s trategic a pproach t o m edicines s afety a role for e nd p roduct t esting mark oldcorne wrexham...
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STRATEGIC APPROACH TO MEDICINES SAFETY
A ROLE FOR END PRODUCT TESTING
Mark Oldcorne
Wrexham Maelor Hospital
North Wales NHS Trust
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?
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
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
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.
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
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.
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
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
BP 2009 MONOGRAPH STRUCTUREUNLICENSED MEDICINES
Identical to Licensed Product Monographs
Description Identification Related Substances Assay Endotoxins Sterility Testing Particulate Dissolution
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
STRATEGIES FOR MONITORING THE QUALITY OF PRODUCTS 2
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
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
END PRODUCT METHODOLOGYTRADITIONAL 2
Endotoxins LAL test Rabbits - pyrexia
Sterility Sterility test
Particles Sub-micron laser particle counting
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???
END PRODUCT METHODOLOGY TRIGGER\RAPID METHODS - MICROBIOLOGICAL
Rapid Microbiological Environmental Methods
Rapid Sterility Testing
Endotoxin testing gross G-ve contamination
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
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
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
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)
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
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+??
“MANCHESTER INCIDENT” 1994
Inprocess checks - NO FPT – Sterility test not feasible Trigger parameters - MAYBE
Rapid ‘sterility test’ Endotoxins – depends on organism
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
CONCLUSIONS
Yes there is a role for FPT
BUT
As an integrated part of QA systems