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- 12. MOVING SERIALIZATION FORWARD: USING AUTOMATED PROCESSES TO CONNECT PHARMACEUTICAL MANUFACTURING WITH THE SUPPLY CHAIN Having studied logistics, Michiel has experience working for the Dutch Department of Defense and in automation systems simulation and analysis. Before joining Swisslog, he spent 5 years optimizing warehouse operations and IT systems for a pharmaceutical wholesaler. Michiel Dutch Department of Defense and in automation systems simulation and analysis
- 13. While the requirements for serialization in the pharmaceutical supply chain are generally regarded as inevitable - counterfeiting is simply too large of a problem to not be addressed - there is some uncertainty around the specifics, particularly globally.
- 14. Regulations are advancing at various speeds around the world and, to date, global standards as to how serial numbers should be formatted have not emerged. This uncertainty has required that pharmaceutical manufacturers move forward cautiously in their approach to serialization. They must take steps to prepare without locking themselves into technologies that may not support future requirements. To that end, many have put in place the systems required to apply and capture serialization data in their packaging processes, but, have, in general, not addressed the impact of tracking these numbers across the supply chain. This is partly due to the nature of the typical pharmaceutical supply chain, which is more dependent on third-party logistics providers (3PLs) for downstream processes than other industries. These providers enable pharma companies to minimize supply chain assets and focus their capital on research and development, but they tend to limit their own investments in automation because short-term contracts don’t enable them to realize a return on their investment within the contract period. The other consideration is the different priorities that have existed in the pharma industry compared to other industries. Where retailers and e-commerce companies, in particular, have adopted warehouse automation to achieve the speed and efciency they need to be competitive, the focus in pharma has been on risk mitigation. Pharma companies have historically been willing to accept some inefciency if it means less risk. Based on those factors, it’s tempting to conclude that this is not a good time for pharma companies to invest in supply chain technology. In fact, the opposite is happening. Serialization requirements are continuing to advance and the process of managing serial numbers requires signicant changes to the IT systems and processes that support the supply chain. Pharma companies are also now increasing their focus on supply chain efciency. Forward- thinking manufacturers are taking steps to address these challenges today by evaluating the processes, software and machinery in the supply chain in light of serialization requirements. They are nding they can make investments that move them closer to meeting future serialization requirements, have value beyond serialization and are exible enough to adapt to requirements as they evolve.
- 15. One area of focus is the IT systems that support the supply chain. Serialization data must be maintained and reconciled across the product, case and pallet in the warehouse and will ultimately be required to be tracked across the supply chain. That adds signicantly to the data being captured and stored; yet, few manufacturers currently have the ability to use that data to achieve product visibility across the supply chain. One problem many face is the fragmented nature of supply chain IT. IT systems have generally been deployed on an asneeded basis, creating a distributed IT support system that isn’t well suited to the future demands of serialization. The process of centralizing these systems will be time consuming in some cases and it isn’t too early to start down that path. This is an effort that makes sense for manufacturers because, in addition to simplifying the management of serialization data, it creates opportunities for them to advance Industry 4.0 initiatives by using big data analytics to reduce risk, improve supply chain performance and gain insights into market requirements and demands. SUPPLY CHAIN IT REQUIREMENTS Another area of focus is warehouse management software (WMS). Most WMS systems in use today have the basic capabilities to support serialization, but may not be well suited to support the supply chain of the future. Introducing state-of-the-art warehouse management software today can help facilitate the evolution to serialization while adding support for supply chain technologies that minimize risk and enable new capabilities. The WMS must be able to support aggregation of salable product serial numbers across cartons and palettes so every unit can be tracked to a specic carton and pallet. That’s generally not too complicated—until you start moving cartons between pallets or products between cartons. In this case, the operator must have the ability to easily update the serial numbers on both the pallet or carton from which product was moved and the pallet or carton to which it was moved. WAREHOUSE MANAGEMENT SOFTWARE REQUIREMENTS 15VOL. ISSUE April 20183 I
- 16. WAREHOUSE MANAGEMENT SOFTWARE REQUIREMENTS Beyond serialization, there are other capabilities that are important to ensure the WMS can support the warehouse as serialization and other warehouse technologies continue to evolve, including ease-of-integration, virtualization and support for automation. Integration with MES and ERP systems is already essential to managing materials in pharma manufacturing. But, this has traditionally required expensive and time-consuming custom programming. Newer generation warehouse management systems are moving away from proprietary protocols and embracing common standards that greatly simplify software integration. This will become more important as systems across the supply chain are integrated to enable product tracking from manufacturing to dispensing. Virtualization is emerging as a key technology that creates a host of new opportunities to improve how warehouses are operated and maintained. Within the WMS, sensor data from processes and equipment is merged with virtual warehouse models and simulations to create a digital copy or shadow of the warehouse. Already, virtualization is enabling functions such as real-time condition monitoring and material ow monitoring and much more is possible. Solutions where this data is used to see into the future by combining real-time data with simulated changes to material ows are not too far away. As it evolves, virtualization will become a valuable tool in the design and implementation of warehouse processes and changes, allowing pharma companies to evaluate the impact of new equipment, processes changes or new products virtually to optimize processes and material ows in the design phase. Virtual reality technology is advancing rapidly and it won’t be long before supply chain and warehouse managers are donning virtual reality glasses to “walk through” and explore warehouse changes virtually in the design phase. A nal consideration for the WMS is its support for automation.
- 17. Many pharma manufacturers already rely on automated storage and retrieval systems to provide materials to manufacturing. These systems increase the accuracy of intralogistics processes; however, compared to the systems available today, they are expensive, lack exibility and could be difcult to implement. This limited their application for large companies with stable processes. New modular automation systems and collaborative robotics work with automated guided vehicles (AGVs) to make automation more exible, cost-effective and easier to implement. Downstream from manufacturing, new requirements, including serialization, SKU growth, and the need to support smaller batches, has increased the logistics effort in general, which makes automation of these processes more attractive. Companies that were previously limited in their ability to use automation can now tap into new less expensive and easier-to- deploy solutions to address these challenges. These include: • Production order picking systems that allow operators to easily and accurately collect the products and quantities required for the next production order on a pallet that is then delivered to the production line. These systems bring product to the picker to eliminate walking distance and ensure controlled picking processes through scanning, line clearing and pick-to-light technology. • Pallet systems that provide automated storage of raw materials, semi-nished goods and nished goods, which can include goods-to-person stations that support order preparation, production and shipping. These systems can be used to store semi-nished goods in the warehouse to enable just-in-time delivery to production. They can also support different temperature zones for manufacturers who must maintain tight temperature control over some products. They use automated cranes to move pallets within storage and AGVs to transport pallets from production and packaging lines. • Shuttle systems and miniload cranes that provide dynamic storage and retrieval of light goods. Shuttle systems can consolidate and release totes with product at high rates in sequence. USING AUTOMATION TO MITIGATE RISK 17VOL. ISSUE April 20183 I
- 18. Miniload cranes transport light goods like totes and trays fast and reliably for production storage. The crane moves up and down a single aisle to store and retrieve products in a single-deep or doubledeep conguration. Although these technologies have been around for awhile, new modular designs, smart software and increased performance now make them even more attractive for pharma companies. While older WMS systems are not designed to support automation, requiring an additional software layer between the WMS and the automation system, new modular, automation-centric WMS platforms eliminate this extra layer and greatly simplify the transition to automation. By automating product movement in packaging, pharma manufacturers can minimize the risk of human error, increase efciency and improve the management of product recalls. A newer, automation-centric WMS can enable this transition while also providing easier integration with other software systems, support for virtualization and the ability to leverage self- learning capabilities for process optimization in the future THE END OF THE ROAD FOR SERIALIZATION While the long-term goal of serialization is track- and-trace capabilities across the supply chain, the initial requirements widely focus on the rst and last leg of the supply chain: the manufacturing packaging process and the retailers and pharmacies dispensing pharmaceuticals to customers. In the near-term, pharmaceutical distributors are exempt from capturing and communicating serialization data. The impact of serialization at the end of supply chain is similar to that at the beginning. Hospitals and pharmacies are preparing for serialization but uncertain as to when compliance will be required. Hospitals, in particular, have implemented GS1-compliant automated inventory management systems that provide track-and-trace capabilities. This is particularly valuable in larger hospitals that may have products distributed around the facility—and may be required to locate a specic batch of a product subject to recall. Similar to the manufacturer’s packaging operation, these pharmacies are turning to automated storage and retrieval systems to minimize the risk of human Automated pallet handling systems, such as the Vectura stacker crane from Swisslog, can be used to maximize space efciency in the storage of raw materials, semi-nished goods and nished goods.
