1. IMP/Placebo Sourcing, Release, Storage and Reconciliation. Ms Caroline Whiriskey Research Pharmacist, HRB Clinical Research Facility Galway.

2. Sourcing of IMP/Placebo A sponsor responsibility Sourcing of product(s) of acceptable quality Blinding / production of placebo Labelling Quality and stability assessments Documentation

3. Sourcing of IMP/Placebo Quality Required amount of correct drug, within acceptable limits No harmful excipients Fit for the purpose of the trail Sufficient stability for duration of trial Documentation to prove this Acceptable to participants See EMEA CHMP: Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (2006)

4. Sourcing of IMP/Placebo Quality

5. Sourcing of IMP/Placebo Blinding Over-encapsulation Manufacture of placebo Opaque covering for infusion / syringe Adverse effects may unblind the participants James Lind 20th of May 1747

6. Sourcing of IMP/Placebo Labelling EudraLex, Volume 4: EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use: Annex 13 Investigational Medicinal Products Labels should include: a) name of the sponsor; b) pharmaceutical dosage form, route of administration, quantity of dosage units (and name/identifier of the product and strength/potency in case of open trial); c) the batch and/or code number to identify the contents and packaging operation; d) the trial subject identification number, where applicable; e) directions for use; f) “for clinical trial use only”; g) the name of the investigator (if not included as a code in the trial reference code); h) a trial reference code allowing identification of the trial site and investigator; i) the storage conditions; j) the period of use (use-by date, expiry date or re-test date as applicable), in month/year); k) “keep out of reach of children

7. Sourcing of IMP/Placebo Documentation Application to the HPRA must include: Investigational Medicinal Product Dossier (IMPD)/ Simplified IMPD (incl. Section 2.1 Pharmaceutical information, Section 2.2 Pre- Clinical information, Section 2.3 Clinical Information) for all IMP and for placebo –a) Summary of Product Characteristics (SmPC) for products with marketing authorisation in the Community Investigator’s Brochure (IB) Examples of labelling

8. QP Release A statement by a Qualified Person confirming that the product has been manufactured to the standards which are appropriate for the product and the way the product is intended to be used. Required for all IMP. IMP sourced outside of the EU must also be released by an EU QP before it can be sent to investigational sites The first step of the procedure, ‘QP Certification’ ensures that the product has been manufactured in accordance with the requirements of EU Good Manufacturing Practice (GMP). The second step is the release of the IMPs by the Clinical Trial Sponsor, which confirms fulfilment of the requirements of Article 9 of the 9 of the EU directive 2001/20/EC (e.g. approval/favourable opinion from IRB/IEC and regulatory authority(ies))

9. Storage: In transit Transit storage is the responsibility of the trial sponsor Depending on stability of IMP, distance travelled, climatic conditions, may require transport in a temperature-controlled shipper, +/- inclusion of a data logger to demonstrate transit temperatures Responsibility of the investigator to follow sponsor procedures for assessment of transit conditions

10. Storage – at site Secure location – locked room or locked cabinet. Appropriate temperature: Ambient 15-25  C or 15-30  C » Refrigerated 2-8  C Protection from light may be needed Humidity may be an issue in some climates. Monitoring, to verify that IMP was stored appropriately at all times Report temperature excursions ASAP Alarm system See HPRA Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances. (2011 )

11. Storage – temperature mapping All rooms where trial drugs are stored are temperature mapped before IMP is stored in them. All fridges and freezers are temperature mapped before initial use. (full and empty) Temperature loggers are placed in expected hot and cold areas. (e.g windows,doors, near air conditioning units) Initially carried out summer and winter for three years.

12. Storage – temperature mapping

13. Storage: Fridges and freezers Fit for purpose Calibration prior to use Temp mapped Do not over fill IMP storage only Ongoing performance qualification Annual preventative maintenance and calibration.

14. Storage: temperature loggers Annual calibration Three point calibration over the range it’s being used at. Alarm logger and monitoring logger are separate.

15. Storage: temperature loggers

16. Reconciliation: ICH GCP 4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who is designated by the investigator/institution, should maintain records of the product's delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial subjects. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor.

17. Reconciliation: Accountability logs

18. Standard Operating Procedures

19. Some useful documents HPRA guide to clinical trial applications: v8 Aug 2014 European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations, 2004, SI No 190 of 2004 and amendments Eudralex, Volume 10: Guidance Documents Applying to Clinical Trials, Questions and Answers EudraLex, Volume 4: EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Annex 13 Investigational Medicinal Products IMB (HPRA) Guide to control and monitoring of storage and transportation temperature conditions for medicinal products and active substances (Oct 2011) EMEA CHMP: Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (2006)