Product Lifecycle Management: A European Perspective By Salma Michor, PhD, RAC

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roduct lifecycle management (PLM) can be defined as the process of managing the entire lifecycle of a product from its conception, through design and manufacture, to service and disposal.1 Products that have been put on the market change over time and this process must be managed as it moves through its successive stages.2 PLM has its origins in the automotive and other engineering industries; the main aims were to reduce time to market, reduce cost, improve quality, optimize

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processes and reduce waste, utilizing workflow. The pioneer in PLM was American Motors Corporation with the introduction of computer aided design (CAD). Other systems include computer aided manufacturing (CAM) and product data management (PDM). Although PLM software solutions are commonplace in engineering industries, similar software and services solutions represent a nascent market for the pharmaceutical industry.3 In the pharmaceutical and medical device industries, lifecycle management plays an important role that is foreseen in national laws and regulations. On 10 June 2008, the EU Member States approved a new draft Commission Regulation concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products, which will replace existing Regulations (EC) No. 1084/20034 and 1085/2003.5

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Legal Basis and Variation Application Process Regulations (EC) No1084/2003 and (EC)1085/2003 address the issue of variations and postregistration changes to products licensed via the Mutual Recognition Procedure/ Decentralised Procedure (MRP/DP) and Centralised Procedure, respectively. The idea was to provide a quick, simple notification procedure to enable the introduction of certain minor changes without prior evaluation by the Reference Member State (RMS) in an MRP/DP product. This was, however, foreseen only for those types of changes that did not affect the product’s approved quality, safety or efficacy. In cases where an evaluation was necessary, it would be done by the RMS for MRP/DP products and by EMEA for centrally registered products. Variations to registered products in the EU are classified as: • Type Ia: Examples include: 1. change in the marketing authorisation holder (MAH) name and/or address 2. change in the name and/or address of an active substance manufacturer where no Ph.Eur. Certificate of Suitability is available 3. change in the finished product manufacturer name and/or address • Type Ib: Examples include: 1. change in the name of the medicinal product 2. minor change in the manufacturing process of the active substance 3. change in test procedure for an active substance or starting material, intermediate or reagent used in

the active substance manufacturing process that includes a replacement or addition of a test procedure Type II: Any change that is not a Type Ia or Type Ib, but is also not so major as to warrant a line extension or new application is considered to be a Type II (major) variation. For the sake of clarity, line extensions are changes that fall outside the normal definition of a variation and need to undergo a new evaluation, albeit abridged, by the Competent Authority. Examples include the same active ingredient but a different dosage (200 to 400 mg) or different dosage form (capsules to effervescent tablets).

Both Type Ia and Ib variations are considered to be minor whereas type II variations are those that cannot be deemed to be minor. Type Ia Variations For Type Ia variations, the MAH must submit a variation application simultaneously to the RMS and the Concerned Member States (CMSs) where the medicinal product has been authorized. In order to assist this process, the Commission has published Guideline on dossier requirements for Type IA and IB notifications6 and a harmonized application form, “Application for variation to a marketing authorisation.” Both these documents are available on the Internet under Notice to Applicants Vol. 2C: Regulatory Guidelines. The following documents are needed for a Type Ia variation: • all necessary documents including all amendments • list of the CMSs and an indication of the RMS • relevant fees A separate application must be filed for each variation unless consequential changes that can be bundled are involved. Consequential changes to the Summary of Product Characteristics (SPC), labeling and/or the package insert are considered to be part of the variation and do not need a separate application. If all requirements are met, the RMS Competent Authorities acknowledge the application’s validity within 14 days following receipt of the application and inform the other Member States involved and the applicant accordingly.

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Type Ib Variations The procedure for Type Ib variations is the same as for Type Ia variations. A variation is sent simultaneously to all Member States where the product has been approved, i.e., the RMS and CMSs. The documents needed are the same as noted above for Type Ia variations and consequential changes can be bundled into one application. The single notification must contain a description of the relationship between the consequential Type Ib variations. If all requirements are met, the RMS Competent Authorities acknowledge validity of the application and start the procedure. If, within 30 days of the date of the acknowledgement of receipt of a valid application, the applicant has not received a negative opinion from the Competent Authority of the RMS, the variation can be deemed to have been accepted. In case of a negative opinion the MAH may, within 30 days of receiving the opinion, amend the notification. Type II Variations For Type II variations, the applicant must submit an application simultaneously to the RMS and CMSs, accompanied by the following documents: • relevant particulars and supporting documents referred to in Articles 8 to 12 of Directive 2001/83/EC or Articles 12 to 15 of Directive 2001/82/EC • supporting data relating to the variation applied for • all documents amended as a result of the application • addendum to or update of existing expert reports/overviews/summaries to account for the variation applied for • list of the Member States concerned by the application for the major Type II variation and an indication of the RMS for the medicinal product under consideration • relevant fees as specified in the applicable national rules in the Member States concerned4 Each Type II variation must be applied for separately; consequential changes can be bundled together with an explanation of the relationship between the changes. Where a variation requires consequential revision of the SPC, labeling or package leaflet/insert, this is considered as part of the variation. The RMS will acknowledge the validity of the application. Within 60 days, an assessment report must be written by the RMS and a draft

