Guidance for Manufacturers What is required to be ready to connect to the EMVS?

Transcription

1 European Medicines Verification System: Guidance for Manufacturers What is required to be ready to connect to the EMVS? Version V 1.0 Authors: Christoph Krähenbühl, Marian Omtzigt, Stefan Artlich, Peter Maarssø and Thomas Valerius

2 Approvals Name Capacity Review Stages Dated Signature Work stream 3 C n.a. Review Process Review Stage A B C Review Purpose Verify that the requirements specified are complete and correct Verify that the document is in accordance with EFPIA quality standards Verify that the document is acceptable for release Document History Revision Who By Dated Brief Description of Change V 1.0 C. Krähenbühl Release incorporating stakeholder feedback and approved by the Manufacturers representatives (EFPIA and EAEPC) on the ESM Technical Workstream EMVS Manufacturer Readiness Guidance Page 2

3 Table of Contents 1 Introduction Purpose of this document The time for wait-and-see is over Key messages for Manufacturing Authorisation Holders: What does Manufacturer Readiness mean? Understanding the context Implication for Manufacturers Consensus Getting Ready for the EMVS Brief Overview: ESM and EMVS EMVS Scope and Relevance for Manufacturers Wider Readiness Preparations Getting Started - Dangers of Delay Basic Capabilities required Wider field of activities Conclusion Recommendations Glossary of Terms Questions and Answers EMVS Manufacturer Readiness Guidance Page 3

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5 1 Introduction 1.1 Purpose of this document EFPIA and EAEPC have produced this document that describes what Manufacturers (also referred to as Manufacturing Authorisation Holders 1 - MAH) should consider today and what actions they should urgently take in order to be in a position to comply with the provisions of the European Falsified Medicines Directive (EU-FMD). This document will give a brief background on the EU-FMD (section 2) and the European Medicines Verification System (EMVS) that sits at the core of the European Stakeholder Model (ESM, introduced in more detail in section 3). Section 4 will then set out what the implications are for Manufacturers are; these are summarised briefly in section 5. The document concludes with a glossary (section 6) and a Question and Answers section (7). It is clear that this document cannot serve as a full and detailed implementation guide: To cover all areas that manufacturers will have to consider in the necessary level of details would be an endeavour far beyond the ambitions of this document. Instead, the intention is threefold: to argue the case that despite the impression that still prevails amongst many organisations that will be affected, enough detail is known about what compliance with the EU-FMD requires from manufacturers; to provide advice to Manufacturers in order to prevent a delay in getting started on their response; to raise the awareness that there is a risk that the Manufacturer s response may focus too narrowly on the establishment of technical capabilities only instead of covering the complete area of impact: The learning from early adopters is that although focus on the technology is an important part of an effective response, there are wider areas of impact that need to be considered from the start and that manufacturers are well advised not to ignore. It is the intention to keep this a living document that will be revised regularly (such as when the EMVS design phase is completed in Q2 2013). 1.2 The time for wait-and-see is over There is a widespread perception amongst Manufacturers that the scope, the technical details and the timing of the EU-FMD are still uncertain and, furthermore, that - as the legislation does not mandate a specific system approach the field of possible solutions is still wide open and equally uncertain. 1 Please note that the definition of Manufacturing Authorisation Holder (MAH) used in this document is in line with the use of the term in the Memorandum of Understanding (MOU), see glossary. EMVS Manufacturer Readiness Guidance Page 5

6 While there are understandable reasons why this perception has come about, in reality these areas and degrees of uncertainty are clearly limited. There is now clarity about the general shape of the requirements posed by the EU-FMD, there is good understanding down to a reasonable level of detail and there is agreement about the order in which further clarification will be achieved and the timescales involved. As far as Manufacturing Authorisation Holders are concerned, it can be taken as read that there is reasonable understanding of what the system landscape will look like that sets the framework within which Manufacturing Authorisation Holders and other stakeholders will operate in the future European pharmaceutical supply chain. Furthermore, while it is not a given fact that the European Stakeholder Model and the European Medicines Verification System will prevail, it is nevertheless clear that whatever will be implemented in Europe will look similar to the systems approach that the ESM stakeholder group has described. In fact, given the focus on cost-effectiveness, simplicity of approach and minimal impact on all the key stakeholders represented in that coalition, it is likely that the approach described by the European Stakeholder Model (ESM) defines a minimum set of requirements that any Manufacturer who intends to remain active in the European market in the post-2017 timeframe ought to aspire to comply with. 1.3 Key messages for Manufacturing Authorisation Holders: As this paper will show, the take-away messages for Manufacturers are: In order to be able to be fully in compliance with the EU FMD in 2017, which is the likely date when compliance is mandatory in all EU member states, Manufacturers will need to start work on their internal roadmap urgently 2. It is especially important that longer-lead time work and projects are planned in time for sanction during the next budget cycle. Readiness to participate comprises information technology/systems, engineering serialisation capability and packaging operations as well as master data management and data quality. Artwork and package design as well as internal organisation and processes will also be impacted as will the people who will be supporting this capability going forward. 2 See following section for more clarification regarding the date of 2017 and the assumption regarding which member states might benefit from the extended timeframe. EMVS Manufacturer Readiness Guidance Page 6

