Earlsfort Centre Earlsfort Terrace Dublin 2 Ireland

Transcription

1 Earlsfort Centre Earlsfort Terrace Dublin 2 Ireland GUIDANCE NOTE ON THE WHOLESALING OF MEDICINAL PRODUCTS FOR HUMAN USE IN IRELAND OCTOBER 2004 This guidance note does not purport to be the definitive interpretation of the law and/or regulations and is for guidance only. Irish Medicines Board 1/30

2 Section INDEX 1. Introduction 2. Legislative basis 3. European Union (EU) Guidelines on Good Distribution Practice 4. Exemptions from the requirement for a wholesaler s licence 5. Wholesaling of Unauthorised Medicinal Products, Physician s Samples and wholesaling to certain categories of persons. 6. Control Reports and Control Authority Batch Release Certificates. 7. How to apply for the issue, Renewal or Variation of a Wholesaler s Licence 8. IMB Inspections in Relation to Applications for the issue, Renewal or Variation of a Wholesaler s Licence 9. Licence Issue, Renewal, and Variation 10. Licence Suspension, Revocation and Rejection of an Application 11. Recall Procedure 12. Fees Payable 13. Routine Inspections Appendix 1. Appendix 2 Appendix 3 Appendix 4 Conditions to a Wholesaler s Licence. EU Guidelines on Good Distribution Practice for Medicinal Products for Human Use Directives, Acts and Regulations pertaining to the Wholesaling of Medicinal Products List of Abbreviations Irish Medicines Board 2/30

3 1 Introduction The purpose of this document is to provide guidance on the regulations covering the wholesale distribution of medicinal products for human use in Ireland. Sale by wholesale means sale or supply for the purposes of sale in the course of a business or for administration to patients in the course of a professional practice and cognate words shall be construed accordingly. This includes all activities consisting of procuring, holding, supplying or exporting medicinal products, apart from supplying medicinal products to the end-user (patient) (ref: 92/25/EEC). Wholesale and distribution of medicinal products are considered to be synonymous. Persons who, in the course of a business, whether acting as sole traders, in partnerships, or in limited liability companies, are engaged in wholesale distribution of medicinal products for human use, require a Wholesaler s Licence, unless exempt under the regulations, and must comply with the regulations, Directives and guidelines discussed in this document. This Guidance document covers the wholesale distribution of medicinal products for human use and includes: - A brief history of the legislative basis upon which wholesale distribution activities are licensed in Ireland - A summary of the regulations applicable to wholesale distribution activities in Ireland - A summary of the EU Guideline on Good Distribution Practice, with which a wholesaler must comply in order to become licensed and to retain that licence - Clarification of exemptions from the requirement for a Wholesaler s Licence - Procedures to follow in order to apply for a Wholesaler s Licence, renewal of a licence, or to make a variation to an existing licence - Procedures followed by the Irish Medicines Board (IMB) in examining an application for the granting, renewal or variation of a licence, including procedures for inspecting the applicant s premises and the timelines set down in the Directive and regulations for completing the examination, inspection and reporting process - Procedures followed o o by the Management Committee of the IMB to approve or reject a recommendation for the issue or renewal of a licence by the Inspector to approve a variation to a licence, and Irish Medicines Board 3/30

4 o by the Inspectorate to prepare and issue the Wholesale Licence document to the Responsible Person with the standard conditions attached. - Procedures that a licensed wholesaler shall put in place, to be followed in the event of the recall of a medicinal product - Information on the Fees payable to the IMB Wholesalers of medicinal products for veterinary use are regulated under the Animal Remedies Regulations, , as amended, and are not discussed in this guidance document. The licensing authority for the wholesaling of medicinal products for veterinary use is the Department of Agriculture and Food ( 2 Legislative basis Wholesaling of medicinal products in Ireland was formerly covered by the Medical Preparations (Wholesale Licences) Regulations, These were later superseded by the 1993 Regulations referred to below. At European level, the initial legislation which introduced the concept of wholesale distribution, European Directive 92/25/EEC, was adopted for the purposes of exercising control over the entire chain of distribution of medicinal products within Member States, and also where wholesaling operations covered several Member States simultaneously. Directive 92/25/EEC has since been incorporated into Directive 2001/83/EC of the Community code relating to medicinal products for human use. Directive 92/25/EEC was originally transposed into Irish legislation by the Medical Preparations (Wholesale Licences) Regulations, (S.I. No. 39 of 1993 and S.I. No. 188 of 1999). The functions of the IMB are set out in section 4(1) of the Irish Medicines Board Act, 1995 (No. 29 of 1995) and include (a) the licensing of the manufacture, importation, distribution and sale of medicinal products. Section 32 of the Act authorises the Minister for Health and Children to make regulations for the purposes of the Act. Section 34 (4) of the Act permits any relevant Regulation made before the commencement of the Act to continue in force and, if necessary, to be amended or revoked as if made under Section 32. The Medical Preparations (Wholesale Licences) Regulations, S.I. No. 39 of 1993, fell into the latter category. These regulations are the primary legislative basis for wholesaling of medicinal products for human use, and were made when the Minister for Health and Children was the competent (licensing) authority. Irish Medicines Board 4/30

