MHRA第三国GMP检查

Workshop on GMP/Pharmacopoeia/APIsBeijing 11-12 July 2012GMP Inspections in Third Countries by EU Member StatesGerald W HeddellDirectorInspection, Enforcement & Standards DivisionMedicines & Healthcare products Regulatory Agency©GMP/药典/APIs研討會北京2012年7月11-12日由成员国进行的第三国GMP检查Gerald W HeddellDirector检查, 执行& 标准部英国药品和医疗产品监督局（MHRA）©34MHRA –Our MissionThe MHRA’s mission is to enhance and safeguard the health of the public by ensuring that medicines and medical devices work and are acceptably safe©MHRA –我们的使命MHRA的任务是通过保证药品和医疗器械有效且安全可控，以强化和保障公众健康©35MHRA’s Regulatory FunctionsClinical Trials AuthorisationsMarketing AuthorisationsRegulation of Post Marketing Safety MonitoringmedicinesLicensing of manufacturers and wholesale dealersInspectionsEnforcement and ProsecutionOverseeing Notified BodiesRegulation of medical Post Market Surveillance/inspectiondevicesEnforcement and prosecutionAdverse Event reportsBlood Safety andInspectionsquality©MHRA的监管职能临床试验许可（CTA）市场许可（MA）药品监管上市后安全性监察生产和零售商许可现场检查实施和执行监管报告主体医疗器械监管上市后警戒/检查实施和执行不良反应报告血液安全性和质量检查©36A New PerspectiveNIBSC: National Institute for Biological Standards and ControlCPRD: Clinical Practice Research Datalink ©新的展望NIBSC: 国立生物制品标准和控制研究院CPRD: 临床实践研究数据链接©37The European network•27 Member States in EU (population: 500 million) •Legislation set up at European level•European Medicines Agency (EMA): agency of the European Commission with a coordinating role•Heads of Medicines Agencies network©欧盟网络•欧盟有27个成员国（人口：5亿）•在欧盟层面上的立法•欧洲药品管理局：欧洲委员会的机构，负责协调•药品管理局局长的网络©38How EU GMP inspections in third countries are organised (1)Supervisory Authority•has granted the Manufacturing Authorisation for the importer of a medicinal product.•is responsible for verifying the GMP compliance status of manufacturers located in third countries based on:·An inspection performed by the Supervisory Member State.·Information supplied by another EEA Competent Authority.·An inspection report or statement of GMP compliance issued by the Competent Authority in which the manufacturer is located under an operational MRA.©如何组织在第三国的欧盟GMP检查(1)监管机构•已经为药品进口商授与生产许可.•基于以下考虑，有责任确认位于第三国的生产商GMP的符合性状态:·现场检查由负责监管的成员国完成.·由欧盟其他主管部门提供的信息.·由主管部门颁发的检查报告或共同认可协议（MRA）的成员国范围内GMP符合性声明，其中，生产商位于.©39How EU GMP inspections in third countries are organised (2)Inspection Planning•For existing third country manufacturing sites for which MHRA is the Supervisory Authority inspections will be planned in accordance with the Risk Based Inspection programme.•Triggers for inspection of new third country manufacturing sites named on Marketing Authorisation (MA) Applications:-National MA Applications and applications through the Decentralised Procedure where the MHRA is the reference member state.-Centralised MA Applications -inspections requested by the Committee for Medicinal Products for Human Use (CHMP) through the EMA.©如何组织在第三国的欧盟GMP检查(2)检查计划•对现有的第三国生产场所，MHRA作为监管机构，将会按计划进行基于风险控制的现场检查.•第三国生产场所检查由上市许可申请而发起:-成员国及分散型上市许可申请-其中MHRA被列为参照国.-集中型上市许可申请-应欧盟人用药品委员会的进行检查.©40How EU GMP inspections in third countries are organised (3)Marketing Authorisation•lists the companies responsible for:·Manufacture of the drug substance·Manufacture of the drug product·Quality Control·Packaging·Importation ·Batch Release•Where manufacture of the drug product is conducted in a country located outside the EU there is a requirement for a pre-approval GMP inspection against EU GMP. ©如何组织在第三国的欧盟GMP检查(3)上市许可•公司责任清单:·原料药的生产·药品的生产·质量控制·包装·进口·批放行•当药品生产在欧盟以外国家进行时，则存在批准前GMP检查的相关要求. ©41MHRA: Inspection model•Aligned to the Compilation of Community Procedures published by EMA•Risk Based•Daily fees per inspector charged©MHRA: 检查方式•与由欧盟药审局公布的有关程序一致•基于风险•每位检查员按每天收费©42MHRA: Where do we inspect?©MHRA: 我们到哪里检查?©43MHRA: Where do we inspect?Everywhere, except EU and Mutual Recognitioncountries:•Switzerland•Australia •New Zealand•Canada (except blood) •Japan(except sterile products)©MHRA: 我们到哪里检查?除了欧盟境内和互认国家以外的任何地方:•瑞士•澳大利亚•新西兰•加拿大(除了血液制品) •日本(除了无菌产品)©44MHRA: International CollaborationRussiaIndiaCanada*Saudi ArabiaChina*Japan*USA*INTERNATIONAL INFLUENCEMexicoSingapore*Brazil**GhanaNew Zealand*South AfricaAustralia*Information exchangeBRICS country* Agreement/MOUSource countryOther** Negotiating agreement/MOU©MHRA: 国际化合作俄罗斯印度加拿大*阿联酋中国*日本*美国*INTERNATIONAL INFLUENCE黑西哥新加坡*巴西**加纳新西兰*南非澳大利亚*信息交流金砖国家* 协议/备忘录来源国其他** 协议/备忘录进行中©45MHRA: The inspection process•Inspections are performed to assess compliance with:--the Marketing Authorisation (product licence).European guidance on good manufacturing practice and/or good -distribution practice.the Medicines Act 1968, as amended•This involves an assessment of personnel, premises, processes and procedures to ensure the quality of the medicinal products.•inspection will be raised as a deficiency.Any deviations from the above discovered during the course of the •inspection findings.Licence holders are required to provide an action plan to address any •Following approval of the action plan manufacturers will be issued with a GMP certificate for the activities and dose forms inspected.©MHRA: 检查过程•执行检查以评估以下符合性:--市场许可-欧盟(产品许可).药品法GMP/GDP1968, 已修订指南.•涉及人员，设施，过程以及程序的评估，以保证医药品的质量.•在检查过程中从于以上项目中发现的任何偏差，均会被认定为缺陷.•要求许可持有人提供行动计划，以解决任何检查中的发现.•行动计划得到批准后，生产商将会得到针对有关活动和检查的剂量剂型的GMP证书©46MHRA: Inputs to the inspection•Inspection content based on standard approach plus particular areas of focus as determined by the inspector based on preparation.-Defective Medicines Notifications-Review of Marketing Authorisations particulars-Review of Previous Inspection Reports·Including review with previous inspector-Review of changes formally notified-Review of other correspondence with site-Review of other “Regulatory Body” inspection reports e.g. PIC/S, TGA, FDA etc©MHRA: 检查的输入•检查内容：基于标准方法和检查员已准备关注和确定的特定范围.-可检测药品通知-上市许可细节的审核-先前检查报告的审核·包括对先前的检查员的审核-正式通告的变更审核-生产场所的其他回应信息审核-其他药监机构的检查报告审核，如，PIC/S，TGA，FDA等©47MHRA: General Inspection Approach•Systems overview-Tell me how it works•Procedural review-Show me the written procedure•Record Review-Demonstrate how it works in practice•Data Review-Prove it works-Training linked to SOP’s-Calibration and maintenance records-Analytical raw data and calculations©MHRA: 通用检查方法•体系概述-告诉我它如何运作•程序审核-给我展示书面程序•记录审核-声明在实践中如何有效运作•数据审核-证明有效-与SOPs有关的培训-校准和记录维护-分析原始数据和计算©48MHRA: What we findTop 10 Deficiency Categories -UK inspections:1.Documentation –SOPs 2.Quality Management3.Documentation -Manufacturing4.Supplier & Contractor Audit5.Complaints and Recall6.Quality Management –Change Control7.Product Quality Reviews8.Investigation of Anomalies9.Batch Release Procedures10.Supplier & Contractor Technical Agreements©MHRA: 我们发现了什么排在前10位的缺陷分类–英国检查:1.文件–SOPs 2.质量管理3.文件–生产4.供应商&外包商审计5.投诉和召回6.质量管理–变更控制7.产品质量审核8.异常情况调查9.批放行程序10.供应商&合同商技术协议©49MHRA: What we findTop 10 Deficiency Categories -3rd Country inspections: 1.Contamination, chemical/physical –potential for2.Supplier & Contractor Audit3.Investigation of Anomalies4.Line Clearance & Segregation5.Documentation -Manufacturing6.Design & Maintenance of Premises7.Quality Management –Change Control8.Quality Management9.Process Validation10.Handling Packaging Components©MHRA: 我们发现了什么排在前10位的缺陷分类–第3次国家检查: 1.污染，化学/物理的–潜在的2.供应商&外包商审计3.异常情况调查4.清场&隔离5.文件–生产6.设计&设施维护7.质量管理–变更控制8.质量管理9.过程验证10.处理包装组件©50SUMMARYEU GMP in China:-Based on European legislation-European Medicines Agency co-ordinates for Centralised licences-Member States do inspections-Facility as well as Quality System issues©总结欧盟GMP在中国:-基于欧盟立法-欧洲药品管理局对集中许可的协调-成员国进行检查-设施以及质量体系问题©51WORKING TOGETHERGood ManufacturingPractice for Drugs(2010 Revision)Center for Certification of Drug, SFDAJan. 2012©协同工作Good ManufacturingPractice for Drugs(2010 Revision)Center for Certification of Drug, SFDAJan. 2012©52© Crown Copyright 2012About copyrightAll material created by the Medicines and Healthcare products Regulatory Agency, including materials featured within these MHRA presentation notes and delegate pack, is subject to Crown copyright protection. We control the copyright to our work (which includes all information, database rights, logos and visual images), under a delegation of authority from the Controller of Her Majesty’s Stationery Office (HMSO). The MHRA authorises you to make one free copy, by downloading to printer or to electronic, magnetic or optical storage media, of these presentations (excluding Agency logos) for the purposes of private research, study and reference. Any other copy or use of Crown copyright materials featured on this site, in any form or medium is subject to the prior approval of the MHRA.Further information, including an application form for requests to reproduce our material can be found at www.mhra.gov.uk/crowncopyrightMaterial from other organisationsThe permission to reproduce Crown copyright protected material does not extend to any material in this pack which is subject to a separate licence or is the copyright of a third party. Authorisation to reproduce such material must be obtained from the copyright holders concerned.