SUPPLY CHAIN AND LOGISTICS FOR ADVANCED THERAPIES

Transcription

1 SUPPLY CHAIN AND LOGISTICS FOR ADVANCED THERAPIES

2 2 CONTENTS CHAPTER 1 Introduction CHAPTER 2 Case Study: Fibrocell s Commercialisation Journey CHAPTER 3 Supply Chain and Logistics Market Insights CHAPTER 3 8 steps to Implementing a Robust Supply Chain Strategy CHAPTER 4 Taking Temperature Control: The Logistics of Cell and Gene Therapy CHAPTER 5 Global Supply Chain Regulations CHAPTER 6 Video Library CHAPTER 7 The Logistics Hub, Miami CHAPTER 8 About Phacilitate Thank you to all of our authors and contributors:

3 3 INTRODUCTION In a nutshell, we define an advanced therapy as a medicinal product derived from genes, cells or tissues, thus providing an all encompassing term for cell and gene, immuno and regenerative therapies. This definition is based on the European Medicine Association s regulatory definition, which can be found here. The advanced therapies industry is maturing and more and more products are nearing the market. However, the challenges of regulatory approval and creating a commercially viable product are far from being solved. One of the main barriers to commercial viability is the supply chain, which contributes hugely to the overall cost of goods (COGs) and is limited by infrastructure, temperature requirements and, of course, the time frame for transportation vs. cell viability. An often overlooked but major challenge of the supply chain in addition to these factors is the when. When is the optimum time to start designing your commercial supply chain and how will it look in relation to your clinical supply chain? One of the most important elements of the when is understanding how the formulation of a product impacts the supply chain and its cost and flexibility. Left unconsidered, this can render an advanced therapy product essentially useless, as the costs are too high and the market cannot afford to pay for it. This story played out a few years ago during the well documented failure of Provenge. In fact, the FDA s review of the Dendreon drug cited that In this e-book we explore the impact of the supply chain on commercialisation and provide in depth insight and knowledge from the industry to prevent further failures and ensure the best levels of patient care can reach the market, including: Designing a robust, flexible supply chain design The impact of product formulation on storage needs and supply chain costs LN2 vs. dry ice Or to learn more in the real world, register for the Phacilitate Leaders Forum in Miami this January, where there will an entire stream dedicated to the supply chain and logistics of advanced therapies, including an interactive logistics hub! David McCall, Content Director Phacilitate, a Clarion Events Company

4 4 JEREMY CRESS LOGISTICS HUB CASE STUDY This is why the supply chain should be considered as early as possible in (pre)clinical development. At what temperature does the final product need to be stored and shipped and what impact does this have on the supply chain flexibility? How do you extend the final product s shelf life? What are the associated limitations and cost implications of not doing this? When should this decision point occur, considering the outcome may be to develop a new formulation and product. Have commercial feasibility studies been carried out and when? Are you able to react to your findings to ensure your final product is commercially viable? Or is it too late? CASE STUDY OUTLINE PRODUCT Development stage Therapeutic area Number of patients in each phase Typical patient: how mobile, well are they, age Allogeneic or autologous (if applicable) Commercial feasibility studies PATIENT POPULATION Global or regional Annual patient numbers projected MANUFACTURING Regional hub, on site etc. In house or outsourced, why? Raw materials LOGISTICS Storage and shipping requirements Temperature; LN2, deep frozen? Shelf life of end product Courier general or specialist, one or multiple? Packaging needs and validation Tracking and monitoring needs/considerations Risk assessment Clinical vs commercial supply chain needs DRUG DELIVERY Last mile description Who administers to patient, do they need training? Thawing on site needed? How many doses and frequency? Follow up care