5 These regulations were amended by the Medical Preparations (Wholesale Licences) (Amendment) Regulations, S.I. No. 41 of 1996, which were put in place primarily to designate the Irish Medicines Board as the competent authority. The Medicinal Products (Amendment) Regulations, S.I. No. 188 of 1999, amended the term medical preparation to the term medicinal product within the body of the 1993 and 1996 Regulations. The following is a summary of Articles 1 to 13 found in the Medical Preparations (Wholesale Licences) Regulations, (Refer to Appendix 1 for the Conditions subject to which a Wholesaler s Licence is granted): Article 1 Article 2 Article 3 Article 4 Article 5 Article 6 Article 7(1) Article 7(2) Article 8 Article 9 The name of the Regulations the Medical Preparations (Wholesale Licences) Regulations, Revocation of previous regulations Definitions The statement that no person shall keep or offer for sale by wholesale, or sell by wholesale, any medicinal product except in accordance with a Wholesaler's Licence Exemptions from requirement for a Wholesaler s Licence (see section 4 of this Guidance Note) Definition of the scope of a Wholesaler's Licence, i.e. may relate to all medicinal products, specific classes of medicinal products or to named medicinal products. Where applicable the licence will also state the name of the product authorisation (PA) holder where the wholesaler is the agent for that PA holder or where the wholesaler is responsible for first making a product available to the Irish market, i.e. where the product is not received from an Irish based wholesaler or manufacturer. The statement that a Wholesaler s Licence may be granted following receipt of an application by the IMB and demonstration by the applicant that he has suitable premises, equipment and staff and suitable arrangements for record-keeping, handling, storage and distribution. Note: This is achieved by the applicant demonstrating compliance with the guidelines on Good Distribution Practice. (Refer to Appendix 2) This article outlines the general conditions which are attached to a Wholesaler s Licence. These conditions are reproduced in Appendix 1. Other specific conditions may also be attached to the licence by the IMB as appropriate. Defines the period of validity for a Wholesaler s Licence. This is up to a maximum of three years unless sooner revoked by the IMB. Sets out requirement for annual fees to be paid to the IMB. (Refer to Section 8 of this Guidance Note on Fees Payable ) Irish Medicines Board 5/30

6 Article 10 Defines the powers for refusing to grant a licence, and for revoking a licence which has already been issued. The procedure and timing for refusing or revoking a licence is also defined. Article 11 Defines the powers of enforcement and execution of the provisions of these Regulations. The IMB is responsible for the inspection and licensing activities under these Regulations. Enforcement against non - compliance with these Regulations may be carried out by the IMB, officers of the Minister for Health and Children, Health Boards and their officers and, in defined circumstances, the Pharmaceutical Society of Ireland and its officers. Article 12 Defines persons authorised to certify the testing, examination or analysis of a sample where the certificate of evidence may be accepted in any proceedings concerning an offence in relation to these Regulations. Article 13 Defines the form for the certificate referred to in article 12. Note regarding references to Wholesaling in other Regulations: Wholesaling and Wholesale dealing are referred to and defined in other Regulations and persons Wholesaling medicinal products covered by such Regulations should be cognisant of the definitions of wholesaling contained therein. Other Regulations which also deal with Wholesaling: Poisons Regulation, 1982 Medicinal Products (Prescriptions and Control of Supply) Regulations, 1996, as amended. Medicinal Products (Licensing and Sale) Regulations, 1998, as amended Note regarding Controlled (MDA) Drugs: At the time of going to print, the storage of controlled drugs requires a special additional licence from the Controlled Drugs Section, Department of Health and Children, Hawkins House, Dublin 2. Note regarding Parallel Distribution of Centrally Authorised Products: Interested parties should refer to the Human Medicines section of the EMEA website: Copies of the Regulations referred to throughout this document are available from the Government Publications Sales Office, Molesworth Street, Dublin 2 (Tel: to order by post) or may be viewed and downloaded from the Attorney General s website, Irish Medicines Board 6/30

7 3 European Union Guidelines on Good Distribution Practice Article 80(g) of Directive 2001/83/EC (formerly Article 6 (g) of Directive 92/25/EEC), refers to the requirement that Wholesalers of medicinal products for human use must comply with the Guidelines on Good Distribution Practice of Medicinal Products for Human Use. These guidelines (hereafter referred to as the GDP guidelines) are published separately and form the basis for Quality Systems for Wholesalers. Compliance with the EU Guidelines on GDP is the minimum requirement that a wholesaler must meet in order for a wholesaler s licence to be issued. The full text of these guidelines is included in Appendix 2. The GDP guidelines are structured into a number of sections which cover the necessary components of a quality system for Wholesalers and include the following: Quality Systems Personnel Documentation Premises and Equipment Deliveries to Customers Returns Self Inspections The following is a brief description of the requirements of the different sections and is not exhaustive. Quality Systems. The wholesaler is required to have a Quality System. A Quality System requires that the wholesaler has a documented set of procedures which describe, in sufficient detail and contain all the activities which could affect the quality of the medicines. The Quality System comprises mainly of standard operating procedures (SOPs) and training in the use of these SOPs. The section on Documentation (below) describes SOPs in more detail. In particular, the SOPs which form the basis of the Quality System should: Ensure products are authorised for marketing in Ireland Ensure storage conditions are observed at all times Prevent cross contamination from other products Ensure adequate and timely turnover of products Ensure traceability of all faulty product and an effective recall Procedure Ensure storage in appropriately safe and secure areas Ensure products are delivered only to persons entitled to receive them Ensure that products are only received from persons authorised to supply them. See also sections on Documentation and Procedures below. Irish Medicines Board 7/30