©© Crown Copyright 2012关于版权所有由MHRA创建的材料，包括MHRA的陈述观点和委托信息，均受版权的保护。在得到皇家出版局(HMSO)的授权委托下，我们在工作中控制有关版权（包括所有的信息，数据库版权，标志以及可视的图片等）：基于私人研究、学习和参考的目的,MHRA授权你可通过下载到打印机或到电子，磁性或光存储媒介，免费制作一份这些PPT复制件(不包括机构的标志). 除此以外，任何其他形式的拷贝或使用该版权材料，必须得到MHRA的提前批准.详细信息,包括要求复制我们材料的申请表可以从该网站下载：www.mhra.gov.uk/crowncopyright来自其他机构的材料允许复制受版权保护的材料不会扩展到本文件夹中的任何材料，必须遵循单独的许可来自第三方的版权许可，授权以复制那样的材料必须获得相关持有人的许可.©53Thank you for your attentionGerald W HeddellDirectorInspection, Enforcement and Standards DivisionMedicines and Healthcare products Regulatory Agency+44 (0) 203 080 6500gerald.heddell@mhra.gsi.gov.uk©谢谢关注Gerald W HeddellDirectorInspection, Enforcement and Standards DivisionMedicines and Healthcare products Regulatory Agency+44 (0) 203 080 6500gerald.heddell@mhra.gsi.gov.uk©54供参考的其他幻灯©MHRA: Inspection Process•Organisational structure and reporting relationships•Batch record review•Annual product reviews•Complaints, recalls•Non conformance/deviation reports•OOS Results©55MHRA: Inspection ProcessPlant tour•Raw material controls•Housekeeping•Maintenance•Status/identity labelling•Work flows (Potential for cross contamination)•Packaging/labelling control©MHRA: Inspection ProcessPlant tour•Operating procedures•Equipment calibration•Process records•Automated systems•Sampling points•In-process testing©56MHRA: Inspection Process•Maintenance•Calibration•Support systems (water, air, vacuum)•QC services•Staff training programme and records•QA functions including batch release and internal audits©MHRA: Inspection Process•Documentation systems•Validation -qualification of facilities and equipment-process validation-cleaning-computer systems-change control©57MHRA: Inspection ProcessClosing meeting•Observations and comments•Formal list of deficiencies •Classification•Acceptance of factual accuracyLetter to company by inspector within 7 days of the inspection©INSPECTION FINDINGS –Top 10 Categories1.Investigation of anomalies2.Quality management (Change Control)3.Corrective action/preventive action (CAPA)4.Complaints and Product Recall5.Quality management©58INSPECTION FINDINGS –Top 10 Categories6.Supplier and Contractor Audit7.Contamination, Chemical/Physical –Potential For8.Documentation –PSF/Procedures/Technical Agreements9.Documentation –Manufacturing10.Process Validation©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories1 -Investigation of AnomaliesContinuing to be the number 1 deficiencyThe management of ‘high’ risk deviations was deficient:•The investigation into 2 positive sterility tests recovered in November 2011 was not complete at the time of the inspection; only a one page interim report was available on day 1 of the inspection.•The November 2011 Sterility test failure investigation appeared prejudiced to implicating sterility testing; for example sterility testing had been immediately suspended but manufacturing operations had not been suspended.•There was no overall assessment of the 4 sterility test failures that had occurred in 2011.©59Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories1 -Investigation of AnomaliesControl of Investigations was deficient:•The procedure allowed up to 60 days for the completion of the investigations categorised as critical. This was considered too long to ensure a timely review and impact assessment to be performed.•The procedure did not detail a system for reviewing of overdue investigation and an appropriate extension process.•A large number of investigations were seen that were not closed in a timely manner or were still open a number of months beyond the stipulated expected closure time. There was no assessment of the impact of these overdue investigations and no assessment as to the root cause of the failure to follow the procedure.•A number of investigations were seen that did not include detailed robust root cause investigation. Therefore potential impacts were not fully assessed and the root cause and subsequent CAPA were not robust.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories1 -Investigation of AnomaliesThere were multiple examples from the inspection where deviations had not been raised in circumstances where the procedures in place indicated that such documentation was required.On-going serious deviation (related to human operational failures) had not been resolved in a robust and timely manner.Deviations were routinely incorrectly classified in a lower classification than required by the SOP.The Deviations procedure was lacking in that:•There was no detail provided with respect to how investigate and assess the impact of an incident.•There was no requirement to consider the implications for other batches.•There were no defined timelines associated with investigations ie raising, approval by QA and closure.•Stability OOS/OOT incidents were not managed by the Non-conformance /Deviations procedure.©60Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories1 -Investigation of AnomaliesThe quality of investigations performed was not of the required standard to consistently identify the root cause of the issue and hence suitable corrective and preventative actions, including a robust assessment of the impact of the findings on other batches or systems. A number of specific examples are documented below; these are examples of issues found rather than a comprehensive listing of all issues noted.The investigation into the recall arising from the …..l complaint batch no. …. concerning a carton of 8 mg …. containing 2 mg blister was deficient in that:-•There was no documented consideration of other components received from the supplier. At the time of the inspection items from this supplier were still on stock, although in quarantine triggered by retest date.•There was no documented consideration as to whether similar issues could exist at alternate suppliers given a common approval process.•The investigation did not consider other ways that electronic identification systems could be bypassed –for example during line set up.•There was no justification from the findings for the retraining of manufacturing staff for example. A number of the investigations appeared to place an over reliance on retraining in the absence of a critical review of systems and supporting documentation in place at the time of the incident.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories1 -Investigation of Anomalies•There appeared to be a discrepancy between supplier status on SAP and the approved vendor list as … was listed as an approved supplier on the list dated 1 July 2011.•There appeared to be an excessive time delay between the decision to block … following the audit on the 25 January 2011, email request on 25 March 2011 and confirmation of status change on 26 April 2011.•The current mechanism for transferring actions between complaint form and CAPA and subsequent tracking does not adequately distinguish between actions of different priority. The CAPA for the above complaint was not signed off until 10 June 2011.•There was a noted discrepancy for investigation status between SAP print (open) for … (foil) and investigation report (closed).•There were a number of examples observed where SAP data errors were being corrected using the change control processes without the supporting notification to understand how and why the error arose.•The reviewed investigation into the supply of product using the incorrect grade of … had not adequately documented the root cause; hence it was difficult to assess the quality of the actions taken.©61Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories2 –Quality Management –Change Control2010 –2011 was number 4Change Control was deficient in that:•There was no comprehensive change control checklist.•The management of artwork changes was lacking as there was no mechanism to ensure that variations were implemented in a timely fashion or in line with competent authority notifications, neither the change control procedure nor changes reviewed detailed time in pack requirements.•There was no change control for the new Braille label print machine.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories2 –Quality Management –Change ControlProcedures for Management of Changeas defined in SOP were not being satisfactorily applied as exampled by: •The acceptance of post of major changes by customer is not permissible as some major changes include registered details.•No Change Control was raised for the change in supplier of …. from …. to …..•The change of primary packaging from PE bag to PE lined aluminium bag was seriously mismanaged in that: •The change control … was raised on 24/12/10 after changes to specifications to permit the aluminium bag had been made on 24/8/10.•The change was classified as minor resulting in no detailed impact assessment.