Transcript Unlicensed Medicinal Products

Quality Control North West
Education and Training Services
Unlicensed Medicinal Products Under Scrutiny
Mark Jackson
Deputy Director QCNW
The Challenges
• How can we guarantee quality?
• What expertise is there to manage unlicensed
medicines?
• Is there any way to reduce costs?
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Under Scrutiny - Cost
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Press and Government scrutiny on “specials”
“inappropriate use of specials”
Primary focus on non sterile products
Inappropriate prices e.g. £13 - £812 PACT data for
omeprazole.
Brokering services – cost driven, not quality
Are all specials the same?
What are the risks associated with variable
quality products?
Should a premium be paid on quality?
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What can go wrong – patient harm?
• Phosphate Incident – Heartlands Hospital
• “Neglect and failure at Birmingham hospital
led to woman's death, inquest rules”
Birmingham Post - Dec 23 2009
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Phosphate Incident – Heartlands Hospital
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Rosemary McFarlane
64yrs grandmother of 5
Routine Bronchoscopy Procedure
Phosphate buffer saline passed into
lungs during procedure
Given 10 times overdose
Severe burning in chest
Immediately treated, but condition
deteriorated
Died 10 days later of multiple organ
failure
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Investigation
• Current product out of stock, pharmacy
Technician asked to source alternative supply
• Two lines available as special: 1X, 10X
• 10X line ordered and received
• No quality checks carried out in pharmacy
• Product contained no information regarding the
concentration
• Dr and Nurse both assumed the new solution was
the same strength as the previous
• 10x assumed to be part of labelling code
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Inquest - Verdict
• “ Failures by the pharmacy team as a group
and the doctor who conducted the procedure
are gross failures and they have sufficient
cause of connection to the death”
• “We trust you to inject things into us and the
thought that some people in the NHS do not
check what they are giving to us is appalling”
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Learning Points
Inadequate systems in place
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Unlicensed medicine policy?
Purchasing for safety?
Quarantine on receipt?
QA Assessment & formal release?
Change control?
Failure to adequately check the product:
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When ordering from supplier
On receipt into pharmacy
When sent to Clinical area
Prior to administration – Nurse & Doctor
Assumptions – devolved responsibility
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What can go wrong - sourcing Pitfalls
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Bespoke specials
Clarify status when ordering
“Special” or “Section 10” release by pharmacist
What are you paying for?
Someone to make the product for you or….
A fully validated formulation, consistently
prepared to the same standard with documented
evidence.
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Demeclocycline HCl Oral Suspension 300mg in
5ml
• “We didn’t think we needed to send it to QC as it was sourced
from a reputable specials manufacturer”
• Manufacturing method –open capsules and suspend
• No data - published or unpublished to support the formula
• No analysis carried out
• 90 day shelf life assigned
• Prepared under a section 10 exemption, not under licence.
• £500
• Decision – Rejected!
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Learning Points
• Cannot assume you are getting a special even
if supplier holds a manufacturing licence
• Cannot assume supplier has validated the
formula and shelf life
• Quality is not assured
• Need QC expertise to assess evidence
• Responsibility and liability lies with purchaser!
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What can go wrong - variable
Formulations: Captopril
• Warning on child heart drug doses - BBC News 27th March 2007
• “Children with congenital heart failure may be at risk from
discrepancies in doses of a heart drug designed for adults,
researchers have warned”
• “The amount and formulation of captopril vary widely across the
UK when it is given to children, a study shows - and may mean
the amount given is incorrect”.
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Captopril Study
• Study, by Glenfield Hospital in Leicester
• Based on survey returns from 13 children's specialist heart
centres and 13 large referring hospitals.
• Four pharmacies dispensed captopril tablets for crushing and
dissolving in water.
• The other 22 used nine different liquid formulations
• Three came from specials manufacturers, one from an NHS
manufacturing unit, four were prepared "in-house" and one was
imported from Australia.
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Captopril Study
• Three hospitals recommended different formulations for use
after discharge from those that had been used while the child
was an inpatient.
• Only three specialist centres used the same liquid formulations
as their referring hospitals; 10 others used completely different
formulations.
• The stated shelf life of the formulations varied from a couple of
weeks to several months.
• But with one exception, the time limit was not confirmed by
hard data.
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Captopril Study
• “Failure to use a standard formulation could mean that some
children were not getting effective medication - and that their
health could be compromised as a result.
• In the short term, pharmacists working in hospitals and the
community need to ensure that children are given the same
formulation of Captopril wherever it is dispensed.
• "The long term solution is for the pharmaceutical industry and
regulatory authorities to work together to develop an optimum
formulation of liquid Captopril."
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Learning points
• Variations in formulations and method of preparation affects product
quality and patient care
• Lack of consistency in treatment decision making process
• Standard approach to risk assessment required considering:
• Bioequivalence
• Patient group
• Drug toxicity (TI)
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Common procurement strategy needed - quality driven
Consider patient journey – seamless care
Standard formulation required with supporting stability data
Wide availability
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How can we guarantee quality?