7 2 What does Manufacturer Readiness mean? 2.1 Understanding the context The key provisions of the EU-FMD that set the context for the Manufacturers are set out under the heading of Safety Features. The Safety Features section of the EU-FMD legislation is being implemented using the Delegated Acts process (introduced under the Lisbon Treaty) which allows EU member states to delegate power to the EU Commission for non-essential elements of legislation, such as a technical annex to an act. It is, essentially, a shortcut where EU Parliament and Council chose to regulate only partially, leaving the Commission to flesh out ( supplement ) the law. This means that the legislation as it stands today (and as it will be adopted into national law in January 2013) sets out provisions at a high level, such as describing Safety Features that would enable relevant persons to: Verify pack authenticity Identify individual packs Provide evidence of tampering and setting out general provisions that would mean that Prescription-only medicines would be included by default, over-the-counter medicines would be excluded; list of excluded POMs and included OTCs to be drawn up by the Commission after risk-based assessment; There is an obligation on Repackagers to replace safety features with equivalent safety features; Member states could also use the system once implemented for reimbursement and/or pharmacovigilance purposes Manufacturing Authorisation Holders would pay for the repositories systems. It is, however, left to the Delegated Act to determine technical and procedural details, such as the Characteristics and technical details of the unique identifier (i.e. a unique serial number per pack), Criteria for the risk assessment & process for notification of products that are in- or out-ofscope (e.g. Prescription only, OTC-products, Blacklists / Whitelists ) Extent and modalities of verification of the safety features to ensure the verification of authenticity of each dispensed pack Establishment (including accessibility) of the repositories This brings uncertainty about what the EU-FMD Safety Features provisions mean for Manufacturers as the technical details will only be fixed when the relevant Delegated Act comes into force, expected to be in the first half of 2014, thereby setting the final milestone for compliance: EMVS Manufacturer Readiness Guidance Page 7

8 Delegated Act Publication + 3 years for member states without pre-existing measures (i.e. most EU member states) and Delegated Act Publication + 9 years for member states with pre-existing measures (It is currently unclear which EU countries fall into the second category, however the number will be very limited in any case Belgium and Italy are generally counted in that category) Figure 1: EU-FMD Timeline However, as will be set out below, there is growing agreement as to what the Safety Features Delegated Act may contain and therefore what areas that Manufacturing Authorisation Holders will need to focus their readiness preparations on. 2.2 Implication for Manufacturers While the European Stakeholders believe that the proposed European Stakeholder Model and the European Medicines Verification System currently under development offer the most cost-effective and realistic approach to satisfying the requirements of the EU-FMD, other models and approaches may well form part of the overall future system landscape in Europe. Nevertheless EFPIA and EAEPC believe that whatever systems emerge, the design principles that have guided the development of the EMVS are soundly based on a realistic assessment of costbenefit and also take into account the most likely outcome of what the Delegated Act will prescribe. Given the focus on cost-effectiveness, simplicity of approach and minimal impact on all the key stakeholders represented in the ESM coalition, it is likely that the approach described by the ESM model defines a minimum set of requirements that any Manufacturer who intends to remain active in the European Market in the post-2017 timeframe ought to aspire to comply with. Manufacturing Authorisation Holders are therefore well advised to engage (for example through their Membership Associations) with the proposed ESM solution to understand what technical and EMVS Manufacturer Readiness Guidance Page 8

9 organisational capabilities they need to establish to be in a position to participate effectively and with the least impact on their operations in the future European medicines supply chain. 2.3 Consensus The key message to manufacturers is not to delay starting work on EU-FMD readiness and to approach the task with the awareness that a broad focus is required. Waiting until 2014 is leaving things too late. The recommendation from those manufacturers who have been pro-active in this area is to start now while there is still time to implement a realistic, time-phased project and allow for a staged deployment across all areas of the organisation that are involved. The starting point should be the best understanding of what the technical requirements in the two key areas will be: Pack coding and Data compliance reporting. On both points there is already now considerable agreement as to what the provisions of the Delegated Act may include, not least based on the published output of the European Commission consultation that was carried out between Nov 2011 and April This consultation showed emerging alignment on: Harmonisation through regulation International standards 2D Data Matrix bar code with 4 data elements Inclusion of national numbers where necessary (flexibility at national level) Mandatory Point-of-Dispensing check with optional random verification by wholesalers Data sensitivities and the need to protect patient and commercial data There is widespread agreement that this means that Manufacturing Authorisation Holders will need to 1. Serialise pharmaceutical products packs: apply a (most likely) 2D Data matrix bar code to each pack that carries four elements: Product code (GTIN in most markets) Batch/lot number Expiry date Unique randomised serial number 2. Apply appropriate tamper-evident features 3 See responses to the EC Consultation at: EMVS Manufacturer Readiness Guidance Page 9