•The customer and assessor have not been notified of nor authorised the change although batches of material are already being packed in the new format.•The Change Control log is not an authorised, version controlled document.©62Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories2 –Quality Management –Change ControlChange management was deficient in that:•No change controls had been raised for several engineering changes for example, fan and filter changes on the HVAC system and the introduction of the … detection system or the … sampling system.•Change controls started in 2010 had not been signed had not been completed by QA.•Change control was not used for the introduction of new products and there was no new product introduction procedure.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories3 -Corrective action/preventive action (CAPA)2010 –2011 was also number 3There was a lack of a robust investigation for the reviewed compounding complaints and non conformances designed to identify root cause and hence appropriate actions to minimise the potential for reoccurrence. It was noted that the frequent use of terms such as ‘human error’, ‘isolated occurrence’ and ‘no trend’ appeared to limit the investigation conducted.The CAPA raised for the leaking of terminally sterilised product did not include a review of the completeness of the validation process for the introduction of automated handling equipment to ensure that future exercises cover the lessons learnt.Non conformance Report …. was lacking in that the batch disposition by the QP was not clearly stated and the corrective and preventative actions (CAPA) were weak in that there was no clear action to prevent reoccurrence within the commercial department and there was no conclusions drawn with respect to the review of the appropriate technical agreements.©63Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories3 -Corrective action/preventive action (CAPA)Several investigations were reviewed and were found deficient in the following areas:•It was not possible to piece together the events or any accompanying risk evaluation which may have taken place.•Root cause, implications for other batches, CAPA and batch disposition were not clearly defined.•Investigations were not raised in a timely fashion as evidenced by ….. In addition it was not clear if … had been contacted and / or if a variation had been raised.•Lack of investigation as evidenced by …. temperature excursions.The site had failed to instigate effective remedial actions in a number of areas as evidenced by deficiencies raised at this inspection being of a similar nature to those raised at previous MHRA inspections. This indicated that the quality management system was focussed on dealing with the specifics of the deficiency rather than taking a holistic view to enable the quality management system and site practices to be strengthened.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories3 -Corrective action/preventive action (CAPA)Deviations:•Procedural NCRs were only logged on a spreadsheet and were not formally approved by the Operations Executive or QP.•Investigations were not fully documented.•There was no evidence of corrective and/or preventative actions being performed.•There was no batch disposition decision recorded for batches subject to a NCR.Non conformance procedure & corrective action procedure did not consider the implication for other batches to be affected.Non-conformances reviewed failed to identify the implications for other bathes to be affected and the preventative action stated by the company for repeat issues with label reconciliation were not documented in the investigations.©64Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories3 -Corrective action/preventive action (CAPA)CAPA was deficient as evidenced by:•CAPA was not being applied to the full scope as defined in SOP … as the only evidence of use presented encompassed actions following internal or external site audit.•There was no chronological log of CAPAs whereby actions may be tracked to completion. •It is unclear how Quality Assurance can fulfiltheir requirement to review the effectiveness of CAPAs as there was no forward tracking procedure.•There was no evidence that the CAPA procedure had been applied to ensure the increased observation of batches of …. and … was being documented following the identification of significant trends during Product Quality Review. ©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories4 –Complaints and Product Recall2010 –2011 was number 7There was no mock recall exercise performed in 2009. This is a repeat deficiency, failure in post inspection commitment and non compliance with the company’s recall procedure.Complaints Process was deficient in that:•There was no trending upon receipt.•Timelines associated with complaints management were not being adhered to as define in the procedure.•Complaints were not reviewed by the QP as defined in the procedure.©65Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories5 -Complaints and Product RecallComplaints Procedurewas deficient in that: •The Complaints Handling procedure makes no reference to the requirement to verify complaint for counterfeit product. •There is no historical review of the complaint on receipt.•There is no assessment of possible impact on other related batches or products.•The complaints log is being completed as ‘closed’ when CAPA actions remain outstanding eg three complaints were received from the same customer for out of specification related substances of ….. The recommendation to discuss possible causes with the customer has not been fulfilled although documented to do so on 1April and again 11 August 2011. •No documentation could be found for Complaint ….. although the log indicated closure on 11February 2011. •The root cause of the complaint of out of specification water content of …. has not been adequately investigated and documented. ©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories4 –Complaints and Product RecallRecall Procedure …: •The Recall procedure does not require periodic challenge of the system when no actual recalls have been required. •There was no required assessment of the possible impact of the recall on other batches or products. There was no procedure for the management of complaints against suppliers to ensure a timely and comprehensive investigation designed to minimise the potential for recurrence. Such a process should also include a review of the supplier status and the impact on materials already in the supply chain.©66Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories5 -Quality Management (systemic issues across all systems)2010 –2011 was number 2The site had failed to instigate effective remedial actions in a number of areas as evidenced by deficiencies raised at this inspection being of a similar nature to those raised at previous MHRA inspections. This indicated that the quality management system was focussed on dealing with the specifics of the deficiency rather than taking a holistic view to enable the quality management system and site practices to be strengthened.The trending of deviations was only performed at a 6 monthly frequency and failed to address the root causes. The site would thus not become aware of emerging issues to enable appropriate remedial actions to be taken.The recalls process was restricted to use with the complaints process. No reference to the possibility of a deviation or OOS result triggering a recall was considered.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories5 -Quality Management (systemic issues across all systems)Remediation proposals submitted by the company in response to the 2010 inspection had not been implemented or maintained in accordance with the commitments given, as evidenced by:•A number of the actions were not completed in line with the committed timeframe. No communication of the departure from the agreed plan was made to the Agency –for example via an interim update.•The remedial actions had not always delivered the desired outcome. Examples include:•The records relating to the previous (inspection of 2010) finding … indicated that … was a potential contaminant of the …. from the …. company but there was no documented explanation as to why QC testing did not look for this contaminant.•There remains no record of the retrieval / destruction of superseded copies of procedures. •Despite uniquely identifying dispensary buckets, there remains inconsistency in the approach to the dedication of all product contact materials in the dispensary. There was no documented risk assessment / justification for the approach taken with respect to controlling risks of cross contamination. ©67Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories5 -Quality Management (systemic issues across all systems)•The cleaning process and associated records remain unclear. The process for cleaning between different materials (e.g. API and excipient) remains poorly defined.