V Final report. Final Report GMP inspection Hospira Enterprises B.V. Almere January 15, Utrecht, 2015

Transcription

1 Final report Final Report GMP inspection Hospira Enterprises B.. Almere January 15, 2015 Utrecht, 2015

2 Final report Report Reference no.: ame of product(s) and pharmaceutical form(s): GR Inspected site(s): Hospira Enterprises B.. Randstad B Almere EudraGMP reference number: Site location identifier (DUS number/gps coordinates): 2. Activities carried out: Human eterinary IMP GDP activities: Manufacture of finished products Sterile on-sterile Biologicals Sterilisation of excipient, active substance or medicinal product Primary packaging Secondary packaging Quality control testing Importing Batch certification Storage and distribution Manufacture of active substance Other: Procurement Holding Supply Export Broker Other activities: 3. Inspection date(s): Inspector(s): Expert(s): ( ) ame(s) of expert/assessor (if applicable): 5. References: 4149F and 4469G ame(s) of the Competent Authority(ies): 6. Date(s) of previous inspection: ame(s) of inspector(s) involved in previous inspection: (...) 7. Introduction: Hospira Enterprises B.. (hereafter HEB) is part of the Hospira group. The company is tasked with managing the supply chain for the Europe, Middle East and Africa regions. The warehouse function for HEB is outsourced to (...) at Roermond. In the GMP area of the (...) warehouse site occasionally repacking activities take place to rework Finished Product for HEB in the etherlands. Repacked products are re-released by one of the HEB QPs. In other European countries (see paragraph 11.8) also repacking takes place by CMO s to secondary pack unlabeled product to finished product. For these reasons HEB holds a manufacturing authorization. At the same address there is (...). This company holds a WDA under 4468G. Since this authorisation is never used it was decided that the company will ask Farmatec to delete the license. Major changes since the previous inspection: the company has grown, resulting in a greater number of batches being released.

3 Final report International cooperation: The Competent Authority of the country where the inspection took place was/was not informed and took/did not take part in the inspection. ot applicable 8. Brief report of the inspection activities undertaken: GMP GDP GcLP Defect otification Routine Requested by: Product specific: Legal references: Geneesmiddelenwet (8 februari 2007, Stb. 93), Regeling Geneesmiddelenwet (25 juni 2007, nr. GMT/MG , Stcrt. 123). Wet Dieren (19 mei 2011), Besluit Diergeneesmiddelen (2 november 2012), Regeling diergeneesmiddelen (12 december 2012). EU Guidelines to Good Manufacturing Practice for medicinal products for human and veterinary use (EUDRALEX olume 4). EU Guidelines on Good Distribution Practice of medicinal products for human use 2013/C 343/01 (amended version ovember 2013) Other: 9. Inspected activities/subjects: X X r. Activity/subject r. Activity/subject 1 Quality management 9 Outsourced activities Personnel Premises and equipment Documentation Production Quality control Qualification of suppliers and customers Complaints Returns Falsifications Recalls Self inspections Transportation Receipt, storage, order picking, order preparation, despatch, destruction = inspected X = not inspected = ot applicable 9. Inspected area(s) and main steps/history of the inspection: Quality system, batch release process Activities not inspected:

