Drug Supply Management

SOP Reference Number: Page 1 f 9 Versin n. and date: Standard perating prcedure title: Drug Supply Management SOP Reference number: Versin Number and Date: Supersedes versin: Issue date: Review date: Authr Name Psitin Apprved by Signature Date Name Name Psitin Psitin Signature Signature Date Date This is a cntrlled dcument d nt make cpies Created by the ICRIN (QM subgrup) Versin XX Date XX/XXX/XXXX

SOP Reference Number: Page 2 f 9 Versin n. and date: Table f cntents INTRODUCTION... 3 1. Purpse... 3 2. Respnsibility... 3 2.1. Trial Management Team (TMT)... 3 2.2. Clinical Trial Supplies (CTS) Representative... 4 2.3. Site Pharmacists fr drugs supplied via lcal supply chain... 4 3. Prcedures... 5 3.1. Drug Supply Planning and Frecasting... 5 3.2. IMP Labelling... 5 3.3. Ordering f Drug Supplies... 5 3.4. Distributin, Receipt and Strage... 6 3.5. Quarantine... 7 3.6. IMP Accuntability... 7 3.7. Change f IMP Shelf-Life... 8 3.8. Return and Destructin f IMP... 8 3.9. Cmplaints... 9 3.10. IMP Recall... 9 Glssary f terms, acrnyms and abbreviatins will be prvided in a separate dcument fr all SOPs This is a cntrlled dcument d nt make cpies Created by the ICRIN (QM subgrup) Versin XX Date XX/XXX/XXXX

SOP Reference Number: Page 3 f 9 Versin n. and date: INTRODUCTION Within the INSTITUTION, trials, studies and ther research activities are identified and cnducted in different ways and therefre the fllwing tasks may be perfrmed at different stages. Indeed, sme may nt be relevant t all trials r studies. If this is the case then a justificatin shuld be filed in the Trial Master File. The SOPs in principle, apply t all research activities, whether they are trials with an Investigatinal Medicinal Prduct, randmised trials lking at ptimal treatment regimens in the licensed indicatins, cmparisn f surgical r ther nn-drug treatment interventins r bservatinal studies. Trial specific wrking practices will prvide supplemental infrmatin n the specific prcedures applying t each trial. In the case f bservatinal studies and sme randmized trials where n investigatinal prduct is being studied, the EU Directive requirements, in the main, are nt applicable, hwever, the principles f GCP are adhered t in all INSTITUTION research activities. 1. Purpse The purpse f this SOP is t: Describe the steps fr which trial-specific practices must be develped t enable a full traceability and quality f Investigatinal Medicinal Prduct (IMP) during trial cnduct, Outline the respnsibilities which must be delineated (where applicable) between INSTITUTION persnnel, cllabratrs (industry and nncmmercial) third party suppliers and site pharmacists (where lcal supply chain is used) and ther service prviders with regards t the management f IMP during an INSTITUTION managed r spnsred clinical trial This SOP applies t all INSTITUTION persnnel, including cntracted persnnel invlved in the management f IMP. It als extends, where applicable t cllabratrs and service prviders perfrming activities n behalf f INSTITUTION. This SOP cvers planning, frecasting and rdering supplies f IMP fr clinical trials; the supply f IMP frm a distributin site t a clinical investigatr site; IMP accuntability, return and destructin. 2. Respnsibility 2.1. Trial Management Team (TMT) The Trial Management Team (TMT) is led by the Principal Investigatr (PI) and is respnsible fr leading all activities assciated with trial management. Because management f a trial requires specialised expertise frm multiple functins, the TMT is cmprised f representatives frm many departments. The respnsibilities and membership f the TMT is described in the TMT charter. The TMT is a grup established by the Principal Investigatr t manage the trial. Membership will include the Principal Investigatr, Trial Physician, Trial Statistician and Trial Manager. It may als include a Pharmacist, Research Nurse, ther This is a cntrlled dcument d nt make cpies Created by the ICRIN (QM subgrup) Versin XX Date XX/XXX/XXXX