•The installation of hooks to enable drainage of water hoses was observed to be ineffective. In Room … the water hose was hanging on the hooks system but standing water remained trapped within the hose loops.•A remedial action appeared to have subsequently reverted back to the identified deficient process. The 2010 response to previous finding detailed the planned approach to weighing … charge; the site has since reverted to accepting the weight as received from the vendor. No communication to this effect been made to the Inspectorate.Site quality systems, facilities and controls were considered inadequate to provide sufficientassurance of the quality, integrity and security of supply of ………©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories5 -Quality Management (systemic issues across all systems)The Company failed to demonstrate satisfactory application of the Quality System asexampled by the following incidents:•Batch Manufacturing Record number for the …, permitted a batch size of 40kg +/-10kg with no validation to justify this range.•The subsequent increase in the routine batch size from 40kg to 48kg was not documented through the established quality system.•Attempts to establish a method for the re-processing of … back to …, step …had been made outside of a formal validation exercise.•Approval for the use of …. beyond its approved shelf-life was granted although the purity result at 98.33% failed the specification of >/= 98.5%. No deviation was raised or justification documented. •Sodium Bicarbonate … was manufactured and released on 9 April 2009 before validation of the process which was not completed until 30 December 2010.•The change control for the introduction of a new bag sealer was raised on 2 May 2011 but validation of the equipment commenced on 29 April 2011.•The procedure for the Handling and Re-use of Recovered Solvent, … required that testing must include reference to the number of recovered cycles. In the example reviewed this had not been included.©68Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories5 -Quality Management (systemic issues across all systems)•The procedure for Rework and Reprocessing, … required reprocessing to be validated over three batches and included in the stability programme. It was identified that reprocessed batches had been released although there was no validation data to support this. The Inspector acknowledges that the reprocessed batches will not be supplied to the EU markets.•The above procedure still did not provide clear instruction that rework was not permitted for EU markets or that reprocessing was not permitted to certain customers as defined in the Technical Agreements.•The procedure for handling Critical Process Parameters … required period review of the CPPs by Production and Quality Management. Outside of the Annual Product Review this was not defined.•No Risk Assessment had been performed to evaluate the wider impact of the new factory.•There had been no consideration of the requirement to increase environmental monitoring during the build period.•Change Control procedures were deficient in that there was no established system within the Change Control process for documenting required completion dates and tracking on-time closure.•The Change Control procedure did not identify the additional application forms required to be raised for individual changes.•There was ambiguity as to the status of completed actions eg validation and calibration log revision for the thermal sealer.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories6 –Supplier and Supplier Audit2010 –2011 was number 11Supplier Audits was deficient in that:•Not all suppliers had been audited in line with the stated annual frequency.•The Contract laboratory, had not been audited, nor was it detailed on the audit schedule.•The audit report for ……. was reviewed. The inspectors commented that on review significant issues were identified, all of which were classified as minor. Issues identified related to the control and management of artwork. The company had experienced incorrect artwork being supplied by the vendor.The Audit procedure was not approved. The draft document was reviewed and found lacking in a number of areas, for example (but not limited to):•Audit frequency for suppliers.•Definitions for critical, major and minor deficiency classification.•The actions to be taken if critical observations are identified during a supplier audit.•There was no checklist for auditing.•Auditor competency, skills or knowledge was not defined. ©69Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories6 –Supplier and Contractor AuditSupplier Assurance was deficient in that:•There was no process for periodic on-going evaluation of suppliers. Supplier de-qualification was defined in …. however the latter in essence was based on rejections and out of specification (OOS) results and was purely reactive.•The applicable procedure … was deficient in that:•Primary, Printed Packing materials and brokers were not defined and as such the suppliers were not assessed or audited. •Audit of materials including Active Pharmaceutical Ingredients (API) was not required if the manufacturer was not local i.e. within India.•There was no audit period defined for critical Excipients.•The evaluation and approval procedure did not define the actions to be taken if critical observations were obtained at a supplier audit.•The de-qualification procedure was not linked to the deviation quality system as such it was not clear if the implications for batches in the manufacturing stream and supply chain would be assessed. In addition this was purely focussed on API and not all materials.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories6 –Supplier and Contractor Audit•Audit reports performed were to a predefined general generic checklist, there was no data to support the audit except ticks on the checklist. There was no information relating to date of audit, auditor knowledge and experience, the standard against which the supplier was assessed, what areas were audited, observations made and hence how the impact assessment on the material in question was derived. All audits performed had been done in this manner and as such no audits were available for inspection.•The audit plan was not generated in line with QA. Note in the inspectors opinion the plan is unrealistic and unachievable as 706 were required in the year.©70Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories6 –Supplier and Contractor AuditControl of Starting Materials with specific respect to … was deficient in that:•Neither the supplier, … nor the manufacturer, … had been subject to site audit contrary to GMP expectation and the Company’s own internal procedure for Vendor Qualification and Audit.•The above procedure permits qualification of a critical raw material supplier up to 3 months before the manufacturer is audited.•The evaluation questionnaire has been completed by the supplier who is not qualified to complete on behalf of the manufacturer.•The Certificate of Analysis supplied by … specifically states that the company “ makes no warranty as to the suitability of the goods for any purpose whatsoever.” This was not acceptable for as material destined for subsequent intravenous use.•There was no Technical Agreement in place between … and …©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories6 –Supplier and Contractor AuditVendor Assurance activities were deficient in that:•A QP API declaration had been approved without an acceptable audit having occurred. The QP had approved the API declaration pending the performance of an acceptable audit occurring.The control of API site audits was deficient in that:•There was no mechanism to ensure that API site audits performed by 3rd party companies (e.g. Indian manufacturing sites) occurred in a timely manner.•The audits of the manufacturing sites did not consider the API site audit process.•Two API site audits had not had the deficiencies classified. It was not clear if these were deficiencies or recommendations.©71Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories7 –Contamination, Chemical/Physical –Potential For2010 –2011 was number 13Cleaning Validation was deficient in that:•Whilst the site had proposed a matrix approach to cleaning validation, the identified API candidate in respect to toxicity and solubility, …., had not been subjected to cleaning validation. It was noted that two more potent candidates were available but assay methods on site were inadequate to detect the required levels of these compounds.