Page 1 of 16 STANDARD OPERATING PROCEDURE FOR TRIAL SUPPLIES AND LABELLING (NWORTH 3.08) Approvals Principal Author Name: E. Bedson Signature: E. Bedson Date:15/06/10 Quality Assurance Officer Name: D. Skelhorn Signature: D. Skelhorn Date: 17/06/10 NWORTH Director Name: R.T. Woods Signature: R.T. Woods Date: 19/07/10 North Wales Organisation for Randomised Trials in Health (& Social Care) (NWORTH) Institute of Medical & Social Care Research (IMSCaR) Neuadd Ardudwy, Holyhead Road, Bangor University, Bangor, Gwynedd, LL57 2PX Telephone: 01248 388095 Email nworth@bangor.ac.uk
SOP number: NWORTH 3.08 Page 2 of 16 DOCUMENT HISTORY Version number Effective date Authorship 1 30/05/07 (compiled) E. Bedson S. Roberts 2 19/12/07 E. Bedson S. Roberts 3 19/07/10 E. Bedson D.Skelhorn Summary of changes updates SOP number changed from 11 to 3.08, format updated, flow chart added, references updated, section 5.4 expanded re. expiry dates on drugs, minor text amendments. 1. Table of Contents 1. Table of Contents... 2 2. Purpose... 3 4. Responsibilities... 3 5. Procedure... 3 5.2 Trial Supplies... 5 5.3 MHRA approval... 5 5.4 Cost of IMP... 5 5.5 Manufacture and Production of the IMP... 6 5.6 Obligations of a manufacturing authorisation holder... 6 5.7 Ordering... 6 5.8 Product Specification File... 7 5.9 Principles applicable to comparator product... 7 5.10 Blinding operations... 7 5.11 Randomisation code... 7 5.12 Packaging... 8 5.13 Labelling... 8 5.14 Quality Control... 9 5.17 Shipping... 9 5.18 Storage and pharmacy controls... 10 5.19 Prescriptions for IMPs... 10 5.20 Recalls... 10 5.21 Returns of IMP... 10 5.22 Destruction of IMP... 11 5.23 Drug Accountability Logs... 11 5.24 Incident reporting... 11 6. Training plan for SOP implementation... 11 7. Glossary of Terms... 12 8. References... 14 9. Referenced SOPs... 14 10. Appendices... 14 Appendix 1 Trial supplies checklist... 15 Appendix 2: IMP recall reconciliation... 16
SOP number: NWORTH 3.08 Page 3 of 16 2. Purpose To describe the purpose of manufacturing, packaging, labelling, distributing, prescribing, storing and accountability of trial supplies. 3. Scope This standard operating procedure applies only to clinical trials of Investigational Medicinal Products (IMP). 4. Responsibilities Co-operation is required between trial sponsors, trial staff and IMP manufacturers. This procedure applies to all staff associated with NWORTH, particularly staff working in clinical trials with IMPs. The Sponsor has responsibility for: all aspects of the clinical trial including trial supplies (refer to NWORTH Sponsorship SOP 4.04), overall, delegating (if necessary) the responsibility for IMPs to the Chief Investigator (CI), delegated responsibilities should be clearly documented. The Chief Investigator is responsible for: ensuring that the requirements of this SOP are adhered to; specific tasks can be delegated to the Trial Manager (TM), ensuring that when tasks specified within this SOP are delegated to the TM, that the TM has a thorough understanding of, and training in, the application of GMP to IMPs, GCP and all clinical trials (CT) regulations (ref. to the SOP 4.02 and SOP 4.01). The Trial Manager is responsible for: ensuring that all assigned tasks are carried out in accordance with the requirements of this SOP, the requirements of GMP and GCP. 5. Procedure An IMP is defined as A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorisation when used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form [1]. All IMPs should be produced in accordance with the principles and the detailed guidelines of Good Manufacturing Practice (GMP) for Medicinal Products[2]. The GMP guidelines are intended to ensure that trial participants are not placed at risk from unsatisfactory manufacture, and that the results of clinical trials are unaffected by inadequate safety, quality or efficacy arising from unsatisfactory manufacture. The principles of Good Manufacturing Practice for marketed products and IMPs are given in European Commission Directive 2003/94/EC [3]. The supporting document Annex 13 [1] gives detailed guidance on good manufacturing practices of IMPs. This latter document sets out requirements for labelling, ordering, shipping and returning IMP supplies. The
