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1 GMP Case Study: Lessons from FDA 483s & Warning Letters The GMP Think-Tank

2 목차 목차 1. L. Perrigo Company : 미국 : 일반의약품 Rhone-Poulenc Inc. : 미국 : 원료의약품 Pharma Fab : 미국 : 비무균의약품 Genentech Inc. : 미국 : 무균의약품 Allergan Inc. : 아일랜드 : 무균의약품 Lake Erie Medical and Surgical Inc. : 미국 : 페니실린 Changzhou SPL Company Ltd. : 중국 : 원료의약품 H&P Industries Inc. : 미국 : OTC 의약품 Hospira Inc. : 미국 : 무균의약품 (LVP) Celltex Therapeutics Corporation : 미국 : 줄기세포 주 : 본문가운데괄호로표시된부분은미국 FDA 가 Warning Letter 나 483 문서를 공개하기전에해당업체와협의하여기밀등의이유로지운것입니다. 2

3 Allergan Inc. through July 배치또는원료가지정규격에부합하지않은부적합상황또는설명되지않는차이를철저하게조사하지않았다 [21 CFR ]. 예를들어 1998년 3월 9일충전시에충전실 [ ] 에서발생한환경기준일탈에따라정한시정조치모두를추진하지않았는데, 1998년 5월부터 7월사이에무균핵심지역과무균시험시설에서동일한미생물 ([ ]) 이분리되었기때문이다. 3. Failure to establish and/or follow appropriate written procedures designed to prevent microbial contamination of drug products purported to be sterile [21 CFR (b)] in that: 무균의약품의미생물오염을방지하기위한절차문서를적절하게확립 / 준수하지않았다 [21 CFR (b)]. a. The media fill protocol #RVB811 does not provide specific instructions for performance of media fill interventions nor does it provide instructions for remedial actions in the event of a failure; 메디아필프로토콜 #RVB811에는메디아필간섭조작에대한구체적인설명이나이상발생시의구제조치에대한설명이없다. b. The media fill protocol #RVB811 allows for invalidation of media filled vials post incubation if vials are cracked or incorrectly stoppered without inspection of the vials prior to incubation; 메디아필프로토콜 #RVB811에의하면, 배양에앞서바이알을검사하지않고, 바이알에균열이있거나제대로타전되지않은경우에배양이후메디아필바이알을무효처리하게되어있다. c. Water for Injection (WFI) is not sampled in the same manner as it is used in production; 생산작업과동일한방식으로 WFI 의검체채취를실시하지않았다. d. There are no written procedures for qualification and requalification of personnel working in the aseptic core. 무균핵심지역에서일하는작업자의적격성평가및재적격성평가에관한절차문서가없다. 37

4 Lake Erie Medical and Surgical Inc. 3. Failure to test non-penicillin drug products for the presence of penicillin if a reasonable possibility exists that non-penicillin drug products have been exposed to cross-contamination with penicillin [21 CFR ]. Specifically, no testing of the non-penicillin drug products for penicillin is performed. The only testing done is for the presence of beta-lactams in the non-betalactarn production areas but the methods used, as described in SOP 01.18, have not been qualified for their intended purpose [See Form FDA-483 # 1,D.]. 비페니실린의약품이페니실린과의교차오염에노출된다는합리적인가능성이존재한다면, 비페니실린의약품에대하여페니실린의존재여부를시험해야하는데, 그렇게하지않았다. [21 CFR ] 구체적으로설명하면, 피페니실린의약품을대상으로한페니실린시험을전혀수행하지않았다. 비베타락탐생산지역의베타락탐존재여부만유일하게시험했으나, 그방법 (SOP 01.18) 은목적용도에적합한지적격성을평가하지않았다. 4. Adequate written procedures applicable to the quality control unit have not been established and followed [21 CFR (d)]. Specifically: QCU 에적용되는적절한절차문서를확립 / 준수하지않았다. [21 CFR (d)] a. Written procedures do not assure that correct package inserts are included with repackaged product [See Form FDA-483 #2.B.1]. 절차문서는올바른포장인서트가재포장제품에포함되도록하지못한다. b. Written procedures specifying double counting of tablets or capsules during production and requiring installation and annual calibration of magnahelic pressure gauges by a certified HVAC company are not followed [See Form FDA-483 #2.A.,B.4,]. 생산시에정제나캡슐의이중계수를규정하고지정 HVAC 회사가차압계를설치하고매년교정하도록요구한절차문서를준수하지않았다. 5. Failure to include in the batch production and control records, complete labeling control records, including specimens of all labeling used for each drug product [21 CFR (b)(8)]. Specifically, there is no assurance that package inserts attached to batch records are the same version shipped with the repackaged product. Inserts are not included with each with each 45