•Whilst line one was used for the filling of all regulated products, it was also available for all other products made on site. As a consequence of the lack of adequate cleaning validation, no assurance was available to demonstrate that residual material from one product did not cross contaminate the following products, which may have potential for causing patient harm.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories7 –Contamination, Chemical/Physical –Potential ForProvisions to prevent Cross Contamination of product, equipment and personnel are deficient in that:•With the exception of …. which was manufactured in dedicated rooms a range of prostaglandins and non-prostaglandins were being manufactured and packed in common areas. (NB Prostaglandins are classified as Class 1B products with the requirement to be manufactured in either dedicated facilities or in infrequent campaign runs in an appropriate area.)•The common air handling system utilising recirculation and make-up air drawn from the open roof space was insufficiently secure for a facility where there was no dedicated area for the segregation of Class 1 product.•There was no differential pressure between area … used for prostaglandins and adjoining room … used for non-prostaglandins with increased risk of cross contamination.•No local extract is used when adding solids to the re-crystallisation vessel in room….•Dirty equipment and gowns were put in a sealed bag for transfer to the wash bay but there was no process of cleaning the outside of the bag with possibility of contaminating other areas and equipment.•There was no differentiation of gowns worn by operators for processing of prostaglandins and it was unknown if the cleaning process followed by an external company was adequate to remove traces of prostaglandin contamination.©72Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories7 –Contamination, Chemical/Physical –Potential ForThe current cleaning validation exercise was carried out in 2005 and there had been no subsequent review.•There was no documented rationale or comparison with new products to confirm the products chosen for the cleaning validation exercise were still relevant with respect to potency and solubility.•There was no documented risk assessment for the need for microbiological monitoring and none had been carried out apart from on the final rinse water used for cleaning.•No deviation had been raised for a failure in purified water monitoring results.•The …. filling machine was not subject to any routine strip down or clean. Large amounts of residue were seen in the product transfer pipe work.•There was no Validation Master Plan for cleaning or process validation.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories7 –Contamination, Chemical/Physical –Potential ForControls surrounding the prevention of cross contamination were lacking in that: •Air was recirculated from different processing rooms, which could manufacture different products, by one air handling unit. The grade of filters used was less than those expected for such a situation to prevent cross contamination. •The documented rationale for selecting worst case products for cleaning validation studies was not an approved, controlled document. •…, as a coated tablet, was not deemed to be the worst case choice to be used to perform packing cleaning validation. •There was no cleaning validation performed of multi-product fluid bed drier filter socks. •The validation of …. batch campaign length found the Fluid Bed Drier was not visually clean after one Clean In Place cycle, however the cleaning procedure was accepted and had not been updated to reflect that a second cycle was required. •Differential pressures across solids manufacturing areas were only being read once per month. ©73Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories7 –Contamination, Chemical/Physical –Potential For•Several instances of out of limit pressure differentials in solids manufacturing were seen, with no documented investigation or assessment performed. •Operators may dispense different active agents while wearing garments that have previously been exposed to different products. •…..forming head was labelled as clean but had white residue seen on it. The company had failed to meet the commitment from the previous inspection to improve the compression area HVAC to reduce the risk of cross contamination. The action had been due for completion by April 2010.Cleaning of production drums had occurred in the Liquids area processing vessel without a completed change control in place. There was no SOP, training records or validation to support this revised cleaning practice. It was noted that the process vessel appeared to have been contaminated by this cleaning activity despite the room documentation indicating that the vessel was clean and QA approved as such.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories8 –Documentation –PSF/Procedures/Technical Agreements2010 –2011 was number 5There were no technical agreements with the manufacturers / suppliers of unlicensed medicinal products.Documentation –generation, control and completion.There were uncontrolled, incorrect and out of date documents throughout the operation. Examples include:•uncontrolled “Accepted” status labels on the QA table in secondary packaging•detailed instructions for change parts•on line identifiers of hot spots.•a sign relating to the tin line head in the Balm production room.•out of date cleaning logs in a cleaners cupboard.©74Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories8 –Documentation –PSF/Procedures/Technical AgreementsTechnical Agreements (TA) was deficient in that:•TA were not in place with all supplier’s as per detailed in the procedure (GN003) as evidenced by:•Contract laboratories.•The TA with…, Authorisation …. was lacking in the following areas:•Documentation retention periods specified were not compliant as they failed to meet the requirement of expiry + 1 year, or 5 years from certification, whichever is the longer.•The responsibility for transportation and assurance with product label claim was not defined.•Other records such as the documentation made available to the QP for certification were not defined.•There was no review / expiry date.•The TA with …..was very high level and was found significantly lacking in a number of areas for example (but not limited to), investigations (Out of Specification & Deviations), Change Control, Starting Materials, TSE etc•The TA procedure was lacking as no review period for TA’s was defined and the procedure stated that a TA must be in place prior to first batch being released, this is deemed to be inappropriate.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories8 –Documentation –PSF/Procedures/Technical Agreements•Warehouse SOPs were observed stored in a locked cupboard restricting access to all relevant staff.•Reviewed SOPs lacked detail or were not available for a number of operations including:-• There was no procedural requirement for the PQR to be sent to the MAH/QP• No requirement for line clearance for dispensing of printed packaging items• The Warehouse returns procedure was not clear as to what printed packaging items can be received back from production e.g. intact bundles or loose leaflets (inserts)• There were apparent anomalies regarding the use of the balance for label dispensing and the requirement for a manufacturing licence on incoming goods check• The use of the received CoA as part of goods receipt was not adequately described in the procedure•Scheduling of stability studies•Item code translation for leaflets• Soft copy control and Corporate responsibilities for artwork generation and control.©75Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories9 –Documentation –Manufacturing2010 –2011 was number 6There were a number of deficiencies in the batch manufacturing documents and related standard operating procedures. In general they were lacking in detail.Batch Documentation practices were unsatisfactory in the following:•Expected criteria was not always included at all IPC steps where actual data eg temperature or humidity was being recorded. There was therefore no opportunity for the operator to be alerted to a possible processing issue.•Print had faded to the point of being illegible in the raw data included in ….Batch record for Lot ….. Additionally, photocopies taken to preserve raw data print outs were almost totally blank. Of concern was the fact that the batch record had been reviewed by both Production and Quality personnel with no comment made.•No sample labels were included in the batch document sets for finished API.•There was no documented reconciliation of labels.•The above batch failed specification for residual solvent and subsequently rejected. However there was no clear indication of batch status on the document.