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decision circulated among the CMSs. The assessment period may be reduced or increased to 90 days. Interim Safety Restriction6 This is an interim change to product information related to: the indications, posology, contraindications, warning, target species or withdrawal periods due to new information affecting the product’s safe use. Centralised Procedure In the Centralised Procedure, the Type Ia and Type Ib variations are sent to the Central Information Group. The documents needed and the timelines are similar to those noted above for MRP/DP authorizations. For Type II variations, the following documents need to be submitted: • supporting data relating to the variation applied for • update or addendum to quality summaries, nonclinical overviews and/or clinical overviews; when nonclinical/clinical study reports are submitted, their relevant summaries should be included in Module 2 • for variations requested by CPMP following assessment of a Follow-Up Measure/Specific Obligation or Periodic Safety Update Report (PSUR), a copy of the EMEA outcome letter should be annexed • if changes applied for are class-labeling statements as requested by CPMP, a copy of the CPMP request should be annexed • if changes affect the SPC, labeling and/ or package leaflet, the affected revised product information must be submitted; please note all Annexes I , II and III need to be provided • for proposed consequential changes, the MAH must include a description of the relationship between the concerned change(s) in the application form to justify that they are consequential • applicable fee(s) New Proposed Regulation The main objective of the new regulation is to establish a simpler, clearer and more flexible legal framework, while at the same time keeping the same level of health protection. The idea is to reduce the number of variations to be assessed to those that really impact product quality, safety and/

or efficacy. In this respect certain minor variations that would normally fall under the notification system could be bundled and notified annually.7

Pharmaceutical Product Lifecycle Management Technology Driven by increasing regulatory pressure and competition, pharmaceutical companies are starting to adopt PLM software and services. This regulatory pressure forces companies not in compliance to implement costly software solutions under very tight deadlines. This in turn costs companies millions of dollars worth of resources and can prove to be very capital intensive. Although it may take many years of intensive work to research, develop, manufacture and register a product, the most resourceintensive phase of bringing drugs onto the market is postregistration. Companies must ensure that they not only meet the regulatory requirements by applying for variations, but also are in a position to ensure traceability. A company with a poor postregistration change control system is likely to end up in noncompliance. Numerous software solutions are available; however, due to the diversity of postregistration issues, commercial software on offer may not yet interconnect properly. Document Management It is common practice today for pharmaceutical companies to use document management systems such as EMC Documentum. These systems allow all documents to be stored electronically, provide traceability via versioning and ensure controlled access by the use of passwords and electronic signatures. Document management systems can be used at a very early stage in the product lifecycle. Such systems allow for: • appropriate archiving and electronic document management for dossiers, technical files, packaging materials (repository) • versioning and traceability • SOP management Important questions to ask before implementing a document management system include where documents will be located and how they will be retrieved. Security also plays a significant role: how will unauthorized personnel be prevented from reading, modifying or destroying documents? In addition, companies need to have a disaster recovery plan. Other issues to be addressed are related to workflows, document creation and document distribution.

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eCTD This software allows dossiers compiled in a validated document management version system to be saved in the eCTD backbone and sent electronically to the Competent Authorities. The eCTD software has a printing and publishing feature that is very useful during dossier compilation. However eCTD does not provide for document management. Dossiers created in this environment are not versioned and do not allow for traceability. This is a good tool; however, it should not be used to contribute to lifecycle management. Change Control Change control software solutions allow effective control of all postregistration changes to documents. Common change control software such as Trackwise allows effective control of all technical and artwork and labeling changes. The software also has alert functions giving reminders of open tasks and incomplete/open changes. This is a good system to keep track of all postmarket changes ensuring timely delivery and follow-through. To have an effective system, change control software should be backed up by appropriate document management software, either integrated into the system or effectively interlinked. Good change control software should allow: • process flows to be defined • tracking of dossier-/technical file-related changes • tracking of packaging-related changes • lifecycle management tools • SOPs management • appropriate archiving and electronic document management for packaging materials (repository) • revision numbers (versioning) • change control Pharmacovigilance Pharmacovigilance requirements include document management, PSUR management, complaints handling (i.e., product complaints, technical complaints), regulatory assessments (for adverse events), medical information requests (i.e., customer inquiries) and training (employee info and training). Software needed includes: • EudraVigilance database (E2B complaint) + Gateway transmission mode (ESTRI Gateway—ICH M2 compliant) • EVWEB—Web Trader • MedDRA—Medical Dictionary for Regulatory Activities for controlled vocabularies

