Strategic Approach To Medicines Safety A role for End Product Testing

1. Strategic Approach To Medicines SafetyA role for End Product Testing Mark Oldcorne Wrexham Maelor Hospital North Wales NHS Trust

2. Introduction • How do we release products? • ‘Parametric’ release – reliance on parameters that can be observed\collected during preparation • Subjective or objective • Paperwork; signatures; pressures positive and negative; pressure differentials • FMEA – release process • Severity x occurrence x detection • How do we detect errors in products?

3. Orange Guide 2007Licensed Products –MA or Specials • Sole reliance should not be placed on final product testing • Quality assurance not quality control • However still stresses the need to final product testing – prove quality of product before release procedures • Chemical testing • Microbiological testing • Sterility testing

4. Quality Assurance of Aseptic Preparation Services – Unlicensed Products • There should be a planned programme of physical, chemical and microbiological analysis of the finished product as appropriate • Samples obtained • Unused products • Extra specially prepared samples • In process sampling • No sampling after completion of preparation • Validated methods • Chemical • Microbiology - pharmaceutical

5. PIC/S GUIDE TO GOOD PRACTICES FOR THE PREPARATION OF MEDICINAL PRODUCTS IN HEALTHCARE ESTABLISHMENTS • If starting materials are themselves licensed medicinal products then it is not usually necessary to test these before use • If a product is prepared for a single patient, it is assumed that no end product testing will be required • The extent to which physical, chemical and microbiological quality control tests are performed should be defined on the basis of a risk assessment • The risk assessment to define the testing of finished products should especially consider product properties, the use of the product as well as risks associated with its preparation.

6. FMEA – product testing • A. The probability of occurrence of a mistake • Low concentration of a non-dissolved active ingredient • High susceptibility for microbial growth • Longer periods of storage or use • Type of facility where a product is prepared in (risk of contamination in case of non-controlled working environment) • Bad working technique • B. The probability of detection of a possible mistake • Lack of control mechanisms, e.g. monitoring, in process and final controls • C. The consequences of a possible mistake (health risk) • Scale of the operation • Type of product prepared and route of administration, e.g. sterile preparations prepared for intravenous application

7. PIC/S GUIDE TO GOOD PRACTICES FOR THE PREPARATION OF MEDICINAL PRODUCTS IN HEALTHCARE ESTABLISHMENTS • The quality requirements and tests should comply with the applicable Pharmacopoeia • Normally, no quality control testing is performed for extemporaneously prepared products. • Microbiological analysis is not necessary on each batch. • Sampling of the final container after completion of preparation and prior to issue may be a threat to product integrity and is therefore not recommended.

8. Sources of information on final product testing 1 • British Pharmacopeia • Raw\Starting Materials • Final Product Monographs • Made with products conforming to BP raw materials monographs • If product is in BP – should be prepared to the standards mentioned in BP • Morphine Sulphate Injection = Morphine Sulphate Injection BP

9. Sources of information on final product testing 2 • Establishment of Unlicensed Medicines Expert Advisory Group • 2007 • 0 monographs • Concepts for unlicensed • 2008 • 9 monographs • 2009 • 16 monographs? • At least 12 more monographs in advance state

10. BP 2009 Monograph StructureUnlicensed Medicines • Identical to Licensed Product Monographs • Description • Identification • Related Substances • Assay • Endotoxins • Sterility Testing • Particulate • Dissolution

11. Strategies for Monitoring the quality of Products 1 • QA prime importance; QC confirmatory • QC only relevant if samples are representative of total batch • Concept of individual products vs campaigns vs batches

12. Strategies for Monitoring the Quality of Products 2

13. Product requirements • Final Product Testing • Batch production • Samples representative of the whole batch • Long shelf life • 7 days for environmental monitoring • 14 +3 days for sterility test • Specials  • Section 10 products  • Options – introduce approaches such as Dose Banding

14. End product methodologyTraditional 1 • Identity • Chemical tests x 2or more • FT-IR • Related Substances • HPLC • GC • Assay – stability indicating • Titration (aqueous and non-aqueous) • UV\vis spectrometry • HPLC • GC • Ion selective electrodes

15. End product methodologyTraditional 2 • Endotoxins • LAL test • Rabbits - pyrexia • Sterility • Sterility test • Particles • Sub-micron laser particle counting

16. End product methodology Trigger\Rapid methods - Chemical • 7 day expiry limit – limits methodology • Facilities available – centralisation of QC laboratories • Trigger signs • Weights – correct volumes added • Trigger components • TPN • RI • Na+ • K+ • Care – are you compromising batch???

17. End product methodology Trigger\Rapid methods - Microbiological • Rapid Microbiological Environmental Methods • Rapid Sterility Testing • Endotoxin testing • gross G-ve contamination

18. Regulatory Pressure • MHRA • Clear segregation Specials and Section 10 preparation • Clear segregation of • Final product testing and formal release procedures after FPT • Parametric release approach with limited data on release

19. Specials licences • MHRA pressure • QA processes • In-process checking • Final Product Testing • Chemical ID • Assay • Sterility Test • Environmental Monitoring • Subject to formal released procedure – Pharmacist • Final Product testing becoming imperative

20. Section 10 units • Hub and spoke modernisation • Implications – only make products until source from • NHS Specials unit • Industry based Specials Units • Should we \ can we test? • Dependant on • Local QC units or facilties • Trigger\Rapid methods

21. Could we have detected problems with products using product testing • Microbiologically • Chemically • Errors are and can be detected • Aminophylline Injection – neonate • Heparin Dilution • Insulin dilution • Morphine sulphate for neonates • Mode of Failure • Poor mixing (typically 70-130%) • Preparation errors • Calculation errors – 10-1000 fold errors eg microgram – milligram)

22. 2006 “HOSPITAL'S BLUNDER OVER SUGAR THAT KILLED TWIN BABY” • “40% glucose instead of 4% after the wrong number was entered into a mixing machine” • “A system of checks in the pharmacy unit at the hospital in South London, failed to spot the error” • “Jada died a day after the blunder - the third day of her short life” - of heart failure and brain damage • “Solicitor said the hospital failed to act after a similar error in 2005” • The hospital has introduced • Assay for glucose

23. Las Vegas – Zn overdose in TPN“Did This Baby Have to Die?” • order for zinc was written in quantity per volume rather than in quantity per patient weight • Pharmacist recalculated the zinc order to convert it from mcgs/deciliter to mcgs/kg but selected “mg” not “mcg” 1000x overdose • 3 pharmacist checked and missed • 45-48 vials Zn used • Inprocess checks - NO • FPT -YES • Trigger parameters - MAYBE • Volume • Na+, K+, Ca2+??

24. “Manchester Incident” 1994 • Inprocess checks - NO • FPT – Sterility test not feasible • Trigger parameters - MAYBE • Rapid ‘sterility test’ • Endotoxins – depends on organism

25. Conclusions • Pressures to Final Product test • Regulatory • Error reduction How many errors are product related?? • Limitations with Section 10 products • Time • Facilities • Appropriate validated methods • Development of Rapid and Trigger Indicators

26. Conclusions Yes there is a role for FPT BUT As an integrated part of QA systems