浠婂ぉ鏄細

瀹為獙瀹よ祫璁綉

FDA鍙戝竷璀﹀憡淇″己璋冭川閲忛儴鏉冨姏

瀹為獙瀹よ祫璁綉鏃堕棿:2018-02-11 鐐瑰嚮: 娆?/span> 鐧惧害鎼滅储

銆愬璇汇€?/strong>杩戞棩锛孎DA鍙戝竷璀﹀憡淇¤按璐f煇鍏徃鐨勮川閲忛儴闂?娌℃湁鍏ㄩ潰灞ヨ鍏舵潈鍔涘拰/鎴栬亴璐?銆傚苟 瑕佹眰鍏徃蹇呴』涓鸿川閲忛儴闂ㄦ彁渚涢€傚綋鐨勬潈鍔涖€佽冻澶熺殑璧勬簮鍜屼汉鍛樻潵灞ヨ鍏惰亴璐o紝鎸佺画纭繚鑽搧璐ㄩ噺 銆?璇ュ叕鍙哥己闄?.....
TAG鏍囩锛?FDA 璀﹀憡淇?/a> 寮鸿皟璐ㄩ噺閮ㄦ潈鍔?/a> 璐ㄩ噺閮?/a>

杩戞棩锛孎DA鍙戝竷璀﹀憡淇¤按璐f煇鍏徃鐨勮川閲忛儴闂ㄦ病鏈夊叏闈㈠饱琛屽叾鏉冨姏鍜?鎴栬亴璐c€傚苟瑕佹眰鍏徃蹇呴』涓鸿川閲忛儴闂ㄦ彁渚涢€傚綋鐨勬潈鍔涖€佽冻澶熺殑璧勬簮鍜屼汉鍛樻潵灞ヨ鍏惰亴璐o紝鎸佺画纭繚鑽搧璐ㄩ噺銆?nbsp;

 

璇ュ叕鍙哥己闄疯繕鍖呮嫭濡備笅锛?/p>

·        鏈鍋忓樊/绋冲畾鎬уけ璐ヨ繘琛岃皟鏌?/p>

·        宸ヨ壓杩樺湪鎽哥储锛屼絾宸茶繘琛屽晢涓氱敓浜у苟鏀捐

·        宸ヨ壓楠岃瘉涓嶅厖鍒?/p>

·        鏈垎鏋愬伐鑹烘尝鍔ㄧ殑鏉ユ簮

·        浠呬粎鐢ㄤ竴鎵瑰伐鑹虹‘璁ゆ潵璇佸疄宸ヨ壓锛屾湭璇佸疄宸ヨ壓閲嶇幇鎬?/p>

·        绋冲畾鎬уけ璐ヤ絾鏄湭閲囧彇閫傚綋鐨勬帾鏂?/p>

·        璐ㄩ噺閮ㄩ棬鏉冨姏涓嶈冻

 

璀﹀憡淇$浉鍏崇己闄锋憳璇戝涓嬶細

 

1.      Your firm failed tothoroughly investigate any unexplained discrepancy or failure of a batch or anyof its components to meet any of its specifications, whether or not the batchhas already been distributed (21 CFR 211.192).  

浣犲叕鍙告湭鑳藉交搴曡皟鏌ユ墍鏈夊凡鏀捐鍜屾湭鏀捐鐨勬壒娆℃垨鍏舵垚鍒嗕换浣曚笉鏄庡師鍥犵殑涓嶅悎鏍兼垨寮傚父锛?1 CFR211.192锛夈€?nbsp;

 

You failed tothoroughly investigate release and stability testing failures concerning twobatches of your (b)(4) drug products. These product failures includedviscosity and appearance. During stability testing, you also identifiedpackaging defects. You did not initiate investigations for each of these drugquality issues. When you did investigate, you failed to adequately evaluate themanufacturing process and associated records, identify root causes, andimplement effective corrective actions and preventive actions (CAPA). 