SOP number: NWORTH 3.08 Page 4 of 16 Medicines for Human Use (Clinical Trials) Regulations 2004 [4] aimed to implement the Directive from 1 May 2004. 5.1 Procedure Flow Chart Information gathered for grant and funding applications including outlined CTIMP s cost Process for Investigational medicinal product Process for other trial supplies Identify supplier (MHRA/CA approved) All other trial supplies identified Obtain quote Costing compiled Agree lead time with supplier (in writing if possible) Funding sought and approved Collate information for Competent Authority: - supplier - trial Approvals: Competent Authority and REC Set up contract with supplier Manufacturing completed Supplies ordered from BU approved supplier where possible Material shipped Material received - checked and released Purchase orders, invoices checked and retained as per BU procedures Stocks dispensed Stored (trial sites) Periodic stock checks Distributed to trial units (if applicable) Supply accountability - dispensing - recalls - returns - stock checks - destruction Re-stocked as required
SOP number: NWORTH 3.08 Page 5 of 16 5.2 Trial Supplies Clinical trial supplies are the supplies provided to conduct the study and include drugs, devices, meters, laboratory kits and other special equipment. The provision of clinical supplies is highly regulated and it is important to ensure compliance with GCP requirements. Trial supplies should be considered during the protocol development phase (please refer to NWORTH Protocol Development SOP 3.02) and sufficient resources should be requested to cover the cost of all trial supplies. The importance and time needed to set up the trial supplies should not be underestimated. Non- IMP related supplies should be ordered in accordance to the University s usual purchasing procedures, e.g. VAT exemption etc. IMPs are a special kind of trial supply which require regulatory approval from the MHRA (please refer to the NWORTH MHRA SOP 4.02). This SOP is aimed specifically at the trial supplies of IMPs and details the additional requirements above and beyond those for non-imp trials supplies. Please refer to the clinical trials toolkit for trial supplies flow charts. [5] A trial supplies checklist has been compiled as a guide; it should be tailored to individual trials (see appendix 1). 5.3 MHRA approval The regulations prohibit anyone from selling or supplying an IMP to those involved in a clinical trial unless certain conditions are met. CTIMPs must be approved by the MHRA and products without a UK valid marketing authorisation which are made abroad have to meet certain quality testing requirements. The regulations prohibit the manufacture, assembly or import of an IMP other than in accordance with a manufacturing authorisation granted for the purpose, unless the product has a marketing authorisation. It is therefore important that a Clinical Trial Authorisation (CTA) is obtained from the MHRA (ref. SOP 4.02 MHRA) before supplies are ordered. The MHRA will request detailed information about the IMP. Before any applications are made to the MHRA it is vital that a manufacturer with the appropriate authorisations is identified and is willing to provide the trial drugs or devices. It can take time to identify an appropriate manufacturer so it is vital to contact them at the earliest possible stage. It is important to ensure good communication flows between the trial team and the manufacturer, as the manufacturer will have to provide all appropriate information needed about the drug or device (ref. SOP 4.02 MHRA for further guidance on how to obtain a CTA). 5.4 Cost of IMP The CI on behalf of the sponsor (when Bangor University (BU) is the sponsor the CI must be employed by BU) of a clinical trial should ensure that the IMPs used in the trial, and any devices used for the administration of such products, are made available to the trial participants free of charge if they are not covered by a prescription charge (in Wales prescriptions are currently free funded by the Welsh Assembly Government) and other NHS charges. The CI may choose to pay all the charges, but this would need to be included in the budget. The charges raised must be handled separately from any clinical trial payments, as per pharmacy department policy. For clinical trials that are placebo-controlled the trial drugs must be provided free of charge. Thus it is important to calculate the cost of the supplies accurately and these should be reflected in the budget of any grant application. Expiry dates of the drugs should also be taken into account when deciding on the quantity of drugs to purchase, i.e. if the drugs expire before the end of the trial you will need to schedule in another shipment of drugs for delivery prior to the expiry date of the first batch.