10 3. Report the data asset (i.e. the serial numbers for all packs of a production run intended for the market in one of the EU member states) in a controlled and secure manner to a repository (database system) 4. Be in a position to receive and respond to all queries regarding any of the codes relating to their packs quickly and effectively 5. Be in a position to support exception handling, reverse logistics including recall, further queries and investigations. Additionally, Repackagers will need to 6. Be able to record and report the numbers for all packs that they decommission (and apply, record and report the new serial numbers that they apply). The lessons learned from those manufacturers who are in the vanguard of putting in place systems that comply with serialisation and coding requirements similar to the requirements of the EU-FMD is that serialisation and coding technology and systems are an essential starting point but that there are wider areas of work and additional stakeholders that also need to be involved from the start in order to develop an integrated and comprehensive compliance programme: Processes Organisation Governance Packaging Operations / Engineering Coding Technology Stack IS Function Master Data Pack Design / Artwork Mgmt. Figure 2: Manufacturer Readiness - Areas of Work EMVS Manufacturer Readiness Guidance Page 10

11 Examples of what this means for your organisation: Coding Technology stack (including Engineering, Operations etc.) Governance Organisation IS function Artwork and Pack Design Master Data Establish the coding and serialisation capability from line-level to site- and enterprise-level repository Set up appropriate internal organisation structures to support the management of the serialisation capability to ensure delivery of quality bar codes and to deal with exceptions and queries in a responsive fashion Make sure that the IS function is capable of supporting the compliance and information traceability requirements Be aware of the impact that the requirement to apply serial numbers and batch variable information, carried in a 2D Data Matrix bar code (2D DM), and tamper-evidence to packs will have on all aspects of your artwork process Master Data Management systems and processes need to be capable to deal with the enhanced demands of at-line variable coding: They need to ensure that the correct product codes (such as GTIN) are served reliably to the line equipment, these codes well-understood and managed reliably across your global organisation, that any issues such a duplicate codes, packs with multiple bar codes etc. have been identified and dealt with EMVS Manufacturer Readiness Guidance Page 11

12 3 Getting Ready for the EMVS 3.1 Brief Overview: ESM and EMVS The European Stakeholder Model (ESM) is based on the Point-of Dispensing (PoD) Verification concept; its technical implementation is the European Medicines Verification System (EMVS): Figure 3: The Point-of-Dispense Verification Concept Key features of this concept are: Every pack is serialised with a unique randomised number, which is an attribute of the product identification number. These unique serial numbers are checked in to the European Medicines Verification repository by the manufacturers. Wholesalers have the option of voluntarily verifying the pack serial numbers; however, these numbers are NOT routinely traced or checked while in transit. The checking out of the number at the point of dispensing, however, is mandatory. At the dispensing point in the process the serial number is verified against the repository to establish whether the number is valid and whether any alerts have been raised against the serialised product code. The incorporation of the batch number and expiry date also allows an automatic check against this additional information that is critical from a patient safety consideration. The checked in/check out concept has also been designed to provide support elements that are typical of the European pharma supply chain such as multi-market packs, the participation of repackagers/parallel distributors and will obviously handle the whole range of exceptions and special cases that have to be expected (missing serial numbers, double scanning etc.) The EMVS is the Joint Stakeholders proposed system approach to implement this PoD Verification concept: EMVS Manufacturer Readiness Guidance Page 12

13 Figure 4: EMVS Overview Key points to note are: Verification takes place in the pharmacy system that is interfaced to the corresponding National System National Systems can be pre-existing, adapted national systems set up initially for reimbursement control, electronic dispensing etc. or they can be new systems developed to provide compliance with the EU-FMD. If there is no pre-existing national system, the EMVS scope includes a National Blueprint System template that offers countries (or group of countries) an out-of-the box solution to allow quick and cost-effective implementation. The European Hub only serves as a router and does not register or hold numbers long-term. There will be no feedback of routine verification events back to Manufacturers. Manufacturers will, however, need to put systems and processes in place to be able to respond to exceptions and critical queries. 3.2 EMVS Scope and Relevance for Manufacturers Key components for Manufacturers both manufacturer and parallel distributors are the European Hub and the interfaces to/from the Manufacturer s systems to the European Hub: EMVS Manufacturer Readiness Guidance Page 13

