4. Clinical Trials Supply Investigational Medicinal Products

1. 4. Clinical Trials SupplyInvestigational Medicinal Products

2. Orange Guide Annex 13IMPs should be produced in accordance with the principles and the detailed guidelines of GMP for Medicinal Products Principles • Need to be flexible • Accommodate changes as product & process knowledge increases • Appropriate to the stage of development • IMPs are complex in comparison to marketed products • lack of fixed routines, novel formulations and processes • Non-GMP to GMP transition • variety of clinical trial and packaging designs • increased risk of product cross-contamination and mix up • limited knowledge of the potency and toxicity of the product • Blinding and randomisation • In-complete process validation • Marketed products which have been re-packaged or modified in some way • Manufactures Licence • Specific to dosage form and type of activity: eg oral solid dosage form; sterilisation; packaging & labelling • Thorough understanding, training and application of GMP is required • Co-operation with trial sponsors is essential • They have ultimate responsibility for all aspects of the clinical trial including the quality of the IMPs. http://www.medicinescomplete.com/mc/orange/current/c02sec1158.htm

3. Spot the difference?

4. Blinding • Open • Single blind • Double blind • Double blind; double dummy • Identical? • Appearance • Taste • Feel • Smell

5. Comparator products • If product is modified • Data to show quality characteristics of the product have not been significantly altered. • comparative dissolution, bioavailability, stability • repackaged in a different container? • Determine a suitable use by date • date should be justified • must not be later than the expiry date of the original package. • compatibility of expiry date and clinical trial duration

6. Product Specification File • Specifications and analytical methods • starting materials, packaging materials, intermediates, bulk and finished product • Manufacturing process description • in-process testing and methods • Copy of approved label • Relevant clinical trial protocols and randomisation codes • Relevant technical agreements with any contractors • Stability data • Storage and shipping conditions • Used to assess the suitability for certification and release of a particular batch by the Qualified Person

7. Qualified Person • Named on the manufactures licence • Certify each batch and record in a register before it is released • Satisfies the IMPD registration conditions, protocol and randomisation code • Source of the IMP & comparators: • within EU but not subject to an EU marketing authorisation • open market within EU in accordance • imported directly from a 3rd country • Ensure Good Manufacturing Practice has been adhered to for each batch • Requirements of the manufacturer’s licence have been met • Manufacturing and testing processes have been appropriately validated • All quality control checks and tests have been completed • Trained and nominated by Royal Society of Chemistry, Society of Biology or Royal Pharmaceutical Society • In UK, MHRA are responsible for determining who can be named as a Qualified Person on a manufacturer's licence

8. Randomisation code & labelling • Procedures to describe • generation, security, distribution, handling and retention randomisation code used • code-break mechanisms. • Records maintenance • Name, address and telephone number of the sponsor, contract research organisation or investigator • main contact for information on the product, clinical trial and emergency un-blinding

9. Shipping • IMPs should remain under the control of the sponsor until certification by the Qualified Person • De-coding arrangements should be available to the appropriate responsible personnel before IMPs are shipped. • Detailed inventory of the shipments made by the manufacturer or importer should be maintained, in case a re-call is necessary. • Transfer of IMP from one trial site to another on an exceptional basis only. • Advice and oversight by QP. • the product should be returned to the manufacturer, or another authorised manufacturer for re-labelling, • Re-certification by a Qualified Person. • Records retained and full traceability ensured.

10. Complaints • Must have a complaints procedure • Must be investigated if product quality is implicated • Discussed between the manufacturer or importer and the sponsor (if different). • Involve the Qualified Person • Assess any potential impact on the trial, on subjects and product development • Documented, out-comes (CAPAs) implemented • Trends reviewed: • Product • Supplier: manufacturing/packaging site CAPA= Corrective Action/Preventative Action

11. Recalls & Returns Recalls • Must have procedures for retrieving IMPs • Document the recall • Investigator and monitor need to understand their obligations under procedure. • Includes comparators • Quality Incident investigation and CAPAs. Returns • Returned on agreed conditions defined in approved written procedures. • Clearly identified and stored in an appropriately controlled, separate, dedicated area. • Inventory record of the returned products should be kept.

12. Destruction • Sponsor is responsible for the destruction of unused and/or returned IMPs • Should not be destroyed without prior written authorisation by the Sponsor. • The delivered, used and recovered quantities of product should be recorded, reconciled and verified • for each trial site and each trial period. • Destruction only after satisfactory reconciliation • any discrepancies must be investigated and satisfactorily explained before the destruction takes place • Record of destruction • Dated certificate of destruction provided to the Sponsor. • clearly identify/allow traceability to, the batches and/or patient numbers involved and the actual quantities destroyed.