SOP number: NWORTH 3.08 Page 6 of 16 5.5 Manufacture and Production of the IMP Clinical trial supplies should be of a high quality and produced to a high standard. The process of manufacturing can be lengthy particularly if a placebo needs to be manufactured, and any process that may be required to secure blinding. It is important to identify a manufacturer at the same time that the protocol is being developed. Discussions should start at an early stage with the manufacturer to ensure that they can provide all the supplies that are needed. Once agreed wherever possible the requirements should be documented in a contact with the supplier, some of the items that should be included are: lead time, guaranteed delivery date(s), labelling and packaging requirements, any special storage conditions, change management requirements. Manufacturers cannot manufacture, assemble or import any IMP unless they hold a current Manufacturing Authorisation. Hospital pharmacies are exempt from this manufacturing authorisation for reconstitution or repackaging of IMPs provided they are used within the hospital site. Note that although some pharmaceutical companies will provide the IMP and placebo for trials this is not always the case. Alternative companies may need to be sourced who can provide the placebo, they will also need to conform to the regulations and will need to provide information to the MHRA before they can manufacture the placebo. 5.6 Obligations of a manufacturing authorisation holder The Regulations require the holder to comply with the principles and guidelines of GMP and The Medicines for Human Use (Clinical Trials) Regulations 2004 [4]. The manufacturing authorisation holder must have the services of a "qualified person". The qualified person should have the necessary qualifications and experience which are set out in the regulations. In particular the person must check production batches of manufactured products and certify that they are of a satisfactory quality. To verify compliance with the provisions on GCP and GMP the manufacturers will be inspected by the MHRA. They will check the trial site or sites, the manufacturing site of the IMP, any laboratory used for analyses in the clinical trial and/or the sponsor's premises. Further guidance on manufacture and production of IMPs can be found in the Medicines for Human Use (Clinical Trials) Regulations 2004 document[4]. 5.7 Ordering CI or TM may order the IMPs on behalf of the sponsor. The order should request the processing and/or packaging of a certain number of units and/or their shipping. It should be in writing (paper or e-mail), and precise enough to avoid any ambiguity. It should be formally authorised and refer to the Product Specification File (see section on following page) and the relevant clinical trial protocol. When ordering the IMPs, ensure that a delivery date is agreed at the start to avoid any delays in the start of recruitment. It is good practice to involve a qualified pharmacist associated with the trials unit, experienced in dealing with trial supplies, at this (or preferably earlier) stage in the process.
SOP number: NWORTH 3.08 Page 7 of 16 5.8 Product Specification File The Product Specification File (PSF) is a reference file that contains, or refers to files containing, all the information necessary to draft the detailed written instructions on processing, packaging, quality control testing, batch release and shipping of an investigational medicinal product. The PSF should be continually updated as development of the product proceeds, ensuring appropriate traceability to the previous versions. It should include, or refer to, the following documents: Specifications and analytical methods for starting materials, packaging materials, intermediate, bulk and finished product. Manufacturing methods In-process testing and methods Approved label copy Relevant clinical trial protocols and randomisation codes, as appropriate Relevant technical agreements with contract givers, as appropriate Stability data Storage and shipment conditions The contents will vary depending on the product and stage of development. The information should form the basis for assessment of the suitability for certification and release of a particular batch by the Qualified Person and should therefore be accessible to him/her. All correspondence and files to and from the manufacturer should be held by the sponsor or delegated person as these will be requested in any MHRA inspection. The CI or TM should ensure that the manufacturer communicates any changes to the documents 5.9 Principles applicable to comparator product If a product is modified, data should be available (e.g. stability, comparative dissolution, bioavailability) to demonstrate that these changes do not significantly alter the original quality characteristics of the product. A suitable use-by date, taking into account the nature of the product, the characteristics of the container and the storage conditions to which the article may be subjected, should be determined by or on behalf of the sponsor. Such a date should be justified and must not be later than the expiry date of the original package. There should be compatibility of expiry dating and clinical trial duration. 5.10 Blinding operations Where products are blinded, systems should be in place to ensure that the blinding has been successful while allowing for identification of blinded products when necessary, including the batch numbers of the products before the blinding operation. In a blinded trial it is vitally important that nothing on the labelling or packaging unblinds the trial drug. However, it is important that in an emergency situation the identification of product can be revealed. Trial procedures should be in place for all the trial team on how to deal with an emergency code break. 5.11 Randomisation code Procedures should describe the generation, security, distribution, handling and retention of any randomisation code used for packaging IMPs, and code-break mechanisms. Appropriate records should be maintained. (see NWORTH Randomisation SOP 5.01)