14 Figure 5: EMVS Scope and Relevance for Manufacturers The areas highlighted in the orange boxes, describing the interfaces between the European Hub and the manufacturer / parallel distributor systems, are outlined in brief below. Note: The technical details of the specifications of these interfaces of the European Hub will be defined in due course and described in the detail design of the system, to be developed in Use Cases The Manufacturer Interface will cover the following use cases: o Transmission of manufacturing master data for both single and multi-market packs. o Transmission of product pack data for both single and multi-market packs. o Transmit information on a product recall for a batch (complementing a regulatory recall procedure). o Verify product pack, a transaction that is initiated by a manufacturer and subsequently routed through the European Hub to the respective national system. o Decommission packs e.g. as part of a product recall, a transaction to be routed through the European Hub to the applicable national system. o Undo Decommission Packs, a transaction to be routed through the European Hub to the applicable national system. o Manufacturer reports related to data / master data transmission to the European Hub. o Handling of functional and system exceptions including those originating from a national system if they fall into the applicable exception category. EMVS Manufacturer Readiness Guidance Page 14

15 The Parallel Distributor / Re-packager Interface will cover the following use cases: o Use cases as described for the Manufacturer Interface (blue side) o Decommission packs that are supposed to be used in a repackaging activity, a transaction to be routed through the European Hub to the applicable national system. o Undo Decommission Packs, a transaction to be routed through the European Hub to the applicable national system. o Transmission of manufacturing data for repacked products including a link to the original manufacturer s batch to allow for reconciliation on dose level. o Handling of functional and system exceptions including those originating from a national system if they fall into the applicable exception category Data Flows Data exchange between the European Hub and the manufacturer will take place exclusively on a system-to-system level i.e. no manufacturer users will have direct access to the European Hub. Translating this into reporting capability, requests for information from the European Hub through reporting need to be initiated on the Manufacturer s system from where the request is sent to the Hub. Also the ability to receive alerts / acknowledgments from the European Hub is managed through a system-to-system connectivity, i.e. through interfacing or through alerts. In the sections below three different information flows have been identified that exist between the Manufacturer s system and the European Hub, i.e. interfaces, notifications and reports. EMVS Manufacturer Readiness Guidance Page 15

16 Figure 6: Data Flows Manufacturer s systems - European Hub Testing environments Setting up the European Medicines Verification landscape will require intense testing as part of the quality requirements that need to be fulfilled in system development and operation. To allow for proper testing of individual system components prior to integration tests, a series of test environments will be developed as part of the EMVS implementation to be used to on-board Manufacturers systems Notification requirements Regardless of the message format and technical means of transmission, it is clear that there is a set of obligations on Manufacturing Authorisation Holders: Provide a single point of contact for all notifications and related communications IS organisation / Service Desk that is capable of implementing and supporting standard data exchange protocols and provide state-of-the art Event and Incident Management capabilities Internal business organisation that will monitor and process notification messages that are received in a timely manner and maintain a service level. External escalation: Secondary / stand-by communication paths need to be established and shared with EMVS stakeholder organisation in case primary path fails (contact phone numbers etc.) It is strongly recommended that the Manufacturers implement a ITS (Incident Ticket System) to support this function. EMVS Manufacturer Readiness Guidance Page 16

17 4 Wider Readiness Preparations 4.1 Getting Started - Dangers of Delay The obvious starting point of getting ready for EU-FMD compliance for Manufacturers will be the coding technology stack, from line-level printing and vision systems, to site- and enterprise-level repository and other components. Many Manufacturers may already have programs in place to deploy such capabilities, possibly as a result of their response to earlier requirements such as Turkey ITS/PTS, France CIP-13, preparation for California epedigree etc. Manufacturers will find that the investments they have made in these solutions are putting them in a good position for the requirements of the EU-FMD, and manufacturers who have not yet started on such solutions can nevertheless benefit from the technology vendors who have moved along the learning curve delivering solutions for the early adopters. However neither group can be complacent: Even if there is in-house experience, implementing such technology more widely will still be a challenge and for Manufacturers that will be starting at point zero, the task ahead and the time required - is significant. Both groups also face the challenge that because of the number of lines that need to be equipped to cope with the imminent coding requirements around the globe (of which the EU-FMD is just one regional example), technology vendors are already facing the strain and there is a real risk that demand over the next few years will hugely outstrip all available capacity. 4.2 Basic Capabilities required The following list suggests key areas that Manufacturers need to establish to be in a position to participate in the ESM / link to the repositories to be established under the terms of the EU-FMD. Line Serialisation Capability This is generally well understood and will not be discussed in any details here. The main technical capabilities that manufacturers need to put in place are: Provision of 4-element (in some instances 5-elements are required) 2D Data Matrix bar codes on packs (Many Manufacturers will chose to do this by implementing at-line printing) Reading and verifying the 2D DM at line, including check against any human readable information Collecting the numbers, including the correct handling of exceptions such as rejects, at-line sampling etc. There are different options open to Manufacturers to achieve retail package serialisation in the context of a wider program for compliance, such as at-line serialisation, near-line serialisation, preencoding of folding cartons prior to packaging etc. Until the details of the Delegated Act are known it is not possible to give clear guidance as to the preferred approach. However, what is clear is that all Manufacturers need to be in a position to ensure that 100% of the physical packs carry serial EMVS Manufacturer Readiness Guidance Page 17