8 Personnel The wholesaler is required to appoint a Management Representative in each distribution centre known as the Responsible Person (RP). The RP must ensure that the conditions of the wholesaler s licence (WL) have been and are being complied with and that these guidelines on Good Distribution Practice (GDP) are being met. A number of the GDP requirements can be delegated by the RP to other members of staff, however, he/she must personally - ensure that the Quality System is implemented and maintained - release returned products to saleable stock - approve, sign and date all Standard Operating Procedures In addition, he/she should be involved in the process whereby any decision is made to quarantine and dispose of returned, rejected, recalled or counterfeit products. Where relevant, the marketing authorisation holder should be involved in the decision making process relating to recalls. The decision should be documented and recorded. The RP should be appropriately qualified. Although a degree in Pharmacy is desirable, there is no statutory requirement for the RP to be a pharmacist. However, he/she should have access to pharmaceutical knowledge and advice when it is required and he should have personal knowledge of: (a) the conditions of the Wholesaler s Licence for which he/she is nominated. Refer to Appendix 1, (b) The products wholesaled under the licence and the conditions necessary for their safe storage and distribution (c) relevant provisions of the Directives, Acts and Regulations pertaining to the wholesaling of medicinal products. Refer to Appendix 3. Training is a key component of the Quality System. Staff involved in the storage of medicinal products and the processing of orders should be trained in the appropriate Standard Operating Procedures (SOPs) to ensure that they are capable of performing their duties. Documentation The wholesaler is required to have a documentation system. Documents should be in the format of Standard Operating Procedures (SOPs) and forms. SOPs relating to activities in certain areas (e.g. receipt of material at the Goods Inwards area) should be available at the relevant area for reference when necessary. The documents should be controlled in a manner such that only up to date SOPs and forms are available in relevant areas and obsolete copies are destroyed. Procedures Written procedures (SOPs) should describe the different operations, which may affect the quality of the products. For example, there should be procedures in place for Irish Medicines Board 8/30

9 Receipt and checking of deliveries Storage Cleaning and maintenance of premises Recording of storage conditions Security on site or in transit Withdrawal from saleable stock (Quarantine) Records of - Orders - Deliveries - Returned products Recall plans Self Inspection Procedures for various operations should be approved, signed and dated by the Responsible Person Records Records should be made when each operation is taking place by the member of staff who performed the operation. Based on the records, the activities and events relating to the medicinal products should be traceable. All records should be readily available during an inspection and retained for at least 5 years. For each purchase and sale the following records should be kept: date product/quantity name and address of supplier/consignee For transactions between manufacturers and wholesalers and for transactions between wholesalers, there must be traceability of the origin or destination of products, for example by use of batch numbers, so that all the suppliers of, or those supplied with, a medicinal product can be identified in the event of a recall. Premises & Equipment The premises must be suitable and adequate to ensure proper conservation/distribution of medicinal products. Temperature monitoring devices should be calibrated (i.e. certified that they are operating correctly and the certification should be traceable to a National Standard) to cover the operating range. Receiving Receiving bays protect deliveries and should be separate from storage areas. Deliveries are examined on receipt for damage and to ensure that the goods correspond to the order. Medicinal products requiring refrigerated and / or secure Irish Medicines Board 9/30

10 storage should be moved to their appropriate storage areas immediately following receipt and checking. Storage Medicinal products should be kept separate from other goods. Storage conditions are normally specified on the containers, for example keep the container in the outer carton, keep the container tightly closed, Store between 2 to 8 o C, or Do not store above 25 o C. Products must be stored in accordance with these conditions. Where there are no specified storage conditions, the products may be stored at temperatures up to 30 o C. Temperature monitoring must be performed and documented in order to ensure that the appropriate conditions are maintained. Products should not be stored in close proximity to unit heaters and should not be stored directly on the floor to ensure proper air circulation and reduce the risk of rodent effects. Temperature monitoring records should be reviewed and approved regularly to ensure compliance with the required conditions. Temperature mapping should be performed of all storage areas and cold rooms to ensure that all locations are likely to remain within the specified temperature limits over the seasons of the year. Appropriate stock rotation should be performed. Storage Facility The storage facility should be clean, free from litter, dust, and pests and free from spillage or breakage. 1. Crossover should be prevented by storing products and batches separately. 2. Storage of personal medication, food & drink should be prohibited. Deliveries to Customers Deliveries may only be made to other Authorised Wholesalers or persons authorised to supply Medicinal Products to the public. It is the responsibility of the Wholesaler to ensure the bone fides of customers and, where necessary, to request appropriate documentary evidence. The IMB will look randomly at the customer list and request such evidence. The link between the wholesale premises and the sales department are particularly Irish Medicines Board 10/30

