Clinical Trials and Pharmacy
Angela Hallam
SMPU
Cardiff and Vale University Health Board
Angela.Hallam@wales.nhs.uk
Aims of Presentation
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The aim of today is to provide information
regarding the manufacture of Investigational
Medicinal Products (IMPs).
Relate this to Good Manufacturing Practice
(GMP).
Relate this to a Good Clinical Practice (GCP).
Objectives
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(1)
Commercial and Non Commercial Trials
Legislation
Investigational Medicinal Products (IMPs)
Non Investigational Medicinal Products
(NIMPS)
Terminology used in Manufacture
Manufacture
Qualified Person (QP)
Technical & Regulatory Release
Objectives
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(2)
Pharmacy/IMP related GCP issues
• Storage
• Accountability
• Documentation
Commercial Trials
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These are sponsored by Industry and their
aim is to conduct clinical trials with an
unlicenced Investigational Medicinal Product
(IMP) to prove efficacy and safety. The
ultimate goal is to obtain a marketing
authorisation.
Non Commercial Trials
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These trials form no part of the development
plan towards a marketing authorisation for a
profit organisation.
The trial is designed and conducted by
researchers.
The data generated by the trial is the
property of the Sponsor.
The Sponsor is often an educational
organisation or a health board.
The Directives
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The European Directive on GCP in Clinical
Trials 2001/20/EC (Clinical Trials Directive)
The European Directive 2005/28/EC (GCP)
The European Directive 2003/94/EC (GMP)
UK Legislation
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The Medicines for Human Use (Clinical Trials)
Regulations 2004 (SI 1013)
This is the transposed Directive 2001/20/EC.
The Medicines for Human Use (Clinical Trials)
Amendment Regulations 2006 (SI1928)
This is the transposed Directive 2005/28/EU.
Investigational Medicinal Product
(IMP) (1)
Name
• Manufacturer &
Importer (if imported
from a third country)
• Pharmaceutical form,
dose, duration and
total dose a patient
can receive.
• Product Licence if a
marketed product.
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IMP
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Investigational Medicinal
Product Dossier (IMPD)
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Non Clinical Data
It will detail the method
of development,
manufacture,
packaging, storage,
stability,
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(2)
Investigators Brochure
(IB)
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Contains Clinical and
Non Clinical Data
Novel IMP
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Unlicensed in EU or in a
third country.
• Sterile
• Non Sterile
• Aseptic
Investigational
Medicinal Product
Dossier (IMPD)
• Investigators
Brochure (IB)
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(3)
Licensed Medication
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Licence within the UK
Or
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A licence within the EU
Or
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A licence in a third
country.
(4)
Non IMPs
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(5)
Non IMP i.e. NIMPs are not listed on the CTA.
NIMPs tend to be challenge or rescue agents.
NIMPs can be licensed products from the EU
or a third country.
NIMPs must be sourced appropriately.
Where necessary NIMPs can be specials.
Terminology
(1)
Starting material – Any substance used in the
production of a medicinal product, but excluding
packaging materials.
• Intermediate product – Partly processed material
which must undergo further manufacturing steps
before it becomes a bulk product.
• Bulk Product – Any product which has completed all
processing stages up to, but not including, final
packaging.
• Finished Product – A medicinal product which has
undergone all stages of production, including
packaging in its final container.
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Terminology
(2)
Manufacture – All operations of purchase of
materials and products, production, quality control,
release, storage, distribution of medicinal products
and related controls.
• Packaging – all operations, including filling and
labelling, which a bulk product has to undergo in
order to become a finished product. NB sterile filling
would not normally be regarded as part of packaging,
the bulk product being the filled, but not finally
package, primary containers.
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Terminology
(3)
Reconciliation – A comparison, making allowance for
normal variation, between the amount of product or
materials theoretically and actually produced or used.
• In-process control – checks performed during
production in order to monitor and if necessary to
adjust the process to ensure that the product
conforms it specification. The control of the
environment or equipment may also be regarded as
part of in-process control.
• Batch Number (or lot number) – A distinctive
combination of number and/or letters which
specifically identifies a batch.
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EudraLex Vol 4 Good Manufacturing Practice
Manufacture
(1)
(2)
Starting Material
Manufacture
Finished Product
Intermediate Product
Packaging
Manufacture
Bulk Product
Manufacture
(3)
The manufacture of an IMP must take place in a unit with a
licence to manufacture IMPs and must be certified to the
Sponsor by a QP named on that units licence.
IMPs with a product licence have already been released on to
the market by a QP. If they have an EU licence and are being
used in their licensed form then a further QP certificate is not
required.
If a licensed product is repacked, relabelled or manipulated
then this will need to be done in a unit with a MIA(IMP)
licence and a further QP certificate will be required.
NHS hospitals and health care centres can provide simple
reconstitution and labelling under section 37 of the Clinical trials
directive and this process does not require a QP certificate.
What do you need to know about
your manufacturer? (4)
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Name
Copy of MIA(IMP)
licence
Name of QP
Are they importing?
QP Declaration
What are they
manufacturing?
Qualified Person
UK SI 2004/1031 as
amended.
• No person shall sell or
supply any IMP to an
Investigator etc for the
purposes of administering
that product in a trial
unless the batch of IMP
has been checked and
certified by a QP pursuant
to Article 13(3) and (4) of
the directive.
(1)
What does the QP do?
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(2)
Certification of every batch used
Confirmation of manufacture in an approved
facility
Approval for use in THAT trial.