浣犳湭鑳藉交搴曡皟鏌?鎵筙X鑽搧鐨勬斁琛屽拰绋冲畾鎬ф祴璇曞け璐ャ€傝繖浜涗骇鍝佸け璐ュ寘鎷矘搴﹀拰澶栬銆傚湪绋冲畾鎬ф祴璇曚腑锛屼綘浠繕鍙戠幇浜嗗寘瑁呯己闄枫€備綘浠湭瀵硅繖浜涜嵂鍝佺殑鎵€鏈夎川閲忛棶棰樺彂璧疯皟鏌ャ€傚湪浣犱滑璋冩煡鏃讹紝浣犱滑鏈兘鍏呭垎璇勪及鐢熶骇宸ヨ壓鍜岀浉鍏宠褰曪紝璇嗗埆鍑烘牴鏈師鍥狅紝浠ュ強瀹炴柦鏈夋晥鐨勭籂姝f帾鏂藉拰棰勯槻鎺柦锛圕APA锛夈€?nbsp;

 

For example, youfound tubes swelling at the 3-month stability time point. You did not investigatethis significant defect, which can be indicative of microbial growth andspoilage. Notably, your packaging stability specification requires “no change inpackaging.” 

渚嬪锛屼綘浠湪3涓湀绋冲畾鎬ф椂闂寸偣鍙戠幇绠¤啫鑳€銆備綘浠湭璋冩煡姝ら噸澶х己闄凤紝杩欏彲鑳芥槸寰敓鐗╂粙鐢熷拰鑵愯触鐨勭幇璞°€傚挨鍏舵槸浣犱滑鐨勫寘瑁呯ǔ瀹氭€ф爣鍑嗚姹?ldquo;鍖呰涓嶅緱鍙戠敓鍙樺寲”銆?nbsp;

 

In response to ourfindings, your customer recalled the remaining in-date batch of this product onNovember 28, 2017.

鍦ㄥ洖澶嶆缂洪櫡鏃讹紝浣犱滑鐨勫鎴蜂簬2017骞?1鏈?8鏃ュ彫鍥炰簡褰撴椂鍓╀綑鐨勮鑽搧銆?nbsp;

 

For more informationabout handling failing, out-of-specification, out-of-trend, or other unexpectedresults and documentation of your investigations, see FDA’s guidance document, InvestigatingOut-of-Specification (OOS) Test Results for Pharmaceutical Production, athttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070287.pdf. 

鍏充簬澶勭悊涓嶅悎鏍笺€丱OS銆丱OT鍜屽叾瀹冮潪棰勬湡缁撴灉浠ュ強璁板綍浣犱滑璋冩煡鐨勬洿澶氫俊鎭紝鍙傝FDA鎸囧崡鏂囦欢“鑽搧鐢熶骇涓璒OS缁撴灉璋冩煡”銆?nbsp;

 

2.      Your firm failed toestablish adequate written procedures for production and process controldesigned to assure that the drug products you manufacture have the identity,strength, quality, and purity they purport or are represented to possess (21CFR 211.100(a)).  

浣犲叕鍙告湭鑳戒负鐢熶骇鍜屽伐鑹烘帶鍒跺缓绔嬩功闈㈢▼搴忥紝浠ョ‘淇濅綘浠敓浜х殑鑽搧鍏峰鍏堕壌鍒€佸惈閲忋€佽川閲忓拰绾害(21 CFR211.100(a))銆?nbsp;

 

The processes used tomanufacture your (b)(4) drug products have not been shown to beconsistent and reliable, and consequently batches of your drug products arelikely to significantly vary in strength, quality, and purity. 