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories9 –Documentation –ManufacturingThe documentation in place was inadequate in that:-•There were numerous examples of a poor integration and conflicts between the electronic ERP system (SAP) and local document systems.•Batch documentation was lacking as evidenced by:-•The Batch Manufacturing Record (BMR) reviewed did not provide detailed stepwise processing instructions following the sequence of required activities.•There was evidence of unofficial calculations on the SAP screen shot included as part of the reviewed batch documentation. There were no instructions available to describe this action.•The risks associated with transcription for BMR had not been adequately assessed nor was there a robust process to ensure independent checks on calculations including details of source data e.g. potency.•Sample of IPC labels were not included as part of batch documentation. In addition there was not a consistently identified step to ensure the clearance of the print station before printing such labels.•The document summary sheet did not provide an accurate listing of documents. In addition the SOP listing was manual without any clear instruction as to how to complete. ©76Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories9 –Documentation –Manufacturing•Raw data used to derive IPC results was not included as part of BMR.•There was no code number for polyethylene bags used for storage (product contact).Documentation: •The requirement to sign the register for entering production areas was not specified in the SOP. •There was insufficient instruction available at the point of use to enable production processes to be completed in a consistent manner •The bulk solution sterilisation time was critical to ensure correct viscosity but there was no procedure which described how it was calculated. •Checks on vacuum distillation temperature only reported a single value and did not confirm the temperature was in specification for the whole process. •There were no instructions available with respect to the preparation and use of the filtration area heat exchanger, used to heat or cool WFI. In addition, no reference was made by site staff to ensuring that the device was suitably sanitised prior to use. •There was a lack of evidence within the batch record reviewed with respect to the required filling line recovery time following a power failure. ©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories9 –Documentation –ManufacturingThe batch records and procedural documentation reviewed did not contain sufficient detail,laid out in an orderly fashion to establish, control, monitor and record all activitieswhich directly or indirectly impact on all aspects of the quality of medicinal products suppliedby the site in that:-•There was no procedure to describe the switching off and restarting of HVAC units, including muting of alarms, or to confirm the satisfactory operation of the required HVAC overnight before commencing operations.•The observed practice of back calculating the reconciliation of packaging items negates the value of this exercise. The checks in place on document completion had not detected this practice. (This inspector accepted that there was no attempt to hide issues rather the detail of the process and subsequent instructions had not been adequately established.)•The batch release SOP sequencing is not in line with the practice observed.•Risks associated with transcription on the batch documentation had not been adequately identified and controlled, for example potency derivation and calculation and batch number / expiry date assignment.•There was evidence of the use of uncontrolled documentation systems. An electronic document issued by QC detailing required sample quantities was found on the PC in the IPC area.•The batch documentation did not provide limits for recorded variables such as rpm for IPC blender and blister machine speed (see previous inspection).©77Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories9 –Documentation –Manufacturing…. tablets with known manufacturing issues were being inspected in an unofficial and undocumented way. Unofficial documentation in the in-process batch indicated that 8 out of 10 tablets weighed did not meet the applied specification. No deviation had been raised and the company had assumed that the packing operators, with no formal instruction, procedure or validated training, would inspect out all damaged and underweight tablets. All unofficial records were removed from the final batch records thereby reducing the visibility of this issue.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories10 –Process Validation2010 –2011 was number 21Validation was deficient as evidenced by:-•Analytical laboratory risk assessments for both method and equipment did not contain a full list of methods and equipment was reviewed.•A number of methods and equipment had the same score but were then not prioritised within the group.•There was no review of how these plans were connected to the Production equipment remediation plan and process validation plans.•None of the plans were linked to the Site Validation Master Plan.•There were no details on how the plans would be tracked and monitored and how this would link to the Batch disposition process.•The IQ/OQ for the Drum Hoop Mixer did not contain sufficient details with regard to the acceptance criteria or how the protocols were enacted. A discrepancy was identified but no explanation or impact was documented.•There was no requirement within the IQ/OQ documentation that the calibration and or maintenance requirements had been identified and included within the pm system.•The validation status of …. products was not clear in terms of batches produced changes made and conclusions drawn. The documentation for ….. did not describe the blender used nor did it explain why the 60minutes data was out of specification or reference what CAPA actions were to be taken.©78Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories10 –Process ValidationThe arrangements for validation of equipment and processes were deficient in that:•The blister packing machine range of temperatures mentioned on the batch documents for forming and sealing had not actually been validated. Instead the company had chosen an intermediate temperature to run the machine at and had not demonstrated that all temperatures in the ranges given were acceptable. Furthermore, the speed of the machine had not been specified. •Validation of the pvc film was last performed in 2006 and the pvdc film had not been qualified.•It was noted that there were at least two types of pvc film, white and clear, and that the company had not identified unique materials codes on either the validation or batch documents so it was unclear which product had been used in the qualification work.•There was no list of equipment to aid in assessing the need for periodic evaluation of its validation status.•The list of laboratory equipment requiring calibration was incomplete.•There was no requirement in the product quality review procedure for an assessment of the validation status of the product.•There was no pre-authorised validation protocol for the …. process. •No report had been written for the validation of the product. There was no conclusion stating that the validation had been successful.©Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories10 –Process ValidationThe management systems required to ensure compliance (regulatory and GMP) with the Marketing Authorisation were still inadequate:-•There was no cohesive plan that defined all activities that were required to be performed to ensure all GMP and regulatory compliance aspects were completed in a timely manner.•Validation activities were only considered as part of a products technical transfer and were not considered if the manufacture stayed at the existing company resulting in a number of products that have incomplete process validation, analytical validation and artwork issues.•The gap analysis template used to determine the scope of work did not include validation activities (process or Quality Control).•Justification for delays in the programme was not formally documented as seen in the example ……… for ……….. tablets.•There was no risk assessment available for each product for which the validation/qualification activities had not been performed.•There was no formal process to track due dates of activities that had been identified for some products and therefore no impact assessment was performed when overdue.©79Safeguarding public healthINSPECTION FINDINGS –Top 10 Categories10 –Process ValidationThe companies’ validation system had consistently failed to identify and controls the risks associated with process and equipment changes. This issue had been raised in previous MHRA inspections and the company had yet to fully address it.