on the impact of the material on product quality.
(5) Product quality review: The enterprise failed to conduct annual quality review by varieties.
5. Computer System. The enterprise has developed document system for computer system management, but did not conduct classification management in accordance with the system, and did not take effective measures to reduce risks for the situation that existing conditions failed to comply with the document; there was no permission setting for the login screen of HPLC testing equipment in quality verification laboratory, and no measures to prevent the login by the unauthorized person.
(V) Blood product manufacturers
In the inspections on 25 enterprises, 13 major deficiencies and 241 general deficiencies were identified, and no critical deficiency was identified.

　　Main findings:
1. Institutions and Personnel. There lacked training for the personnel at some posts.
2. Premises and Facilities. The contamination and cross contamination cannot be effectively controlled.
3. Equipment. Some sensors failed to cover the actual use range; some instruments and equipment for testing were not regularly calibrated or insufficiently calibrated, and the records were incomplete; the equipment had no status identification and calibration identification.
4. Materials and Products. There lacked the source, validity period and other information on the label of the cryo in allocated supply, and the label was a card, which was easy to be lost and confused.
5. Verification and Qualification. In simulated filling test of culture media, sampling monitoring was conducted for both hands, forearms and chest of operators only after the production was over, and the sampling of clothes as well as the confirmation was not specified.
6. documentation Management. The technological procedure and operating procedure was not specific in content, poor in operability and not standardized in the provisions..
7. Production Management. There lacked microbial control measures for the octylic acid sodium solution added before inactivation; The time to place the settlement plate under Level A laminar flow was not /confirm/ied.
8. Quality Control and Quality Assurance
(1) Management of quality control laboratories: the machine account for the receiving and dispatching of tested products had incomplete content, and there was no receiving information of the test samples of intermediates and semi-finished products; the plate culture medium outsourced for environmental monitoring was not tested; negative control was not set for sterility test in accordance with the pharmacopoeia;
(2) Product stability study: Invalidity period was formulated for intermediate products, but there lacked the support of continuous stability investigation or validation data;
(3) Change control: Change control and management was not in place. Some changes were not or insufficiently assessed;
(4) Deviation handling: the enterprise failed to timely initiate the investigation for individual deviation; some deviation investigation and corrective and preventive measures were insufficient;
(5) Supplier management: The allocated suppliers of cryo was not included in the directory of qualified suppliers of the enterprise;
(6) Product quality review: Some information was not included in annual product quality review;
(7) Product delivery and recall: The enterprise failed to specify the shipment means for the sample in batch release;
(8) Computer System: there were incomplete documents for computer system, and there lacked comprehensive and effective control and assessment for internal computer system and relevant data. There was no auditing and tracking function for some instruments and equipment in QC laboratory; the system did not set access permission at different levels, and there was a risk of data and system modification; the safety and reliability of HPLC data transfer was not /confirm/ied.
(VI) The manufacturers issued with Warning Letter in 2015
For the inspections on 32 manufacturers, a total of 2 critical deficiencies, 32 major deficiencies and 328 general deficiencies were identified.

　　Main findings were as follows:
1. Problems in data integrity
2. No records and investigations for the deviations
3. There were certain problems in sterility guarantee and relevant verification and qualification work was inadequate.
(VII) The Sterile Drug Manufacturers Passing Provincial Certification
In the inspections on 21 enterprises, a total of 15 major deficiencies and 209 general deficiencies were identified, but no critical deficiency was identified.

　　The main problems identified manifested as: there is insufficient risk assessment for sharing production line in the production of small volume injection; there was cleaning validation for single variety, but no cleaning risk assessment for all the varieties; some inspection records had incomplete content; the validation and audit of computer system has not yet been carried out; materials were improperly managed, and there were risks of confusion and error.
(VIII) Special inspections on high-risk varieties
In the inspections on 61 enterprises, a total of 3 critical deficiencies, 64 major deficiencies and 658 general deficiencies were identified.