18 numbers and that these serial numbers are collected consistently to be made available for transmission to the repository system for every pack that is put in the market. Serial Number Repository Manufacturers will need to establish a serial number repository that collects the data generated at line to make them available to be exported to the European Hub at the appropriate point in time. This repository will need to be Secure: Access to the numbers must be strictly controlled and measures must be in place to prevent any data loss Data Volumes Capable: The assumption is that manufacturers need to hold onto the numbers that they have generated for at least the pack shelf-life of the serialised items in order to be able to respond to any queries, deal with exceptions etc. The repository that manufacturers have to operate will therefore need to be able to cope with large data volumes Computer Validation Compliance: Manufacturers are advised to take the working assumption that GAMP compliance should be assumed Data export/import capability e.g. the ability to send the serial numbers to the European Hub and to receive back alerts and other messages Serial Number Management Uniqueness and randomness of the pack serial numbers is a crucial requirement and any failures in this area will fatally undermine the whole Point-of-Dispense Verification approach. The point of the randomness is to prevent anyone guessing the values that genuine numbers could take by analysing ranges of authentic serial numbers. This means that within a given number space only few numbers should be used as genuine serial numbers with the majority of numbers in that space being left unused (guidance is that In order to provide a reasonable level of complexity within the serial number, the probability that a valid serial number can be guessed should be a minimum of 1 in 10,000, see glossary: randomisation ). This means that manufacturers need to establish capabilities to Generate or acquire serial numbers that are highly random and will be globally unique (in combination with the product code) Ensure that the process used to generate these serial numbers will not slow down the line operation Keep these numbers highly secure to prevent unauthorised access to copying/extraction of these serial number and allowing genuine serial numbers to fall into the hands of counterfeiters Need to put measures in place to prevent the introduction/insertion of fake serial numbers that would then be legitimised and could present a valuable opportunity for counterfeiters to introduce falsified medicines into the genuine supply chain EMVS Manufacturer Readiness Guidance Page 18

19 Process Capability Effective manufacturing in a serialised context relies entirely on robust processes at every level and manufacturers are well advised to review all their existing processes against the new requirements. At the packaging line, the introduction of serialisation changes existing ways of working significantly. It requires a level of discipline that currently may not be present and certainly cannot be taken for granted. It therefore requires the technician staff to be effectively trained. Learning from early adopters has been that the common approach of having technicians work alongside the suppliers engineers during the commissioning of the new equipment is not adequate. Everyone involved in the serialisation operation has to be aware of the context and understand to give just a couple of examples that: every single pack has a unique identity defined by its serial number, packs are therefore no longer interchangeable; for every pack that is put in the market, the corresponding serial number must be transmitted to the repository (in the case of the ESM, MAHs will achieve that through data upload to the European Hub); it is therefore recommended best practice to put in place procedures that allow for the decommissioning of the serial numbers corresponding to any pack that has been removed from the line (for example if damaged, removed as QA sample etc.); At the level of repositories, robust processes need to be put in place to handle the data integrity, file reconciliation and also to ensure that the interfaces are triggered at the appropriate event (link to distribution processes will need to be established). At a corporate level, the Manufacturer will need to establish an organisation to support the interaction with the European Medicines Verification Organisation (EMVO; see glossary) that will be operating the EMVS and that will be supporting special processes such as batch recall, product returns etc. 4.3 Wider field of activities While it is appropriate to start any implementation project with the Coding Technology Stack described above, to focus exclusively on the serialisation technology will blind Manufacturers to the need to start work across a wider field of activities. In fact, the lesson learned by those manufacturers who have started to face these challenges is that there are many areas of work and many additional stakeholders that need to be involved from the start in order to develop an integrated and comprehensive compliance programme. Some of these are closely linked to the implementation of coding technology and are therefore likely to be part of the initial programme of work that Manufacturers initiated: System and Information security measures EMVS Manufacturer Readiness Guidance Page 19