4 Final report 10. Personnel met during the inspection: (...) Deputy Quality Director (...) Head Integrated Business Planning (...) Operations Coordinator (...) Quality Manager Devices EMEA (...) Regional Lead endor Quality Assurance, EMEA (...) Biosimilars Supply Chain Manager (...) Quality Manager Batch Release (...) HR Advisor (...) Scribe (...) Compliance Manager EMEA (...) Quality Supply Chain Manager and EUAR (...) EMEA Qualified Person (...) EMEA Quality Director and Qualified Person (...) Supply Chain Manager EMEA, Generics (...) Director, HEB/HHB (...) EMEA Quality Operations Manager, Qualified Person (...) CS and Logistics Manager (...) Packing Operations Manager 11. Inspectors findings and observations relevant to the inspection; and deficiencies: 11.0 Major deficiencies during last inspection There were no major deficiencies in the last inspection Pharmaceutical Quality System The 2013 PQR was seen for ivestim. Over the year (...) batches of packaged product were released by the HEB QP. An incident was reported (#154714) whereby for transportation of this 2-8 o C product an unqualified transporter was selected by (...). As a consequence during transportation to Finland a temperature excursion occurred. On the investigation no comments were made. It was suggested to include information in the PQR on falsifications, if only to record that no signals have been received Personnel 11.3 Premises and Equipment 11.4 Documentation The documentation system is all electronic and accessible through SharePoint. o comments were made on the setup of document Production There is no actual production at HEB; activities are limited to release of batches that were packaged in country specific packs for smaller EU markets. For this many QPs have been added over time to the manufacturing authorisation. It was discussed that QPs (...)can be removed. QP (...) is working at the site of Hospira UK Ltd. while QPs (...) are physically working from the Zagreb plant. At these sites releasing is done under responsibility of HEB. The reason for this is that HEB is mentioned as release site in the MA dossier and therefore also on the packaging materials. HEB will be introducing an electronic system for tracking batch release processes shortly. An overview of batches that were released in 2014 can be seen from the QP Disposition Registers per QP. QPs are not always on site at the warehouse to physically inspect the goods and take samples. Compared to the previous inspection the number of products has increased. The first biosimilar product that was launched end 2013 into the EU market has been released by HEB until recently. A transfer is in progress to have this product released in Zagreb. A second product was transferred to Zagreb in April The SOP on Batch Certification SOP-EMEA was seen. On the content of this SOP no comments were made. The review date 02 ovember 2014 was missed. The company had seen this omission,

5 Final report and initiated a CAPA to improve the system of document review. Batch manufacturing records were seen for (...) batches. These all looked fine. There is a backlog in processing batch records leading to delays of several months before batches can come onto the market. The electronic batch release system should speed up the process Quality Control 11.7 GDP activities Storage of products is in a contract warehouse. The RP is (...). A backup RP will be notified to Farmatec Outsourced activities A number of products are being repackaged for smaller EU markets by 3 CMOs in Belgium, Czech Republic and The etherlands under the responsibility of HEB. Because of the small batch sizes this is performed many times a year. HEB will remain the release site for the time being. Quality Technical Agreements were seen for a number of situations. A multi-party Agreement including Hospira Zagreb, Hospira UK, a contract laboratory in Croatia and HEB was compliant with GMP. A second multi-party QTA took three Hospira sites under the term Hospira. Release for the EU was a Hospira responsibility. In a further agreement between HEB and Hospira UK this was specified to be the QPs of Hospira UK. Since in this case the site of release in the MA dossiers was HEB this arrangement was not acceptable. Although some of the HEB products are being produced at a Czech company, there is no QTA in place between the two companies. A QTA was shown between Hospira UK and the Czech company, but this is not acceptable. Between the Belgium CMO and Hospira UK a QTA exists that claims Hospira UK to act on behalf of HEB. Indeed, in a QTA between Hospira UK and HEB, signed on 13 January 2015, it was stated that UK may act on HEB s behalf. A QTA was seen between HEB and the Dutch CMO that does packaging activities. o comments were made Complaints and Product Recall In the investigation of complaints no specific attention is given to the risk of falsification Self Inspection ot inspected Distribution and shipment Questions raised relating to the assessment of a marketing application Other specific issues identified It was discussed that a backup RP for WDA 4469G will be notified to Farmatec. This person has been trained for GDP in the UK. Exportation needs to be added to WDA 4469G. QPs that are not actually involved in the release of products under HEB responsibility will be removed from the license 4149F. (...) still holds a licence under 4468G that has never been used. The company will request this license to be cancelled. It was suggested to include information in the PQR on falsifications, if only to record that no signals have been received.