SOP number: NWORTH 3.08 Page 8 of 16 5.12 Packaging The trial supplies should be packaged individually for each patient. The number of units to be packaged should be specified prior to the start of the packaging operations, and should include units necessary for carrying out quality control and any samples that need to be retained. Sufficient reconciliations should take place to ensure the correct quantity of each product required has been accounted for at each stage of processing. For blinded trials, it is important that the IMPs and comparators are packaged identically so as to avoid unintentional unblinding. Likewise, it is important that specifications and quality control checks are in place to guard against unintentional unblinding due to changes in appearance between different batches of packaging materials. Precautions against mis-labelling such as label reconciliation, line clearance, in process control checks by appropriately trained staff should accordingly be intensified. The packaging must keep the IMP in good condition during transport and storage. Any opening or tampering of the outer packaging during transport should be evident. 5.13 Labelling All IMPs and comparators should be labelled appropriately and comply with the requirements of Directive 91/356 as amended for IMPs. The labelling must ensure that trial participants are protected, for example, there should be clear instructions on how to use and store the product. The regulation also provides an exemption from these requirements for products with a marketing authorisation, if they are prescribed by a doctor, dentist or pharmacist/nurse prescriber, labelled in accordance with the existing UK requirements for medicines dispensed by pharmacists, and are to be used in a clinical trial on patients for which the product is indicated in that authorisation [1]. For all trial IMPs the following information should be included on labels: a. name, address and telephone number of the sponsor, contract research organisation or investigator; b. pharmaceutical dosage and form, route of administration, quantity of dosage units, and in the case of open trials, the name/identifier and strength/potency; c. the batch and/or serial number; d. a trial reference code allowing identification of the trial, site, investigator and sponsor if not given elsewhere; e. the trial subject identification number and where relevant, the visit number; f. the name of the investigator (if not included in (a) or (d)); g. directions for use; h. the following phrase For clinical trial use only ; i. storage conditions; j. period of use (use-by date, expiry date or re-test date as applicable), in month/year format. k. the following phrase keep out of reach of children except when the product is for use in trials where the product is not taken home by trial participants. The address and telephone number of the main contact for information on the
SOP number: NWORTH 3.08 Page 9 of 16 product, clinical trial and for emergency unblinding need not appear on the label where the subject has been given a leaflet or card which provides these details and has been instructed to keep this in their possession at all times. For a summary of the information that is needed on outer packaging, immediate packaging and blister packs see Annex 13 of GMP [1]. 5.14 Quality Control As processes may not be standardised or fully validated, testing takes on more importance in ensuring that each batch meets its specification. Quality control should be performed in accordance with the Product Specification File and in accordance with the information in the Directive 2001/20/EC [6]. Samples of each batch of IMPs, including blinded products should be retained for the periods specified in the Directive as amended for IMPs [6]. Consideration should be given to retaining samples from each packaging run/trial period until the clinical report has been prepared to enable confirmation of product identity in the event of, and as part of an investigation into inconsistent trial results. The CI or TM should check with the company providing the IMP that samples will be retained and if not provision should be made to store the samples. 5.15 Release of Batches IMPs should not be released by the manufacturer until the Qualified Person (QP) has certified that the requirements of Directive 2001/20/EC [6] have been met. Where IMPs are manufactured and packaged at different sites under the supervision of different Qualified Persons, the recommendations listed in Annex 16 to the GMP Guide [7] should be followed as applicable. Where, permitted in accordance with local regulations, packaging or labelling is carried out at the investigator site by, or under the supervision of a clinical trials pharmacist, or other health care professional as allowed in those regulations, the Qualified Person is not required to certify the activity in question. The sponsor is nevertheless responsible for ensuring that the activity is adequately documented and carried out in accordance with the principles of GMP and should seek the advice of the Qualified Person in this regard. A copy of the QP batch release should be retained in the trial master file. 5.17 Shipping Shipping of IMPs should be conducted according to instructions given by or on behalf of the sponsor in the shipping order. IMPs should remain under the control of the Sponsor until after completion of a two-step release procedure: certification by the Qualified Person; and release following fulfilment of the requirements of Article 9 (Commencement of a clinical trial) of Directive 2001/20/EC [6]. The sponsor should ensure that these are consistent with the details actually considered by the Qualified Person. Both releases should be recorded and retained in the relevant trial files held by or on behalf of the sponsor. De-coding arrangements should be available to the appropriate responsible personnel before investigational medicinal products are shipped to the investigator site/s.
