又一家中國藥企EUGMP檢查失敗！法國、意大利紛紛禁令

日期：2016/3/3

公司名稱：Dongying TiandongPharmaceutical Co., Ltd.  東營天東

檢查日期：2015-12-9

檢查地址：No. 1236, Nan-erRoad, Dongying City, Shandong Provice, China

檢查方：法國藥監

產品：原料藥ENOXAPARIN SODIUM依諾肝素鈉

原料藥HEPARIN SODIUM肝素鈉

Nature of non-compliance : 不符合情況

Overall, 10 deficiencieswere observed during the inspection, 2 Critical and 3 Major deficiencies:

檢查期間總共發現10個缺陷，其中2個關鍵缺陷，3個主要缺陷：

[Critical 1] PCR results ofCrude Heparin showing the presence of ruminant DNA received from approvedsuppliers were manipulated. There was no evidence that the samples retestedcame from the same batch tested initially;

【關鍵缺陷1】肝素粗品PCR結果顯示從批準的供應商處接收的反芻動物類DNA是偽造的。沒有證據證明復測樣品與初測樣品來自同一批次；

[Critical 2] The qualitysystem implemented by the company for ensuring the full traceability of crudeHeparin was identified as very weak : e.g., the traceability fromslaughterhouses/abattoirs was not available and not assessed during the auditsof the suppliers (lack of supporting documents for the received lots) ;

【關鍵缺陷2】公司執行的確保肝素粗品可追溯性的質量體系很差，例如，從屠宰場開始的可追溯性沒有，對供應商審計期間并沒有進行評估（接收批次缺乏支持性文件）；

[Major 1] Misunderstandingof the basic GMP principles for handling of out of specification (OOS) resultsand deviations (e.g., 7 batches of crude Heparin received in 2014 and 2015 wereobtained OOS for potency and used for the manufacturing of finished APIs withoutany OOS investigation);

【主要缺陷1】對處理OOS結果和偏差的基本GMP原則有誤解（例如，2014年至2015年接收到的7批肝素粗品效價結果為OOS，沒有進行任何OOS調查即用于原料藥成品的生產）；

[Major 2] The evaluation ofthe new suppliers of crude Heparin was deficient: the procedure was notfollowed, no delivery documents were available, the testing was notsystematically recorded in the equipment logbook, the samples from approvedsuppliers were contaminated during the sampling operation, etc. ;

【主要缺陷2】肝素粗品新供應商的評估有缺陷：未遵守程序，沒有送貨資料，檢測儀器日志沒有系統記錄檢測，從批準的供應商處送來的樣品在取樣操作中受到污染等。

[Major 3] The assessment of1 H NMR spectrum (Heparin Sodium) and 13 C NMR (Enoxaparin Sodium) used foridentification test were deficient (e.g., the presence of an additional peak atthe C13 NMR obtained by a subcontracted laboratory was not identified andinvestigated)

【主要缺陷3】用于鑒別測試的1H NMR圖（肝素鈉）和13C NMR圖（依諾肝素鈉）評估有缺陷（例如，在合同化驗室做的C13 NMR圖中有多余的峰出現，沒有鑒別沒有調查）。

措施：

1.   吊銷現有EU GMP證書

2.   要求上市許可提交變更

3.   已放行批準要求召回

4.   禁止銷售

5.   擱置CEP2005-258

Actiontaken/proposed by the NCA :

Withdrawal,of current valid GMP certificate No. GIF-IW-N-4022/68/13 

Using QRMprinciples, consideration of withdrawal of current valid EU GMP certificateissued by the Main Pharmaceutical Inspectorate of Poland (GIF-IW-N-4022/68/13).

RequestedVariation of the marketing authorisation(s) 

Using QRMprinciples, the removal of the site from MAs should be considered.

Recallof batches already released 

Considerationof a recall of product should be given due to the critical findings observed.Using QRM principles, National supply situation and clinical requirementsshould be taken into account when making this decision.

Prohibitionof supply 

The sitehas been issued a statement of non compliance and should not be named on anymarketing authorisations whilst this statement remains in place.

Suspensionor voiding of CEP (action to be taken by EDQM) 

Suspensionof CEP 2005-258 (Enoxaparin sodium).

以下內容為蒲公英提供和翻譯

－－－－－－－－－－－－－

意大利藥監同時禁令：

 英文概要 ：
The Health Authorities are advising all Market Authorization Holders that if they have DONGYING TIANDONG PHARMACEUTICAL Co., Ltd. – No. 1236, Nan-er Road, Dongying City, Shandong Provice - CHINA.
as authorized supplier of Enoxaparin and/or Heparin Sodium and/or intermediates in their registration documentation  they need to replace the supplier with a new one.
 
Meaning: the above manufacturer of Enoxaparin and Heparin Sodium and/or intermediates has been found inadequate and is no more acceptable (banned).
 
The above is applicable for finished products distributed in Italy or exported elsewhere. (Equivalent to the US FDA ban)
  
中文概要：
意大利藥監AIFA建議所有的上市許可持有人，若在其注冊申報中將位于中國山東東營南仁路1236號的東營天東制藥有限公司作為供應商提供伊諾、肝素及其中間體的話，請即更換相應供應商。
 
這意味著這家提供伊諾、肝素及其中間體的企業被發現有不符合要求之處且不再被認為是可接受的企業（禁止）。
 
這個建議適用于在意大利境內銷售或出口到其他地區的制劑產品（相當于美國FDA的禁止令）。
 
意大利藥監AIFA網站原文：
Verifica Officina Farmaceutica: Dongying Tiandong Pharmaceutical Co. LTD. (China) (12/02/2016)
Avviso alle Aziende Farmaceutiche

Si chiede alle Aziende titolari di AIC di medicinali ad uso umano e/o alle Aziende produttrici di medicinali destinati al mercato comunitario o all'esportazione in Paesi terzi di verificare, con urgenza, se per i medicinali contenenti le seguenti sostanze attive e/o intermedi di produzione ENOXAPARIN SODIUM, HEPARIN SODIUM, autorizzati per il mercato italiano e/o prodotti per l'esportazione, risulti presente come fornitore autorizzato, l’Officina Farmaceutica: DONGYING TIANDONG PHARMACEUTICAL Co., Ltd. – No. 1236, Nan-er Road, Dongying City, Shandong Provice - CHINA.
Solo in caso di riscontro positivo l’Azienda dovrà darne immediata comunicazione, indicare l’eventuale presenza di un sito di produzione alternativo a quello in oggetto e procedere alla richiesta di variazione per l'eliminazione del sito suindicato ovvero indicare l'assenza di sito di produzione alternativo e procedere alla richiesta di variazione per sostituzione del sito cinese in oggetto.

Si precisa, infine, che, nella suddetta comunicazione, la dichiarazione riportata dovrà contenere  espressa menzione dell’assenza del produttore in oggetto, non solo tra i fornitori autorizzati di “principio attivo”, ma anche degli “intermedi di produzione”.

Si richiede, da ultimo, per i medicinali autorizzati con procedura di Mutuo Riconoscimento, di specificare il codice di procedura europea.
La comunicazione deve pervenire entro e non oltre il giorno 18 FEBBRAIO 2016, alla seguente casella di posta:

? infocepgmp@aifa.gov.it

信息來源：蒲公英