20 Computer System Validation Likewise companies will have some form of external requirements monitoring ( Radar ) and impact assessment process in place and they will have made provisions for incident management, investigations and enforcement. There are, however, areas where many Manufacturers underestimate the impact that these new coding and serialisation requirements have, as shown in the following examples: Example 1: Artwork Applying a Data Matrix (DM) with a unique Serial Number does not just require new approaches to at-line technology but they may very well also mean that changes have to be made to the pack artwork. Questions that need to be asked include: Is the artwork appropriately designed? Is there space for the 2D Data Matrix bar code and additional human readable information? Consider pre-printed prefixes (Exp or Lot No etc.) Is the printing technology and substrate up to the job? (and remember that you may need to look at several lines if the same SKUs is manufactured on more than one line) Interaction with Tamper-Evident technology needs to be considered: accommodating labels in the artwork, possible interaction of the label with the new variable data etc. Consider the implications of placing the 2D Data Matrix in relation to other barcodes, as the Sweden Pilot has shown that carrying codes in close proximity will lead to read errors. It is therefore strongly recommended to place the 2D DM on a separate side of the pack to any other barcodes. Don t forget that all of these considerations gain an extra dimension when dealing with small packs/presentations. Related to but wider than the artwork design considerations is the need to review the processes supporting artwork creation and management: Moving from static artwork to variable coding introduces significant differences: The timelines are quite different: The values that are currently applied to packs off-line now need to be served up in the right format and at the right time to the packing line This automatically involves additional domains in the organisation such as master data management and systems, different IS systems to the artwork project management / graphics design applications traditionally supporting this process, involving line engineering and packaging on site etc. Finally, it is important not to forget any regulatory implications: Co-ordination with markets and their regulations is essential when it comes to adding Safety Features such as Tamper-Evidence and Serialisation and it may well be that stock build is required. Artwork and/or registration samples may be required as part of the approval process, the production of which will need to be planned in early. EMVS Manufacturer Readiness Guidance Page 20

21 Example 2: Multi-market / shared packs The EMVS concept relies on the premise that there is a reliable correlation between the physical packs that are presented for dispense and the corresponding serial numbers. There are a number of areas where the existence of multi-market packs (see glossary) poses particular challenges not only for the EMVS concept but also for manufacturers (It would be beyond the scope of this document to cover the details of blue box requirement for multi-market packs / centrally registered products. It is expected that there will be additional guidance from the forthcoming Delegated Acts and the legislation / regulation based on those acts). The EMVS has had to be designed to incorporate functionality to deal with multi-market packs, estimated to make up between 5% and 15% of European pack volumes. Because it is not clear at the point of production in which market the pack will eventually be dispensed, the European Hub will therefore send the pack serial data to multiple markets, or, to be precise, to all the national systems that cover the markets where the packs may be presented for dispensing. Once a pack has been dispensed in one market, the serial number will be routed back through the European Hub to ensure that the multiple instances of this serial number will be marked as dispensed in all markets. The master data that drives this functionality is the concept of the Target Market (described in functional documents). The implications for manufacturers are: They need to ensure that the packs carry the correct product codes, including the appropriate National Numbers (possibly as 5 th element in the 2D DM) but also address the issues created by multi-market packs that have been issued with more than one GTIN/NTIN. They need to be able to upload and maintain the Target Market attribute in order to ensure that the pack serial numbers data is available for verification in all the appropriate markets. A particular issue that needs careful control is presented during the transitional period when some markets will already participate in the EMVS but other markets are benefitting from the extended timeline due to the pre-existence of appropriate safety features in that market. One special situation occurs when one of the potential markets where a multi-market pack is sold is a non-european market, out of scope of the EU-FMD and therefore the EMVS, for example French market packs that are also often sold to French-speaking overseas markets. In order to ensure that the serial numbers for all the French packs sold to France (but not those sold to non-european markets) are reported correctly, manufacturers will need to put provisions in place to handle such cases. EMVS Manufacturer Readiness Guidance Page 21