 

　　Main findings were as follows:
1. Ossotide injection
(1) The company bought 7 batches of foreleg bone from XX Co. Ltd., but failed to conduct procurement and acceptance inspection according to stipulations. The company failed to formulate procurement order according to procurement SOP. After the arrival of materials, the company failed to request and check the inspection report issued by the supplier in accordance with the SOP for the acceptance inspection, warehousing and storage of materials; for the acceptance inspection, the company failed to request temperature monitoring record of cold chain transportation of pig legs.
(2) The virus inactivation for the stock solution of compound ossotide was not validated; there was validation data to support that the four pig legs shall be stored for 25 days after requisition and the time from filling to sterilization initiation of compound ossotide injection is five hours; the time from the end of preparation to the end of the filling of compound ossotide injection was 10 hours, which lacked the microbial limit detection data.
(3) The continuous stability test scheme failed to set and inspect such activity indicators and related safety indicators as allergic experiment, pyrogen, and abnormal toxicity.
2. Fructose diphosphate injection
(1) The criteria for microbial limit in internal control standard of fructose diphosphate manufacturers failed to be revised in accordance with corresponding provisions in Chinese pharmacopoeia (2015 edition).
(2) For the compound enzyme reagent used for the content determination of the APIs of fructose diphosphate, the expiration date was December 2015. It was found in on-site inspection that the enterprise still used such enzyme reagent to conduct content determination of 14 batches of APIs of fructose diphosphate after the expiration date.
3. Citicoline sodium injection
(1) The inner quality standard for the APIs of citicoline sodium was unreasonably developed, and the item of toluene residue was not added with reference to the quality standard of APIs manufacturers.
(2) For the comparison of the content determination methods of intermediates and finished products of citicoline sodium injection, it was conducted only for the detection result of one batch and was not representative.
(3) The enterprise of citicoline sodium injection failed to conduct process validation for the APIs of different manufacturers respectively; the enterprise failed to provide compatibility test data of sterilizing filter for citicoline sodium injection.

Part IV Unannounced Inspection for Pharmaceuticals

　　I. Overview of Inspection

　　In accordance with the requirements for relevant departments of CFDA, based on the Working Procedure for Unannounced Inspection on Pharmaceutical GMP, a total of 45 unannounced inspection tasks from CFDA have been received in 2016, of which 39 unannounced inspections on Pharmaceutical GMP have been completed with the results reported, and others are on-going. The 39 inspections with the results reported involved 20 provinces (municipalities) including Beijing, Jiangsu and Guangdong etc., and covered 9 manufacturers of biochemical drugs, 20 manufacturers of TCMs, 9 manufacturers of chemicals and 1 manufacturer of blood product. The distribution was as follows:
Of the unannounced inspection tasks in 2016, 33 tasks were from the Department of Drug and Cosmetics Supervision of CFDA, and 6 tasks were from the Department of Drug and Cosmetics Registration and other departments of CFDA. The tasks from the Department of Drug and Cosmetics Supervision of CFDA accounted for 85%, which was the main source of unannounced inspection tasks. Among 39 unannounced inspections, the inspections on TCMs accounted for 51% of all the unannounced inspection work while that on chemicals and biochemical drugs accounted for 23%, respectively. In the unannounced inspection in 2016, 21 drug manufacturers failed, accounting for 54%. It was suggested to revoke the pharmaceutical GMP certificate of 14 enterprises and to open an investigation for 10 enterprises. The problematic products of 7 enterprises were ordered to be recalled. In pharmaceutical GMP unannounced inspection, TCMs and chemical drugs were identified to have more problems. All issues found in unannounced inspection have been dealt in accordance with the law.