5 CASE STUDY: LAVIV (azficel-t) 5 THE PRODUCT LAVIV is an autologous adult human dermal fibroblast treatment for the improvement of the appearance of moderate to severe nasolabial fold wrinkles in adults. Fibrocell received FDA approval in June 2011 (CBER OCTGT). LAVIV is the first and only cell therapy product for aesthetics. Shipping demographic: Domestic Only (No International Shipping) Final Product to be shipped: Vials containing 10 to 20 million autologous human dermal fibroblasts per ml suspended in media Dosage: Injected at a dose of 0.1ml per linear cm 2 along the nasobial fold How many doses and frequency? 3 doses 3 6 weeks apart Shelf Life: 24 hours from courier pick-up Thawing on site needed? Not for LAVIV, but potentially for future indications DESIGNING THE SUPPLY CHAIN MANUFACTURING Location: Centrally produced exclusively at the Fibrocell science facility in Exton, PA under cgmp and FDA regulations In-house vs outsourced: In-house manufacturing selected because COGS/ Manufacturing scheduling is much more controllable. Starting materials: 3 x 3mm tissue biopsies (Different API for each incoming lot) Critical raw materials: Media, Reagents LOGISTICS Cell population stored at -130 degrees celsius in cryogenic storage system. Cells are thawed, washed and prepped for final product using standard methods Drug product has shelf life of 24 hours requiring rapid cold chain solutions Shipment: Given short shelf life of final product multiple variables are taken into consideration such as inclement weather (departing, intermediate and destination cities), courier capabilities (specialty service level/standard overnight), patient appointment times, distance from facility etc. to determine the proper method of shipment. Couriers utilized at Fibrocell are Fedex, UPS, World Courier, Priority Solutions. Each courier offers something unique that can be used in the risk assessment process to help ensure the final product is delivered in a timely manner.

6 CASE STUDY: LAVIV (azficel-t) 6 Packaging considerations: Establish the impact of shipment on container integrity, cell viability and productivity. Study should mimic actual shipping conditions and methods: Max and min capacities Temperature control Air travel and ground transport Intended destinations Live shipment runs with evaluation of cell characteristics upon return Testing prior to and upon return shipment may include: sterility, cell count/viability, potency Temperature mapping under simulated extreme temperature conditions (IATA) Shipper integrity Must be performed over replicates of autologous cell lots Will be considered when establishing shelf life, and the time when clock starts CMC requirement (BLA Module 3, Quality) Final Drug Product storage is short (same day) Must be segregated in a controlled manner Dedicated to commercial drug product storage only Controlled access If possible, the process should account for the storage of excess cells in the event of later loss Customer Management: Established a dedicated Customer Service Center to interface with physician sites Coordinate orders, biopsy kit shipments and Drug Product administration dates Works directly with the Operations Logistics group to coordinate commercials activities Coordinate physician site training Constantly update site on culture progress and inventory availability Goal is customer satisfaction, but also aids in reducing product loss Procedures reviewed by FDA Tracking and monitoring needs/considerations: Select a courier that offers electronic tracking and has a notification system (Fedex Priority Alert and World Courier offer both of these service levels). Inventory control: After harvest, must validate the time cells can be held prior to freezing procedure Cryostorage inventory system must provide: Enough control to track multiple autologous lots stored in same cryogenic unit Quick and accurate retrieval of vials to avoid prolonged exposure Physical segregation of stored product material Quarantine/release units and controlled access Physician s Office Logistics Customer Service Center Quality Manufacturing

7 CASE STUDY: LAVIV (azficel-t) 7 Point of care training: Skills based training for each participating physician site Site Training: ordering instruction, importance of biopsy technique, biopsy kit packing, product preparation Physician Training: product handling, injection technique, setting expectations Setting patient expectations Ensure proper handling of a living cell product vs. dermal filler Educate site on the importance of donor tracking Close the loop CHALLENGES Challenge #1 Physicians site compliance was a major hurdle post commercialization. During our clinical trials we had the luxury of selecting a few sites and had a high level of control over site process compliance. When we launched LAVIV following our BLA approval. We found that training over a 1000 sites in year (1) was a major challenge. Corrective Action - we were successful in this project by implementing a robust training program that was rolled out through our sales team to ensure each site was trained in the same manor. Additionally, we had sales staff onsite for the first few biopsies as well. CONCLUSION Controls Ensure all controls are well documented and understood by employees Verify all critical steps Inventory is reliably traceable and retrievable Provide a full validation package that is reflective of your intended distribution path During Product Development Consider distribution as part of early product development Test alternative shipping conditions against cell viability and potency Room temperature Dry ice shipment Hypothermic storage media Design payload of shippers to protect the product and maximize shipment times Considering commercial feasibility on early stage product development is essential. Discovering downstream issues with your Product stability, Shipping validation, Raw material qualification, Single- sourced vendors etc. can cause millions of dollars in re-work costs not to mention unnecessary delays to your project timelines. Challenge #2 With a shelf life of 24 hours (EST rules applying) on your final product shipping was a difficult challenge during seasons that saw an influx of inclement weather (Winter/Summer) especially to the west coast given the loss of (3) hours due to time differences. Resolution we developed a comprehensive Risk Assessment process that would allow us to determine what couriers to use whenever a specific weather related event (Ice, Snow, Thunderstorm, Hurricanes etc.) presented itself in either the departing, intermediate or destination city. This process has allowed Fibrocell to provide our sites with a 99.6% on time delivery rate.