11 Important. In this regard systems should be in place to ensure that each customer is legally entitled to receive a particular medicinal product from the wholesaler. The Responsible Person has a particular responsibility in this area. On the supply document, the following information should be provided: Date Name and Pharmaceutical Form Quantity supplied The name and address of the supplier and of the consignee Transportation The wholesaler should ensure that medicinal products are transported in such a way that: The identification is not lost Contamination is avoided Products are secure Breakage and theft are avoided They are protected from inappropriate environmental conditions e.g. harsh weather. Cold Chain Products requiring refrigeration must be delivered in either refrigerated transportation or in insulated boxes. The Wholesaler must validate the worst case situation likely to be encountered during transport and ensure that the product does not come in direct contact with cool-packs. The Responsible Person must ensure that adequate delivery conditions are maintained for all deliveries. If cool-packs are in use, there should be a system in place to control the re-use and rotation of cool-packs to ensure that incompletely cooled packs are not used in error. Controlled Drugs The wholesaler must maintain the security chain for controlled drugs, in accordance with the Misuse of Drugs Act and Regulations made thereunder. There should be separate control of these drugs in deliveries to facilitate transfer of the products. The deliveries should be made directly to the pharmacist at the hospital or retail pharmacy, and appropriate documents signed on receipt. Irish Medicines Board 11/30

12 Returns Returns may only be accepted and returned to stock for non-defective medicinal products. Returns should be segregated from Saleable Stock until checked in accordance with the SOP for checking of returned products. The Products must be in good condition in the original unwrapped containers and there must be an appropriate level of assurance that the products were stored under proper conditions. The products must be within expiry and have an acceptable shelf life remaining. It is the personal responsibility of the Responsible Person to release suitable returned products to saleable stock. There must be a policy regarding the return of refrigerated products. It is generally considered to be highly inadvisable to release to saleable stock returned refrigerated products, unless maintenance of cold chain can be definitively established. If the wholesaler chooses to accept returned refrigerated products and return them to saleable stock, the IMB will review the policy and practices of the wholesaler in great detail during an inspection. Product Disposal All returned (and rejected), rejected or recalled products should be destroyed in an appropriate and timely manner and in accordance with waste legislation. The decision to dispose of products should be documented and recorded. Records of destruction should be maintained. Self Inspection It is necessary to conduct and record Self Inspections (internal audits) to monitor the implementation of, and compliance with, GDP. Self Inspections should be performed in a manner and frequency in accordance with the Self Inspection Procedure. There should be available Inspection Reports with a list of follow up actions, and an Inspection Log which lists the Self Inspections performed. The full text of the GDP Guidelines is included in Appendix 2. 4 Exemptions from requirement for a Wholesaler s Licence (i) If an authorised medicinal product is imported from a third country (i.e. outside the EU or European Economic Area (EEA)) the importer must hold a manufacturer s licence (not a wholesaler s licence). Hence the importer is required to comply with all the relevant provisions of a manufacturer s licence. (Interested parties should contact the Inspectorate of the Irish Medicines Board for further assistance on this issue). Irish Medicines Board 12/30

13 (ii) An import agent (i.e. carrier) of medicinal products, who does not own the products and acts solely as a carrier or import agent for medicinal products imported from third countries i.e. outside the EU or EEA, generally does not require a wholesaler s licence provided they are delivered to a licensed manufacturer or wholesaler. However, if an import agent holds medicinal product for any appreciable length of time (>48 hours) a Wholesaler s Licence is required. For refrigerated product any storage at the premises of a carrier may be regarded as falling within Wholesale Licence requirements. (iii) Further activities that are not wholesale distribution and are, therefore, not licensable as such, are: A pharmacist in a registered pharmacy or hospital who sells or supplies a medicinal product in accordance with a registered doctor s or registered dentist s prescription. Retail outlets selling medicinal products directly to the public. The sale or supply or the keeping or offering for sale or supply of a medicinal product by a person who has manufactured it in accordance with a manufacturer's licence held by him under the Medical Preparations (Licensing of Manufacture) Regulations, (S.I. No. 40 of 1993, S.I. No. 68 of 1993 and S.I. No. 42 of 1996). This means that a person who holds a Manufacturer s Licence issued by the IMB does not need a Wholesaler s Licence if he/she only distributes products manufactured at the manufacturing site and all wholesaling activities are performed at the manufacturing site. However, a manufacturer must hold a wholesaler s licence if it distributes any of its own medicinal products from a site other than the one at which manufacture takes place. Also, a licensed manufacturer requires a Wholesaler s Licence if he/she distributes a medicinal product manufactured in its entirety by another manufacturer. The sale by retail of a medicinal product to a registered medicinal practitioner or a registered dentist for administration to his patients. Persons who hold a Wholesaler s Licence in another EEA Member State and who distribute directly to their customers, in Ireland, from that other State. Arrangements for the wholesaling of medicinal products amongst themselves by one member of a group of persons not exceeding three in number who co-operate in the purchase by wholesale of those medicinal products for subsequent retail sale by individual members. However, if the group has a legal entity separate from the identities of the individual members, a licence may be required. Similarly if a group sells its purchases, either to more than three individual members and/or to other persons for subsequent sale, a licence will be required. In such situations it is recommend that IMB advice be sought. Irish Medicines Board 13/30