- 19. ABOUT SWISSLOG Swisslog designs, develops and delivers best-in-class automation solutions for forward-thinking health-systems, warehouses and distribution centers. We offer integrated systems and services from a single source – from consulting to design, implementation and lifetime customer service. Behind the company´s success are 2,500 employees worldwide, supporting customers in more than 50 countries. Swisslog is a member of the KUKA Group, a leading global supplier of intelligent automation solutions. error. Automated storage systems not only eliminate picking errors and increase safety at the dispensing stage, but also create a more efcient pharmacy workow. AN INDUSTRY IN TRANSITION The challenge of serialization is a massive undertaking for the pharma industry, which is still clouded by uncertainty. Yet, pharma manufacturers have made signicant progress in establishing the foundation for compliance. They have the technology and processes in place to track materials as they move through manufacturing to become semi-nished goods and then nished goods and many are now using the impetus of coming regulations to replace outdated WMS software and increase their use of automation to mitigate risk and bring new levels of intelligence and sophistication to the pharmaceutical supply chain.
- 20. THE USE OF GAMMA STERILIZED, PRE-FILLED SYRINGE PLUNGERS FOR READY-TO-USE PRIMARY PACKAGING COMPONENTS Educated in pharmaceutical science, chemical engineering and organic chemistry, Philippe Le Gall joined the field of elastomeric closures for injectables in the late 1980’s. His work experience, mostly with Stelmi which became Aptar Pharma in 2012 has included tenures in technical services, quality, business & marketing, project management, regulatory affairs and pharmaceutical compliance. Today he is Director, Technical Support & Regulatory Affairs for Aptar Pharma. Philippe Le Gall Director, Technical Support & Regulatory Affairs, Injectables at Aptar Pharma
- 21. Historically, injectable drugs have mostly been packaged aseptically, with pharmaceutical laboratories carrying out the sterilization of the primary packaging components internally. The conventional solution is for pharmaceutical laboratories to sterilize components before use, generally using steam. Yet, the alternative solution is to use packaging components which are sterilized beforehand, by manufacturers. In this instance, the syringe is sterilized with ethylene oxide after assembly of the tip cap’s needle shield. The syringe’s rubber plunger is then sterilized by gamma irradiation, which has proved to be an efficient means of sterilizing packaging components. This case study by Aptar Pharma explores how gamma sterilization effectively provides pharmaceutical laboratories with all the necessary safety requirements, to ensure product release. Arnaud Fournier graduated from IPAG Business School Paris and is specialized in Marketing. He joined Aptar Pharma in 2004 as Marketing Project Manager and oversaw marketing studies. Arnaud changed position in 2013 to Business Support Manager, and 2018 to Senior Business Project Manager. He now supports and promotes Aptar Pharma’s range of elastomeric components for vials and Pre-Filled syringes, and is involved in the developments of new products and more particularly PremiumCoat™, within Aptar Pharma’s coated range of products. Arnaud Fournier Senior Business Project Manager, Injectables at Aptar Pharma
- 22. Ready-to-Use gamma sterilized components The transfer of washing and sterilization operations from the laboratory to the plunger supplier has several advantages for pharmaceutical laboratories: • Reduction in human reliance • Improved productivity • Economic advantages – reduced need to invest in equipment • Reduced stock levels Addressing issues of risk Ionizing radiation has the advantage of sterilizing syringe plungers within their packaging. The risk of contamination is reduced to the handling stage, when components are transferred to the sterile zone of drug product ll & nish. At this stage, the exterior of the double packaging is chemically decontaminated before removal. Equally, containers equipped with double-port transfer systems (Rapid Transfer Port - RTPs) can be used for the aseptic transfer of materials and components in isolators and RABS. Gamma rays are highly penetrating and can be used for treating whole pallets, with the added benet that exposure dose is well controlled and can be easily recorded. Ensuring a regulatory environment The Pharmaceutical cGMPs Guidance for Industry states that containers and closures should be rendered sterile and, for parenteral drug products, nonpyrogenic. The process used depends on the container type or its closure material, and written evidence must specify the validation and revalidation of these processes. The sterilization of rubber plungers requires the close involvement of three different parties: the elastomeric component manufacturer, the sub-contractor performing the sterilization and the pharmaceutical laboratory using the sterilized components. Compatibility of the elastomer formulation Gamma irradiation can lead to the degradation of some materials. Its inuence on the rubber formulation properties must be studied to ensure the performance characteristics of the plungers are not affected by the sterilization. The irradiation inuence on a given property can be different depending on the formulation. Yet, the resistance to gamma sterilization can be modied by the selection of a suitably-designed rubber formulation. Some formulations are more sensitive to radio sterilization, and the evolution of the property affected is not necessarily proportional to the level of radiation received. Predicting the inuence of ionizing radiation on a given type of rubber is therefore impossible without research. The inuence of gamma radiation The inuence of gamma irradiation must be assessed with regards to Figure 1: • The mechanical, chemical and functional properties of the formulation
- 23. • The biological properties of the formulation for irradiation levels of 25 and 50 kGy, corresponding to one and two radio sterilizations respectively, according to the recommendations of the standard pharmacopoeias. Sterile plungers: Validation Obtaining “Ready-to-Use” syringe plungers requires control of all applicable pharmaceutical requirements, which mainly affect the nishing steps (washing and sterilization). The manufacturing process must be validated to ensure the required quality. Validation of washing procedures Historically, preparation of pharmaceutical plungers has been carried out by pharmaceutical laboratories themselves. These procedures for preparing primary packaging components are precisely described in the registration les of each injectable drug which has been registered with both the FDA and the European regulatory authorities. These operations are now largely undertaken by component manufacturers who market "Ready- to-Sterilize" products. Regulatory requirements concern mainly the quality of the uids used, the environment and the validation of the procedure. The quality of water to be used is clearly dened in the Guidelines issued by the FDA and the EMEA (1) (2). In both cases, it must comply with the “Puried Water” or “highly puried water” Monographs for the washing and rst rinsing operations, and the “Water for Injection” Monograph for the nal rinsing. The environment should not allow any re-contamination after washing. The sensitive item being packaged should take place in an ISO 5 standard classied zone. To meet these requirements, Aptar Pharma uses the UltraClean 6 evolution washing process for plungers, obtaining the highest particulate and microbiological cleanliness. 23VOL. ISSUE April 20183 I Penetrability Fragmentation Functional tests (Eur. Ph.) Self-sealing Biological tests Cytotoxicity Hardness Tensile strength Modulus 100 Mechanical properties Elongation at break Compression set Turbidity Reducing matter Acidity, Alkalinity Physical / Chemical tests (Eur. Ph./USP) Zinc Chlorides UV curve, etc. Figure 1
