Unlicensed Medicinal Products - Under Scrutiny

1. Quality Control North West Education and Training Services Unlicensed Medicinal Products - Under Scrutiny Mark Jackson Deputy Director QCNW

2. The Challenges • How can we guarantee quality? • What expertise is there to manage unlicensed medicines? • Is there any way to reduce costs? Quality Control North West Education and Training Services

3. Under Scrutiny - Cost • Press and Government scrutiny on “specials” • “inappropriate use of specials” • Primary focus on non sterile products • Inappropriate prices e.g. £13 - £812 PACT data for omeprazole. • Brokering services – cost driven, not quality • Are all specials the same? • What are the risks associated with variable quality products? • Should a premium be paid on quality? Quality Control North West Education and Training Services

4. What can go wrong – patient harm? • Phosphate Incident – Heartlands Hospital • “Neglect and failure at Birmingham hospital led to woman's death, inquest rules” Birmingham Post - Dec 23 2009 Quality Control North West Education and Training Services

5. Phosphate Incident – Heartlands Hospital • Rosemary McFarlane • 64yrs grandmother of 5 • Routine Bronchoscopy Procedure • Phosphate buffer saline passed into lungs during procedure • Given 10 times overdose • Severe burning in chest • Immediately treated, but condition deteriorated • Died 10 days later of multiple organ failure Quality Control North West Education and Training Services

6. Investigation • Current product out of stock, pharmacy Technician asked to source alternative supply • Two lines available as special: 1X, 10X • 10X line ordered and received • No quality checks carried out in pharmacy • Product contained no information regarding the concentration • Dr and Nurse both assumed the new solution was the same strength as the previous • 10x assumed to be part of labelling code Quality Control North West Education and Training Services

7. Inquest - Verdict • “ Failures by the pharmacy team as a group and the doctor who conducted the procedure are gross failures and they have sufficient cause of connection to the death” • “We trust you to inject things into us and the thought that some people in the NHS do not check what they are giving to us is appalling” Quality Control North West Education and Training Services

8. Learning Points Inadequate systems in place • Unlicensed medicine policy? • Purchasing for safety? • Quarantine on receipt? • QA Assessment & formal release? • Change control? Failure to adequately check the product: • When ordering from supplier • On receipt into pharmacy • When sent to Clinical area • Prior to administration – Nurse & Doctor Assumptions – devolved responsibility Quality Control North West Education and Training Services

9. What can go wrong - sourcing Pitfalls • Bespoke specials • Clarify status when ordering • “Special” or “Section 10” release by pharmacist • What are you paying for? • Someone to make the product for you or…. • A fully validated formulation, consistently prepared to the same standard with documented evidence. Quality Control North West Education and Training Services

10. Demeclocycline HCl Oral Suspension 300mg in 5ml • “We didn’t think we needed to send it to QC as it was sourced from a reputable specials manufacturer” • Manufacturing method –open capsules and suspend • No data - published or unpublished to support the formula • No analysis carried out • 90 day shelf life assigned • Prepared under a section 10 exemption, not under licence. • £500 • Decision – Rejected! Quality Control North West Education and Training Services

11. Learning Points • Cannot assume you are getting a special even if supplier holds a manufacturing licence • Cannot assume supplier has validated the formula and shelf life • Quality is not assured • Need QC expertise to assess evidence • Responsibility and liability lies with purchaser! Quality Control North West Education and Training Services

12. What can go wrong - variable Formulations: Captopril • Warning on child heart drug doses - BBC News 27th March 2007 • “Children with congenital heart failure may be at risk from discrepancies in doses of a heart drug designed for adults, researchers have warned” • “The amount and formulation of captopril vary widely across the UK when it is given to children, a study shows - and may mean the amount given is incorrect”. Quality Control North West Education and Training Services

13. Captopril Study • Study, by Glenfield Hospital in Leicester • Based on survey returns from 13 children's specialist heart centres and 13 large referring hospitals. • Four pharmacies dispensed captopril tablets for crushing and dissolving in water. • The other 22 used nine different liquid formulations • Three came from specials manufacturers, one from an NHS manufacturing unit, four were prepared "in-house" and one was imported from Australia. Quality Control North West Education and Training Services

14. Captopril Study • Three hospitals recommended different formulations for use after discharge from those that had been used while the child was an inpatient. • Only three specialist centres used the same liquid formulations as their referring hospitals; 10 others used completely different formulations. • The stated shelf life of the formulations varied from a couple of weeks to several months. • But with one exception, the time limit was not confirmed by hard data. Quality Control North West Education and Training Services

15. Captopril Study • “Failure to use a standard formulation could mean that some children were not getting effective medication - and that their health could be compromised as a result. • In the short term, pharmacists working in hospitals and the community need to ensure that children are given the same formulation of Captopril wherever it is dispensed. • "The long term solution is for the pharmaceutical industry and regulatory authorities to work together to develop an optimum formulation of liquid Captopril." Quality Control North West Education and Training Services

