1. Clinical Trials and Pharmacy
Angela Hallam
SMPU
Cardiff and Vale University Health Board

2. Aims of Presentation
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).

3. Objectives (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

4. Objectives (2) Pharmacy/IMP related GCP issues Storage Accountability
Documentation

5. Commercial Trials
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.

6. Non Commercial Trials
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.

7. The Directives
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)

8. UK Legislation
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.

9. 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.

10. IMP (2) Investigational Medicinal Product Dossier (IMPD)
Non Clinical Data
It will detail the method of development, manufacture, packaging, storage, stability,
Investigators Brochure (IB)
Contains Clinical and Non Clinical Data

11. Novel IMP (3) Unlicensed in EU or in a third country. Sterile
Non Sterile
Aseptic
Investigational Medicinal Product Dossier (IMPD)
Investigators Brochure (IB)

12. Licensed Medication (4)
Licence within the UK Or
A licence within the EU
A licence in a third country.

13. Non IMPs (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.

14. 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.

15. 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.

16. 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.
EudraLex Vol 4 Good Manufacturing Practice

17. Manufacture (1)

18. Starting Material (2) Manufacture Finished Product
Intermediate Product
Packaging
Manufacture
Bulk Product

19. 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.

20. What do you need to know about your manufacturer? (4)
Name
Copy of MIA(IMP) licence
Name of QP
Are they importing?
QP Declaration
What are they manufacturing?

21. Qualified Person (1) 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.

22. What does the QP do? (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

23. Technical and Regulatory Release (1)

24. Technical and Regulatory Release. (2)
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.

25. Storage (1) IMP in Pharmacy
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).

26. Storage (2) off site
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.

27. 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.

28. Documentation (1) Standard Operating Procedures
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.

29. Documentation (2) IMP related
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.

30. Documentation (3) Training Records
Updated and maintained.
Process of training for new or temporary staff.
Keep a log of all personnel with trial-related duties.
Ensure that people are qualified and capable of doing the allocated jobs.

31. Documentation (4) Study Specific
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.

32. What can go wrong! SOPs which don’t reflect current practice.
Lack of version controlling of documentation.
QP certification
MIA(IMP) licence
Lack of regulatory green light.

33. Accountability(1)

34. Accountability (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.

35. Accountability (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.

36. Accountability (4) Receipt of IMP into Pharmacy
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

37. Accountability (5) Record the receipt of IMP into Pharmacy contd.
Record details of any delays in receipt
Record the temperature and condition of received materials.
Record what you did following receipt.

38. Accountability (6) IMP movement within Pharmacy
Develop a system which will allow you to record the ‘status’ of the IMP whilst in pharmacy e.g. quarantined, approved for use etc.

39. Accountability (7) Dispensing of IMP
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.

40. Accountability (8) Recalls & Returns
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.

41. Accountability (9) Destruction
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.

42. Treat your IMP like a Controlled Drug

43. What can go wrong! 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.

44. Audit Audit your files Audit your procedures Act on your audit.
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

45. 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.