8 8 Jeremy Cress Director Of Operations- Fibrocell Science Entering my 13th year in the Biotech/Pharma industry and my 6th year at Fibrocell in which I oversee Manufacturing/Supply Chain commercialization efforts of the first approved Cell therapy for Aesthetics (LaViv Azficel-T). Currently working in collaboration with Intrexon Corporation to advance multiple early phase clinical and Pre-clinical Gene therapy indications affecting the skin and connective tissue including our lead candidate FCX-007 for the treatment of recessive dystrophic epidermolysis bullosa (RDEB). Prior to Fibrocell I worked 7 years with Fisher Clinical Services overseeing Clinical Manufacturing, Domestic and International Logistics, Distribution and Supply Chain. I have extensive experience in solutions based strategies for early drug development, Phase I III Manufacturing/ Distribution (Internationally and Domestically) and commercialization of multiple drug products.

9 9 SUPPLY CHAIN AND LOGISTICS MARKET INSIGHTS Industry experts give their insight into the biggest advanced therapy challenges and overcoming the barriers to commerialisation Sven Kili VP and Head of Cell & Gene Therapy Development, GSK Supply chain planning is integral to the development of a cohesive manufacturing process and so should be part of defining a commercially viable manufacturing strategy. The biggest challenge we face is delivering the final product to patients, given challenging shelf lives, and without burdensome requirements placed on the patient in terms of timing and location, as well as in a form that is user-friendly for the clinician and requires no specialised training to administer. The greatest challenge is that this nascent industry has not yet had to deal with these logistical issues on a large scale. The level of risk to hazards that may impact the quality or viability of cell therapies varies and is often dependent upon the levels of service provided by the logistics provider. Shipping via general cargo through a freight forwarder places product at the greatest risk of unwanted exposures. Specialty courier services that offer hand-carried deliveries are the least risky. Somewhere in between are the integrated services (UPS, FedEx, DHL, etc.) and where the bulk of transports of cell therapies occur. Kevin O Donnell Vice President, Cold Chain Standards, Practices & Compliance, BioLife Solutions

10 10 Sam Kent VP Global Sales, Biocision It is important to take a multidisciplinary approach to your supply chain. Only by understanding the demands at all parts of the supply chain (clinical, logistics, manufacturing, quality, regulatory etc.) will you be able to build a supply chain model which is fit for purpose. The discussions must not just focus on a typical supply but should address risk areas and identify strategies to meet potential problems. By having these response strategies defined in advance, your patients will still be able to be treated during potentially challenging supply chain problems. Furthermore, by developing a cohesive collaborative culture in a supply chain a sponsor will benefit from the collective understanding of how a small modification affects all others working to deliver an advanced therapy. Supply chain planning should begin in the preclinical stages of development. The starting point here is to plan for success, in an ideal world, drug product formulation and stability studies should reflect the intended use of the therapy, the size and location of the potential patient population; providing patient and physician-friendly presentations which are (relatively) easy to manage, handle and administer. As many more companies enter late stage clinical trials and approach commercialization, the most significant challenge is scaling their supply chains post-manufacturing. Ensuring that advanced therapies are shipped carefully, stored correctly, handled properly, and administered flawlessly will require significant innovations in instrumentation, processes, and tracking. If advanced therapies are to become ubiquitous, the underlying supply chain must be as revolutionary as the treatments themselves. Miguel Forte MD PhD, Chief Operating Officer, TxCell SA One must start considering the supply chain challenges from the very start of development with the very first TPP. The product, the process development and the clinical evidence generation must be achieved in parallel with the development of a market viable supply chain development. Matthew Lakelin VP Scientific Affairs and Business Development, TrakCel