• Develop hierarchy for procurement based on potential risk.
• Identify evidence required for quality assessment before placing order.
• System for assessing and approving suppliers (manufacturers and
importers).
• Procure, or collaborate with manufacturers to develop, standard high
quality formulations with supportive stability data
• Team approach - Involve key personnel with required expertise
(Procurement, QC, Clinical pharmacist, DTC, Clinician).
And then manage risks by
• Targeting high risk products and vulnerable patient groups
• Monitoring therapy closely and reporting issues
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Purchasing strategy – hierarchy of risk
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Use of categories
Target quality assessment process to category
Identify likely risks in advance
Identify evidence required at point of ordering
Improved turnaround times
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Hierarchy of Risk
(RPS practice guidance on sourcing specials)
Preferred Choice
Lowest net risk
UK Licensed Medicines
Off label use of a UK Licensed Medicine
Import – licensed in country of origin
UK manufactured “special” made in MHRA licensed facilities
Crushing UK Licensed tablets or opening capsules
Extemporaneously dispensed medicine
Import not licensed in country of origin
Last Choice
Non UK made ULM or food supplement
Highest net risk
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Progression of Risk (Beaney 2006)
Sterile Products
Preparation
on wards
Aseptic preparation
in pharmacy
Low
High
Preparation
in licensed
specials unit)
Scale
Relative Clinical Risk
licensed product
High
Low
Non Sterile Products
Preparation
on wards
Extemporaneous
preparation in
pharmacy
Preparation
in licensed
specials unit)
after Alison Beaney
licensed product
20
Quality Assessment – Evidence required
Quality
Assessment
Imports
Specials
Extemps
Manufacturer details
Manufacturer details
Manufacturer details
Licence no.
MS review
Registered pharmacy
Country of origin
Product specification
WDL
Importers details
C of A / C of C
GMP compliance
TSE assurance
Stability report
Valid formula & shelf life
Container integrity data
Product specification
TSE assurance
C of A/ C of C
Raw materials assessment
MEPA
Labelling & packaging
assessment
Labelling & packaging
assessment
Labelling & packaging
assessment
Overlabelling if foreign
Insertion of user information
if required
Insertion of user information if
required
Review of SPC & PIL
No SPC/PIL
No SPC/PIL
Additional information if
required
Clinical review of use –
develop local guidance if
required
Clinical review of use –
develop local guidance if
required
Translations of user
information
Ready to use assessment
Safety &
efficacy
assessment
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Problems
• Reactive approach
• Expertise – formulation, stability,
manufacturing, MEPA, clinical.
• Inefficient, labour intensive
• Often limited availability of data.
• Intellectual property issues
• Variable quality of specials
• Approval not guaranteed - wasted time and
effort if of poor quality
• Delays to treatment
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Variable Quality - Specials
• Are all specials the same?
• Is it a level playing field?
• Quality – formulation and method of
manufacture
• Presentation
• Ready to use
• Can we truly purchase by risk category alone?
• Essential to have QA expertise when
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Preparation in licensed specials units –
Sterile products
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Bespoke aseptic preparation under a licence
Manipulation of licensed starting materials
Extended shelf life
i.e. replacement service
Release against GMP compliance
Or
• Batch manufacture from API, with terminal sterilisation stage.
• Release against analysis and sterilisation assurance.
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Preparation in licensed specials units –
Non sterile products
• Bespoke patient specific extemporaneous
preparation under licence. Oral liquid
prepared by crushing tablets and
suspending/dissolving in vehicle.
Or
• Formulated and validated batch manufacture
with robust supporting stability data and
biostudy
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Progression of Risk (Beaney 2006)
Sterile Products
Preparation
on wards
Aseptic preparation
in pharmacy
Low
High
Preparation
in licensed
specials unit)
Scale
Relative Clinical Risk
licensed product
High
Low
Non Sterile Products
Preparation
on wards
Extemporaneous
preparation in
pharmacy
Preparation
in licensed
specials unit)
after Alison Beaney
licensed product
26
Formulation development & validation
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Active ingredient – full compliance with PhEur
Desk top research & drug behaviour studies
Formulation studies
Forced degradation of actives
Assay development
Establish excipients e.g. buffers/preservatives
Stress testing of formulation
Accelerated and real time stability studies
Specification development
Toxicology assessment of degradants
Biostudy/bioequivalance
• Costs: Quality comes at a premium!
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Barriers – Intellectual Property
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Cost of product development
Stability studies
Manufacturer need to safeguard IP
Loss of income if subsequently licensed by other company
Unwillingness to provide documentation
Purchaser requires evidence to evaluate product quality
Reassurance or assurance
Confidentiality agreements
Are we willing to guarantee we will buy it if developed?
Partnership agreements?
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Level playing field : Challenge to Industry
• What is your minimum standard for developing a special?
• How does your approach differ from developing a licensed product?