14 Should there be any doubt about whether a particular activity is licensable as wholesale distribution, advice may be sought from the IMB s Inspection and Enforcement Department. 5 Wholesaling of Unauthorised Medicinal Products, Physicians Samples and Wholesaling to Certain Categories of Persons 5.1 Unauthorised Medicinal Products In general, any medicinal product placed on the Irish market is required to be the subject of a valid product (marketing) authorisation granted by the IMB in accordance with the Medicinal Products (Licensing and Sale) Regulations 1998, as amended. Certain other products are authorised centrally by the European Commission for marketing in all Member States and are the subject of European Marketing Authorisations granted under EC regulation 2309/93. There are some exemptions in the Medicinal Products (Licensing and Sale) Regulations, 1998, as amended, from the requirement that each medicinal product be the subject of a product authorisation (P.A.). Of relevance to Wholesalers is Article 4 (b), which states that: The provisions of Article 3 (requirement to hold a product authorisation) shall not apply as respects - (b) the importation or sale of a medicinal product by or to the order of a registered medical practitioner or registered dentist for the treatment of a patient under his care; A wholesaler may be requested to supply such an unauthorised product to a retail or hospital pharmacy or directly to a registered medical practitioner or registered dentist. In each case, the wholesaler should obtain written confirmation that the unauthorised product concerned is being requested by or to the order of a registered medical practitioner or registered dentist for the treatment of a patient under his care. The exact nature of the documentation is at the discretion of the wholesaler but the evidence must be available for review by the IMB Inspectorate during an inspection. (Note: It is not necessary for the wholesaler to request or obtain the name of the patient). In accordance with the provisions of the Medical Preparations (Advertising) Regulations , a wholesaler may not advertise the availability of any unauthorised medicinal product. Where any prospective wholesaler intends to supply an unauthorised medicinal product, this should be specified in the application for a wholesaler s licence. For any existing wholesaler, a variation application to permit such supply should be submitted to the IMB. Irish Medicines Board 14/30

15 If acceptable to the IMB, the wholesaling of an unauthorised medicinal product in line with the exemption set out in the Article 4 (b) of the Medicinal Product (Licensing and Sale) Regulations 1998, as amended, will be permitted and will be referred to specifically in the wholesaler s licence. 5.2 Physicians Samples The Medical Preparations (Advertising) Regulations permit product authorisation holders, under defined circumstances, to supply samples of medicinal products to registered medical practitioners and registered dentists. Where such samples are stored by a licensed wholesaler, it is expected that the wholesaler will, in conjunction with the PA holder, ensure that adequate records are maintained to permit the rapid recall of any batch in the event of that being necessary. Normal GDP requirements apply also to the storage of such products. It should be noted that, in accordance with the above regulations, certain categories of medicinal products including controlled drugs, antidepressants, hypnotics or tranquillisers may not be supplied as samples 5.3 Wholesaling to Certain Categories of Persons A wholesaler may supply certain defined classes of medicinal products to a person who requires the product(s) for the purpose of enabling him to comply with any requirements made by or in pursuance of any enactment relating to the medical treatment of persons employed or carried by that person in any trade or business carried on by him. This is set out in the Exemptions section of the Medicinal Products (Prescription and Control of Supply) Regulations,1996, as amended. Any wholesaler wishing to supply medicinal products in accordance with this exemption must include this in his application for a wholesaler s licence or must apply to vary an existing licence accordingly. 6 Control Reports and Control Authority Batch Release Certificates 6.1 Control Reports Article 51 of Directive 2001/83/EC requires that each batch of medicinal product be manufactured and checked in accordance with prevailing laws and in accordance with the requirements of the marketing (product) authorization. It is also required that each batch be released for sale by a Qualified Person who is at the disposal of the manufacturer of the product. Article 51 also states that the batches of medicinal products which have undergone such controls in a Member State shall be exempt from the controls if they are marketed in another Member State, accompanied by the control report signed by the qualified person. Therefore, any licensed wholesaler receiving a batch of medicinal product from another Member State of the EEA should receive, with the batch, a control report confirming that the batch has been manufactured in accordance with Good Manufacturing Practice and in accordance with its product authorisation or European Marketing Authorisation. Irish Medicines Board 15/30