- 24. Validation is divided into three successive phases. • Installation Qualication (IQ) - Checks all the equipment is installed according to the manufacturer’s specications • Operational Qualication (OQ) - Demonstrates that equipment functions as anticipated under normal and extreme usage conditions. • Performance Qualication (PQ) - Shows that the process allows achievement of predetermined product specication. Testing particulate and microbiological cleanliness does not just rely on the washing procedure. All manufacturing processes related to plungers must be optimized to fully limit contamination risks. This optimization allows contamination below 0.1 CFU/cm2 before sterilization to be absolutely guaranteed. Aptar Pharma has prepared a unique DMF for its production sites, ensuring the same quality is provided at every source. Validation of sterilization procedures Validation of the sterilization procedures with gamma irradiation has four steps: Step 1: Determining the maximum dose Determining the permitted maximum irradiation dose concerns both the product itself and its packaging. The most relevant tests are described in the European Pharmacopoeia, applicable to rubber closures (3). They reveal the effect of gamma sterilization on the product’s chemical and functional properties. These tests may be augmented by measuring the mechanical properties in standardized test samples. Figure 2
- 25. The results obtained from chlorobutyl rubber closures (Figure 2) show great stability of all properties studied after exposure to 25 and 50 kGy. Similar results are obtained with bromobutyl rubber formulation tailored for irradiation. The elastomer-based formulations offered by Aptar Pharma for sterile plungers are designed to be compatible with radio sterilization. Exposing the plungers to 25 and 50 kGy either does not affect the investigated properties or has a negligible inuence on these properties. Even when irradiated and aged, these formulations do not approach the limits described in the principal norms and pharmacopoeias. The inuence of ageing was also studied. The tests listed in Figure 1 were performed after one and two years. No notable change in the chemical prole of the elastomer formulation was observed. Step 2: Determination of the sterilizing dose The following stage involves selecting the sterilizing dose. To perform this task, Aptar Pharma has chosen to use ISO regulation 11137 (4) relating to the sterilization of medical devices and, more specically, to use Method 1, which involves working from information about bioburdens. A determination of the bioburden is made from three different batches of syringe plungers and a table provides the dose at which SAL (Sterility Assurance Level) is 10-2 for this bioburden. This value is then used as the verication dose. A sample of 100 syringe plungers is then exposed to this verication dose and the sterility of each product is tested individually. If there are less than two positive tests out of 100, the sterilizing dose where SAL is 10-6 is determined using the same table. Once the dose is determined, a periodic audit must be conducted to conrm the validity of this sterilizing dose. Step 3: Determining dose mapping Gamma sterilization permits full pallets of product to be processed. Therefore, the rst step consists of determining the conguration which allows for the most homogenous irradiation dose possible to be obtained between the different points within the load being treated. Dose-mapping is validated from three different loads. Validation involves distributing the dosimeters to different points within each load and therefore determining the position of the “cold point (minimum dose)” and the position of the “hot point (maximum dose)” so that exposure relating to these points can be compared to a ‘routine’ or reference point. Afterwards, a single dosimeter will be necessary for each load and will be placed at the ‘routine point’. From the irradiation dose measured at the routine point we can deduce the doses received at both the “cold” and “hot” points and, therefore, ensure that each point within the load has at least received the sterilizing dose without exceeding the set maximum dose. Step 4: Determining the expiration date The expiration date is determined following an aging study conducted on the nished product. This allows packaging integrity to be checked alongside the behavior of the irradiated product. Packaging integrity is essential in terms of preserving sterility. The packaging of the sterilized components must provide protection throughout its shelf life. This may be demonstrated by checking the vacuum level in the bags prior to use. 25VOL. ISSUE April 20183 I
- 26. Step 5: Protection of the sterile components The packaging of the sterilized components must provide protection throughout its shelf life. Double packaging is a minimum requirement. However, the sterility of the component depends on the ability to verify that the packaging system has not been damaged during transportation and handling. A suitable packaging system allows to check for its integrity at the point of use. Conclusion Supplying “Ready-to-Use” primary packaging materials is the next logical step resulting from the supply of “Ready-to-Sterilize” components. Gamma sterilization provides the pharmaceutical laboratories with all the necessary safety requirements. The issue of responsibility can be settled within a contractual context where the key points to consider are the validation procedure, the validation les and the data leading to the product being released. References (1) FDA Guidance for Industry. Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice. September 2004. (2) EMEA Note for Guidance on Quality of Water for Pharmaceutical Use. May 2002. (3) European Pharmacopoeia 5.0. 3.2.9. Rubber Closures for Containers for Aqueous Parenteral Preparations, for Powders and for Freeze-Dried Powders. (4) ISO 11137-2:2013 Sterilization of health care products -- Radiation -- Part 2: Establishing the sterilization dose ABOUT APTARPHARMA Aptar Pharma is part of AptarGroup, Inc. (NYSE: ATR), a leading global supplier of a broad range of innovative dispensing and sealing solutions for the beauty, personal care, home care, prescription drug, consumer health care, injectables, food and beverage markets. AptarGroup is headquartered in Crystal Lake, Illinois, with manufacturing facilities in North America, Europe, Asia and South America. For more information, visit aptar.com/pharma.
- 27. www.hhmglobal.com For any queries related to the Portal, Features, and Services contact us at support@hhmglobal.com Plan.. Execute... Explain.. Online Marketing in your control... like never before www.hhmglobal.com is a leading B2B industry portal designed for the Healthcare Sector representing the most advanced healthcare industry information that allows our clients to reach both ends of the healthcare facility procurement chain. The highlight of www.hhmglobal.com is its ability to adjust with your marketing standards and timelines, along with methods that allow you to target and market based on your selected audience and geography. It also allows you to opt for the proven methods: Ø Knowledge Base Marketing Ø Dedicated E-mail marketing with reports Ø Banners on PPC and PPM Ø Company and Product Publicity with SEO www.worldpharmatoday.com or Advertising Queries: e-mail : kathryn@worldpharmatoday.com call to: + 91 88268 49084 Under this option we promote the content delivered by client in the form of Articles, Webinars, White Papers, Press Releases, News etc for entire year. The content which we receive we will also do the below promotional activities to give maximum visibility. Ÿ Will be posted under relevant section of World Pharma Today. Ÿ Will be also posted in our Newsletter which will circulate every week to registered subscribers Globally of World Pharma Today. Ÿ Content will be posted in social media also to give more popularity. Content Marketing Like Never Before
- 28. THE FALSIFIED MEDICINES DIRECTIVE - ARE YOU READY? Based at Leicester, UK, Gill has responsibility for artwork management services and structural design. Gill has responsibility to ensure Cirrus’s various studios offer a full consultancy service covering constructional & graphic design, print and artwork management. Gill has 20 years’ experience in artwork management for pharmaceutical and healthcare industries with roles covering pre- press, artwork and structural design. A graphic design graduate by training, Gill had an early career in the design industry. Gill’s experience covers all paperboard packaging formats including cartons, labels, and leaflets and her role involves a close working relationship with customers. Gill regularly presents to the world’s leading healthcare companies and has an in-depth knowledge of the changing packaging requirements of this highly regulated sector. Gill Wright Design & Development Director Cirrus