SOP Reference Number: Page 4 f 9 Versin n. and date: investigatrs and members f cllabrating grups wh are invlved in the decisin making prcess and prvide trial-specific additinal expertise e.g. a pharmaceutical cmpany representative. The divisin f respnsibilities will be prepared fr each TMT and will be filed in the Trial Master File (TMF). The Trial Management Team (TMT) is the peratinal team that undertakes the day t day management f the trial. The TMT is lead by the Principal Investigatr (PI) and the Trial Manager (TM) and cnsists f the fllwing members wh shuld be represented at all meetings as required: Principal Investigatr Trial Manager Trail Pharmacist Database Prgrammer Trial Physician - if applicable Data Manager Bistatistician Trial Assistant The TMT is respnsible fr ensuring that each trial has apprpriate trial-specific wrking instructins t be able t cmply with the applicable elements f this SOP. The PI and TM are respnsible fr ensuring apprpriate delegatin f activities where entities utside the INSTITUTION are respnsible fr any aspect f drug supply management. 2.2. Clinical Trial Supplies (CTS) Representative This may be an External Cllabratr/Pharmaceutical Cmpany, third party vendr r site pharmacist(s) wh is respnsible fr the rganisatin and management f drug supplies. This may als be the Qualified Persn (QP) wh is ultimately respnsible fr all aspects f the drug supply chain. As many f the INSTITUTION trials and clinical activities invlve IMP and ther drug supplies and devices being prvided by partners and cllabratrs r via the lcal supply chain, respnsibilities fr btaining QP release, imprtatin, distributin and supply management are taken n by ne r mre f these grups. The detailed breakdwn f thse respnsibilities will be dcumented in the trial specific delegatin f respnsibilities and in the cntract with cllabratrs r suppliers. 2.3. Site Pharmacists fr drugs supplied via lcal supply chain Where trials are using drug supply frm the lcal supply chain at the site pharmacy, lcal site pharmacy SOPs which are adequate t cver the drug supply management must be in place, under guidance frm the TM The Trial Manager and the pharmacist must make arrangements t train all pharmacy staff n their respnsibilities and ensure all dcumentatin required t accurately track and manage the drug supplies are maintained in the site pharmacy files, patient recrds and/r CRFs. This is a cntrlled dcument d nt make cpies Created by the ICRIN (QM subgrup) Versin XX Date XX/XXX/XXXX

SOP Reference Number: Page 5 f 9 Versin n. and date: 3. Prcedures 3.1. Drug Supply Planning and Frecasting IMP planning and frecasting begins at the time f the initial grant prpsal develpment, as the drug supply fr many INSTITUTION trials may be prvided by ne r mre cllabratrs. This is an estimate f trial supply needs as it is nt yet knwn if the trial will be accepted by the funding bdy. Once the prpsal is funded and prtcl develpment is underway, a mre accurate and detailed frecasting f trial supplies is perfrmed by the TM. The frecast is delineated further fr each prvider f IMP and cmmunicated t apprpriate Clinical Trial Supplies (CTS) representative(s) invlved in the supply chain management. The TM must dcument cnfirmatin f cmmitment and clarificatin f respnsibilities in drug supply prvisin, Qualified Persn (QP) identificatin and distributin lgistics. This agreement will be dcumented in the cntract between the INSTITUTION and the drug supply partners/cllabratrs/site pharmacist. The CTS representative(s) are infrmed by the TM f any frecast updates accrding t trial prgress and needs. 3.2. IMP Labelling The Trial Manager and apprpriate TMT representatives crdinate with the CTS Representative(s) fr IMP labelling in cmpliance with the prtcl and any applicable natinal regulatins. An apprved label is required fr all packaging (primary and secndary cntainers) visible t the patient r investigatinal staff. The investigatinal label shuld state that the prduct is fr clinical research purpses nly and in blinded trials the label shuld nt reveal the identity f the prduct. Fr details f the required elements fr labelling, see: Gd manufacturing Practice Annex 13, http://ec.eurpa.eu The TM/PL and PI will ensure that the apprpriate trial-specific prcedures are dcumented in the TMF and between cllabratrs wh have labelling respnsibilities. Cmment [s1]: Have yu mentined PL befre? 3.3. Ordering f Drug Supplies IMP will be rdered frm the CTS Representative(s) in accrdance with an agreed schedule and a dcumented trial specific wrking prcedure. The Trial Manager prvides updates t the CTS Representative(s) n: Shipment dates required Regulatry Apprvals and Imprt/Exprt Permit status (if required) This is a cntrlled dcument d nt make cpies Created by the ICRIN (QM subgrup) Versin XX Date XX/XXX/XXXX