SOP number: NWORTH 3.08 Page 10 of 16 A detailed record of the shipments made by the manufacturer or importer should be maintained. It should mention to whom the shipment is addressed and delivered to. Transfers of IMPs from one trial site to another should remain the exception. Such transfers should be covered by standard operating procedures (SOPs). The product history while outside of the control of the manufacturer, through for example, trial monitoring reports and records of storage conditions at the original trial site should be reviewed as part of the assessment of the product s suitability for transfer and the advice of the Qualified person should be sought. The product should be returned to the manufacturer, or another authorised manufacturer for re-labelling, if necessary, and certification by a Qualified Person. Records should be retained and full traceability ensured. 5.18 Storage and pharmacy controls Pharmacies must have facilities that allow for IMPs to be stored separately from normal pharmacy stock in an area with restricted access. The instructions of storage should be supplied with the IMP. This should include any information about the temperature range or light conditions. It is the responsibility of the investigator to ensure that the supplies are managed and used correctly at their site. If there is a temperature requirement the trial supplies should be monitored to ensure that storage conditions meet these requirements. If the drugs needs to be kept in a refrigerator there should a temperature-recording device to monitor changes in temperature and it should ideally be alarmed. Procedures should be in place for action to be taken in the event of excursions in storage temperatures. Accuracy and safety checks should be made on the equipment. 5.19 Prescriptions for IMPs Only qualified and registered medical practitioners, supplementary or independent nonmedical prescribers can prescribe IMPs. The IMPs must be prescribed on a study-specific clinical trial prescription form by a prescriber who is recognised as participating in the trial and has signed the delegation and signature log. Prescriptions for IMPs should clearly identify the clinical trial, the subject, and medication required. When an IMP is prescribed for an inpatient, the medicines chart should clearly identify the clinical trial and the IMP and include the words clinical trial. 5.20 Recalls Procedures for retrieving IMPs and documenting this retrieval should be agreed by the sponsor, in collaboration with the manufacturer or importer where different. The investigator and monitor need to understand their obligations under the retrieval procedure [1]. The Sponsor should ensure that the supplier of any comparator or other medication to be used in a CT has a system for communicating to the Sponsor the need to recall any product supplied. A copy of the suppliers recall procedure should be kept in the trial master file. The sponsor should ensure that adequate controls (e.g. drug accountability logs) are in place to enable accurate stock reconciliation. The IMP recall reconciliation form (Appendix 2) should be used to record the recall of IMP from trial sites 5.21 Returns of IMP Investigational medicinal products should be returned on agreed conditions defined by the sponsor, specified in approved written procedures. Returned IMPs should be clearly identified and stored in an appropriately controlled, dedicated area. Inventory records of the returned IMPs should be kept [1].