- 30. The Falsied Medicines Directive - are you ready? The Falsied Medicines Directive 2011/62/EU, which is due for adoption in February 2019, will require pharmaceutical companies to apply serialisation codes to every applicable pack (OTC and some minor exemptions). As a consequence, artwork changes will be required, which all too often are treated as a rushed after-thought. The World Health Organisation estimates that around 50% of product recalls are still attributed to artwork errors and mislabelling. The industry’s ‘speed to market’ requirements have put more pressure on artwork teams across all aspects of the supply chain to deliver ‘right rst time’ and ‘on- time’ for critical product launches. However, it is essential that all brand-owners consider the required changes in good time. Pharmaceutical artwork is a specialist market and artwork creation is often complex so selecting an experienced partner can prevent damaging hard- earned reputations or even product recall. The impending legislation will affect all prescription medicines for the European market. The rst step to comply with this legislation is to get your artwork amended and approved. What will change? The legislation requires a ‘unique identier’ to be placed on product/packaging so it offers full traceability throughout the supply chain. This takes the form of a data matrix code, a randomly generated serial number as well as a national reimbursement number, if present, and batch and expiry dates. It can’t be too hard to add these extra codes to an existing pack – can it? The addition of a new code is relatively simple but creating the required space and its impact on the pack’s overall design is often more involved than imagined. As well as an area for the code, it will also require a surrounding ‘Quiet Zone’ that further reduces the availability of free space. In the past, this panel on the pack only needed to incorporate a batch code and expiry stamp so the additional code may force text to move onto another panel. As the pack’s graphics are reformatted it is essential that compliance with other existing legislation is not overlooked. The inclusion of the proprietary name, generic name and dosage to appear on three opposing faces also needs to be taken into consideration. The Falsied Medicines Directive also requires a brand-owner to add a tamper-evident feature to their packaging which can have a signicant impact on a pack’s real-estate. Tamper evident labels require varnish and text free space so this adds further pressure on already busy pack designs. If the brand-owner decides not to use a tamper- evident label, a mechanical or constructional solution is another option. However in order to achieve this, particularly if the brand-owner is already using a standard reverse tuck-end carton, it may force a move to another carton format, such as a skillet- glued, to further increase available space. It’s here to stay Whatever anyone thinks, Brexit won’t stop the UK implementation of the Falsied Medicines Directive as it was passed into UK law in 2013. Furthermore, the UK Government is being urged to comply with EU legislation to ensure harmonization and avoiding disruptive supply chain issues across Europe. [However, for UK companies, the EMA’s relocation to mainland Europe could have a potential impact leading to another tranche of artwork changes for centrally registered products. The outcome is still unfolding and not yet clear although it is likely will mean a change of MA holder address for centrally licensed products. A changing supply landscape It was previously commonplace for un-audited ‘local’ suppliers to produce market specic artwork, with no asset control of artwork les and even less control if the process was global. The associated risks for error and for non-compliance were high in this scenario. A typical ‘Big Pharma’ organisation, even today, would
- 31. have multiple vendors, some compliant and some not. The market is seeing a signicant shift to control artwork lifecycle changes and new product launches via a truly complaint artwork partner. Why do things still go wrong? In order to comply with the new directive it is essential to allow adequate time for potentially signicant artwork changes. The pressure to get compliant products quickly into the marketplace can impact on the quality of the artwork brief. This inevitably results in more artwork cycles due to errors and omissions whilst further extending lead-times and escalating costs. The issues can be numerous and largely stem from a lack of understanding of what’s required. In order to develop the right artwork briefs, it’s essential to build a partnership that is set-up for success with both parties working to get the best output. Leading artwork providers will be dealing with many different customers, with 1000s of artwork requests, all with differing needs and requirements. All customers are different and an agency will need to be sure it is delivering exactly what’s required. Selecting the right artwork partner Pharmaceutical artwork is a specialist market and any supplier’s workow should be compliant with PS9000 / ISO9001, audited and dedicated to providing an artwork service. A supplier’s artwork systems should t in with your own ways of working and they should have enough capacity to deal with these changes in addition to regular artwork lifecycle tasks. There should also be a clear understanding that the approved artwork le should not require any further manipulation by the print vendor so there are no touch-points in the process. The use of an automated workow will signicantly reduce the potential of any errors. Non-compliance will put both supply and sales at risk. Remember, the clock is ticking…February 2019 isn’t that far away. ABOUT CIRRUS MPS is a leading global provider of value- added packaging solutions to a diverse customer base across the healthcare, consumer and multi-media markets. MPS provides its customers with an extensive array of print-based specialty packaging solutions, including premium folding cartons, inserts, labels and rigid packaging across a variety of substrates and finishes. MPS has over 70 manufacturing locations across North America, Europe and Asia and employs approximately 10,000 people. Cirrus offers a full artwork creation and lifecycle management service as well as packaging design, print and artwork consultancy. Cirrus delivers an independent service, while enjoying the added benefit of being part of a leading manufacturer of consumer packaging which ensures stability and financial support for large projects. Expert artwork creation and management is available for all packaging components, including cartons, labels, leaflets, foils, information booklets, sachets, shrink wraps and technical documentation.
- 32. SOLVING THE PATIENT RECRUITMENT DILEMMA Katheryn Shea is Global Biobanking Lead at Brooks Life Sciences. She is an accomplished biobanking expert with 20+ years of industry experience, author of peer-reviewed publications, former President of ISBER, a current member on technical, legal and ethical committees, and an active member of the College of American Pathologists Biorepositories Accreditation Programme. Katheryn Shea Biobank Business Lead
- 33. Patient recruitment is often cited as one of the biggest challenges faced by clinical trial professionals. Many clinical trials fail because sponsors cannot recruit sufficient patients to reach their target sample size [1, 2]. In fact, only 55% of trials reach enrolment targets within their specified patient recruitment period [1]. This causes extensions and time delays which can cost biopharmaceutical companies up to $8 million a day in lost sales [3]. The problem of patient recruitment is industry-wide, affecting all disease areas and all countries in which clinical trials take place [2, 4]. It is further complicated by patient dropout rates of up to 40% in longitudinal studies. Biopharmaceutical companies spend considerable time and money on patient recruitment and retention. The average cost to recruit and retain patients for clinical trials of a single drug is nearly $900,000 [2]. Despite this investment, many patient recruitment efforts fail.