6 Final report Site Master File A Site Master File was not available. A Site Master File, version 5, dated 07 January 2015 was available. The inspector finds this SMF acceptable. 12. Miscellaneous: ot applicable Samples taken Legal issues 13. Distribution of report: IGZ CBG-MEB Company European Medicines Agency 14. Annexes attached: Definition of Significant GMP Deficiencies Definitie van Significante GDP Tekortkomingen (in Dutch) 15. List of deficiencies classified into critical, major and others: 15.1 Critical deficiencies one of the deficiencies is classified as Critical 15.2 Major deficiencies one of the deficiencies is classified as Major 15.3 Other deficiencies In the Quality Technical Agreement between HEB and Hospira UK the release of products for which HEB is registered as the only site of QP certification can be done by Hospira UK. (EU-GMP Ch1 Principle; 7.2; Annex 16, 2.2.) Currently there is no valid Quality Technical Agreement with the Czech contract manufacturer. (EU-GMP 7.1) 15.4 Legal issues 15.5 Comments 16. Inspectors comments on the manufacturer s response to the inspection findings: On 5 March 2015 HEB submitted a corrective action plan for both Other deficiencies. The inspector finds this plan acceptable. Inspectors comments on the questions/issues raised in the assessment report: Recommendations for further actions:

7 Final report 17. Summary and conclusions: Based on the findings of this inspection the company Hospira Enterprises B.. at Almere is in general compliance with the requirements of Directive(s) 2003/94/EC and/or 91/412/EEC. The company is acceptable for the products in question. will only be in general compliance with the requirements of Directive(s) 2003/94/EC and/or 91/412/EEC after a satisfactory action plan is received for the correction of the Major deficiencies. Until then the company is not acceptable for the products in question. is not in general compliance with the requirements of Directive(s) 2003/94/EC and/or 91/412/EEC. The company is not acceptable for the products in question. Signature: Date: ame: (...), inspector Organisation: IGZ

8 Final report Definition of Significant Deficiencies 1 Critical Deficiency: A deficiency which has produced, or leads to a significant risk of producing either a product which is harmful to the human or veterinary patient or a product which could result in a harmful residue in a food producing animal. 2 Major Deficiency: A non-critical deficiency: which has produced or may produce a product, which does not comply with its marketing authorisation; or which indicates a major deviation from EU Good Manufacturing Practice; or (within EU) which indicates a major deviation from the terms of the manufacturing authorisation; or which indicates a failure to carry out satisfactory procedures for release of batches or (within EU) a failure of the Qualified Person to fulfil his legal duties; or a combination of several other deficiencies, none of which on their own may be major, but which may together represent a major deficiency and should be explained and reported as such; 3. Other Deficiency: A deficiency, which cannot be classified as either critical or major, but which indicates a departure from good manufacturing practice. (A deficiency may be other either because it is judged as minor, or because there is insufficient information to classify it as a major or critical).

9 Definitie van Significante GDP Tekortkomingen Final report 1. Kritische Tekortkoming Elke afwijking van het GDP richtsnoer(guideline), die resulteert in een geneesmiddel met een significant risico voor de patiënt en de volksgezondheid. Een combinatie van verschillende belangrijke tekortkomingen die wijzen op een ernstige fout in het systeem. 2. Belangrijke Tekortkoming Een niet-kritische tekortkoming: - die wijst op een belangrijke afwijking van Goede Distributie Praktijken; - die heeft geresulteerd of mogelijk kan resulteren in een geneesmiddel dat niet voldoet aan de handelsvergunning, in het bijzonder de bewaar- en transportcondities; - die wijst op een belangrijke afwijking van de bepalingen en voorwaarden van de groothandelsvergunning; - een combinatie van verschillende andere tekortkomingen, die op zichzelf niet belangrijk zijn, maar samen een belangrijke tekortkoming vormen. 3. Overige tekortkoming Een tekortkoming die niet als kritisch of belangrijk kan worden geclassificeerd, maar wel wijst op een afwijking van het GDP richtsnoer (Guideline).