Transcript Strategic Approach To Medicines Safety Can End Product

STRATEGIC APPROACH TO
MEDICINES SAFETY
A ROLE FOR
END PRODUCT TESTING
Mark Oldcorne
Wrexham Maelor Hospital
North Wales NHS Trust
INTRODUCTION
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How do we release products?
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‘Parametric’ release – reliance on parameters that
can be observed\collected during preparation
Subjective or objective
 Paperwork; signatures; pressures positive and negative;
pressure differentials
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FMEA – release process
 Severity x occurrence x detection
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How do we detect errors in products?
ORANGE GUIDE 2007
LICENSED 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
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Chemical testing
 Microbiological testing
 Sterility testing
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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
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Unused products
 Extra specially prepared samples
 In process sampling
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No sampling after completion of preparation
 Validated methods
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Chemical
 Microbiology - pharmaceutical
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PIC/S GUIDE TO GOOD PRACTICES FOR THE
PREPARATION OF MEDICINAL PRODUCTS IN
HEALTHCARE ESTABLISHMENTS
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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
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A. The probability of occurrence of a mistake
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B. The probability of detection of a possible mistake
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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
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
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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.
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SOURCES OF INFORMATION ON
FINAL PRODUCT TESTING 1
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British Pharmacopeia
Raw\Starting Materials
 Final Product Monographs
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Made with products conforming to BP raw
materials monographs
 If product is in BP – should be prepared to the
standards mentioned in BP
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Morphine Sulphate Injection = Morphine
Sulphate Injection BP
SOURCES OF INFORMATION ON
FINAL PRODUCT TESTING 2
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Establishment of Unlicensed Medicines Expert
Advisory Group
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2007
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2008
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9 monographs
2009
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0 monographs
Concepts for unlicensed
16 monographs?
At least 12 more monographs in advance state
BP 2009 MONOGRAPH STRUCTURE
UNLICENSED MEDICINES
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Identical to Licensed Product Monographs
Description
 Identification
 Related Substances
 Assay
 Endotoxins
 Sterility Testing
 Particulate
 Dissolution
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STRATEGIES FOR MONITORING THE QUALITY OF
PRODUCTS 1
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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
Inprocess Tests
Trigger Tests\Rapid Methods
Partial BP Final Product Testing
Full BP Final Product Testing
PRODUCT REQUIREMENTS
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Final Product Testing
Batch production
 Samples representative of the whole batch
 Long shelf life
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7 days for environmental monitoring
14 +3 days for sterility test
Specials 
Section 10 products 
Options – introduce approaches such as Dose
Banding
END PRODUCT METHODOLOGY
TRADITIONAL 1
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Identity
Chemical tests x 2or more
 FT-IR
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Related Substances
HPLC
 GC
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Assay – stability indicating
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Titration (aqueous and non-aqueous)
UV\vis spectrometry
HPLC
GC
Ion selective electrodes
END PRODUCT METHODOLOGY
TRADITIONAL 2
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Endotoxins
LAL test
 Rabbits - pyrexia
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Sterility
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Sterility test
Particles
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Sub-micron laser particle counting
END PRODUCT METHODOLOGY
TRIGGER\RAPID METHODS - CHEMICAL
7 day expiry limit – limits methodology
 Facilities available – centralisation of QC
laboratories
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Trigger signs
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Weights – correct volumes added
Trigger components
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TPN
RI
 Na+
 K+
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Care – are you compromising batch???
END PRODUCT METHODOLOGY
TRIGGER\RAPID METHODS - MICROBIOLOGICAL
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Rapid Microbiological Environmental Methods
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Rapid Sterility Testing
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Endotoxin testing
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gross G-ve contamination
REGULATORY PRESSURE
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MHRA
Clear segregation Specials and Section 10
preparation
Clear segregation of
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Final product testing and formal release
procedures after FPT
Parametric release approach with limited data on
release
SPECIALS LICENCES
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MHRA pressure
QA processes
 In-process checking
 Final Product Testing
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Chemical ID
 Assay
 Sterility Test
 Environmental Monitoring
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Subject to formal released procedure –
Pharmacist
Final Product testing becoming imperative
SECTION 10 UNITS
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Hub and spoke modernisation
Implications – only make products until source
from
NHS Specials unit
 Industry based Specials Units
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Should we \ can we test?
 Dependant on
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Local QC units or facilties
 Trigger\Rapid methods
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COULD WE HAVE DETECTED PROBLEMS WITH
PRODUCTS USING PRODUCT TESTING
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Microbiologically
Chemically
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Errors are and can be detected
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Aminophylline Injection – neonate
 Heparin Dilution
 Insulin dilution
 Morphine sulphate for neonates
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Mode of Failure
Poor mixing (typically 70-130%)
 Preparation errors
 Calculation errors – 10-1000 fold errors eg microgram –
milligram)
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2006
“HOSPITAL'S BLUNDER OVER SUGAR THAT
KILLED TWIN BABY”
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“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
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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
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Inprocess checks - NO
 FPT -YES
 Trigger parameters - MAYBE
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Volume
 Na+, K+, Ca2+??
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“MANCHESTER INCIDENT” 1994
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Inprocess checks - NO
FPT – Sterility test not feasible
Trigger parameters - MAYBE
Rapid ‘sterility test’
 Endotoxins – depends on organism
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CONCLUSIONS
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Pressures to Final Product test
Regulatory
 Error reduction
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How many errors are product related??
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Limitations with Section 10 products
Time
 Facilities
 Appropriate validated methods
 Development of Rapid and Trigger Indicators
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CONCLUSIONS
Yes there is a role for FPT
BUT
As an integrated part of
QA systems