　　II. Main findings

　　(I) Main problems identified in TCMs manufacturers
In 2016, a total of 66 person-times in 18 teams of inspectorates were sent for unannounced inspections on 20 TCMs manufacturers, of which there were 6 manufacturers involving letter reporting, there were 3 manufacturers of calculus bovis factitious, 7 manufacturers of the products containing bezoar, 3 enterprises identified to have problems in exploration study and inspection and 1 manufacturer of prepared slices of Chinese crude medicines.
In the unannounced inspection on 20 TCMs manufacturers, 12 manufacturers failed to meet pharmaceutical GMP requirements, of which three manufacturers were transferred to provincial administration for handling relevant problems, one manufacturer was issued with Warning Letter, one manufacturer had no relevant production and three manufacturers met the requirements.
1. Chinese patent medicine manufacturers
(1) The problem of unauthorized changes to the process was prominent.
In order to reduce the production cost of oral preparation of Chinese patent medicine, the phenomenon of unauthorized changes to the pretreatment and extraction process is still a prominent problem. The unannounced inspections conducted this year were due to the problems identified in exploratory inspection, such as the enterprise failed to extract some Chinese herbal medicine in the prescription that should be extracted in accordance with technological procedure, but conducted a direct feeding after smashing.
(2) The Chinese herbal medicine and prepared slices of Chinese crude medicines was in disordered management.
In order to cope with the supervisory inspection by the drug regulatory authorities at all levels, individual manufacturer of Chinese patent medicine falsified machine account of warehouse materials and stock in and stock out record. The relevant machine account and records of the materials for internal operation in such enterprises can correspond to each other, but failed to respond to the invoice or voucher for the purchase. Or, such enterprises took advantage of such policy that the Chinese herbal medicine can be purchased directly from farmers, reversely inferred the usage of Chinese herbal medicine from the production of Chinese patent medicine, and then fabricated the machine account of materials according to the demand.
(3) The purchased Chinese herbal medicine and prepared slices of Chinese crude medicines were not subject to strict full inspection and the data integrity was doubtable.
Traditional manufacturers of Chinese patent medicine have many varieties of products and involve may varieties of Chinese herbal medicine and prepared slices of Chinese crude medicines. Because the precision analysis instruments and QC personnel equipped were not adapted to the scale of production, it cannot be ensured that each batch of the purchased Chinese herbal medicine and prepared slices of Chinese crude medicines can be inspected, resulting in no full inspection for the Chinese herbal medicine and prepared slices of Chinese crude medicines of some batch, or using a graph for multi-purpose to deal with the inspection.
2. Calculus bovis factitius
Because calculus bovis factitious is marketed under the classification of “Medicinal Materials and Prepared Slices” in the Chinese pharmacopoeia, it belongs to raw materials for Chinese patent medicine, resulting in that relevant enterprises cannot organize the production in accordance with pharmaceutical GMP requirements. In particular, there were seriously insufficient requirements for the auditing and management of the suppliers of upstream industry chain of calculus bovis factitious, causing that hygienic conditions of processing site were bad, the raw materials could not be traced and the processing process was uncontrollable. Main fingings:
(1) The management of suppliers was weak.
(2) The authenticity of microbial limit test was doubtful.
(3) It failed to be included in quality assurance system.
3. Prepared slices of Chinese crude medicines
A variety of information showed that the dispensing for sales was very common for the prepared slices of Chinese crude medicines outsourced. The problems in content determination of purchased Chinese herbal medicines or process products were prominent, dyeing and weight increment problems occurred occasionally, and authenticity of batch production records was doubtful.
(1) Untruthful batch production records.
(2) Being suspected of dispensing and sale of outsourcing prepared slices.
(3) Authenticity problems in data integrity.
(II) Biochemical drugs
1. Inspection on " monosialotetrahexosylganglioside sodium”
In 2016, a total of 4 manufacturers of " monosialotetrahexosylganglioside sodium” were inspected, and it was found that there was certain risk in the management of the quality of raw materials and the pig brain suppliers.
(1) Supplier management shall be improved, for the management of suppliers by the enterprise cannot ensure effective traceability.
(2) There was insufficient management of electronic data of the monitoring of cold chain transport of pig brain.
2. Inspection on " hepatocyte growth-promoting factors for injection”
In 2016, a total of 4 manufacturers of " hepatocyte growth-promoting factors for injection” were inspected, of which 2 manufacturers had their Pharmaceutical GMP Certificate revoked while 2 manufacturers were issued with Warning Letter.
(1) Fabricate the record file.
(2) Problems in data integrity
(3) Inconsistency with registered production process
(4) Unable to effectively ensure the quality of the liver as raw material.

Part V Overseas Inspections for imported Pharmaceuticals

　　I. Overview of Inspections

　　(I) Overview of annual inspection tasks
The total number of CFDA Overseas Inspection was 49 inspections.

　(1) The inspection tasks in 2016 involved 19 countries. There were relatively more varieties in Europe and North America, the varieties of such countries with high regional quality risks as India and Vietnam account for certain proportion, and at the same time, the inspection on the varieties in South America and Australia was also intensified.　

(2) The inspection followed the principle that inspection shall serve the evaluation and approval and took into consideration the safety requirements for the marketed products. The proportion of the varieties under review was increased, and the product under application for clinical trials, application for production and re-registration and in the stage of supplementary application shall all be included in the scope of inspection. The reason for the inspection on the marketed products was mainly port quality inspection problems. The iodoprestamine injection, a variety with high risks in adverse reaction monitoring manufactured by a foreign company, was added for inspection.

　　(3) The inspection tasks were characterized as comprehensive varieties and broad dosage forms, and the extended inspection on chemical preparations was intensified. 40 chemicals were involved, including injections, solid preparations, implant and nasal sprays, of which there were 3 biochemical products, 6 APIs for extended inspection; 11 vaccines, blood products and therapeutic biological products; and 4 botanical drugs.

