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