16. Learning points • Variations in formulations and method of preparation affects product quality and patient care • Lack of consistency in treatment decision making process • Standard approach to risk assessment required considering: • Bioequivalence • Patient group • Drug toxicity (TI) • Common procurement strategy needed - quality driven • Consider patient journey – seamless care • Standard formulation required with supporting stability data • Wide availability Quality Control North West Education and Training Services

17. How can we guarantee quality? • Develop hierarchy for procurement based on potential risk. • Identify evidence required for quality assessment before placing order. • System for assessing and approving suppliers (manufacturers and importers). • Procure, or collaborate with manufacturers to develop, standard high quality formulations with supportive stability data • Team approach - Involve key personnel with required expertise (Procurement, QC, Clinical pharmacist, DTC, Clinician). And then manage risks by • Targeting high risk products and vulnerable patient groups • Monitoring therapy closely and reporting issues Quality Control North West Education and Training Services

18. Purchasing strategy – hierarchy of risk • Use of categories • Target quality assessment process to category • Identify likely risks in advance • Identify evidence required at point of ordering • Improved turnaround times Quality Control North West Education and Training Services

19. Hierarchy of Risk (RPS practice guidance on sourcing specials) Preferred Choice Lowest net risk UK Licensed Medicines Off label use of a UK Licensed Medicine Import – licensed in country of origin UK manufactured “special” made in MHRA licensed facilities Crushing UK Licensed tablets or opening capsules Extemporaneously dispensed medicine Import not licensed in country of origin Non UK made ULM or food supplement Last Choice Highest net risk Quality Control North West Education and Training Services

20. Progression of Risk (Beaney 2006) SterileProducts Preparation on wards Aseptic preparation in pharmacy Preparation in licensed specials unit) • licensed product Low Scale High Relative Clinical Risk Low High Non SterileProducts Preparation in licensed specials unit) Extemporaneous preparation in pharmacy • licensed product Preparation on wards after Alison Beaney

21. Quality Assessment – Evidence required Quality Control North West Education and Training Services

22. Problems • Reactive approach • Expertise – formulation, stability, manufacturing, MEPA, clinical. • Inefficient, labour intensive • Often limited availability of data. • Intellectual property issues • Variable quality of specials • Approval not guaranteed - wasted time and effort if of poor quality • Delays to treatment Quality Control North West Education and Training Services

23. Variable Quality - Specials • Are all specials the same? • Is it a level playing field? • Quality – formulation and method of manufacture • Presentation • Ready to use • Can we truly purchase by risk category alone? • Essential to have QA expertise when evaluating and comparing unlicensed medicines Quality Control North West Education and Training Services

24. Preparation in licensed specials units – Sterile products • Bespoke aseptic preparation under a licence • Manipulation of licensed starting materials • Extended shelf life • i.e. replacement service • Release against GMP compliance Or • Batch manufacture from API, with terminal sterilisation stage. • Release against analysis and sterilisation assurance. Quality Control North West Education and Training Services

25. Preparation in licensed specials units – Non sterile products • Bespoke patient specific extemporaneous preparation under licence. Oral liquid prepared by crushing tablets and suspending/dissolving in vehicle. Or • Formulated and validated batch manufacture with robust supporting stability data and biostudy • Release against analysis Quality Control North West Education and Training Services

26. Progression of Risk (Beaney 2006) SterileProducts Preparation on wards Aseptic preparation in pharmacy Preparation in licensed specials unit) • licensed product Low Scale High Relative Clinical Risk Low High Non SterileProducts Preparation in licensed specials unit) Extemporaneous preparation in pharmacy • licensed product Preparation on wards after Alison Beaney

27. Formulation development & validation • Active ingredient – full compliance with PhEur • Desk top research & drug behaviour studies • Formulation studies • Forced degradation of actives • Assay development • Establish excipients e.g. buffers/preservatives • Stress testing of formulation • Accelerated and real time stability studies • Specification development • Toxicology assessment of degradants • Biostudy/bioequivalance • Costs: Quality comes at a premium! Quality Control North West Education and Training Services

28. Barriers – Intellectual Property • Cost of product development • Stability studies • Manufacturer need to safeguard IP • Loss of income if subsequently licensed by other company • Unwillingness to provide documentation • Purchaser requires evidence to evaluate product quality • Reassurance or assurance • Confidentiality agreements • Are we willing to guarantee we will buy it if developed? • Partnership agreements? Quality Control North West Education and Training Services

29. Level playing field : Challenge to Industry • What is your minimum standard for developing a special? • How does your approach differ from developing a licensed product? • Should it be different during the formulation development stage? • Why not market your approach? Threats by cost pressures and unscrupulous brokers. • We want to reduce costs not quality. • Be proactive – help us define a minimum standard for quality Quality Control North West Education and Training Services

30. Cost saving options • Rationalisation – economy of scale • One–stop shop? • Brokering? Must be quality driven! • Quality and price (QIPP) • Common procurement and quality assessment support – do it once! • Tenders • Services • Products Quality Control North West Education and Training Services