11 11 DAN O DONNELL 8 STEPS TO IMPLEMENTING A ROBUST SUPPLY CHAIN STRATEGY 1. TIMING Firstly, timing is critical when planning your supply chain strategy the sooner the better! The clinical trial design and supply chain design stages should be carried out as in tandem, if possible. In fact, these two processes should be integrated, as they are inherently linked and without considering the supply chain, you could come up against some obstacles when it comes to executing your trial plans which will have a direct impact on time, cost, and scale. Once you have formulated your product and understand the temperature requirements, you should begin designing your supply chain and logistics strategy. What is the infrastructure and possible limitations on your product at these temperatures? Lastly, what impact will that have at a commercial scale, both in terms of volumes and cost? Does the cost render your product commercially unfeasible? 2. PACKAGING The packaging of the product should also be considered during the very early stages of product development. If not, the result may be that the package necessitates additional handling for storage and distribution, resulting in a higher potential risk of temperature excursion as well as higher costs. Bulky storage configurations can require extensive customization and add cost and risk to the logistics process. Effective packaging takes into consideration the storage requirements, transit requirements, processing requirements and the administration requirements of the material.

12 12 3. VALIDATION OF SHIPPING AND STORAGE SOLUTIONS Shipping A qualified shipping solution is a critical element for ensuring that your therapy is judged on its clinical efficacy and not by deficiencies created by packaging or shipping failures. The stages where shipping and packaging qualification are needed are; Collection and pack out Transit Distribution It is imperative that each individual dry shipper is tested. There can be significant variation between different dry shippers both between different makes and models, and the same model and same lot. Storage A qualified shipping solution is a critical element for ensuring that your therapy is judged on its clinical efficacy and not by deficiencies created by packaging or shipping failures. The stages where shipping and packaging qualification are needed are; Collection and pack out Transit Distribution It is imperative that each individual dry shipper is tested. There can be significant variation between different dry shippers both between different makes and models, and the same model and same lot. Just as the shipper must be qualified, the storage equipment can also vary in performance and must be validated to perform in the specific way it is to be used relative to the material. The critical risk stages for equipment validation are: Storage and monitoring At the clinical site As an example, let s say the finished drug product has a maximum storage temperature of -150 C and will be stored in a vapor phase dewar. In any vapor phase vessel there are variations; the temperature is always colder at the bottom and warmer at the top. In order to determine the optimum storage location in the tank we must validate with multiple probes to determine the temperature gradient of the vessel.

13 13 4. PROCESS QUALIFICATION In much the same way we validate equipment to ensure it will meet requirements, we must also test the procedures used for handling. At any point where temperature-sensitive material is physically handled, a process qualification should be considered. In general, process qualification ensures that the integrity of the material is maintained while it is outside qualified/validated equipment and being handled by trained personnel. Process qualification ensures that it is maintained within acceptable temperature ranges and is strongly recommended when: The volume of material is small (less than 2ml) The temperature windows are particularly tight (for instance, no warmer than -150 C or colder than -180 C) Significant handling is involved, such as re-packaging or labeling in large batches 5. DOCUMENTATION Maintaining suitable documentation of a supply chain can be far more difficult than it first appears. Because processes occur in different settings and by multiple individuals and organizations it is imperative that a robust procedure be in place to ensure that the requisite data is compiled and collected in a standardized fashion. This documentation must be maintained at a per dose level and be readily available for review when necessary. 6. TEMPERATURE CONTROL To be commercially successful, cell therapies must retain their viability and potency, and this requires protection from exposure to adverse temperatures. Any given individual dosage of a cell-based therapy is potentially exposed to multiple adverse temperature events between manufacture and patient administration. Another temperature consideration is the dose s relative position in the storage unit. For example, the temperatures inside a LN2 storage tank vary from about -130 C at the top to -190 C at the bottom. Repeated ambient exposure while in storage can also be a problem: individual units of a cryogenically frozen cell-based therapy are typically placed in slots in a rack that is lowered as a unit into the LN2 tank. If the rack holds 10 doses, then the dose which is removed first is exposed only once when it is removed from the storage tank. However, the unit on the bottom in the 10th slot may have been exposed to ambient or near-ambient temperatures nine additional times before it is removed from the tank.