- 34. Why is Patient Recruitment Such a Signicant Problem? There is a large body of scientic literature examining the challenges of patient recruitment and discussing potential solutions to this industry-wide problem. Many factors contribute to difculties in recruiting and retaining patients. The biopharmaceutical industry is becoming increasingly competitive, and often two or more large companies run simultaneous clinical trials in the same disease area. Consequently, these companies must compete for the same population of patients [2]. Patients and physicians are not always aware of, or understand the benets of new clinical trials [2, 4]. Clinical trial failures are often widely publicized in the mainstream media which can cause mistrust in the general population. Certain community groups may have social and cultural aversions to clinical trials [2, 4]. Many solutions have been proposed to solve the challenges of patient ecruitment and retention. These include: increasing public awareness through videos, podcasts, advertising and social media; offering incentives to clinical trial staff and participants; training staff on patient engagement; face-to-face discussions with patients; and trialing new patient engagement methods such as gamication, medical animations and patient engagement platforms [5]. However, due to the complex nature of clinical trial design, most patient recruitment studies have been qualitative and few proposed solutions have been rigorously tested by quantitative, controlled scientic experiments [5]. Sample Repurposing Can Solve the Problem of Patient Recruitment Reusing stored clinical samples in multiple non-interventional research studies can relieve some of the burden of patient recruitment. In the last decade, research technologies and tools have advanced, and many newer assays are signicantly more sensitive, and require less starting material than older technologies. Therefore, it is now possible to generate more data from clinical samples. With the correct patient consent, samples can be aliquoted and used across multiple studies. Many government and medical research funding agencies advocate for the reuse of clinical samples. The Medical Research Council in the UK recently published ethical guidelines stating that research organizations should actively maximize the research use of all research samples [6]. Sample repurposing offers signicant nancial and time- saving benets to biopharmaceutical companies. It reduces not only patient recruitment and retention costs, but also physician and clinical staff costs, clinical procedure costs and clinical trial site costs. Together, these factors can add up to more than 50% of the total cost of a clinical trial [2]. Therefore, sample repurposing can translate into hundreds of millions of dollars in savings. Reusing existing samples can also accelerate clinical trial timelines as it can take years to organize facilities and recruit staff and patients for a new clinical trial [2]. Careful planning is required to reuse clinical samples. Under current US law, de-identied samples can be used in new research studies without further consent [7]. However, this may change in the future. Furthermore, other regulatory regions require adequate informed consent from patients before their samples can be repurposed. This is called ‘broad and enduring’ or ‘generic’ consent [6]. Broad consent is not considered valid in some EU member states [8]. Therefore, if conducting trials in those countries, sponsors could use two- part consent, which asks for separate consent for the planned study and for storage and future use [6]. Informed consent protocols should be culturally sensitive to all patients [9]. Sample processing and storage procedures will also affect whether clinical samples can be used in future studies [6]. Sample integrity
- 35. impacts the quality of any data generated from that sample [10]. For clinical samples to be successfully repurposed, they must be collected, stored and transported using procedures that maintain sample integrity and comply with international regulatory requirements. Sample Hub™ Integrated Lifecycle Management Integrated, standardized clinical trial sample management allows companies to repurpose samples for multiple research studies. Housing samples within a single multicenter platform can streamline workow, accelerate clinical trial timelines and maximize the value of clinical samples. Brooks Life Sciences’ Sample Hub platform is a global interconnected network of sample storage, transport and processing biorepositories. The biorepositories are staffed by a team of experts who can help clients navigate the complex international regulatory landscape when designing and running multicenter clinical trials. Sample Hub facilities and staff operate with standardized training, procedures, protocols and quality control systems. This ensures all sample handling and data generation is standardized across multicenter clinical trials and across multiple clinical trials. Sample Hub is a exible, integrated platform that can be customized to each client’s individual sample management needs. This includes managing sample handling, analysis and storage for active studies; archiving samples for completed studies; and planning and project managing future studies. By consolidating samples within the Sample Hub platform, biopharmaceutical companies can reduce the cost and timeline of clinical trials. This is because samples are stored, transported and analyzed within a single platform which streamlines workows and minimizes sample handling delays. Samples can be retrieved within 24 hours and all vendor relationships are managed at a central point, sending samples to central labs, specialty labs or CROs as required. This integrated system ensures sample integrity, chain of condition, chain of identity and chain of custody are maintained throughout the sample management process. The platform also offers connected informatics and real-time sample tracking. Caption: Brooks Life Sciences' Sample Hub platform offers integrated clinical sample management solutions to help solve the problem of patient recruitment and reduce the cost of clinical trials. 35VOL. ISSUE April 20183 I
- 36. ABOUT BROOKSLIFE SCIENCES Brooks Life Sciences provides innovative, comprehensive clinical sample management solutions. Brooks Life Sciences’ global network of biorepositories and sample bioprocessing laboratories ensures chain of condition, chain of identity and chain of custody for all client samples. Biorepositories and co-located sample bioprocessing laboratories are strategically located in North America, Europe and Asia and staffed with clinical sample management and QC/QA experts. All facilities adhere to consistent best-practice protocols, with certification that includes FDA approval, ISO 9001:2015 accreditation, CAP and CLIA certification. Brooks Life Sciences’ subject matter experts partner with clients to configure clinical sample management solutions to individual workflow requirements. By repurposing clinical samples and using an integrated, standardized approach to sample management, such as the Sample Hub platform, biopharmaceutical companies can help reduce the problems of patient recruitment and lower the cost of clinical trials. References 1.Sully, B.G., S.A. Julious, and J. Nicholl, A reinvestigation of recruitment to randomised, controlled, multicenter trials: a review of trials funded by two UK funding agencies. Trials, 2013. 14: p. 166. 2. Sertkaya, A., et al., Examination of Clinical Trial Costs and Barriers for Drug Development. 2014, U.S. Department of Health and Human Services. 3. The Expanding Web of Clinical Trial Patient Recruitment. 2014. 4. Kadam, R.A., et al., Challenges in recruitment and retention of clinical trial subjects. Perspect Clin Res, 2016. 7(3): p. 137-43. 5. Bower, P., et al., Interventions to improve recruitment and retention in clinical trials: a survey and workshop to assess current practice and future priorities. Trials, 2014. 15: p. 399. 6. Human Tissue and Biological Samples for Use in Research: Operational and Ethical Guidelines, M.R. Council, Editor. 2014, Medical Research Council. 7. Federal Policy for the Protection of Human Subjects, U.S.H.a.H.S. Department, Editor. 2018. 8. Sariyar, M., et al., Sharing and Reuse of Sensitive Data and Samples: Supporting Researchers in Identifying Ethical and Legal Requirements. Biopreserv Biobank, 2015. 13(4): p. 263-70. 9. Tindana, P., et al., Ethical issues in the export, storage and reuse of human biological samples in biomedical research: perspectives of key stakeholders in Ghana and Kenya. BMC Med Ethics, 2014. 15: p. 76. 10.NCI Best Practices for Biospecimen Resources. 2016.
- 37. FOR PHARMA INDUSTRY REVIEWS LEADING MAGAZINE TO DISCUSS ANY ADVERTISING OPPORTUNITIES PLEASE CONTACT E: kathryn@worldpharmatoday.com T: +91 40 4203 0405 M: +91 8826849084 Hard copies 16000+ Visitors P.A 100 K + E-book copies 90000 New visitors 40%+
- 38. A COLLABORATIVE APPROACH TO INNOVATION IN PHARMA Jamie is Director of Product Innovation at ICON and has more than 15 years’ experience in the CRO environment and began his career in Data Management, leading the protocol interpretation, CRF and eCRF development of over 300 studies across clinical phase’s I-IV, before working with ICON Central Laboratories in developing global standards. Jamie then took the opportunity to work in IT as a Solutions Specialist Architect focusing on Enterprise Portal and Content Management strategy and solutions. The last 4 years Jamie has been a member of the ICON Innovation group creating, developing and implementing ICON’s global innovation model, process and methodologies. Jamie Tallon Director, Product Innovation - ICON
- 39. “IGNITE is a creative environment that fosters innovative thinking and encourages new ideas and enables users to have their voice heard in overcoming challenges that are faced to find new ways to better deliver quality data, speed up clinical development, lower cost to drug and device developers, and, to improve patient safety.” Imagine the possibilities if we worked together towards these goals combining all of our strengths in new and uniquely partnerships, our goal to solve the challenges of tomorrow, together, today.
- 40. ICON is continuing to demonstrate its commitment to collaborative innovation through the release of its new digital innovation platform, IGNITE, to foster cross collaboration and ideation. This is the second ideation platform to be launched by ICON. In January 2015 ICON launched its multi award winning internal Idea Management Solution called SPARK. The platform enables all ICON employees to have their voice heard by contributing their ideas, thoughts and insights to challenges that are released on the SPARK platform. Each challenge has an Executive Sponsor to ensure the support and alignment against company goals and objectives, and to also commit to the prioritization of resource and budget based on the output of the challenge. Challenges can be targeted to any demographic breakdown of the organization, for example controlling access by position, country, department or management level. But the power is in the crowd, and the majority of challenges that are released are open to any employee to participate in. Employees have a wide spectrum of experiences from previous roles and positions within ICON, or at other organizations, and employees are encouraged to tap into this unique combination of knowledge by offering wide opportunities to contribute. All ICON employees are encouraged and challenged to submit their ideas and insights to a challenge, and are given the opportunity to comment and develop the thoughts and ideas of their fellow colleagues, as well as being able to cast their vote on which ideas they feel will deliver the greatest value. All input and contributions are then reviewed by an assigned team of Subject Matter Experts against the core goals and objectives that have been set out by the Executive Sponsor. An inbuilt review functionality called head to head, enables all ideas to be weighted against each other through the review methodology, bubbling the top ideas that best meet these goals and objectives to the top. This review approach enables a large amount of reviews to be done accurately in a very short period of time. Once the review is completed, alignment of the SME teams reviews and results can be viewed, comparison against user voting can be completed, and each goal and objective results looked at individually.