16 It is recommended that the requirement for the product authorisation holder or manufacturer to supply a control report with each batch be formally included in any distribution agreement. This should be an original signed document. An IMB inspector, may, in the course of an inspection, ask to see the control report relating to any batch which that wholesaler has received directly from another Member State of the EEA. The requirement for a wholesaler to have a control report does not apply where: I. The wholesaler has been supplied with any particular batch by another Irish based wholesaler. II. The wholesaler has been supplied directly by an Irish based manufacturer. III. The wholesaler is distributing parallel imported products which are the subject of parallel product authorisations in Ireland. IV. The wholesaler is engaged in the parallel distribution of centrally authorised medicinal products. 6.2 Control Authority Batch Release Certificate Under Article 114 of Directive 2001/83/EC, the Competent Authority of a Member State may require the holder of a marketing authorisation to submit samples from each batch of certain products for examination by a State Laboratory, or a Laboratory designated for that purpose, before release of the batch on to the market. If the laboratory is satisfied that the batch is of appropriate quality for marketing it issues a Control Authority Batch Release (CABR) Certificate for the batch. This CABR requirement may be applied only to certain categories of medicinal products including Live vaccines Immunological medicinal products used in primary immunisation of infants or of other groups at risk Immunological medicinal products used in public health immunisation programmes New immunological medicinal products or immunological medicinal products manufactured using new or altered technology or new for a particular manufacturer Medicinal products derived from human blood or plasma Any wholesaler receiving a batch of medicinal product covered by CABR requirements from another Member State of the EEA should receive, along with the control report for the batch, a copy of the CABR certificate for the batch. It is recommended that the requirement for the product authorisation holder or manufacturer to supply a CABR certificate with each relevant batch be formally included in any distribution agreement. An IMB inspector may, in the course of an inspection, ask to see the CABR certificate relating to any relevant batch, which that wholesaler has received directly from another Member State of the EEA. Irish Medicines Board 16/30

17 The requirement for a wholesaler to have a CABR certificate does not apply where: I. The wholesaler has been supplied with any relevant batch by another Irish based wholesaler. II. The wholesaler has been supplied directly by an Irish based manufacturer III. The wholesaler is distributing relevant parallel imported products, which are the subject of parallel product authorizations in Ireland. IV. The wholesaler is engaged in the parallel distribution of relevant centrally authorised medicinal products. 7 How to apply for the Issue, Renewal or Variation of a Wholesaler s Licence In order to apply for a Wholesaler s Licence, to renew a current wholesaler s licence, or to make a variation to a wholesaler s licence, complete the appropriate standard application form and forward to the Inspectorate Department, Irish Medicines Board, Earlsfort Centre, Earlsfort Terrace, Dublin 2, together with the appropriate fee and any relevant supporting information. These standard application forms are available from the IMB website ( To find the form, go to the Inspectorate Publications page. When applying for a wholesaler s licence, the Medical Preparations (Wholesale Licences) Regulations , require that the following information be provided to the IMB: Name and address of applicant. The period for which the licence is desired, if less than three years. The different classes of product to which the licence will relate, i.e. whether the products are Prescription Only Medicines, Pharmacy Confined Medicines, medicines which can be supplied from non-pharmacy outlets, herbal remedies, homeopathics, or other particular classes of product. Where the applicant proposes to supply unauthorised medicinal products, this should be specified. Where the applicant proposes to supply medicinal products to persons in accordance with the exemptions set out in the Medicinal Products (Prescription and Control of Supply) Regulations 1996, as amended, this should be specified. Address of each site from which wholesale distribution (i.e. procurement, storage, sale, supply or export of medicinal products) takes place together with an indication of the general range of medicinal products to be stored at each. The name, address, and qualifications of the Responsible Person (see Section 3, Personnel, above). Irish Medicines Board 17/30

18 A copy of the applicant s recall procedure see also Section 11 below. Applications for renewal or variation of wholesaler licences should be made on the appropriate forms. 8 IMB Inspections in Relation to Applications for the Issue, Renewal or Variation of a Wholesaler s Licence The completed application will be assessed by the Inspectorate of the IMB. For the issue or renewal of the licence, this assessment will generally consist of an inspection of the premises and the wholesaler s Quality System. Assessment of an application for a variation to a licence may not necessarily involve an inspection. Article 78 of Directive 2001/83/EC (formerly Article 4 of Directive 92/25/EC), states that Member States shall ensure that the time taken for the procedure for examining the application does not exceed 90 days from the day on which the competent authority of the Member State concerned receives a valid application. To meet this requirement the application is examined for completeness and any outstanding information is requested. Only then does the 90 day period begin. An inspection shall be scheduled based upon the 90 day target for completing and reporting the inspection, and approval or initiation of the rejection of the application. Article 78 of Directive 2001/83/EC also states that the competent authority may, if need be, require the applicant to supply all necessary information concerning the conditions of licensing. Where the authority exercises this option, the 90 day period may be suspended until the requisite additional data has been supplied. For example, issue of an inspection report which outlines non compliance with GDP requirements stops the clock. The clock restarts when a written reply setting out proposed corrective actions is received from the applicant. The purpose of the inspection is to confirm that licence holders are complying with the conditions of their licences, with the provisions of the Regulations relating to the wholesale distribution of medicinal products and with Good Distribution Practice (GDP). (Refer to Appendices 2 and 3). New applicants need to demonstrate that they can comply with GDP. Amongst other things, Inspectors are empowered to: (a) (b) (c) inspect distribution premises; take samples, without payment, for test, examination or analysis; examine and, if he/she thinks fit, take copies of any document or entry in a register It is a requirement of both EU and Irish national legislation that licence holders shall make their premises available for inspections by the IMB at any time. Following an inspection, the Inspector prepares a report of his/her findings. A letter is sent to the licence applicant or holder noting any deficiencies found and asking for Irish Medicines Board 18/30

