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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

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Strategic Approach To Medicines Safety A role for End Product Testing

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Strategic Approach To Medicines SafetyA 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


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