1. www.intertek.com1 Safety is a Must not a Choice Andrew Swift1, Christopher Vernall2 and John Dale3 1 Intertek Global, 5th Floor, S J Tower, Abu Dhabi, UAE 2 Intertek Pharmaceutical Services, Saxon Way, Melbourn, Cambridge, UK 3 Intertek MSG, Wilton, Cleveland, UK 2. www.intertek.com2 Recent Statistics (UK) In 2014 the IME reported that there were over 13,500 cases of medical devices failing to work correctly in the UK National Health Service (NHS) alone[1] 309 cases had resulted in patient fatality ~5000 others experienced serious harm Product Safety Testing in medical devices leaves no margin for error If a faulty device doesnt cause fatality ... then retrieving and replacing it may . [1] Institute of Mechanical Engineers, 25th July 2014 3. www.intertek.com3 Reaction . Technology is leading to huge advances in healthcare, but this technology is dependent on the work of biomedical (test) engineers who are inadequately recognized and in short supply.. .. all incidents of faulty medical machinery be reported correctly, as they are reviewed and analyzed for learning and can lead to vital safety information being distributed. 4. www.intertek.com4 There is no Substitute for Experience Laboratories testing & certifying safety of pharmaceuticals, medical & drug dispensing devices are heavily regulated to international standards Notified body status is a privilege subject to regular audit by the relevant regulatory body However, they also need to be: Equipped with the latest analytical capabilities Abreast of the latest technological advances and tomorrows regulation Experienced in all aspects of materials science 5. www.intertek.com5 Laboratory Proficiency This paper will proceed to illustrate the critical importance of laboratory proficiency and experience for: Root cause analysis of the failure of implant medical devices A forensic analysis of post-operative retained extraneous matter Reliable measurement of meter dose inhalers for certified release testing 6. www.intertek.com6 Catastrophic Failure of a Catheter Catastrophic failure of a weld in a catheters delivery system was firstly investigated using Thermal Analysis and Hot Stage Microscopy. Consequently a doping method was deployed for the in production weld and monitored by surface science techniques coupled with FT-IR. The work was carried out to UKAS quality standards and to the satisfaction of the clients Quality System and the FDA. The investigation led to imposition of in-process controls which eliminated all product failures on site and in the field 7. www.intertek.com7 Blooming of a Medical Device Sub-assembly Internal (patient contact) surface blooming of a medical device sub- assembly was investigated using a selection of expert microscopy tools and Nuclear Magnetic Resonance spectroscopy (NMR) The investigation found the root cause to be due to a poorly specified polymer in the supply chain. The impact of exposure to this material upon the patient was evaluated working closely alongside the producers regulatory department. NMR was then used to track raw material quality and optimize the production process to mitigate the issue to within a safe limits 8. www.intertek.com8 During the autopsy following a post-surgery fatality, a fragment of material was found retained the patients heart The excised material was fully investigated using polarized light microscopy The results compared to analysis of a series of surgical instruments used during the operation The data clearly identified the specific faulty instrument Forensic Investigation 9. www.intertek.com9 Drug Delivery by Inhalation Respiratory therapies generated >$35bn in 2013 Asthma & COPD treatments accounted for 75% of sales other diseases treated include Cystic Fibrosis and Diabetes Asthma & Chronic Obstructive Airway Disease (COAD) increasingly common in Middle East 20-25% prevalence rate amongst Saudi patients in 2013[2] Complex dosage form with many formulation and device considerations 3 main product types pMDI, DPI and nebuliser [2] Shrestha Ashis MBBS, MD, Middle East Journal of Family Medicine, Volume 9, Issue 1, January 2011 10. www.intertek.com10 Metered Dose Inhalers Most prescribed inhaled dosage form globally (>200m 2014) Cheaper to develop and manufacture than DPIs High prevalence in Asian and Middle-Eastern markets Portable devices, unlike majority of nebulisers. Limited to lower dose ranges Active delivery, requires some coordination Device handling constraints Widely accepted that even with proper technique on 15% of active drug reaches target site of the lung[3] [3] Muhammad Adnan, Shahid Karim, Shamshir Khan, Naser A. Al-Wabel, Saudi Pharmaceutical Journal, 23 June 2014, Elsevier B.V. 11. www.intertek.com11 Formulation Strategies Formulation consists of API in solution or suspension with propellant (HFA 134a or 227) Majority of MDIs are suspensions - can cause problems with the formulation & product performance Excipients such as ethanol & oleic acid often added to prevent agglomeration, floccing & adhesion to canister walls Suspension products need clear shaking & actuation regime in order to accurately deliver the labelled dose 12. www.intertek.com12 pMDI Formulation 13. www.intertek.com13 Analytical Testing Considerations MDI product performance can be modelled well using in-vitro studies Cascade impactors, dose uniformity sampling apparatus and equipment to model spray pattern and plume geometry are essential Accurate and reliable data depends on excellent product understanding and tightly controlled sampling conditions Shake and fire regime and environmental conditions are particularly pertinent when designing methodology to test MDIs 14. www.intertek.com14 Shake and Fire Regime Single most important consideration when testing suspension MDIs Detailed protocols required during in-vitro testing; eventually feed into PIL Excessive shaking can lead to foaming & inaccurate dosing Time between ceasing of the shake & actuation also critical; sedimentation can occur within 3 seconds for some formulations => inaccurate dosing 15. www.intertek.com15 Environmental Conditions Critical to control temperature and humidity during analytical testing Product should work at the conditions of all target markets the Middle East has very different climatic conditions to Europe, for example Electrostatic charge can also influence product performance, particularly at low humidity By controlling humidity, the effects of electrostatic charge can be minimised 16. www.intertek.com16 Other Analytical Considerations - Patient in-use Full study performed that models performance through - life, as per dosing regime from PIL. Effect of cleaning also investigated. - Effect of valved holding chamber Holding chamber used with patients who struggle to co-ordinate breathing & actuation (e.g infants & the infirm). Dose actuated into chamber, held & then inhaled at patients convenience. Effect on performance must be characterised. 17. www.intertek.com17 Other Analytical Considerations - Extractables & Leachables (E&L) E&L study needs to be performed to model potential compounds that may be extracted or leach from the valve or canister components - Priming and Re-Priming The valve on MDIs requires priming to accurately meter. The number of shots it takes before administering correct dose is measured. The duration that the device remains primed is also modelled. 18. www.intertek.com18 Conclusions Technology advances and global growth in healthcare spending are rapidly increasing the arrival rate of new biomedical devices to markets worldwide When testing healthcare products safety is a must Laboratory proficiency means more that accreditation It requires a well equipped laboratory and, for reliable results, it also requires product and process experience 19. www.intertek.com19 Valued Quality. Delivered. 20. www.intertek.com20 GMP Pharmaceutical lab in Cambridge, UK Accredited by both the US FDA and UK MHRA Particular expertise and experience in analytical testing and development of OINDPs (Orally Inhaled and Nasal Drug Products) Largest CRO in Europe to test these products.