©INSPECTION FINDINGS –Additional categories from Third Countries1.Supplier Contractor Audit2.Line Clearance, segregation and potential for mix-up3.Design and maintenance of premises4.Handling and control of packaging components©80INSPECTION FINDINGS –Additional categories from Third Countries1 -Supplier Contractor AuditSupplier Assurance was deficient in that:There was no process for periodic ongoing evaluation of suppliers. Supplier de-qualification was defined in QA004 however the latter in essence was based on rejections and out of specification (OOS) results and was purely reactive.The applicable procedure (QA004) was deficient in that Primary Printed Packing materials and brokers were not defined and as such the suppliers were not assessed or audited.Audit of materials including Active Pharmaceutical Ingredients (API) was not required if the manufacturer was not local i.e. within India.There was no audit period defined for critical ExcipientsThe evaluation and approval procedure did not define the actions to be taken if critical observations were obtained at a supplier audit.©INSPECTION FINDINGS –Additional categories from Third Countries1 -Supplier Contractor AuditThe de-qualification procedure was not linked to the deviation quality system as such it was not clear if the implications for batches in the manufacturing stream and supply chain would be assessed. In addition this was purely focussed on API and not all materials.Audit reports performed were to a predefined general generic checklist, there was no data to support the audit except ticks on the checklist. There was no information relating to date of audit, auditor knowledge and experience, the standard against which the supplier was assessed, what areas were audited, observations made and hence how the impact assessment on the material in question was derived. All audits performed had been done in this manner and as such no audits were available for inspection.The audit plan was not generated in line with QA. Note in the inspectors opinion the plan is unrealistic and unachievable as 706 were required in the year.©81INSPECTION FINDINGS –Additional categories from Third Countries1 -Supplier Contractor AuditWritten procedure XXXX “Pre-Buying Control” did not require that all potential new API vendors must be audited although this was required by the associated report form. The abovementioned procedure did not state the number of vendor samples to be obtained for laboratory evaluation.The questionnaire sent to North-East General for supply of Ascorbic Acid did not include questions on the usage of the plant e.g. dedicated or multi-purpose or if sensitising materials were made or handled in the same plant. The audit report for the above supplier did not classify the findings made during the audit as required by the abovementioned procedure. The report for the audit of ABC for supply of………… was insufficiently detailed to provide assurance that a sufficiently thorough audit had been performed. ©INSPECTION FINDINGS –Additional categories from Third Countries1 -Supplier Contractor AuditABC was also approved for supply of ………. however no documentation was available in support of this decision. The vendor questionnaire originally issued to the ABC site was not re-issued to the vendor on relocation of production to ……… There were no BSE/TSE statements to cover supply of …………. from North-East General or for supply of from ABC. Whereas SOP xxx required API manufacturers to be re-audited every three years, there was no evidence that asdf (formerly ) had been re-audited since original approval in March 2008. The vendor audit schedule for 2012 listed 12 planned audits however none of these were for API manufacturers (e.g. dfg). There was no system for de-selection of poorly-performing suppliers from the approved supplier list. ABC was not included as an approved supplier of ……. in the UK dossier for ………©82INSPECTION FINDINGS –Additional categories from Third Countries1 -Supplier Contractor AuditSupplier AuditsNot all suppliers had been audited in line with the stated annual frequency.The Contract laboratory, CSRA had not been audited, nor was it detailed on the audit schedule.The audit report for Phoenix Printing was reviewed. The inspectors commented that on review significant issues were identified, all of which were classified as minor. Issues identified related to the control and management of artwork. The company had experienced incorrect artwork being supplied by the vendor.The Audit procedure was not approved. The draft document was reviewed and found lacking in a number of areas, for example (but not limited to):Audit frequency for suppliers.Definitions for critical, major and minor deficiency classification.The actions to be taken if critical observations are identified during a supplier audit.There was no checklist for auditing.Auditor competency, skills or knowledge was not defined.©INSPECTION FINDINGS –Additional categories from Third Countries2 -Line clearance, segregation and potential for mix-upLine clearance procedures observed within secondary packaging were not fit for purpose in that they did not provide sufficient detail as to what was required.The carton coding line xxxxx whilst signed off as clean and clear in the appropriate log was observed to have cartons and labels relating to the last print job online.Batch specific data was not removed from the carton coding machines as required bythe procedure.The inspectors observed leaflets which had been on the floor being returned to thepacking line and not being rejected during the hand packing of xxxx (Blister Line Z Hand packing line Y.The appropriate procedure for the encapsulation machine line clearance was not available to production staff who were required to perform the procedureUnused cartons and leaflets were permitted to be returned to the warehouse with associated issues of potential mix-up.Line clearance of the Aerosol line following batch Lot code ……. is deficient in that:The hopper on the aerosol line contained an actuator overcap combo despite being signed as cleared from the line centre.The embossing block from the cartonner had been signed as removed from the Line Center (as per batch record and SOP –……) but it was present (in tact) resting on the cartonner.©83INSPECTION FINDINGS –Additional categories from Third Countries2 -Line clearance, segregation and potential for mix-upLine clearance of the Aerosol line following batch Lot code ……. is deficient in that:The hopper on the aerosol line contained an actuator overcap combo despite being signed as cleared from the line centre.The embossing block from the cartonner had been signed as removed from the Line Center (as per batch record and SOP –……) but it was present (in tact) resting on the cartonner.A total of 26 ‘rogue’ tablets and capsules of 5 different types were present just below the conveyor belt at the bottle filling station on the line used for asdf packing. The whole area including the specific area around the conveyer belt had been authorised as being cleaned and cleared. Note asdf was not being packed at the time.Line Clearance procedure (SOP …) is lacking. The document is too high level. It does not detail specific checks to be performed, there is no detailed checklist, and there is no requirement to remove variable data stereos. In addition the procedure does not reflect current changeover types. ©INSPECTION FINDINGS –Additional categories from Third Countries3 –Design and maintenance of premisesThe common air handling system utilising recirculation and make-up air drawn from the open roof space is insufficiently secure for a facility where there is no dedicated area for the segregation of Class 1 product.There is no differential pressure between area X used for prostaglandins and adjoining room Y used for non-prostaglandins.No local extract is used when adding solids to the re-crystallisation vessel in room….The fabric of the facility was deficient as shown by:-The epoxy floor in parts of the goods-in area of the raw material warehouse was damaged exposing the metal and concrete below. This was of particular concern as the area indicated (around the vacuuming robot) was not being used for routine deliveries yet. Similar issues were noted in the xxxx wash room.The base of the wash room storage cabinet adjacent to the raw material warehouse was a sealed unit with holes on the top, meaning that water / debris could enter but could not be removed and cleaned.The facility still had an overuse of silicone sealant that did not afford easy to clean surfaces.The wash room in area ASD contained:-A potable water tap that was leaking. Pneumatic tubing used for blow drying equipment that was old, discoloured and contained traces of paint. A door to the manufacturing area that housed a double glazed window in which water had leaked and mould had started to grow. The issue had not been reported to maintenance.There was a strong solvent odour in the label store as a result of the racking being painted in the label location; no consideration had been given to the solvent contamination of the labels.