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EudraVigilance The EudraVigilance Database Management System is the core element of the European pharmacovigilance database. 1. Database requirements Fully compliant ICH E2B (M) pharmacovigilance database (estimated costs = €250,000). 2. The Gateway transmission mode Reports can be transmitted via the Gateway transmission mode. For the Gateway transmission mode an organization must have a fully compliant ICH E2B (M) pharmacovigilance database. 3. EudraVigilance Gateway The sender’s Electronic Data Interchange system (EDI) must comply with the following standards for the EudraVigilance Gateway certification from EMEA: • S/MIME compatible email system using POP/SMTP, direct connection via HTTP(s) or FTP • support for digitally signed MDNs • X.509 digital certificate support • EDIINT/AS1 compliance certification or AS2 interoperability • direct transmittal of XML documents. It is the sender’s responsibility to conform to the EudraVigilance Gateway, which is a certified interoperable product. EVWEB The EudraVigilance DBMS also provides interactive tools to allow “manual” safety and acknowledgement message generation and administration by a user via a web interface called EVWEB. EVWEB is especially designed for small and medium-sized enterprises (SMEs) that do not have a fully ICH E2B (M) compliant pharmacovigilance system and/or ESTRI gateway in place. The EVWEB allows EDI partners registered with Eudravigialnce to: • generate fully ICH E2B (M) compliant safety and acknowledgement messages and securely transmit those messages electronically via the EudraVigilance gateway to any other EDI partner in the EEA • generate medicinal Product Report Messages and securely transmit them electronically through the EudraVigilance Gateway to EMEA where they are processed and stored in continued on page 27

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the EVMPD access EVWEB for query purposes taking into account agreed Community access policies

Digital certificates are provided for access to the EVWEB, which must be renewed at regular intervals. EVWEB also provides access to standard terminology, e.g., MedDRA. 1.The WEB Trader The WEB Trader transmission mode is an integrated component of the EudraVigilance Gateway designed to support SMEs. It allows SMEs to generate, send and receive Individual Case Safety Reports in a secure way to any registered organization within the EudraVigilance community. The WEB Trader is an integrated component of EVWEB and an alternative to using a local gateway and E2B databank.

Conclusion This article reviews product lifecycle management (PLM) in the pharmaceutical sector. Specifically, it examines the legal situation in the EU and how variations to a pharmaceutical product’s technical information, contained in the registration file, need to be tracked carefully, to allow for traceability and ensure safety. The article also discusses some of the available software solutions commonly used or required in the pharmaceutical sector. Due to the regulatory climate surrounding the pharmaceutical sector, all software solutions must take an integrated approach. In some critical areas like pharmacovigilance, electronic reporting of adverse events is mandatory. Many smaller companies are still struggling to get their pharmacovigilance systems up to date and fully functioning, to comply with the legal requirements. However the company may already have a document management system installed that is not E2B compliant. Buying an E2Bcompliant system for only pharmacovigilance activities is cost intensive and a waste of resources. Similarly, the Quality Assurance department may purchase change control software that is not interlinked with the main document management repository. This would mean that all changes would have to be managed manually PLM in the pharmaceutical industry has not yet been fully maximized; the process must begin earlier and be more comprehensive. In addition, the diverse sectors need to interrelate to make for a meaningful PLM process. More and more

companies are looking to PLM software tools to effectively manage product lifecycle, avoid compliance issues and gain a competitive advantage. It can take from six months to two years to successfully implement PLM software in a pharmaceutical company, which implies that the solutions are still very much customized. There is much room for improvement. In addition, companies must realize that only those PLM technologies aligned with business processes will maximize value within the organization.3 F References 1. http://en.wikipedia.org/wiki/Product_lifecycle_management, accessed 20 June 2008. 2. http://en.wikipedia.org/wiki/Product_life_cycle_ management#cite_note-0, accessed 20 June 2008. 3. www.medicalnewstoday.com/articles/82989.php, accessed 20 June 2008. 4. Commission Regulation (EC) No 1084/2003 of 3 June 2003 concerning the examination of variations to the terms of a marketing authorisation for medicinal products for human use and veterinary medicinal products granted by a competent authority of a Member State (Official Journal L 159, 27/6/2003 p. 1 - 23). 5. Commission Regulation (EC) No 1085/2003 of 3 June 2003 concerning the examination of variations to the terms of a marketing authorisation for medicinal products for human use and veterinary medicinal products falling within the scope of Council Regulation (EEC) No 2309/93 (Official Journal L 159, 27/6/2003 p. 24 - 45). 6. Volume 2A—Procedures for marketing authorisation, “Chapter 5—Variations” (updated February 2004). 7. Draft Revision of the Variations Regulations approved 10 June 2008. Authors Salma Michor, PhD, RAC is CEO and Principle Consultant at Michor Consulting e.U., her recently established regulatory consulting business specializing in regulatory affairs and compliance, Quality Assurance, risk management, and interim management. Previously, she worked in the medical device and pharmaceutical industries for companies including Croma Pharma, Wyeth and Chiesi. She is an independent expert for the European Commission and teaches regulatory affairs and clinical strategies at the postgraduate level. She is a member of the Board of Editors for Regulatory Focus and can be reached at [email protected].

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