SOP number: NWORTH 3.08 Page 11 of 16 5.22 Destruction of IMP The Sponsor is responsible for the destruction of unused and/or returned IMPs. 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 by or on behalf of the sponsor for each trial site and each trial period. Destruction of unused IMPs should be carried out for a given trial site or a given trial period only after any discrepancies have been investigated and satisfactorily explained and the reconciliation has been accepted. Recording of destruction operations should be carried out in such a manner that all operations may be accounted for. The records should be kept by the Sponsor or delegated person. When destruction of IMPs takes place a dated certificate of, or receipt for destruction, should be provided to the sponsor. These documents should clearly identify, or allow traceability to, the batches and/or patient numbers involved and the actual quantities destroyed, this may be in the form of a drug accountability log. 5.23 Drug Accountability Logs The investigator or pharmacist must be able to account for all the supplies sent to him/her. Drug accountability logs should record deliveries from the sponsor, drugs dispensed to patients, unused drugs, returns and disposal records. The records should also include dates for deliveries, drugs dispensed and returned; batch numbers; expiry dates, drug serial number (unique codes) and patient ID numbers. Consideration should be given to conducting periodic stock checks, the frequency should be determined based on trial by trial basis. If a database is used for stock allocation, then the physical count at the trial site(s) should be cross checked against the database as well. Any anomalies must be reported to the trial manager and investigated. For information of monitoring please refer to the NWORTH Monitoring SOP 3.07. 5.24 Incident reporting Any incidents relating to discrepancies with the IMP (e.g. labelling anomalies, storage issues such as temperature excursion, errors noted from stock checks) should immediately be reported to the trial manager so that they can be promptly and thoroughly investigated. 6. Training plan for SOP implementation Training will be carried out in accordance with NWORTH training SOP 2.01 All CIs and trial managers should attend a GCP training course. All staff associated with NWORTH who are involved in CTs should familiarise themselves with this SOP. Staff engaging in CTIMPs should ensure their procedures comply with this SOP. The authors of the SOP can provide training when required.
SOP number: NWORTH 3.08 Page 12 of 16 7. Glossary of Terms API BU Active Pharmaceutical Ingredients Bangor University CI Chief Investigator The investigator with overall responsibility for the research. In a multi-site study, the CI has co-ordinating responsibility for research at all sites. All applications for ethical review should be submitted by the CI. CT Clinical Trial A clinical trial is defined as Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s) and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of one or more investigational medicinal product(s) with the object of ascertaining its/their safety and/or efficacy. CTA Clinical Trial Authorisation The authorisation from the MHRA to conduct a CTIMP. No CTIMP can commence in the UK without both a CTA and a favourable ethical opinion. Applications to the MHRA and the REC may be made in parallel. CTIMP Clinical Trial of an Investigational Medicinal Product Any investigation in human subjects, other than a non-interventional trial, intended: a. To discover or verify the clinical, pharmacodynamic effects of one or more medicinal products; b. To identify any adverse reactions to one or more such products; c. To study absorption, distribution, metabolism and excretion of one or more such products with object of ascertaining the safety or efficacy of those products. EU GAfREC. European Union Governance Arrangements for NHS Research Ethics Committees. GCP Good Clinical Practice as defined by the ICH, see www.emea.europa.eu/pdfs/human/ich/013595en.pdf[8] GMP ICH Good Manufacturing Practice International Conference on Harmonisation of Technical Requirements of registration of pharmaceuticals for human use. IMP Investigational Medicinal Product A pharmaceutical form of an active substance or placebo being tested, or used, or to be used, as a reference in a clinical trial, and includes a medicinal product which has a marketing authorisation but is, for the purposes of the trial: a. Used or assembled (formulated or packaged) in a way different from the form of the product authorised under the authorisation;
SOP number: NWORTH 3.08 Page 13 of 16 b. Used for an indication not included in the summary of product characteristics under the authorisation for that product; c. Use to gain further information about the form of that product which are relevant to the study of the product in human subjects. ISRCTN International Standard Randomised Controlled Trial Number MHRA Medicines and Healthcare products Regulatory Agency MHRA (medicines) is the competent authority for the UK in relation to the EU Directive and the Clinical Trials Regulations. MHRA (Devices) is the competent authority for the UK in relation to the medical Devices Regulations 2002[9]. M REC Multi Research Ethics Committee In the case of multi-site studies, the REC undertaking the ethical review of the application. NWORTH North Wales Organisation for Randomised Trials in Health (and social care) PSF The Product Specification File A reference file that contains, or refers to files containing, all the information necessary to draft the detailed written instructions on processing, packaging, quality control testing, batch release and shipping of an investigational medicinal product. REC Research Ethics Committee A committee established in any part of the UK in accordance with GAfREC. SOP Standard Operating Procedure The written instructions and records of procedures agreed and adopted as standard practice. Sponsor The person who takes on ultimate responsibility for the initiation, management, financing (or arranging the financing) of a clinical trial. TM TMF Trial Manager Trial Master File File kept at NWORTH for each trial containing essential documents for that trial, as defined for CTIMP in section 8 of ICH GCP (www.emea.europa.eu/pdfs/human/ich/013595en.pdf) [9]and following the MRC GCP guidelines for other trials (www.mrc.ac.uk/utilities/documentrecord/index.htm?d=mrc002416)[10] Trial Supplies Clinical trial supplies are the supplies provided to conduct the study and include drugs, devices, meters, laboratory kits and other special equipment.