31. Tendering - Drivers • Capacity – NPSA initiatives • Cost • Lack of local expertise • Equipment/Facilities • Patient safety – Consistent high quality therapy? • Replacement service or to develop better product? • Clear remit helps develop the tender specification Quality Control North West Education and Training Services

32. Tenders – Yorkshire Model • 2 Tenders – compounded specials & Imports • Primary driver – NPSA 20 • Capacity issues locally & products unavailable • Proactive approach • Supplier audit and approval • Tender specification - developed by key stakeholders (procurement, end users & QA) • QA involvement – specification and award criteria • Quality & cost weighted 50/50 for adjudication • Quality element split between supplier and product criteria Quality Control North West Education and Training Services

33. Tender Specification - Overview Evidence required: • Regulatory Compliance • Quality Management • Formulation & Component Materials • Manufacturing Process • Packaging & Labelling • Stability Data • Release Criteria Quality Control North West Education and Training Services

34. Assessment: Regulatory Compliance • Review appropriate sections of the manufacturing licence: • Current • Appropriate to category of product being tendered • Review of MHRA website to ensure licence not recently suspended. • Review most recent audit report by Regional QA Specialist • Evidence of closure of deficiencies Quality Control North West Education and Training Services

35. Assessment: Quality Management • Robust QMS system in place • Management structure • Change control • Document control • Deviation management • Self inspection • Supplier audit • Staff training Quality Control North West Education and Training Services

36. Assessment: Component Materials • Licensed in UK • Pharmacopoeial Grade • QC Tested & Approved against Specification • C of A • TSE free • List of excipients – appropriate for clinical specialty e.g. Paediatrics • CE Mark Quality Control North West Education and Training Services

37. Assessment: Manufacturing Process • Validated Processes, Equipment & Facility • GMP compliance • Consistency of manufacturing method • Individual doses (e.g. aseptic) or from bulk • Identify differences – e.g terminal sterilization vs aseptic • Critical in-process & end of process checks/tests • Environmental conditions – appropriate grade for type of product (aseptic, terminal sterilization etc). • Microbiological Monitoring of process & environment appropriate to GMP requirements Quality Control North West Education and Training Services

38. Assessment: Packaging & Labeling • Description of primary & secondary packaging • Materials used e.g. PVC, Polyolefin etc • Latex free • Sample artwork • Storage conditions • Clarity of labeling – Design for safety: NPSA/MHRA Guidance • MEPA anaylsis • Bar Code Quality Control North West Education and Training Services

39. Assessment: Formula & stability Data • Validated Formulation, shelf life and storage conditions • Stability references • Assay Method; accelerated/real time; relevance to presentation of product (conc, diluent, container etc); conditions – RH, Temp, light etc. • Assay Validation e.g. stability indicating, compliance with ICH, NHSPQA Committee guidance Quality Control North West Education and Training Services

40. Assessment: Formula & stability Data • Pathway & Extent of degradation e.g. T95, significant degradation products (toxic), pH changes • End of shelf life validation • Microbiological integrity data e.g. syringes • Particulates – Visible / Sub visible • Compatibility – containers/giving sets • Closure – integrity/extractables Quality Control North West Education and Training Services

41. Assessment: Release Criteria • Analysis (reference limits, e.g. BP) • Conformity checks against specification – Product; process; equipment/facility; environment • Associated product approval checks – prior to release & retrospective tests / trend analysis • Sterility assurance e.g. autoclave, micro monitoring etc. • On-going validation programme e.g. sterility testing, chemical testing etc. Quality Control North West Education and Training Services

42. Learning points • Tender process assists regional product rationalisation & economies of scale • Short term options: service capacity • Long term: Product development • QA specialist expertise and input essential in tender development and adjudication • Identify award criteria and weightings with the specification • Supplier assessment – auditing more efficient than reviewing evidence from tender returns. Quality Control North West Education and Training Services

43. Learning points • Common tender return format saves time • Product assessment – compare like with like! • Develop product specifications to ensure consistency • Imports – main emphasis on supplier assessment • Specials – equal emphasis (product & supplier • Award across range to minimise errors Quality Control North West Education and Training Services

44. Learning Points • Responsibility & liability for product quality remains with purchaser – evidence required to provided to all recipient Trusts • Barriers: Intellectual property & confidentiality • Manufacturers require commitment from NHS to buy products before development • Change control : suppliers must inform end users of any proposed change that impacts on the contracted product Quality Control North West Education and Training Services

45. Summary • Patient safety before cost • Working collaboratively, procurement & QA can both raise the quality of unlicensed medicines and achieve cost savings. • Build quality and associated costs into purchasing stage • Purchase products “closest” to licence status • Need to work closer with Industry to set a minimum standard for quality of specials – level playing field & improved patient safety. • Consider partnership arrangements to develop products and standardise formulations Quality Control North West Education and Training Services