　　(II) The implementation of the inspections in 2016
Due to the inspection tour of CFDA and CFDI in the first half year, the change in relevant foreign affairs and production arrangement of enterprises, CFDI submit the inspection tasks of 37 varieties throughout the year: the inspection tasks of 15 varieties have been completed, of which on-site inspection was conducted on 7 varieties, and three of them failed, accounting for 42%; the enterprises of 8 varieties proactively withdrew the import registration certificate or had their application returned during the organization of the inspections, account for 17% of total annual plan. For another 21 varieties, due to production scheduling of enterprises, the inspection is scheduled to be completed in the first quarter of 2017, and relevant formalities of foreign affairs are being dealt with. For the other 12 varieties, because the enterprises cannot accept inspection in the first quarter of 2017, CFDI has reported to the Department of Drug and Cosmetics Supervision to include them in the overseas inspections in 2017.

　　II. Main findings in overseas inspections
Among 7 varieties that have been inspected, three varieties failed, and the failure rate was slightly increased compared with previous years. 117 deficiencies have been identified in the inspections, of which there were 3 critical deficiencies and 18major deficiencies. The problems mainly focused on Quality Control and Quality Assurance, Material System and Change Management; and critical deficiencies were mainly the problems in the consistency of production process and data integrity. All issues found in overseas inspection have been dealt in accordance with the law.

　　Main and serious problems were as follows:
1. Actual production process and production site was inconsistent with those in registration application and major changes were implemented without submitting application in China.
2. There were significant problems in data integrity, which serious affected the product quality.
3. There were an increasing number of varieties handled by off-site inspection.

Part VI GSP unannounced inspection

　　I. Overview of Inspections

　　In 2016, China Food and Drug Administration conducted centralized remediation on illegal distribution behaviors in drug circulation field, further reorganized and regulated drug circulation order through self-inspection and rectification by enterprises, supervision and inspection by provincial administration and unannounced inspection by CFDA and cracked down illegal distribution behaviors. Throughout the year, 3 batches of inspections have been conducted on 53 pharmaceutical wholesalers. The results of unannounced inspections were announced by CFDA.

　　The teams of inspectorates conducted unannounced inspection on relevant enterprises based on the Announcement of CFDA on Remediating Illegal Distribution Behaviors in Drug Circulation Field (2016 No.94) and Good Supply Practice for Pharmaceuticals. It was identified in the results that the violations were very common in drug circulation enterprises, and the situation was as follows.

 

　　II. Main findings

　　(I) The situation of violations of CFDA Announcement No.94
Table 6-2 The situation of violations of CFDA Announcement No.94 by enterprises identified in unannounced inspection in drug circulation enterprises

　　Main findings:
1. Fail to store and transport the drugs and monitor the temperature and humidity in accordance with the regulations.
2. For purchase and sales of drugs, the certificate (license certificate), bills (invoice, the sheet along with the goods), account (materials account, financial account), goods (drugs) and money (payment for drugs) cannot be corresponding to or consistent with each other; fail to warehouse the drugs with concealed accounts established, fail to manage the drugs after including them into quality management system, use personal account to conduct business dealings, and other situations.
3. The enterprises falsified the source for drug procurement, fabricated sales flow of drugs, tampered the data of computer system and temperature and humidity monitoring system, and concealed the real drug purchase-sales-storage records, bills, voucher and data, the drug purchase-sales-storage records were incomplete and untruthful and distribution behaviors were untraceable.
(II) The situation of violation of Good Supply Practice for Pharmaceuticals (GSP) of CFDA by enterprises

　　The GSP deficiencies of drug circulation enterprises mainly focused on the General Provisions, Storage and Maintenance, Sales. The main problems were:
1. Fail to conduct business in accordance with the law and have false and cheating behaviors.
The enterprise changed the registered business address without authorization; established warehouses to store drugs beyond the scope of business license; provided conditions for illegal distribution of drugs; falsified the procurement source and sales flow of drugs; concealed bills and provided false materials; provided untruthful self-inspection report; falsified tax return; and tampered temperature and humidity monitoring data.
2. Fail to store the drugs in accordance with regulations and fail to conduct effective monitoring and control of the temperature and humidity of warehouse.
3. The bills, account, goods and payment was inconsistency for the purchase and sales of drugs, and the enterprise failed to implement national regulations for the sales of special medicines.

Part VII GMP Observation Inspection by Foreign Organizations

　　I. Overview of Inspections

　　based on the requirements in the letter from the Department of International Cooperation of China Food and Drug Administration, CFDI organized to complete 81 observation inspections on pharmaceutical manufacturers in 2016, involving 76 manufacturers, covering 20 provinces (municipalities) including Zhejiang and Shandong etc., of which Zhejiang, Shandong, Jiangsu, Guangdong, Hubei, Hainan and Hebei accounted for 80%, which was basically consistent with last year, but the proportion of each province showed a slight change.