14 14 7. STANDARDISATION Vials, bags, and other containers are each associated with varying shipping containers and requirements, and their costs vary considerably as well. Freezing individual doses in a container that does not fit into a standard cryogenic racking system or box will add cost and possibly time-out-of-temperature. Using custom racks will also add to the distribution costs (custom racking may require customized dry shippers), and may also further limit clinical sites to those that can accommodate your racking system. 8. LAST MILE Will your therapy in development require complex preparation for administration? Non-standard administration will necessitate committing resources to training site personnel in preparation and administration procedures, and possibly additional equipment. Is this an autologous therapy? An additional layer of diligence is required for regimens created for a specific patient: great care must be taken to create a robust system that securely pairs the patient to the dose. In addition, the pharmacy staff may require training in any storage or handling variables that are unique to the regimen, particularly in terms of thawing the product. As the cell and gene therapy industry is expands rapidly keep up to date with all the latest news from Phacilitate. Subscribe today...

15 15 Dan O Donnell Dan O Donnell has extensive experience in the development and deployment of strategies for the distribution of clinical agents for phase II and III clinical trials, in both international and domestic locations. He specializes in cryogenic and ultra low temperature (ULT) product management and distribution, with an emphasis on developing chain of custody processes and documentation for compliance with 21 CFR part 11 requirements. Dan is also versed in the validation and qualification of storage and shipping solutions for complex biological applications and possesses an in-depth knowledge of biobanking and management of biologically active pharmaceutical ingredient (bio-api). Previously, Dan served as a Vice President for Disease Management Programs with both Baxter Healthcare and United Healthcare, where he developed population- based health care models and coordination-of-care processes to address high risk patient groups. Dan has also worked extensively in the development of reimbursement models for high cost and high risk disease states and therapies.

16 16 TAKING TEMPERATURE CONTROL: THE LOGISTICS OF CELL AND GENE THERAPY MIKE SWEENEY Global speciality logistics provider World Courier discusses the temperature control requirements in the supply chain, how to ensure compliance and mitigate the risks of temperature excursions. Cell and gene therapy materials with their high value, sensitivity to environmental changes and limited lifespan are particularly vulnerable, so a micro-managed supply chain is vital. In addition to maintaining defined temperature ranges, typically frozen and often cryogenic, other complex requirements for cell and gene therapy transport include: Multi-site and lab set-ups Tight turnaround times of hours from sampling time to start of processing at destination leave minimal room for any margin of error (e.g. flight or customs clearance delays) Unique transport limitations, such as x-ray prevention Distinct contingency, escalation and communication plans Regulatory drivers and industry best practices require pharmaceuticals and biologics be transported within defined conditions to ensure integrity through the supply chain and ultimately for the sake of patient safety. Temperature deviations can have detrimental impacts, such as loss of treatment effectiveness or in some cases the therapy may even be hazardous to the patient.

17 17 TAKING TEMPERATURE CONTROL: THE LOGISTICS OF CELL AND GENE THERAPY How can the risk of delays and temperature excursions be mitigated, especially with so many variables in the cell and gene therapy product handling process including strict temperature and time requirements, differing international regulations and unforeseen logistics challenges? UTILIZE THE RIGHT PACKAGING AND MONITORING Technologies like vacuum-insulated panel boxes and phase-change materials (PCM) are now available at an accessible price point for many shipments. While these newer technologies offer improved performance for 2-8ºC temperature ranges, they cannot replace the need for cryogenic shippers that maintain extremely low temperatures for the transport of certain biologics and cell samples. Cryogenic shipments typically require dry shippers, which are durably engineered dry vapor dewars that contain liquid nitrogen and can transport materials at temperatures as low as -196 C. Temperature loggers are utilized to track and communicate any deviations. This is facilitated by software solutions that monitor the shipment s progress, which in addition to confirming product integrity, also support the supply chain of custody. Clear evidence of temperature stability during the entire transit of the shipment is crucial. A variety of packaging and monitoring solutions are available so making the right choice (based on the expected duration of the shipment, etc.) addresses one key component of safeguarding that products are shipped per expectations. However, even if the most appropriate packaging is selected, several other potential challenges can leave products exposed to time and temperature excursions.