19 proposals for corrective actions. The nature of the letter depends upon the inspection findings. 9 Licence Issue, Renewal, and Variation Once an application for a new wholesale licence or renewal of an existing licence has been assessed and / or inspected, the inspector will make a recommendation regarding the application to the Management Committee of the IMB. The Management Committee is comprised of the officers of the IMB, i.e. the Chief Executive Officer and the Heads of Function of the IMB, namely Human Licensing, Technical, Veterinary, Inspection, Finance and Corporate Affairs, Medical Devices and Information Technology. This Committee deals, in the first instance, with all licensing issues relating to medicinal products on behalf of the IMB and meets approximately fortnightly. The Inspector s recommendation will be positive if he/she is satisfied with the application for a new wholesale licence or renewal of an existing licence. The Inspector s recommendation will be negative if he/she is not satisfied with the application and the proposals for corrective actions from the applicant are not considered to be satisfactory. (see Section 10 below). Once approved by the Management Committee, the licence is issued to the Responsible Person with the standard conditions attached. (Refer to Appendix 1). Applications for wholesale licence variations are generally processed within the Inspectorate, based upon the Inspector s assessment of the application. However, in certain circumstances, e.g. a new facility or additional outlet, the variation may be referred to the Management Committee. 10 Licence Revocation, and Rejection of Application. The Medical Preparations (Wholesale Licences) Regulations, , state that if the IMB proposes to refuse an application or to revoke a wholesaler's licence, it shall notify the applicant or the holder, as the case may be, of the reasons for such a proposal and invite him to make representations in the matter to the IMB within thirty days of the giving of such notice. The IMB is required to consider any such representations. Where, after considering any representations, the Management Committee proposes to reject the application for a licence, or to revoke a licence, it refers the matter to the Advisory Committee for Human Medicines (ACHM). The ACHM is comprised of external experts appointed by the Minister for Health and Children. Where, after considering all relevant information, the ACHM proposes to refuse an application or revoke a licence, it recommends accordingly to the Board of the IMB. The Board consists of external personnel appointed by the Minister for Health and Children. The Board makes the final decision in relation to any recommendation concerning refusal or revocation. Irish Medicines Board 19/30

20 The IMB is also required to inform the applicant or licence holder in writing of the decision regarding such proposed refusal or revocation within sixty days of the initial notice of the proposed action. 11 Recall Procedure The wholesaler is obliged, in accordance with the Regulations and with GDP, to have a Recall Procedure in place. This Recall Procedure must be submitted to the Inspectorate when making an application for a wholesaler s licence. This is to enable the swift and effective recall from the marketplace of defective and/or potentially harmful medicinal products. A comprehensive guideline entitled Guidance Note for Product Authorisation Holders, Manufacturers and Wholesalers in relation to Recall of Medicinal Products is available from the Inspectorate of the IMB, or may be downloaded from the IMB website ( on the Inspectorate Publications page. 12 Fees Payable Fees are payable under the Irish Medicines Board Act, 1995, as amended. Fees are currently payable for the following: (a) (b) (c) (d) (e) Licence applications; Licence variations; Inspections relating to licence applications Non-routine inspections Annually. These annual fees also cover routine inspections by the IMB. A schedule of the current fees is available from the IMB website at (go to Publications section and select Human Medicines ). The schedule is also available on request from the Inspectorate Department, Irish Medicines Board, Earlsfort Centre, Earlsfort Terrace, Dublin Routine Inspections Subsequent to the granting of a wholesaler s licence, the IMB will re-inspect a licensed wholesaler s premises on a regular basis. In general, such inspections are carried out once every three years. A greater frequency may be applied to large wholesalers or to any wholesaler which exhibits a poor record of GDP compliance. A three yearly inspection may coincide with the wholesaler s application for licence renewal. Irish Medicines Board 20/30