鐢ㄤ簬鐢熶骇浣犱滑鐨刋X鑽搧鐨勫伐鑹烘湭鏄剧ず鍑哄叾涓€鑷存€у拰鍙潬鎬э紝浣犱滑鑽搧鐨勫悗缁壒娆″彲鑳戒細鍦ㄥ惈閲忋€佽川閲忓拰绾害鏂归潰鏈夐噸澶у彉寮傘€?nbsp;

 

For example, you lackedadequate process validation studies. Your validation report summarized aretrospective analysis of a single process qualification batch, (b)(4).You manufactured and released this batch in 2015.Notably, testing of this batchfound stability failures of multiple quality attributes, including appearanceand viscosity. Your validation report was approved on March 17, 2017, shortlybefore we inspected your facility. You lack evidence of process validationbecause you have not addressed all potential sources of variation that must becontrolled to consistently yield drugs of uniform character and quality, andhave not demonstrated that the process is reproducible. 

渚嬪锛屼綘浠己涔忚冻澶熺殑宸ヨ壓楠岃瘉鐮旂┒銆備綘浠殑楠岃瘉鎶ュ憡鎬荤粨浜嗗XX鍗曚釜宸ヨ壓纭鎵瑰噯鐨勫洖椤炬€у垎鏋愩€備綘浠湪2015鍚庣敓浜ф斁琛屼簡璇ユ壒娆°€傜壒鍒槸瀵硅鎵规鐨勬娴嬪彂鐜板涓川閲忓睘鎬хǔ瀹氭€уけ璐ワ紝鍖呮嫭澶栬鍜岀矘搴︺€備綘浠殑楠岃瘉鎶ュ憡浜?017骞?鏈?7鏃ユ壒鍑嗭紝灏卞湪鎴戜滑妫€鏌ヤ綘浠伐鍘傚墠涓嶄箙銆備綘浠己涔忓伐鑹洪獙璇佽瘉鎹紝鍥犱负浣犱滑鏈鏄庢墍鏈夋綔鍦ㄧ殑娉㈠姩鏉ユ簮锛岃繖浜涘繀椤诲彈鎺т互鎸佺画浜у嚭鍧囦竴灞炴€у拰璐ㄩ噺鐨勮嵂鍝侊紝涓旀湭璇佹槑宸ヨ壓鏄彲閲嶅鐨勩€?nbsp;

 

Senior managementstated that your firm has struggled with manufacturing this drug product, andthat you were still conducting research to gain better product and processunderstanding. Although you acknowledged a lack of understanding to assureconsistent quality, you still commercially distributed (b)(4) drugproducts to consumers. 

楂樼骇绠$悊浜哄憳绉颁綘浠叕鍙稿湪涓鸿鑽搧鐢熶骇鑰屽姫鍔涳紝浣犱滑浠嶅湪杩涜鐮旂┒浠ヨ幏寰楁洿濂界殑浜у搧鍜屽伐鑹轰簡瑙c€傚敖绠′綘浠煡閬撳湪濡備綍纭繚涓€鑷磋川閲忔柟闈㈣繕缂轰箯浜嗚В锛屼絾浣犱滑杩樻槸鍟嗕笟鍖栭攢鍞簡XX鑽搧缁欐秷璐硅€呫€?nbsp;

 

Each significantstage of a manufacturing process must be designed to assure that raw materialinputs, in-process materials, and finished drugs meet their quality attributesand specifications. Process validation evaluates the soundness of design andstate of control of a process throughout its lifecycle. Process qualificationstudies provide a determination whether an initial state of control has beenestablished. Successful process qualification studies are required prior tocommercial distribution. Thereafter, ongoing vigilant oversight of processperformance and product quality is essential to ensure you maintain a stablemanufacturing operation throughout the product lifecycle. 