18 18 TAKING TEMPERATURE CONTROL: THE LOGISTICS OF CELL AND GENE THERAPY WHAT COULD GO WRONG? Air transport delays can result from mechanical issues, inclement weather, labor strikes or shipment mishandlings. Customs clearance delays can cause shipments to sit for days or weeks while issues are resolved. Adequate infrastructure or support for the level of precision required for critical shipments may not be available on the route. One missed shipping timeline or one missed treatment can have significant ramifications. HOW TO MITIGATE RISK IN THE SUPPLY CHAIN A global specialty logistics provider should proactively gather and share details in advance to aid in making the right decisions on routing, airline, packaging and temperature monitor selections. This partnership should also include feedback on customs documentation in order to address any discrepancies up front. Trained worldwide staff that are capable of executing on agreed procedures and swiftly enacting contingency and escalation plans, as needed, can be vital to ensuring shipments are delivered on time and within temperature. Flawless execution is mandatory for materials that are high value, time and temperature sensitive, essential to a trial, a patient and particularly those that are life-saving. Ultimately, because conditions along any shipping route may change with little or no warning, dedicated focus and experience can go a long way in monitoring shipments through their successful delivery. The commitment of detail-oriented staff on the ground can serve to overcome discrepancies at the point of pickup, delivery or at the airport. Efficiently communicating inconsistencies that could otherwise have a serious adverse impact or going to extraordinary lengths (when necessary) to make sure materials reach their destination in perfect condition represent levels of service and trust that are essential to the cell and gene therapy sector.

19 19 TAKING TEMPERATURE CONTROL: THE LOGISTICS OF CELL AND GENE THERAPY CELL AND GENE THERAPY LOGISTICS: A CASE STUDY In the danger zone: In 2014, World Courier s office in Leipzig, Germany was supporting a global cell therapy clinical trial, of which there were several sites located in the Ukraine, with three patients located in Donetsk. The trial coincided with the outbreak of the Ukrainian-Russian military conflict. World Courier had a plan when no other logistics provider could find one. The World Courier team in Kiev assigned dedicated drivers that successfully delivered 16 shipments in dry shippers with no delays or temperature excursions all while navigating a zone of ongoing military conflict. The last shipment was delivered in October 2014, by which time Donetsk Airport was heavily damaged and closed.

20 20 Mike Sweeney Senior Director, Global Service Development World Courier Management Inc. Mike is currently responsible for the development of World Courier s service offering across 140 company-owned offices in 50+ countries, with specific focus on areas such as direct to patient and cell and gene therapy. Since joining World Courier in 1992, Mike assumed a number of positions in the US within operations, customer service, training, compliance, marketing, sales and clinical trials. He progressed to senior roles, including director of US customer service/operations, director of new service development and director of regional accounts, prior to transitioning into a global IT leadership position. Mike is based in New York and travels extensively throughout World Courier s global network.

21 GLOBAL GLOBAL SUPPLY CHAIN REGULATIONS

22 22 VIDEO LIBRARY Browse the Phacilitate video library for more information, news and reviews on the supply chain and so much more. So many factors impact the road to commercial success for advanced therapies and we discuss them all at the Phacilitate Leaders Forums and beyond... Coming Soon... The Story of Advanced Therapies

23 JANUARY HYATT REGANCY, MIAMI Co-located with MEET THE FUTURE OF CELL & GENE THERAPY As commercialisation heats up, effective design and management of the supply chain is a growing concern and one that still lacks enough intelligent solutions. In partnership with PARTNERS: Phacilitate, in conjunction with expert partners, is hosting an interactive, educational Logistics Hub at Cell & Gene Therapy World, Miami An experiential feature, aimed at supporting advanced therapy developers on improving the clinical and commercial supply chain process. SAMPLE SELECTION & COLLECTION TRANSIT & TRACKING CRYOPRESERVATION STORAGE & MONITORING CLINICAL SITE RECEIPT & ADMINISTRATION SAMPLE SELECTION & COLLECTION TRANSIT & TRACKING STORAGE & MONITORING CRYOPRESERVATION CLINICAL SITE RECEIPT & ADMINISTRATION

24 24 Cell & Gene Therapy World is moving to Miami in 2017, hosting over 850 senior executives for three days of strategic partnering and learning. Do you want to be involved in the most comprehensive cell and gene therapy event in the calendar? REGISTER NOW