22 Example 3: Implications of applying Tamper-Evidence Tamper-Evidencing pharmaceutical packs is part of the measures outlined by the EU-FMD. The choice of tamper-evidence is not the subject of this paper but it is worthwhile to highlight wider areas where the impact of Tamper-Evidence measures needs to be considered: Most pharma companies are familiar with local in-market manipulation of packs to accommodate specific local needs or possibly address shortcomings of existing processes or exception handling (for example replacing patient information leaflets at the request of local regulatory authorities in packed stock that had already been shipped to the market). Such changes will no longer be possible when pharmaceutical packs are tamper-evidenced. The implications are therefore that a close dialogue with the local selling organisations is necessary to ensure that all issues are identified early and that the ways of working are adapted so that these local practices no longer continue. Applying Tamper-Evidence by using hot melt closed folding boxes is common practice in the pharmaceutical industry. Introducing such technology has implications that should not be underestimated, such as impact on the artwork (change of folding boxes outline/dimension, additional tools for cuttings of the thumb whole if used at the supplier, ) or requirements on an additional piece of equipment in the packaging line which in turn will have its impact on the process (speed of the process, output, handling of rejects, rework aspects, ). While it may appear that applying tamper evident labels simply involves adding a labeller to the line, there can be a range of issues created by these apparently simple changes. Impact on artwork design has already been mentioned above, but learning from early adopters has been that every detail needs to be considered, for example the impact of the label feed on the tamper evident labels which are by definition - relatively delicate and can easily sustain damage by certain machine operations after application. 4.4 Conclusion Moving to the production of serialised packs is a challenge for any organisation and the size and impact of this work must not be underestimated. It is a challenge that centres on the coding and serialisation technology stack but reaches out far wider and potentially into all areas of a company s operations. The learning from early adopters has been that this is not easy and will take longer than expected or, indeed, planned. It is also clear that the law of unforeseen consequences applies powerfully, for example be aware that the work to introduce serialisation may well be impacted by other projects that affect the same packing lines, products, manufacturing sites etc. 5 Recommendations Learning from early adopters leads to the following recommendations Start early EMVS Manufacturer Readiness Guidance Page 22

23 Use global standards Keep your technology and processes as standard as is possible Be (and stay) prepared for the unexpected Be aware that this will impact your manufacturing at all levels and that, especially initially, additional manual work will be required Be aware that there is no such thing as a zero footprint implementation: Make sure you plan in enough time to access the lines to fully implement, test and validate your technology Do not forget the people: Training and understanding is key to successful operation EMVS Manufacturer Readiness Guidance Page 23

24 6 Glossary of Terms Term CSV EMVO EMVS ESM European Hub Exceptional event FMD Meaning Computer system validation (CSV) is the documented process of assuring that a computer system does exactly what it is designed to do in a consistent and reproducible manner, (see GAMP) European Medicines Verification Organisation. A not-for-profit organisation responsible to establish and manage the European Hub and to provide e.g. guidance on key principles regarding the setup of the European Medicines Verification System. European Medicines Verification System: The European system for medicines verification consisting of the European Hub, the national Blueprint systems, and the interfaces to the manufacturer / parallel distributor systems and to the national systems. The EMVS is the proposed system that incorporates the ESM vision. European Stakeholder Model: The overall vision of the stakeholders, covering the underlying principles of the joint proposal put forward and based on both the joint 10 Core Principles, the Memorandum of Understanding (MoU) and the technical specifications contained in the Foundation Documents in annex to the MoU. The subsystem of the European Medicines Verification System (EMVS) that serves as a gateway for the transmission of manufacturer and parallel importer data to the national systems. Furthermore: data reconciliation on repackaging activities is performed on the European Hub. Exceptional events are structured into system exceptions and functional exceptions. A system exception is any unexpected maloperation of the system such as e.g. a division by zero or a system crash. A functional exception is any deviation from the To Be process that is expected and therefore considered in the requirements specification e.g. a data matrix code that is unreadable and therefore causes an error message. The functional exceptions are further classified in different categories. The Falsified Medicines Directive (FMD, 2011/62/EU), published in the Official Journal of the EU on 1 July 2011, is a Directive of the European Parliament and of the Council of the European Union whose goal is to secure the supply chain of medicines against the entry of falsified products. EMVS Manufacturer Readiness Guidance Page 24

25 Term GAMP GTIN MAH Multi-market pack National Blueprint System National System NTIN Meaning Good Automated Manufacturing Practice (GAMP) is a set of guidelines for manufacturers and users of automated systems in the pharmaceutical industry which describe a set of principles and procedures that help ensure that pharmaceutical products have the required quality. Current version is the 5 th edition of the GAMP Guide published by ISPE in Global Trade Item Number (GTIN) - The GS1 Identification Key used to identify trade items. The key comprises a GS1 Company Prefix, an Item Reference and Check Digit. See also NTIN. Acronym used for Marketing Authorisation Holder and Manufacturing Authorisation Holder in the EU-FMD. The term MAH Manufacturing Authorisation Holder(s) when used in this paper will follow the usage as agreed by the ESM stakeholders and will, for the purposes of these papers, includes both manufacturers and parallel distributors engaged in repackaging to the exclusion of contractors and subcontractors involved in the manufacturing process but not responsible for putting pharmaceutical products on the market. For the avoidance of doubt, a manufacturer engaging contractors or subcontractors to produce on its behalf shall be considered the Manufacturer. Also referred to as multi-country pack and sometimes known as common packs. A medicine pack where the packaging layout allows the sale in different countries in Europe. The term multi-market pack has been introduced for those packs where the possible target countries are using different national systems for medicines verification. In the case of multi-market packs it is not possible to say in which market the pack will eventually be dispensed. It is therefore necessary to send the pack serial data to multiple markets, or, to be precise, to all the national systems that cover the markets where the packs may be presented for dispensing. A system functionally equivalent with the national systems but operated by the European Medicines Verification Organisation (EMVO) on behalf of the respective national stakeholder organisations. A system in the European Medicines Verification landscape that serves as the verification platform for one country. Pharmacies or other registered parties in this country such as wholesalers check a product s authenticity using a connection to this system. National Trade Item Number (NTIN) - A coding scheme, administered in the Healthcare sector by a national organization for which a GS1 Prefix has been issued to permit its uniqueness within the GTIN pool but without assurance of full compatibility with GTIN functionality. The result is a product identification number assigned by a third party (not the brand owner or manufacturer). Example: the CIP (Club Inter Pharmaceutique) in France administered by the French Health Products Safety Agency (AFSSAPS). See also GTIN EMVS Manufacturer Readiness Guidance Page 25