鐢熶骇宸ヨ壓鐨勬瘡涓噸澶ч樁娈甸兘蹇呴』璁捐浠ョ‘淇濆師鏂欒緭鍏ャ€佷腑闂翠綋鍜屽埗鍓傛垚鍝佺鍚堝叾璐ㄩ噺灞炴€у拰鏍囧噯銆傚伐鑹洪獙璇佽瘎浼颁竴涓伐鑹哄湪鍏剁敓鍛藉懆鏈熷唴鐨勮璁″悎鐞嗘€у拰鍙楁帶鐘舵€併€傚伐鑹洪獙璇佺爺绌惰兘纭畾鏄惁宸插缓绔嬭捣鍒濆鐨勫彈鎺х姸鎬併€傚湪鍟嗕笟鍖栭攢鍞箣鍓嶈姹傛湁鎴愬姛鐨勫伐鑹虹‘璁ょ爺绌躲€備箣鍚庯紝瀵瑰伐鑹烘€ц兘鍜屼骇鍝佽川閲忚鏈夋寔缁殑璀︽儠鐩戠锛屼互纭繚浣犱滑鍦ㄤ骇鍝佺敓鍛藉懆鏈熶腑缁存寔绋冲畾鎬х殑鐢熶骇鎿嶄綔銆?nbsp;

 

See FDA’s guidance document, ProcessValidation: General Principles and Practices, for general principles and approaches that FDA considers appropriate elements of process validation, athttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf. 

鍙傝FDA鎸囧崡鏂囦欢“宸ヨ壓楠岃瘉锛氶€氬垯鍜岃鑼?rdquo;銆?nbsp;

 

3.      Your firm failed tofollow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR211.166(a)).  

浣犲叕鍙告湭鑳介伒瀹堝厖鍒嗙殑涔﹂潰妫€娴嬬▼搴忥紝浠ヨ瘎浼拌嵂鍝佺殑绋冲畾鎬х壒鎬э紝骞朵娇鐢ㄦ绫荤ǔ瀹氭€ф祴璇曠粨鏋滄潵纭畾閫傚綋鐨勫瓨璐潯浠跺拰鏈夋晥鏈?21 CFR211.166(a))銆?nbsp;

 

You did not haveadequate stability data to demonstrate that the chemical and physicalproperties of your (b)(4) drug products remain acceptable throughout thelabeled (b)(4) expiry period. Two lots reviewed during our inspectionfailed on stability at various tests and time points. You distributed these twolots of (b)(4) drug products to the U.S. 

浣犱滑娌℃湁瓒冲鐨勭ǔ瀹氭€ф暟鎹瘉鏄庝綘浠琗X鑽搧鐨勭悊鍖栫壒鎬у湪鏍囩ず鐨刋X鏈夋晥鏈熷唴淇濇寔鍙帴鍙椼€傚湪鎴戜滑妫€鏌ユ湡闂存墍瀹℃牳鐨?鎵圭ǔ瀹氭€ц瘯楠屽涓娴嬪拰鏃堕棿鐐瑰け璐ャ€備綘浠皢XX鑽搧鐨勮繖2鎵归攢寰€浜嗙編鍥姐€?nbsp;

 

Batch (b)(4)failed for viscosity at multiple time points, and you terminated the stabilitystudy for batch (b)(4) after you identified phase separation in allsamples at the 9-month time point. 

鎵规XX鍦ㄥ涓椂闂寸偣绮樺害涓嶅悎鏍硷紝浣犱滑鍦ㄥ彂鐜版墍鏈夋牱鍝佸湪9涓湀鏃堕棿鐐归兘鏈夌浉鍒嗙鐜拌薄鏃剁粓姝簡鎵规XX鐨勭ǔ瀹氭€х爺绌躲€?nbsp;

 

At the time of theinspection, you had not taken appropriate action on these batches, such asnotifying your customer or recalling products from the market. 

