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4. Clinical Trials Supply Investigational Medicinal Products

4. Clinical Trials Supply Investigational Medicinal Products . Orange Guide Annex 13 IMPs should be produced in accordance with the principles and the detailed guidelines of GMP for Medicinal Products. Principles Need to be flexible

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4. Clinical Trials Supply Investigational Medicinal Products

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  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.

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