- 41. This output, based on multiple perspectives enables quicker, better decision making prior to moving forward with a Proof of Concept , road mapping or implementation stage of the project. This initiative, as well as helping ICON overcome challenges identied and faced, helps to create an innovative environment globally throughout the organization to help promote cultural and behavioural change and is supported by the organizations global recognition program which has recognized more than 400 employees since the launch of SPARK. To date there have been more than 25 challenges launched on SPARK engaging nearly 60% of employees who have contributed nearly 3000 ideas and over 6000 comments across a variety of use cases and challenges. This process of continual employees-led innovation has generated a number of new products and services for the life sciences industry. And now it’s time to expand that innovation ecosystem with the launch of IGNITE. IGNITE: Our industry is united by a common goal of accelerating and innovating the development of new and cost-effective treatments. These treatments save, extend and improve patients’ lives across the globe. Imagine the possibilities if we collaborated and worked together towards these goals combining industry-wide strengths in new and unique partnerships and opportunities. We believe this is the key in reaching our common goal to solve the challenges of tomorrow, together, today. IGNITE is ICONs digital open innovation platform that allows users to share challenges with other organizations while also tapping into the knowledge and skills of all ICON employees worldwide. The platform enables users to have their voice heard in overcoming challenges ranging from better ways to deliver quality data, speed up clinical development, lower costs of drug development, and improve patient safety. 41VOL. 3 ISSUE I April 2018
- 42. The IGNITE platform provides the opportunity for collaborations that tackle ICON Lead, Partnership, Hosting or Industry challenges supported through the application of a simple, effective methodology • Frame the problem: Breaking down the problem to identify the core challenge faced, and to rebuild and present the opportunity to the user in a clear, precise and engaging format. • Decide the audience: Understanding who is the target audience of the challenge, what areas should be involved, what service areas or group does it affect, and are there any overlaps with planned or ongoing initiatives to ensure that alignment. • Execute the challenge: Launching the challenge with clear Executive Sponsor support, strong communication and an engaging marketing campaign to help drive participation for the challenge to be welcomed as an opportunity to get involved and have your voice heard in shaping the direction of the project. • Engage and capture: Assigned core challenge-specic SME team engage users on the platform, sharing user submitted ideas and prompting responses and contributions from relevant parties. The Executive Sponsor vocally advocates the challenge and initiative through peers, direct reports and line managers, encouraging participation. • Implement and measure: Continued prioritization and ownership, communication throughout implementation stage showcasing quick wins, short- and long-term roadmaps, and the achievements and benets realized. Clear recognition awards and the celebration of wins and achievements throughout lifecycle. IGNITE helps to breaks down silos within organizations, and by sharing your challenges in IGNITE it allows you to harness ideas within our combined teams, to collaborate and to develop
- 43. ABOUT ICON Since our foundation in Dublin, Ireland in 1990, our mission has been to help our clients to accelerate the development of drugs and devices that save lives and improve quality of life. We do this by delivering best in class information, solutions and performance, with an unyielding focus on quality at all times. We offer a full range of consulting, development and commercialisation services from a global network of offices in 38 countries. We focus our innovation on the factors that are critical to our clients – reducing time to market and cost while increasing quality – and our global team of experts has unparalleled experience in a broad range of therapeutic areas. ICON is a global provider of outsourced drug development services to biopharma, medical device, government, biosimilar and generic organisations. Our services are supported by in-depth therapeutic and regulatory expertise and market-leading technology and analytics. We are the only full service CRO that offers the knowledge, software and systems for adaptive trials. solutions around your needs quickly and efciently. The IGNITE platform can also bring together research teams and patients to gain insights into patients’ needs around treatments and participation in clinical research. IGNITE pushes the boundaries of innovation within our industry by fundamentally changing the ways in which we work together, embedding the collaborative innovation process within your company alongside access to ICONs expertise, and patients’ invaluable experience and expectations. .
- 44. FULL SERVICE: THE EXPERTISE AND EFFICIENCY OF A ONE-STOP SHOP FULL SERVICE: THE EXPERTISE AND EFFICIENCY OF A ONE-STOP SHOP Dr. David Brett studied Biological sciences at the University of East Anglia in the UK. He earned an MBA at the University of Bayreuth, Germany, and a PhD in Biochemistry at Imperial College in London. After postdoctoral positions at the Institute of cancer research, he trained at Bioinformatics with a focus on pharmaceutical drug target screening. In the Siemens Healthcare strategy and innovation department, he worked on a number of topics including protein target molecules for cancer & diabetes, e-health, personalized medicine, and molecular imaging. David joined Vetter in 2010 as product and service manager with a focus on innovation in injectable drug-delivery systems, clinical development and commercial manufacturing. He became Team leader of Product and Service Management in 2015, and is responsible for the development of Vetter’s service offering to optimally fit customer requirements. Team Leader, Product and Service Management Vetter Pharma International GmbH Dr. David Brett
- 45. When it comes to the manufacturing of drugs, particularly highly sensitive biologics, a high-level of expertise is required. Typically, small and medium-sized pharma and biotech companies lack the knowledge and know-how necessary to cover all the processes independently prior to completion of the entire final product. That is why they are dependent on strong partners such as an experienced CDMO for the filling and packaging of the developed substance. From development support to commercial filling and secondary packaging, the accomplished CDMO offers everything at a single source.
- 46. Planning: The sooner the better The establishment of a partnership with an experienced CDMO early in the process can often make the difference. The sooner and more carefully the entire production process is planned, the more value can be maximized from the overall drug package. In addition to comprehensive support during development -- particularly critical for complex active ingredients, this step also includes ll and nish services. The use of high- performance production facilities for clinical lling leads to high- quality and reliable results, even with complex and sensitive substances. Comprehensive support throughout all phases of drug development and manufacturing A qualied one-stop shop provides support not only in the early clinical phases, but also later in the process, for example, when launching the product and commercializing the production process. Such shops offer all services from one single source. Pharma and biotech companies, in particular, benet from a comprehensive range of products and services that are optimally tailored to meet the needs of their substances. In addition to ongoing quality control by means of pharmaceutical analyses in modern laboratory facilities, support for regulatory inspections is also included. After all, experienced CDMOs have long- term relationships and extensive expertise in working with authorities around the world and, as such, are always up to date with the latest regulatory requirements. In addition, they support the preparation and compilation of necessary documentation for clinical trials as well as for market approval. Pharma companies that outsource their processes to just a few service providers can save product and process knowledge throughout the entire value chain. With the help of know-how gained from successfully completed development projects, clinical manufacturing processes can also be transferred more easily to commercial production, thereby shortening process planning, avoiding unnecessary redundancies and reducing both risk and costs.
- 47. Innovative packaging development completes the full service package All phases of product development are accompanied by packaging material development. Competitive advantages can be achieved with vial alternatives such as prelled syringes. It is important to always have the nal product in mind, for example, when the time comes for nding the most suitable secondary packaging such as blistering or cartooning. The use of special injection systems like dual-chamber products, pens, auto-injectors or safety devices make it possible to differentiate oneself from the competition, especially in the area of life cycle management. With a strong full-service provider by their side, pharmaceutical and biotech companies can focus on further product development, while an experienced CDMO like Vetter manages their processes and infrastructure. ABOUT VETTER PHARMA Headquartered in Ravensburg, Germany, Vetter is a global leading contract development and manufacturing organization (CDMO) with production facilities in Germany and the United States. The company has long-term experience offering services ranging from early development support including clinical manufacturing, to commercial supply and various packaging solutions for vials, syringes and cartridges. Vetter’s customers range from small and midsize to the world’s top 20 pharmaceutical and biotech companies. As a leading solution provider, the CDMO recognizes its responsibility in supporting the needs of its customers in developing devices that contribute to increased patient safety, convenience, and enhanced compliance.