SOP Reference Number: Page 6 f 9 Versin n. and date: 3.4. Distributin, Receipt and Strage IMP may nly be distributed t trial sites after receipt and review f QP certificatin plus the fllwing dcumentatin RA/REC apprvals/imp and Imprt Licences btained as relevant. This review may be perfrmed by the CTS representative, the Trial Manager r an external drug distributr. Shipments f IMP must cntain shipping recrds with a minimum f the fllwing infrmatin: Name Strength Dsage frm Batch number(s) Quantities Strage cnditins Shipment date Name and address f recipient(s) IMP must be transprted in suitable cntainers and in accrdance with the registered cnditins. T track this, calibrated and validated temperature data lggers r temperature recrding devices shuld accmpany the shipments if required. The TM may put in place arrangements with the pharmacist and the investigatr t ensure, as far as pssible, that specific accuntability prcedures and recrds fr the trial have been adpted fr a drug managed thrugh the lcal supply chain. This may include dcumentatin in the patient s medical chart r ther surce dcuments, e.g. the patient s diary, and/r the case reprt frm. A trial r sitespecific wrking prcedure will be reviewed t allw the apprpriate tracking and mvement f drug supplies, drug administratin, patient receipt and return, and enable an assessment f drug cmpliance. This will be filed in the TMF. 3.4.1. Receipt Upn receipt f IMP at a clinical investigatr site the investigatr r delegate checks and dcuments the fllwing: Identificatin f the IMP against the shipping recrds, Integrity f packages and seals Temperature recrds r temperature recrding devices QP certificate Where site pharmacy supplies are being used the TM will check that the pharmacy SOPs enable the tracking f prduct batches, shipping cnditins and accuntability. This will be dcumented in the TMF. 3.4.2. Strage IMP must be stred as per prtcl and labelling requirements. The lcatin f the IMP must be identified and dcumentatin f the strage cnditins maintained. This may include: Adequacy f the IMP strage area, namely in a lcked, restricted-access, temperature-cntrlled envirnment, segregated frm ther prducts. This is a cntrlled dcument d nt make cpies Created by the ICRIN (QM subgrup) Versin XX Date XX/XXX/XXXX

SOP Reference Number: Page 7 f 9 Versin n. and date: Temperature cntrl mnitring and recrding with calibrated temperature recrders r devices. When the fllwing unexpected events ccur they are investigated and reprted as a temperature deviatin: 1) an accidental expsure t temperatures utside the recmmended range f strage; 2) a malfunctin r breakdwn f equipment used fr strage r fr temperature cntrl. Humidity cntrl is mnitred and recrded if critical t the quality attributes f the IMP. Full traceability f the IMP when mved frm ne strage lcatin t anther (e.g. central hspital pharmacy t investigatr s ffice). 3.5. Quarantine IMP is placed in quarantine and segregated r adequately identified as separated frm stck in a clinical site upn receipt r during strage when: The required dcumentatin is missing r incmplete upn delivery Damage r degradatin is visible n the packaging Suspected r dcumented temperature deviatins are identified. The prduct has expired The TM, shuld be ntified and immediately ntify the QP wh evaluates the impact f the deviatin n the drugs supplied. The IMP is remved frm quarantine and dispensed t trial subjects nly nce dcumented cnfirmatin is received frm the QP that the IMP is suitable fr use. In the cnverse case, the IMP remains in quarantine, segregated frm ther stck until the site pharmacist is authrised t sign it ff fr return t CTS service prvider r fr destructin at site. Remval frm the investigatr site must take place withut delay. Full traceability f the IMP is maintained up t destructin and written recrds f destructin are kept in the Trial Master File (TMF) with a cpy t the QP. IMP may als be placed in quarantine when the IMP is r will sn expire in rder t avid it being dispensed by errr. In this case, n deviatin is raised. The IMP is mved t anther lcatin and identified by means f clured stickers that it is expired and must be destryed. 3.6. IMP Accuntability Recrds must be maintained thrughut the trial in rder t trace and supprt adequate delivery and receipt, handling, strage, dispensing, recnstitutin and administratin instructins, quantities used by subjects, retrieval f used and unused IMP frm subjects, recnciliatin, delivery t destructin lcatin/facility and final destructin. Furthermre, recrds must be kept f IMP prperties (e.g. Certificates f Analysis), labelling and any changes t these (e.g. shelf-life extensins). In supprt f the full recnciliatin f drug supplies, the TM checks that the investigatr and site pharmacy fulfil all the respnsibilities linked t IMP accuntability at the clinical site n an nging basis thrughut the trial. This is a cntrlled dcument d nt make cpies Created by the ICRIN (QM subgrup) Versin XX Date XX/XXX/XXXX