• Should it be different during the formulation development stage?
• Why not market your approach? Threats by cost pressures and
unscrupulous brokers.
• We want to reduce costs not quality.
• Be proactive – help us define a minimum standard for quality
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Cost saving options
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Rationalisation – economy of scale
One–stop shop?
Brokering? Must be quality driven!
Quality and price (QIPP)
Common procurement and quality assessment support – do it
once!
• Tenders
• Services
• Products
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Tendering - Drivers
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Capacity – NPSA initiatives
Cost
Lack of local expertise
Equipment/Facilities
Patient safety – Consistent high quality therapy?
Replacement service or to develop better product?
• Clear remit helps develop the tender specification
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Tenders – Yorkshire Model
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2 Tenders – compounded specials & Imports
Primary driver – NPSA 20
Capacity issues locally & products unavailable
Proactive approach
Supplier audit and approval
Tender specification - developed by key stakeholders
(procurement, end users & QA)
• QA involvement – specification and award criteria
• Quality & cost weighted 50/50 for adjudication
• Quality element split between supplier and product criteria
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Tender Specification - Overview
Evidence required:
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Regulatory Compliance
Quality Management
Formulation & Component Materials
Manufacturing Process
Packaging & Labelling
Stability Data
Release Criteria
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Assessment: Regulatory Compliance
• Review appropriate sections of the manufacturing licence:
– Current
– Appropriate to category of product being tendered
• Review of MHRA website to ensure licence not recently
suspended.
• Review most recent audit report by Regional QA Specialist
• Evidence of closure of deficiencies
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Assessment: Quality Management
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Robust QMS system in place
Management structure
Change control
Document control
Deviation management
Self inspection
Supplier audit
Staff training
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Assessment: Component Materials
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Licensed in UK
Pharmacopoeial Grade
QC Tested & Approved against Specification
C of A
TSE free
List of excipients – appropriate for clinical specialty e.g.
Paediatrics
• CE Mark
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Assessment: Manufacturing Process
• Validated Processes, Equipment & Facility
• GMP compliance
• Consistency of manufacturing method
• Individual doses (e.g. aseptic) or from bulk
• Identify differences – e.g terminal sterilization vs aseptic
• Critical in-process & end of process checks/tests
• Environmental conditions – appropriate grade for type of product
(aseptic, terminal sterilization etc).
• Microbiological Monitoring of process & environment appropriate to
GMP requirements
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Assessment: Packaging & Labeling
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Description of primary & secondary packaging
Materials used e.g. PVC, Polyolefin etc
Latex free
Sample artwork
Storage conditions
Clarity of labeling – Design for safety: NPSA/MHRA Guidance
MEPA anaylsis
Bar Code
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Assessment: Formula & stability Data
• Validated Formulation, shelf life and storage conditions
• Stability references
• Assay Method; accelerated/real time; relevance to
presentation of product (conc, diluent, container etc);
conditions – RH, Temp, light etc.
• Assay Validation e.g. stability indicating, compliance with ICH,
NHSPQA Committee guidance
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Assessment: Formula & stability Data
• Pathway & Extent of degradation e.g. T95, significant
degradation products (toxic), pH changes
• End of shelf life validation
• Microbiological integrity data e.g. syringes
• Particulates – Visible / Sub visible
• Compatibility – containers/giving sets
• Closure – integrity/extractables
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Assessment: Release Criteria
• Analysis (reference limits, e.g. BP)
• Conformity checks against specification – Product; process;
equipment/facility; environment
• Associated product approval checks – prior to release &
retrospective tests / trend analysis
• Sterility assurance e.g. autoclave, micro monitoring etc.
• On-going validation programme e.g. sterility testing, chemical
testing etc.
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Learning points
• Tender process assists regional product rationalisation & economies of
scale
• Short term options: service capacity
• Long term: Product development
• QA specialist expertise and input essential in tender development and
adjudication
• Identify award criteria and weightings with the specification
• Supplier assessment – auditing more efficient than reviewing evidence
from tender returns.
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Learning points
• Common tender return format saves time
• Product assessment – compare like with like!
• Develop product specifications to ensure consistency
• Imports – main emphasis on supplier assessment
• Specials – equal emphasis (product & supplier
• Award across range to minimise errors
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Learning Points
• Responsibility & liability for product quality remains with
purchaser – evidence required to provided to all recipient
Trusts
• Barriers: Intellectual property & confidentiality
• Manufacturers require commitment from NHS to buy
products before development
• Change control : suppliers must inform end users of any
proposed change that impacts on the contracted product
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Summary
• Patient safety before cost
• Working collaboratively, procurement & QA can both raise the quality
of unlicensed medicines and achieve cost savings.
• Build quality and associated costs into purchasing stage
• Purchase products “closest” to licence status
• Need to work closer with Industry to set a minimum standard for
quality of specials – level playing field & improved patient safety.
• Consider partnership arrangements to develop products and
standardise formulations
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