- 48. Marie-Pierre Pasdelou, PharmD, is a founder and the Chief Development Officer of CILcare, the world-leading services company for drug development in hearing and otic disorders, with unique know-how for assessing the safety and the efficacy of drug candidates and medical devices related to hearing loss. Dr. Pasdelou has more than 24 years of experience in the pharmaceutical industry as a drug developer, and Head of a Regulatory International Department in Sanofi. Michael Naimark is Director of Business Development at CBSET Inc., a GLP-compliant preclinical translational research institute located in Lexington, Massachusetts. Following a career as a study director and project manager, Michael focuses on client- centered outreach in developing new services and capabilities. He holds an MS degree in neurobiology from the University of Tennessee Medical Center and is a co-author of several peer- reviewed publications with an emphasis on stem cell biology and retinal physiology. Marie-Pierre Pasdelou, PharmD CILcare Founder, Chief Development Officer Michael Naimark, MS CBSET, Director of Business Development STEM CELL AND REGENERATIVE THERAPIES FOR HEARING LOSS STEM CELL AND REGENERATIVE THERAPIES FOR HEARING LOSS
- 49. The year 2018 marks a notable milestone in the history of stem cells and regenerative medicine. It was twenty years ago, in 1998, that James Thompson and John Gearhart published methods for the creation of the first human embryonic stem cell (hESC) lines. In the intervening 20 years, the field of stem cell research has made many critical discoveries that advance our understanding of exogenously modified and expanded cells and their therapeutic potential in human medicine. New technologies such as induced pluripotent stem cell lines (iPSCs) and CRISPR/Cas9 editing are expanding the possibilities offered by pluripotent cell therapeutics.
- 50. These two parallel but related elds have begun to deliver on the promise envisioned 20 years ago. Multiple clinical trials are underway for a variety of indications, including diabetes, retinal disorders, and postoperative tissue repair and regeneration. One area that may nally benet from these new technologies is the eld of hearing and ototoxic disorders. These have lagged behind other elds of therapy for several reasons, including the difculty of accessing the relevant anatomy for therapeutic treatments, a lack of suitable preclinical models, and a limited commercial interest in these indications. As of the publication of this article, the FDA still recognizes no efcacious therapy for the preservation or restoration of hearing, an astounding admission in light of the numerous advances seen in other, related areas. Fortunately, recent advances in our understanding of auditory pathways and the discrete mechanisms underlying auditory function lead us to believe that real, viable therapies will become a reality in the near future. At the same time as these cell technologies were being investigated, a parallel interest in activating and utilizing endogenous regenerative capabilities in patient populations has benetted from advancements in molecular assays and information processing. Data-intensive “-omics” and informatics offer the promise of achieving the same regenerative and reparative goals as customized cell implants, with the additional safety benets of recruiting each patient’s own biological mechanisms to create the therapeutic effect.
- 51. Mechanism of disease for hearing disorders Addressing hearing disorders via drug- and cell-based therapies remains a very challenging task due to the functional and anatomical limitations associated with the cochlea: a fully encompassed, closed, and integrated auditory system encased in a dense layer of bone. These delivery barriers are compounded by the complexity of the development, maturation, and functionality of each individual cell type in the cochlea, which together orchestrate an optimally functional hearing mechanism (see Figure 1). Deafness or hearing dysfunction can result from genetics or induced deregulation of one of several cell types in the cochlea. Most research has focused on therapies targeting two cell types of primary functional importance in the cochlea: the hair cells (HC), and the spiral ganglia neurons (SGN). Both cell types are fully differentiated post-mitotic cells, and any HC and/or SGN loss will adversely impact hearing function and acuity. Therapeutic approaches Several possibilities are advancing through preclinical trials and demonstrate great potential to reach the clinic as efcacious therapies. One approach uses a traditional cell-based method of directly replacing the missing cells in situ. This could be achieved through direct injection of differentiated stem cells into the cochlea; these cells could become either HCs or SGNs according to their injection site. Although straightforward, and consistent with previous successful stem-cell- targeting therapies, there are several scientic and regulatory shortcomings associated with this approach (see Table 1). Building on an increased understanding of molecular and cell-based pathways to induce the activation of endogenous Figure 1: Development of the inner ear (Atkinson et al., 2015) Figure 2: Cells with stem-cell-like properties in the inner ear (McLean et al., 2016) 51VOL. ISSUE April 20183 I
- 52. precursor cells in the area of treatment, a second approach seeks to replace the same cellular machinery through the regeneration of damaged or missing cells. In this regenerative-medicine approach, the goal is the activation of endogenous "stem-like cells" through small molecules or biologics in order to repopulate the missing cells. It has been shown that stem-like cells (usually referred to as endogenous precursors) exist in several compartments of the cochlea. These cells are the Lgr5+ cells for the sensory epithelium and the PLP1+ cells for the SGN (see Figure 2). Recent research supports the possibility that such cells could be activated/ reprogrammed through the injection/passive diffusion of small molecules into the cochlea in order to repopulate any damaged sensory epithelium and/or SGN. Advances in microfluidics and Administered locally to site of cell replacement AASDFASASD Introduction of exogenous cells into the inner ear to substitute injured hearing Administered neurons May require an immunosuppressed system Require additional safety testing for cell migration and tumorigenicity Could be effective on hereditary deafness, sensorineural hearing loss Potential difculty to reach the targeted location from the site of transplantation Can be administered systemically, or locally by a less invasive/traumatic route Activate and mobilize endogenous stem cells into new hair cells Doesn’t require an immunosuppressed system Less risks of miss-differentiation, migration or tumor Could be effective on age related and noise induced hearing loss Targeted-site accessibility depends on the route of administration Stem cells Regenerative medicine Table 1: Comparison of stem-cell-based and regenerative-medicine-based therapeutic approaches Company Table 2: Regenerative therapies in the pipeline Compound Target pathway Stage Afchem ASDFASDFASDF Akouos Acousia therapeutic ASDAFSDFASD Frequency Therapeutics Sound Pharmaceuticals Quark Pharma Audion therapeutic & Eli Lilly Novartis & GenVec AF243 ASDFASDFASDFASA Gene therapy OtopotinASDAFSDFAS D FX-322 SPI-5557 (siRNA) QP-HL3 (siRNA) LY3056480 ASDSDFASD CGF166 gene therapy Neuron survival and neuronal differentiation Dedifferentiation supporting cells into progenitor-like cells Progenitor cell activation (PCA) Downregulation of p27Kip1 DFASD Gamma-secretase inhibitor Atoh1 Preclinical ASDFASD Preclinical PreclinicalASDF ASDF Preclinical Preclinical Preclinical Clinical phase I ADFASDFASD Clinical phase II Boehringer Ingelheim & China Southeast University Institute of Life Sciences Inception sciences & Roche Decibel Therapeutics & Regeneron Consortium OTOSTEM Consortium Hearing Restoration Project Regenerate hair cells from inner ear stem cells. Explore key signaling pathways and proteins involved in regeneration of hair cells, with an emphasis on nding small-molecule drugs that could stimulate the process. Create novel drug therapies that target inner ear hair cell protection and regeneration in the cochlea. Build the world’s rst comprehensive, integrated drug discovery, translational research, and drug development platform for hearing loss and tinnitus. Develop 2 strategies for curing hearing loss: 1- stem cell-derived cellular agents for cell-based therapy. 2- stem cell-derived assays as a screening tool to identify novel drugs. Focus on investigating hair cell regeneration as a cure for hearing loss and tinnitus. Stem cells Regenerative medicine
- 53. miniaturization are being applied in research models where a prolonged administration of trophic stimulus may be required for consistent and efficacious cell activation and integration. This allows revolutionary extended therapeutic access to one of the most inaccessible areas for therapeutic intervention. As with other stem cell and regenerative medicine- based therapies, those targeting auditory dysfunction face specic regulatory and technical challenges related to the manufacture and deployment of each treatment. Fortunately, as hearing loss is a lagging indication, the auditory eld can benet from years of safety testing renement by the FDA and its team at CBER (The Center of Biologics Evaluation and Research). This includes well-established guidelines for testing and evaluating both stem-cell-based and regenerative-medicine approaches. Some of the key considerations are summarized in Table 1. It remains to be seen which approach, or combination of approaches, will reach the historic designation of being the rst FDA-approved therapy for the treatment of hearing loss. What is certain is that advances in our understanding of the regenerative and restorative approaches pioneered in other areas of interest have nally reached the eld of ototoxicity and auditory damage. A number of therapies are in the pipeline now (see Table 2). These and others hold the promise of transformative impacts on patient populations in the near future. ABOUTTHE COMPANIES CBSET, Inc. – 500 Shire Way, Lexington, MA, USA – is a not-for-profit translational research institute specializing in the evaluation of drugs, biotherapeutics, combination products, and medical devices. We provide preclinical services, including in-life testing, histopathology, and regulatory consulting. Our GLP-compliant facilities host a multidisciplinary team of medical, scientific and regulatory experts who actively collaborate in getting novel technologies to market. CILcare Inc. is the world-leading services company for drug development in hearing and otic disorders. CILcare has developed unique know-how to assess the safety and the efcacy of drug candidates and medical devices in drug-induced hearing loss, noise-induced hearing loss, age- related hearing loss, salicylate-induced tinnitus, noise-induced tinnitus and otitis.