21 Appendix 1 Conditions to a Wholesaler s Licence. A wholesaler s licence shall be subject to such conditions as the IMB may specify, and may, in particular, require that the licence holder comply with those conditions set out in Article 7(2) of the Medical Preparations (Wholesale Licences) Regulations, In practice, the conditions attaching to a wholesaler s licence at the time of this version of the guidance are very closely based on those set out in article 7 (2). The actual conditions attaching to each wholesaler s licence are reproduced below. The licence holder - THE GENERAL CONDITIONS (a) shall supply a medicinal product only to (i) a person who is in possession of a wholesaler's licence as referred to in sub-article (1) of article 7 of the Medical Preparations (Wholesale Licences) Regulations, 1993 (S.I. No. 39 of 1993) (as amended), or (ii) to a person carrying on a business of shopkeeping provided he has reasonable grounds for believing that the person is a person lawfully entitled to sell that medicinal product by retail sale, or to a hospital, nursing home or other such health institution. (b) shall not sell by wholesale or keep or offer for sale by wholesale - (i) any medicinal product other than those to which the licence relates, (ii) any medicinal product which requires a product authorisation under the Medicinal Products (Licensing and Sale) Regulations, 1998 and which is not the subject of such an authorisation for the time being in force, (iii)any medicinal product otherwise than in conformity with the provisions of the aforementioned product authorisation. (c) shall provide and maintain such premises, equipment and staff, and have in operation such arrangements as are necessary to avoid deterioration of the medicinal product to which the licence relates and shall notify the Board promptly of any material change in such premises, equipment, staff or arrangements. (d) shall undertake procedures for storage, stock turnover and maintenance of records which are in compliance with the particulars furnished in connection with the application for the licence or with such other arrangements as may be approved by the Board from time to time. (e) shall, on being informed by the Board or the manufacturer that any batch or part of a batch of a medicinal product to which the licence relates has been found not to conform as regards the provisions of the relevant product authorisation in force under the Medicinal Products (Licensing and Sale) Regulations 1998, or as regards strength, quality or purity with the appropriate specification of that medicinal product, if so directed by the Board, immediately withdraw from sale any supplies of that batch held by him and immediately recall all supplies already sold or distributed from that batch. (f) shall, on being informed by the Board that a medicinal product to which the licence relates has been found to give rise to unacceptable adverse reactions, if so directed by the Board, immediately withdraw any supplies held by him of that medicinal product from sale and, so far as may be practicable, immediately recall all supplies of it already sold or distributed by him. (g) in order to facilitate the withdrawal or recall as mentioned in paragraphs (e) and (f) of this Schedule, shall keep records either in the form of purchase/sales invoices, or on computer or in any other form giving for any transaction in the medicinal products received or dispatched at least the following information: - date of supply - name of the medicinal product - quantity received or supplied - name and address of the supplier or consignee, as appropriate. Irish Medicines Board 21/30

22 (h) shall keep available the records referred to in paragraph (g) above for inspection by an officer responsible for the enforcement or execution of these Regulations for a period of five years from the date of the transaction to which they relate. (i) shall comply with the principles and guidelines on Good Distribution Practice of Medicinal Products for Human Use referred to in Article 80(g) and Article 84 of Directive 2001/83/EC and published in the EU Guidelines on Good Distribution Practice of Medicinal Products for Human Use (94/C 63/03). (j) shall from time to time, permit such inspections and make available such information as may be required to satisfy the Board that the conditions of the licence are being complied with. (k) shall give, without payment, an adequate sample of the medicinal product to any person authorised to take such a sample. (l) shall furnish with the supply of a medicinal product information confirming: - the date of supply - the name and pharmaceutical form of medicinal product - the quantity supplied - the name and address of the supplier and consignor (m) shall retain this licence at the premises to which it relates and it shall be produced for inspection when required by a person duly authorised under Article 11(1) of the Medical Preparations (Wholesale Licences) Regulations, 1993 (as amended). Irish Medicines Board 22/30

23 Appendix 2 Guidelines on Good Distribution Practice of Medicinal Products for Human Use (94/C 63/03) (Text with EEA relevance) Introduction These guidelines have been prepared in accordance with Article 10 of Directive 92/25/EEC (now covered in Article 84 of Directive 2001/83/EC, the Community code relating to medicinal products for human use). They do not cover commercial relationships between parties involved in distribution of medicinal products nor questions of safety at work. Principle The Community pharmaceutical industry operates at a high level of quality assurance, achieving its pharmaceutical quality objectives by observing Good Manufacturing Practice to manufacture medicinal products which must then be authorised for marketing. This policy ensures that products released for distribution are of the appropriate quality. This level of quality should be maintained throughout the distribution network so that authorised medicinal products are distributed to retail pharmacists and other persons entitled to sell medicinal products to the general public without any alteration of their properties. The concept of quality management in the pharmaceutical industry is described in Chapter I of the Community Guide to Good Manufacturing. Practice for medicinal products and should be considered when relevant for the distribution of medicinal products. The general concepts of quality management and quality systems are described in the CEN standards (series ). In addition, to maintain the quality of the products and the quality of the service offered by wholesalers, Article 6 of Directive 92/25/EEC (now Article 80(g) of Directive 2001/83/EC) provides that wholesalers must comply with the principles and guidelines of good distribution practice published by the Commission of the European Communities. The quality system operated by distributors (wholesalers) of medicinal products should ensure that medicinal products that they distribute are authorised in Accordance with Community legislation, that storage conditions are observed at all times, including during transportation, that contamination from or of other products is avoided, that an adequate turnover of the stored medicinal products takes place and that products are stored in appropriately safe and secure areas. In addition to this, the quality system should ensure that the right products are delivered to the right addressee within a satisfactory time period. A tracing system Irish Medicines Board 23/30