SOP number: NWORTH 3.08 Page 14 of 16 8. References 1. European Commission, Vol 4: Good manufacturing practices - Annex 13: Manufacture of investigational medicinal products. 2003. 2. European Commission, Volume 4 Good manufacturing practice (GMP) Guidelines. 2008. 3. THE COMMISSION OF THE EUROPEAN COMMUNITIES, COMMISSION DIRECTIVE 2003/94/EC. Official Journal of the European Union, 2003. L 262/22. 4. Great Britain, The Medicines for Human Use (Clinical Trials) Regulations 2004: Elizabeth II, Statutory Instrument 2004 No. 1031. 2004, The Stationery Office: London. 5. http://www.ct-toolkit.ac.uk/_db/_documents/flowcharts.pdf. 6. THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION, DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL. 2001, Official Journal of the European Communities. 7. European Commission, Final Version of Annex 16 to the EU Guide to Good Manufacturing Practice. 2001. 8. www.emea.europa.eu/pdfs/human/ich/013595en.pdf. 9. Great Britain, The Medical Devices Regulations 2002. Elizabeth II: Statutory Instrument 2002 No. 618. 2002, The Stationery Office Limited: London. 10. www.mrc.ac.uk/utilities/documentrecord/index.htm?d=mrc002416. 9. Referenced SOPs NWORTH training SOP 2.01 NWORTH protocol development SOP 3.02 NWORTH monitoring SOP 3.07 NWORTH ethics R&D approval SOP 4.01 NWORTH MHRA approval SOP 4.02 NWORTH obtaining sponsorship SOP 4.04 NWORTH randomisation SOP 5.01 10. Appendices Appendix 1 Trial supplies checklist Appendix 2: IMP recall reconciliation
SOP number: NWORTH 3.08 Page 15 of 16 Appendix 1 Trial supplies checklist This checklist is meant as a guide, it should be tailored to individual trials Item Status 1. Identify suppliers and obtain quotes 2. Establish lead times for supplies and agree delivery date(s) 3. Relevant technical agreements e.g. Establish manufacturing contract with IMP manufacture 4. Obtain copy of manufacturing authorisation 5. Confirm MHRA approval is obtained before the drugs and related trial supplies are ordered. 6. Obtain specifications and analytical methods for starting materials, packaging materials, intermediate, bulk and finished product. 7. Manufacturing methods 8. In-process testing and methods 9. Approved label copy 10. Obtain data relating to the stability of the product and shelf life 11. Agree storage and shipment conditions 12. Agree notification of change procedures with suppliers 13. Agree recall procedure (s) 14. Agree Pharmacy controls, and where applicable distribution to other trial sites 15. Establish drug accountability logs and frequency of stock checks.
SOP number: NWORTH 3.08 Page 16 of 16 Appendix 2: IMP recall reconciliation Recall Team:.. Task Assignment:... IMP Information Name:.. Batch Number(s):. Date(s) Manufactured:. Manufacturer s Location: Distributed to sites:... IMP reconciliation data Batch Trial Site Quantity Dispatched Quantity Returned Reconciliation