©84INSPECTION FINDINGS –Additional categories from Third Countries3 –Design and maintenance of premisesThe …………. block loading bay contained an exterior insectecutor for fly control. No consideration had been made in respect of the device attracting flying insects towards this transfer area.The facility was showing signs of wear and tear. There was no formal process to ensure facility inspections were performed and issues documented.There was no approved product contact lubricants list on site.The control of the water system sanitisations was not adequately controlled in that the duration of the sanitisation conditions were not recorded.Facilities for changing clothes were not easily accessible and there was a lack of segregation withrespect to controlled area gowning. The company stated that they had plans to improve such activities.Changes made to remove activities from the warehouse i.e. the relocation of equipment and thesampling to the ……. filling room had not been fully assessed at the time of the inspection inparticular adequate documentation of line clearance and the control of activities.The layout of the packaging lines did not provide adequate segregation from adjacent activities. Packaging materials for the blister line had to be transported across the bottle line. In addition, at the end of packaging, shippers of finished product from either line had to be passed individually through the pass box compromising line integrity and introducing additional risks of mix up.©INSPECTION FINDINGS –Additional categories from Third Countries3 –Design and maintenance of premisesFacility design and operation at ……. is deficient in the following respects:Throughout the compounding areas there are open drains (including trough drains) and associated with these are rubber mats –a number of which were noted to be unclean.The drain in room ……. was not covered.The procedure relating to sanitization of floor drains (SOP ) contains out of date drawingsie. Attachment 1 (Main compounding) does not reflect the trench drain in the refurbished “new”dissolver area.The janitor room within production suite …. was unclean with evidence of pests, an unclean extract panel and obsolete cleaning equipment within the room.The doors and seals in Compounding suite …. show signs of age (seals are degrading) and poor initial design.Vessel … was identified outside building …. It was unclear as to why the vessel was outside and it had not been controlled in an appropriate manner. No works order relating the issue had been raised.The design of the facility did not minimise the risk of cross contamination in the following regards:The oven room was downstream of, and could only be accessed through a compression room. There were no procedural controls to prevent the oven room being used at the same time as the compression room in order to minimise the risk of mix up and cross-contamination of products.The processing rooms had ceiling tiles that were not sealed in place permitting contamination from the ceiling void to enter the processing area.©85INSPECTION FINDINGS –Additional categories from Third Countries4 -Handling and control of packaging componentsThe control of Packaging materials and labels is deficient in the following:Packaging materials are routinely removed from the supplier’s packaging and stored individually on racking in the store. The supplier details including batch number is lost compromising traceability of material. This applies to PE and the PE/Al bag.The Polyethylene bags used as contact material have not been classified as being ‘A’ category material and as such there has been no audit of the supplier.The Certificate of analysis presented as an example of supplier’s external testing was illegible in every way including the inability to identify a lot number for traceability.No TSE certification is available for the bags.Master Labels have no unique identification number or version control.Two Master labels were observed being stored on the same computer.The Master label can be accessed by the operator and details changed without authorisation.There is no log for the printer to record sequential usage, clearance and clean.There was lack of awareness of the actual site of manufacture of both PE bags and fibre drums although both were stated on the regulatory submission. (Subsequent investigation during the inspection confirmed that the items were in fact being supplied correctly indicating a weakness in procedures to ensure control.)©INSPECTION FINDINGS –Additional categories from Third Countries4 -Handling and control of packaging componentsThe line clearance within the blister packaging area was deficient as evidenced by waste being within the bin of a room advised to be clean, clear and checked.There was a lack of suitable contemporaneous completion of seal integrity testing with records to record the test results notbeing available within the area where the test is performed.There was a lack of suitable instruction in the checking of packaging for conformity at the start of the batch. Components were routinely checked onto line on the basis of the goods delivered being correct rather then against a packagingmaster.In the absence of automated on-line verification equipment, there was insufficient confirmatory checks performed with respect tothe packaging in use.There was a lack of evidence available within the batch packaging records in relation to the setup of the on-line check weigh balancePacks removed from the packaging line and placed into the unlabelled reject trays were noted to be placed back on line.There was a lack of control over the issue of numbered challenge test forms with no routine reconciliation of their usage.It was not clear from what document the expiry date format and details were obtained and verified.The control of both printed components and variable data was found to be deficient the production area as evidenced by: There is no electronic verification of printed components for hand packing operations but there is for automated systems. There is no requirement to ensure variable data is removed from lines as part of the line clearance (purge) operations.One of the packaging lines was found to have inserts online, yet the line log stated the line as ‘clear’. Investigations found the line schedule had changed yet the material had been left there for a number of days without being removed.©86INSPECTION FINDINGS –Additional categories from Third Countries4 -Handling and control of packaging componentsPackaging materials control was deficient as there was no consistent use of electronic verification or an equivalent system to ensure the correctness of printed packaging components as part of the packaging operations. The control of printed packaging materials was inadequate as found in the following;There were discrepancies between the bin card stock, actual quantities and the label for the printed carton examined. The bin card stated 161, label quantity was 200 (24/04/11) and the weighed amount was 169. There was no procedure to deal with such discrepancies and subsequent stock adjustments.The area used to dispense printed packaging components was not subject to a documented area clearance.There was an observed loose leaflet in one of the drawers reviewed. Although it was accepted that this leaflet was common to other bagged items in the draw, risks associated with such practice had not been adequately assessed.Staff on the packaging line were observed to retrieve a component from the floor and place it back on the table with other components.The reading of the EAN code on the carton does not give assurance that the correct artwork version is being used. This failure mode had not been considered by the company.There were differences in the IPQA and Production procedure for barcode (EAN) set up for reading carton code.Printed packaging reconciliation on the batch packaging record appears to be on the basis of back calculation which negates the value of such an exercise. For the three batches reviewed all leaflet reconciliation was 100% which is unlikely given the method ofdispensing and calculation of unused items.Previous component labels on the empty cores used on the label counting machine had not been removed.There was no defined link between components on the approved vendor list and the Annex resulting in a lack of clarity regarding which manufacturers were approved for any given component.©87