鍦ㄦ鏌ユ湡闂达紝浣犱滑鏈杩欎簺鎵规閲囧彇閫傚綋鐨勬帾鏂斤紝渚嬪閫氱煡浣犱滑鐨勫鎴锋垨浠庡競鍦轰笂鍙洖浜у搧銆?nbsp;

 

Inadequate Response  

鍥炲涓嶅厖鍒?nbsp;

 

Your April 13, 2017,response to FDA’s inspectional observations wasinadequate. You did not provide sufficient evidence that you are takingcorrective actions to bring your operations into full compliance with CGMP. Inresponse to this letter, provide the following: 

浣犱滑浜?017骞?鏈?3鏃ユ彁浜ら拡瀵笷DA妫€鏌ョ己闄风殑鍥炲鏄笉鍏呭垎鐨勩€備綘浠湭鎻愪氦鍏呭垎鐨勮瘉鎹瘉鏄庝綘浠鍦ㄩ噰鍙栫籂姝f帾鏂戒娇寰椾綘浠殑鎿嶄綔鍏ㄩ潰绗﹀悎CGMP瑕佹眰銆傚湪鍥炲姝ゅ嚱鏃讹紝璇锋彁浜や互涓嬶細 

 

A summary of the actions you     have taken to comprehensively remediate your investigation process, and an     improved procedure. 

浣犱滑宸查噰鍙栫殑鍏ㄩ潰寮ヨˉ浣犱滑璋冩煡娴佺▼鍜屾敼杩涚▼搴忕殑鎺柦鎽樿

 

Your investigations, using your revised procedures, for all drug quality related failures. A detailed summary of your review of all test results, root causes of specification failures, affected batches distributed to the U.S. market, and related CAPA.

閲囩敤浣犱滑淇鍚庣殑绋嬪簭瀵规墍鏈夎嵂鍝佽川閲忕浉鍏冲け璐ヨ繘琛岀殑璋冩煡銆備綘浠鎵€鏈夋娴嬬粨鏋溿€佷笉鍚堟牸鏍规湰鍘熷洜銆佸彈褰卞搷閿€寰€缇庡浗鐨勬壒娆″拰鐩稿叧CAPA鐨勫鏍告憳瑕?/p>

 

A data-driven and scientifically sound process validation program that appropriately identifies sources of variability, and ensures oversight of intra-batch and inter-batch variation on an ongoing basis throughout the product lifecycle.

鏁版嵁椹卞姩鐨勭瀛﹀悎鐞嗗伐鑹洪獙璇佽鍒掞紝閫傚綋璇嗗埆宸紓鏉ユ簮锛岀‘淇濆湪浜у搧鐢熷懡鍛ㄦ湡涓鎵瑰唴鍜屾壒闂村樊寮傜殑鎸佺画鐩戠

 

Timelines for performing prospective process qualification for your drug products.

瀵逛綘浠嵂鍝佸疄鏂藉墠鐬绘€у伐鑹虹‘璁ょ殑鏃堕棿琛?/p>

 

A procedure describing your stability program.

鎻忚堪浣犱滑绋冲畾鎬ц瘯楠岃鍒掔殑绋嬪簭

 

Data for (b)(4) batches successfully manufactured as part of prospective qualification     studies, to demonstrate that these batches are stable over the shelf life.

浣滀负鍓嶇灮鎬х‘璁ょ爺绌剁殑涓€閮ㄥ垎鐨刋X鎵规鎴愬姛鐢熶骇鐨勬暟鎹紝浠ヨ瘉鏄庤繖浜涙壒娆″湪璐ф灦鏈熷唴鏄ǔ瀹氭€?/p>

 

The disposition of (b)(4) batch (b)(4), including whether you plan to distribute it in the     U.S.

瀵筙X鎵筙X鐨勫缃紝鍖呮嫭浣犱滑鏄惁璁″垝鍦ㄧ編鍥介攢鍞?/p>

 

Data to demonstrate that your (b)(4)Test–BP method used to test drug products marketed in the U.S.is equivalent to, or better than, the current USP (b)(4)Test.

璇佹槑浣犱滑鐢ㄤ簬妫€娴嬮攢寰€缇庡浗鐨勮嵂鍝佺殑XX娴嬭瘯-BP鏂规硶绛夊悓浜庢垨浼樹簬褰撳墠USP鐨刋X妫€娴嬬殑鏁版嵁

 

A thorough assessment of your adherence to CGMP requirements, and a CAPA plan to assure full remediation. 