SOP Reference Number: Page 8 f 9 Versin n. and date: Where site pharmacy supplies are being used, the TM will ensure that the pharmacy apprpriately dcuments the use f investigatinal prducts accrding t the prtcl. This may be n a trial specific dcument r n the Case Reprt Frms (CRFs), patient recrds r ther pharmacy recrds. The TM will discuss recrd retentin requirements and respnsibilities will be delegated in agreement with the pharmacy. This will be filed in the TMF. 3.7. Change f IMP Shelf-Life A change f IMP shelf life requires IMP labelling changes. This activity is perfrmed at the manufacturing site respnsible fr IMP packaging and labelling, r is perfrmed at the investigatr site in accrdance with natinal regulatry requirements. CTS (r 3rd party supplier) supply the ntificatin f shelf-life extensin and the labels fr ver-labelling. The TM ntifies sites f this infrmatin. The Trial Manager must verify that ver-labelling has been perfrmed. Dcumentatin f any ver-labelling is filed in the Investigatr File and in the TMF with cpy t the QP and CTS. If the drug is being dispensed via Interactive Vice Respnse System (IVRS), the IVRS entity must be infrmed. In sme cases, the IMP may be retested t validate an extensin f activity and stability and therefre shelf life. This prcedure must be dcumented and signed ff by the QC befre relabelling. 3.8. Return and Destructin f IMP At trial terminatin and during the clse-ut site activities, the TM checks that the apprpriate level f IMP accuntability is dcumented and all unused IMP is destryed at site r tracked fr return t CTS service prvider fr destructin. Each trial will have specific wrking prcedures t describe the authrised methd f IMP destructin. The TM btains sufficient dcumentatin frm the site t check cntrl f the batches and quantities stcked fr return and destructin, at which pint the IMP can be destryed under Gd Manufacturing Practice (GMP) cnditins. Dcumentatin f destructin, including the quantities and batch numbers, is filed in the TMF with a cpy t the QP and CTS. The PI and TM, as well as the legal representative fr the INSTITUTION must ensure that respnsibility and csts f IMP destructin are detailed in cntracts with suppliers and distributrs, as therwise the respnsibility remains with the INSTITUTION r must be delegated t the site. Where site pharmacy supplies are being used, the TM will check that the pharmacy apprpriately dcuments the recnciliatin f drug supplies and will retain the dcumentatin in accrdance with the trial specific dcument retentin requirements. These requirements will be dcumented in a trial agreement and will be filed in the TMF. This is a cntrlled dcument d nt make cpies Created by the ICRIN (QM subgrup) Versin XX Date XX/XXX/XXXX

SOP Reference Number: Page 9 f 9 Versin n. and date: 3.9. Cmplaints Cmplaints related t IMP are cllected, tracked, assessed and mnitred up t clsure. If the cmplaint is identified and received befre administratin f the IMP t a trial subject it is a technical cmplaint nly; if the cmplaint arises after administratin f an IMP t a trial subject the cmplaint may be assciated with an adverse event and shuld be handled as per the prcedure fr adverse event reprting. In all cases the cmplaint is dcumented and frwarded t the QP wh in turn files the case int the apprpriate infrmatin system. 3.10. IMP Recall In rder t supprt recall, the TM crdinates the availability at all times f a centralised list f all nging trial patients, f all active IMP distributrs, and a list f all clinical investigatr sites in pssessin f IMP. Where site pharmacy supplies are being used the TM will check that the pharmacy apprpriately tracks the drug supplies in rder t be able t supprt drug recall prcedures if needed. This is a cntrlled dcument d nt make cpies Created by the ICRIN (QM subgrup) Versin XX Date XX/XXX/XXXX