In 2016, the inspection organizations involved in the observation inspection included 12 international organizations or foreign drug regulatory authorities, such as World Health Organization (WHO), European Directorate for Quality Medicines (EDQM), United States Food and Drug Administration (US FDA), Germany BGV, Agência Nacional de Vigil?ncia Sanitária (ANVISA) and French National Agency for Medicines and Health Products Safety (ANSM). Nine pharmaceutical manufacturers were identified with critical deficiencies and failed the on-site inspections by foreign regulatory authorities / inspection organizations (accounting for 11%).　

Compare with that in 2015, the fail rate was slightly increased. Among 9 enterprises failing in the inspection, most critical deficiencies involved the problems in data integrity (including conducting repeated tests until qualified, conducting tests after changing system time, deleting data, deleting the audit and tracking records, selecively using data, modifying the name of the electronic data, test sample injection, failing to record timely, untruthful records, loss of data and records, insufficient file record control, etc.), and some enterprises involved such aspects as unreasonably developed material standards and inadequate measures to avoid cross contamination. Overall, the problems in the data integrity is relatively prominent and were also the main reasons for the increase of fails of domestic enterprises in foreign inspections in 2016, which also reflects the change tendency of the current drug inspection.
The observation inspections this year involved a total of 172 drugs, including 119 APIs, 23 oral solid preparations, 19 injections，5 biological products and 6 other products. Of the 81 inspections, there were 62 inspections involving APIs, accounting for 69%, and there were 12 inspections involving oral solid preparations, accounting for 13%. Of the drugs involved, APIs had the largest proportion, followed by oral solid preparations, and there was relatively less export of other dosage forms. Compared with that in 2015, the proportion of other dosage forms (including sterile products and biological products) receiving inspection increased, from 10% in 2015 to 18% in 2016.

　　II. Main findings

　　The 1108 deficiencies were identified and recorded in the observation inspection in 2016. It was identified in the classification analysis on the deficiencies based on Chinese GMP (2010 version) that: the deficiencies in six categories including Quality Control and Quality Assurance, documentation Management, Equipment, Materials and Products, Verification and Qualification and Premises and Facilities accounted for 88% of all the deficiencies. Compared with those in 2015, the deficiencies in documentation Management increased from the 4th place to the second place in terms of its ranking and still showed an increase of 7% (from 10.5% to 17.3%) under an atmosphere that enterprises are gradually strengthening the management of data integrity, fully reflecting the concern extent and strict requirements for data integrity in currently foreign inspections.　

In pharmaceutical GMP inspections by foreign organizations, the deficiencies in “Quality Control and Quality Assurance” topped the list, accounting for 27.3%. Main problems focused on the management of computerized analysis instruments in the laboratory, deviation handling and CAPA, product quality review, change control, OOS/OOT result processing, the laboratory’s failing to meet the provisions for control procedure, microbial inspection management, quality risk management and stability test. The deficiencies in “documentation Management” ranked the second, mainly focusing on four aspects including the completeness and traceability of records, life cycle management of documents, document completeness and record operation. The deficiencies in “Equipment” ranked the third, of which the deficiencies in the using and cleaning, calibration, maintenance and repair of equipment and water preparation system accounted for 83.6%. The deficiencies in “Materials and Products” focused on supplier management, identification of materials and products, process management of materials, compliance with material and product standards and release management. The deficiencies in “Verification and Qualification” mainly included the scientificity of validation, validation management and validation documents and records. The deficiencies in “Premises and Facilities” mainly included environmental control, management of storage area, the measures to prevent pollution and cross-pollution and life cycle management of premise and facilities.

　　III. Analysis on pharmaceutical GMP inspection of different organizations

　　In terms of inspection content, there was certain difference in the inspection focus among different pharmaceutical GMP inspection agencies, but it was found in the analysis on the deficiencies identified in the observation inspections in 2016 that there were relatively more deficiencies in six aspects including Quality Control and Quality Assurance, documentation Management, Equipment, Materials and Products, Verification and Qualification and Premises and Facilities. As for the number of deficiencies in the final inspection report,
EDQM and WHO proposed more deficiency data, averaging 20 deficiencies in each inspection. For each deficiency, the problems identified during the inspection have been described. After the finish of inspection, such problems have been organized for preparing final inspection report (usually a month). US FDA proposed relatively less deficiencies in the inspections, averaging 7 deficiencies in each inspection, and did not take all the problems identified during the inspection as final deficiencies. The inspectors proposed the final deficiencies after the judgment based on the problems identified in combination with the product risks, and notify the enterprises in written form (Table 483) when holding the last inspection meeting.

（Note:The English version of this report is for reference only）