瀵逛綘浠伒寰狢GMP瑕佹眰鐨勫交搴曡瘎浼帮紝浠ュ強纭繚鍏ㄩ潰寮ヨˉ鐨凜APA璁″垝

 

You shouldcomprehensively address each of these items in your written response. 

浣犲簲鍦ㄤ功闈㈠洖澶嶄腑鍏ㄩ潰璇存槑姣忎釜椤圭洰銆?nbsp;

 

Quality UnitAuthority  

璐ㄩ噺閮ㄩ棬鏉冨姏 

 

Significant findingsin this letter indicate that your quality unit is not fully exercising itsauthority and/or responsibilities. Your firm must provide the quality unit withappropriate authority, sufficient resources, and staff to carry out itsresponsibilities and consistently ensure drug quality. 

鍦ㄦ鍑戒腑鐨勯噸澶х己闄锋樉绀哄嚭浣犱滑璐ㄩ噺閮ㄩ棬娌℃湁鍏ㄩ潰灞ヨ鍏舵潈鍔涘拰/鎴栬亴璐c€備綘鍏徃蹇呴』涓鸿川閲忛儴闂ㄦ彁渚涢€傚綋鐨勬潈鍔涖€佽冻澶熺殑璧勬簮鍜屼汉鍛樻潵灞ヨ鍏惰亴璐o紝鎸佺画纭繚鑽搧璐ㄩ噺銆?nbsp;

 

Responsibilities as acontractor  

浣滀负鍚堝悓鍟嗙殑鑱岃矗 

 

Drugs must bemanufactured in conformance with CGMP. FDA is aware that many drugmanufacturers use independent contractors, such as production facilities,testing laboratories, packagers, and labelers. FDA regards contractors asextensions of the manufacturer. 

鑽搧鐢熶骇蹇呴』绗﹀悎CGMP銆侳DA鏄庣櫧璁稿鑽搧鐢熶骇鍟嗕娇鐢ㄧ嫭绔嬬殑鍚堝悓鍟嗭紝渚嬪鐢熶骇鍦烘墍銆佹娴嬪疄楠屽銆佸寘瑁呭晢鍜岃创鏍囧晢銆侳DA璁や负鍚堝悓鐢熶骇鍟嗘槸鐢熶骇鍟嗙殑寤朵几銆?nbsp;

 

You and yourcustomer, (b)(4), have a quality agreement for the manufacture of (b)(4)drug products. You are responsible for the quality of drugs you produce asa contract facility, regardless of agreements in place with product owners. Youare required to ensure that drugs are made in accordance with section501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, andpurity. See FDA’s guidance document, ContractManufacturing Arrangements for Drugs: Quality Agreements, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM353925.pdf. 

浣犲拰浣犵殑瀹㈡埛XX鏈塜X鑽搧鐢熶骇鐨勮川閲忓崗璁€傝櫧鐒朵綘浠笌鑽搧鎵€鏈夎€呯鏈夊崗璁紝浣嗕綔涓哄悎鍚屽満鎵€锛屼綘浠浣犱滑鎵€鐢熶骇鐨勮川閲忚礋鏈夎矗浠汇€備綘浠簲纭繚鑽搧鐢熶骇绗﹀悎FDCA绗?01(a)(2)(B)閮ㄥ垎瀵瑰畨鍏ㄦ€с€侀壌鍒€佸墏閲忋€佽川閲忓拰绾害鐨勮姹傘€傚弬瑙丗DA鎸囧崡鏂囦欢“鑽搧鍚堝悓鐢熶骇瀹夋帓锛氳川閲忓崗璁?rdquo;銆?/p> 锛堟湰鏂囨潵婧愶細GMP鍔炲叕瀹?锛?

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