- 54. REBOOTING THE LIFE SCIENCE INDUSTRY WITH DIGITAL TECHNOLOGY Trevor Marshall is director of enterprise system integration at Zenith Technologies and has worked for over 20 years in the pharmaceutical and biopharmaceutical industry. Working as a Business Unit lead for Zenith Technologies he oversees the delivery of projects globally for the company. Trevor also leads the consulting business, advising clients on best practice for implementations of manufacturing systems encompassing DCS, MES and Historian systems. Trevor Marshall Director of enterprise system integration at Zenith Technologies
- 55. Digital technology has been driving change throughout the life science industry for years, however the sector is currently standing on the precipice of revolutionary development – some organizations have already taken the jump towards a more digital future.
- 56. Businesses across the life science industry have been collecting data using large historian systems for years. Many currently have so much data arising from different sources it can be hard to focus on what is important. Right now, almost every device in a GMP manufacturing facility collects data and our clients have been completing projects to physically connect all these devices and systems for many years. The drive to physically connect the systems has come from many strategic objectives, including serialization. All this excellent work has put the industry in a great position to use the data it is currently collecting in the best possible way. Although the robotics and automotive industries may be in a better position to use Articial Intelligence (AI) and self-learning systems to improve manufacturing in efforts linked to Industry 4.0 – the life science industry has been using data and evidence to improve its manufacturing for nearly forty years. New tools and processes are emerging that can enable smart, decentralized production, with intelligent factories, integrated IT systems, the Internet of Things (IoT), and exible, highly integrated manufacturing systems. In addition, future developments may mean that machine learning algorithms will be able to quickly adjust manufacturing lines and production scheduling. New developments will also pave the way for predictive maintenance and the opportunity to identify and correct issues before they happen. Data collection and visualization for decision making to improve the overall performance of the manufacturing supply chain is a huge opportunity for the life science industry, however it’s not about being new – it’s about using proven solutions and approaches to decision making to improve quality, reliability and reducing waste.
- 57. Integrating with single use systems The adoption of single-use technologies, such as single-use bioreactors and other unit operations is on the rise. Fueled by the growing pipeline of high potency and biological drugs and coinciding with the growth in personalized medicine and its inherent need for smaller batches, single-use technology will play an increasingly important role in the coming years. Both upstream and downstream manufacturing processes benet from single-use systems. During this manufacturing method the biopharma process system is disposed of after use as opposed to being cleaned, enabling quick set up while reducing cleaning and validation need. Currently, the integration of manufacturing execution system (MES) solutions with start-to-nish technologies and single-use manufacturing platforms is helping the industry to deploy biopharmaceutical manufacturing with increased productivity and efciency. The upshot is that manufacturers can signicantly reduce the time-to-market for new products. Single-use components are also an enabling technology for smaller scale production of biopharmaceuticals, including antibodies, proteins, vaccines and cell therapies, which would otherwise be much more difcult to produce. Increased productivity and efciency are also a necessity when it comes to manufacturing smaller batches and a wider range of product. In this environment, single-use technology will naturally ourish as a simple, cost-effective solution. Digital manufacturing The rst steps towards fully connected, self-optimizing production processes have been taken – the advent of digital manufacturing is on the horizon. Enterprise Manufacturing Intelligence (MI) involves accessing more meaningful data to give a better, more holistic view of operations and allowing for improved analytics and real-time responsive decision-making to drive continuous improvement. Access to this data, or Big data, also allows for the creation of digital twins. A digital twin can be made up of data captured from the entire end-to-end manufacturing process of a product – this twin can then be used to nd invaluable insights. Extension of the traditional ‘golden batch’, where data was very much process control-based, will be supplemented and surrounded with environmental data, raw material data, training data and any other digital data available that goes towards inuencing the golden batch. With this digital information available across multiple sites, batches and suppliers, sophisticated analytics can provide a digital twin that best represents the golden batch and alerts controllers to any problems based on these specic data sets. 57VOL. ISSUE April 20183 I
- 58. Patient centricity Digital technology is connecting genetic information with real world data and companies are already combining drugs, advanced application devices, and apps to be more patient-centric. This push towards customized medicines solutions, driven by technological advances and pressure from patients who want to be more involved in their own care, will take the market in new directions. The impact on the market, and more notably manufacturers, is that there will be a growing demand for smaller batches which will highlight any inexibility in a manufacturer’s supply chain. The propagation of product variants and smaller batch sizes will mean that launch approaches, process technologies and validation concepts will need to be overhauled. Final thought While the life science industry will, for the most-part, take a graduated approach to adopting new digital technology that builds upon current approaches and enhances the performance of proven solutions, those companies that are already investing will maintain a signicant competitive advantage. Implementing and using digital technologies successfully will see businesses leveraging data analytics that can lead to valuable process improvements and help them to operate with greater agility, cost-efciency and compliance. The introduction of new pharmaceutical products may take weeks, rather than months or even years – the positive impact that digital technology can have on patient lives, which is ultimately what the life science industry strives for, cannot be understated. The adoption of cloud and edge computing to the life science industry truly offers organizations the ability to gain insights that are currently just not available with existing infrastructures and technologies. Digitalizing and connecting the data across the entire supply chain with embedded context will lead to asset performance and utilization improvements, but ultimately will lead to the adoption of advanced analytics that will improve insights gained in the science of making life saving drugs. ABOUT ZENITH TECHNOLOGIES Founded in 1998, Zenith has 16 offices worldwide with over 800 skilled employees, delivering over 3500 years combined engineering experience. The company is a world leader in delivering manufacturing software systems that make businesses compliant and competitive. Zenith specializes in providing enterprise performance solutions comprised of manufacturing execution systems (MES), automation and process control to life science companies globally. Working with 9 out of the top 10 pharmaceutical and biotech companies, Zenith provides performance improvements, reduced costs, total compliance and improved operator effectiveness through combining experienced engineers and consultants, comprehensive design methodologies, and leading-edge technology implementation.