26 Term Randomisation Serial Number Variable Coding Meaning From EFPIA European Pack Coding Guidelines: In order to provide a reasonable level of complexity within the serial number, the probability that a valid serial number can be guessed should be a minimum of 1 in 10,000. Also, in order to minimise the opportunity for a counterfeiter to estimate the randomisation pattern from two or more samples, the following randomisation rules or equivalent apply: Given a sufficiently large set of (randomised) serial numbers for a product, the randomisation substrings of the serial numbers2 have to fulfil the following randomisation criteria: The randomisation substrings must be equally distributed. The randomisation substrings must be independent. The randomisation substrings must not be built using an algorithm that is easy to find out when knowing the given set of serials or a subset thereof. Serial ID s shall not be reused within the shelf life of the product plus a period of seven years. A serial number is a unique number that is assigned for the unique identification of an object. Common usage has expanded the term to refer to any unique alphanumeric identifier for one out of a large set of objects. Refers to the data that is applied at line such as batch / lot number and expiry date (which remain constant for the whole batch) and serial number (which varies for each pack). The term is often used to refer to any data that is printed at line (as opposed to data that forms part of the artwork) and may therefore include data that strictly speaking is fixed for the product / SKU such as the GTIN or other product codes. EMVS Manufacturer Readiness Guidance Page 26

27 7 Questions and Answers Q: When will the project start and how long will it run? A: The European Medicines Verification System (EMVS) will become operational in This is not a time-limited pilot but an implementation of the key components of the stakeholdergoverned solution proposed by the joint stakeholders in real-life ahead of the publication of the European Commission s Delegated Act on Safety Features. The joint ESM stakeholders consider the EMVS as likely to constitute the key solution for future implementation of the Falsified Medicines Directive and therefore plan to prove the efficiency and to demonstrate the viability of the EMVS approach by deploying the key components in the course of 2013: The European Hub, interfaces to manufacturer and parallel distributor systems and to the national systems as well as the template of a National Blueprint System, supported by the EMVO (European Medicines Verification Organisation), a not-for-profit organisation responsible to establish and manage the European Hub and support the operation of the European Medicines Verification System. Q: Who would have access to data in the first phase of the system? A: Several principles regarding data access have been agreed by the joint stakeholders: Ownership is generally determined by who generates the data Transactional data belongs to the pharmacist, or in relation to wholesaler verification, to the wholesaler. However, relevant stakeholders will need to see certain data to help investigate when there is a verification failure, a product recall or a level of unusual activity related to a specific serial number, in accordance with national circumstances. Q: How far in the chain is the initial EMVS implementation going to reach, will it stop at the blueprint or go further on in the supply chain? A: See section 3.2 EMVS Scope and Relevance for Manufacturers. At the present time the confirmed scope extends as far as the National Blueprint system. As the NBP has the full functionality of a National System, that should allow to work through the key end-to-end use cases. However see answer to the following question. Q: Is the initial EMVS implementation going to have an interface with the German / Dutch pilot? A: There are on-going discussions with the German securpharm team aimed at establishing a co-operation between the ESM and securpharm. If successful, then securpharm could become the first live National System that would be linked to the EMVS. EMVS Manufacturer Readiness Guidance Page 27

28 The Dutch pilot has a different focus to the ESM and SecurPharm: It is not aimed directly at responding to the EU-FMD but is an initiative driven by the need of various supply chain partners to improve and simplify the exchange of product master data on the base of the GS1 coding system. Item-level serialisation is not the primary aim of the Dutch initiative but other than ESM and SecurPharm, the Dutch project extends the scope for item coding to Primary Packs. EMVS Manufacturer Readiness Guidance Page 28