An example of a QP certificate is shown in
Annex 13
Technical and Regulatory Release
(1)
Technical
Regulatory
Technical and Regulatory Release.
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The opening of a clinical trial
is a two stage process.
The first stage is the
‘technical green light’
certification by the QP of the
IMP to the Sponsor.
The second stage is the
‘regulatory green light’ by the
Sponsor to allow the trial to
commence.
A technical release is required
for each IMP unless it has a
MA within the EU.
(2)
Storage
(1) IMP in Pharmacy
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Ideally IMPs should be kept in a locked cupboard or
secure storage area with controlled access.
IMPs should have dedicated separate storage to
general hospital medicines.
Each trial should have a dedicated storage space.
Allow areas of storage for e.g. IMPs received,
approved for use IMPs, quarantined IMPs
Temperature monitoring for all IMP storage areas
(fridge and ambient).
Storage (2)
off site
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Consider how the IMP is stored on the
ward/department.
What are pharmacy’s involvement in remotely
stored IMPs.
Does local R&D approval take into
consideration that some trials are stored on
wards/departments.
Is there temperature monitoring for IMPs
stored remotely.
Where things go wrong!
Lack of documentation relating to temp.
excursions.
• Temperature monitoring by date but no time of
monitoring.
• Lack of calibration of thermometers used to
record temp.
• Lack of segregated storage.
• No process in place for the remote storage of
IMPs.
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Documentation (1)
Standard Operating Procedures
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They must reflect current practice.
They must be reviewed and updated.
They must be audited.
They must be version controlled
Evidence of circulation and receipt.
Documentation
IMP related
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(2)
Traceability
Reflects CTA
QP certification
Where necessary a copy of the MIA(IMP)
licence.
QP declaration of importation from a third
country.
Temperature records during transit.
Documentation (3)
Training Records
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Training Records
• Updated and maintained.
• Process of training for new or temporary
staff.
• Keep a log of all personnel with trialrelated duties.
• Ensure that people are qualified and
capable of doing the allocated jobs.
Documentation (4)
Study Specific
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A study file should be set up for each
individual trial.
The file should be segregated in distinct
areas e.g. Quotation and Costs, Contracts,
Protocols & amendments, CTA and
substantial amendments, Product
Specifications, labelling, Release
documentation, Receipts etc
The study file should be updated, maintained
and audited.
What can go wrong!
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SOPs which don’t reflect current practice.
Lack of version controlling of documentation.
QP certification
MIA(IMP) licence
Lack of regulatory green light.
Accountability(1)
Accountability
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(2)
Account for every dose of used and unused
study medication.
It has been reported that more than 30% of
trials have product accountability errors and
discrepancies.
Accountability
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(3)
IMP records need to show WHO got WHAT
and WHEN they got it.
IMP records should document batch numbers
and expiry dates.
Full traceability records of the IMP from the
point of ordering, through receipt and to the
point of transfer to the next health care
professional should be in place.
Accountability (4)
Receipt of IMP into Pharmacy
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Document the total number of subject pack
Document details of individual subject packs
Document quantities of bulk for active and
placebo
Date and time of receipt of IMP from courier
Record batch numbers and expiries
Detail any problems with packaging and/or
delivery conditions
Accountability (5)
Record the receipt of IMP into
Pharmacy contd.
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Record details of any delays in receipt
Record the temperature and condition of
received materials.
Record what you did following receipt.
Accountability
(6)
IMP movement within Pharmacy
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Develop a system which will allow you to
record the ‘status’ of the IMP whilst in
pharmacy e.g. quarantined, approved for use
etc.
Accountability (7)
Dispensing of IMP
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Ensure your forms allow for receipt of IMP by
the next health care professional.
Ensure your forms detail the IMP, form,
strength, batch number, expiry, quantity,
patient details and any special storage
requirements of the IMP being transferred
from pharmacy.
Ensure that the receiving person signs to
accept responsibility of that IMP once it has
left pharmacy.
Accountability (8)
Recalls & Returns
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Pharmacy and the trial team must have a
SOP in place to deal with recalls.
On an annual basis pharmacy and the trial
team should test their recall procedure if a
formal recall hasn’t taken place.
Returns should be stored in a trial specific
segregated area and logged.
No returns should be moved without the
written authorisation of the Sponsor.
Accountability
(9) Destruction
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The Sponsor is responsible for the destruction
of unused and/or returned IMPs
IMPs should not be destroyed without the
prior written authorisation of the Sponsor.
All destruction operations should be properly
recorded and accounted for.
The Sponsor should keep detailed records of
destruction.
Treat your IMP like a
Controlled Drug
What can go wrong!
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Records which are not fit for purpose.
Incomplete records.
Records being completed after the event.
Lack of tamper evidence.
Lack of recall procedure.
Recall procedure not being tested.
Lack of documentation to cover the full
movement of the IMP.
Audit
Audit your files
Audit your procedures
• Act on your audit.
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A good example for a pharmacy audit can be
found in the ‘Guidance Document for Clinical
Trial Activities’ 2009 published by NHS
Pharmaceutical Quality Assurance Committee
Due Diligence
A person does not commit an offence under the
Clinical Trial Regulations 2004 if they took all
reasonable precautions and exercised all due diligence
to avoid the commission of that offence.
• Where evidence is adduced which is sufficient to raise
an issue with respect to that defence, the court or
jury shall assume that the defence is satisfied unless
the prosecution proves beyond reasonable doubt that
it is not.
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