5 Changzhou SPL Company Ltd. no evaluation for degradants during stability program testing. Heparin Sodium USP 의불순물프로파일이확립되지않았으며, 안정성실험시에 분해산물을평가하지않았다. 3. The manufacturing instructions for Heparin Sodium USP are incomplete in that they do not include a description of manual manipulations of the [ ] during processing steps, they do not include the actual, manually entered [ ] set temperatures and times and, operator observations such as level measurements, used in calculations, during the [ ] step are not recorded. Heparin Sodium USP의제조지시문서는충분히자세하게기술되어있지않았다. 예를들어가공작업중의 [ ] 수동조작에대한설명이없고, 실제로는수작업으로입력하는 [ ] 설정온도및시간정보가없었으며, [ ] 단계에서수위를측정하여계산하는데이때의값을포함해작업자관찰사항을기록하지않았다. 4. There has been no test method verification performed for the reported USP test methods, Nitrogen Determination, Protein and Total Aerobic Microbial Count, employed in testing of Heparin Sodium USP and Heparin Crude materials, to show that the methods are suitable under actual conditions of use. In addition, there is no routine test for [ ] residue amount at the time of release. Heparin Sodium USP와 Heparin Crude 물품의 USP 시험방법 ( 질소함량분석, 단백질및총호기균수 ) 이실제사용조건에서적합함을증명하는시험방법베리피케이션을실시하지않았다. 또한출하승인시점에 [ ] 잔류물의양을정기적으로시험하지않았다. 5. Investigations into failed lots and out of trend lots were approved as complete, but did not identify a cause for the problem. For example, 부적합로트와이상경향로트의조사결과가완벽한것으로승인되었지만, 다음의예와같이문제의원인을밝혀내지못했다. Heparin Sodium USP batch [ test and was reprocessed to make [ ] failed the Nitrogen Determination ] without finding the reason 48

6 H&P Industries Inc. alcohol swabstick production lines have [ ] after the product contact area, non-cleanable product contact surfaces on numerous pieces of equipment, lack of a preventative maintenance schedule for the compressed air system, lack of routine preventative maintenance of the [ ] in the Deionized Water system. 의약품생산설비디자인에관련된사람가운데엔지니어링분야의교육을받은자가한명도없다. 예를들어 alcohol swabstick 생산라인에는제품접촉지역이후 [ ], 수많은설비의세척되지않는제품접촉표면, 압축공기시스템의예방유지관리스케줄결여, 탈이온수시스템 [ ] 의일상예방유지관리결여등의문제가있었다. OBSERVATION 15 Employees are not given training in the particular operations they perform as part of their function, current good manufacturing practices, and written procedures required by current good manufacturing practice regulations. 작업자가수행하는업무, CGMP, CGMP 규정에서요구하는절차문서에대한교육훈련을실시하지않았다. Specifically: a) Temporary employees are given cgmp training by the temporary agency that employs them, they do not receive any additional training at this company such as job specific training. In addition, cgmp training is not provided on a routine basis. For example: 임시직작업자를고용한에이전시업체가임시직작업자에게 CGMP 교육훈련을실시하는데, 이회사에배치된다음에는업무특이적인교육훈련등추가적인교육훈련을받지않았다. 또한다음의예와같이 CGMP 교육훈련을일상적으로실시하지않았다. 1) Operator [ ] a temporary employee, received training from the temporary agency on 7/28/09 and started at this company on 7/29/09. Training since that time has included line clearance, raw data integrity and 10-up monthly maintenance. 79

7 Celltex Therapeutics Corporation 세포활성, 지정세포수, 세포종류, 세포의성상등최종제품특성각각과관련하여 배치의균일성과완전성을보장하기위한 MSC 제조공정밸리데이션을실시하지 않았다. B. You have not performed [ ] analyses on the final product to assure [ ] of the [ ] the final MSC's. 최종제품의 [ ] 시험을실시하지않아, 최종 MSC의 [ ] 를 보증하지못했다. C. You have not verified the final product with a [ ] to assure the identity of the cell type in the final MSC's. 최종제품을 [ 보증하지못했다. ] 로확인하지않아, 최종 MSC 에함유된세포종류를 D. You have not performed [ ] assay to verify the [ ] the MSC's. [ ] 분석을실시하지않아, MSC 의 [ ] 를확인하지못했다. E. You have not performed installation qualification, operational qualification, and performance qualification on the biological safety cabinets, the [ ] and the [ ] BSC, [ ], [ ] 의설치적격성평가, 운전적격성평가, 성능적격성평가를실시하지않았다. F. You have not performed a validation of your banking and thawing process to assure viability of MSC's. 뱅킹공정과해동공정을밸리데이션하지않아 MSC 의활성을보증하지못했다. G. You have no requirement for pressure differential between the clean rooms and the exterior rooms to assure that non-controlled air does not flow in the cleanrooms. 깨끗하지않은공기가청정실로유입되지않도록하기위한, 청정실과외부작업실사이의차압에대한기준이없다. H. You have not monitored the temperature or humidity of the processing rooms 149

Validation Plan Template

Validation Plan Template 문서번호(Document No.) : 개정번호(Revision No.) : 00 시행일자(Effective Date) : 페이지번호(Page No.) : 1 of 9 작성자 (Prepared By) 부서 (Dept.) 직위 (Position) 이름 (Name) 서명 / 날짜 (Signature / Date) 검토자 (Reviewed By) 부서 (Dept.)