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Makers of specialty biologics, gene therapies, and other personalized medicines are working to identify and reduce potential supply chain risks both upstream and downstream.
Drug manufacturers involved in the production and dissemination of time- and temperature-sensitive specialty biologic medications, cell and gene therapies (CGT), and other personalized medicines have a lot on their minds, as they ponder factors that could disrupt their various supply chains at any given moment. Considerable effort is required to understand, avoid, and quickly ameliorate diverse factors that threaten both the upstream supply chain connecting them with their own vendors and supply partners, and the downstream supply chain that feeding their distributors, wholesalers, clinical trial settings, physician offices, and ultimately, patients.
Consider the strong growth in CGTs, just one sector of the overall biologics market. As of early 2023, 27 CGT products have been approved for use in the United States, according to FDA, and a handful more have been approved already in early 2023 (1). CVS Health (2) projects 15 new CGT products will be approved in 2023 (including the first expected gene therapy for sickle cell disease), and 17 more in 2024 (including therapies for Duchenne muscular dystrophy, DMD).
Robust, resilient supply chains are important not only to support commercial-scale production, but far earlier during the clinical-development process, as well. Today there are more than 1500 clinical trials for CGTs registered within ClinicalTrials.gov—across many disease categories including oncology, rare diseases, regenerative medicine, and more. This signals great potential for patients—and growing complexity of the sophisticated supply chain infrastructure. “Strong, swift growth in this sector is also creating increased, parallel demand on upstream suppliers, which may lead to longer lead times for delivery,” says Alexander Aust, principal/owner of pharmaceutical consultancy, Aust Business Solutions. “This must be factored in by drug sponsors.”
“Manufacturers are always concerned about large orders of hundreds or thousands of kilos of critical ingredients at a time, but shortages or delays in lower-volume materials that are key to the manufacture of lifesaving biologics can still shut down an entire plant and create disruption,” notes Jim Luchsinger, vice president, business development and international distribution for Spectrum Chemical Manufacturing Corp.
“The most pressing source of risk in the timely production of biologics is manufacturing readiness including material readiness,” says Sigma Mostafa, PhD, senior site head, KBI Biopharma, a global contract development and manufacturing organization (CDMO) and manufacturer of APIs. “To address the risks our clients face and allow them to be able to take drugs to the clinic as quickly as possible, it is of the utmost importance that we maintain our own manufacturing schedule.”
During the pandemic, lead times for many standard materials went from less than a month to over 12 months, says Mostafa. Such uncertainty “created considerable upheaval to our own manufacturing schedule and forced us to slow down the cadence of runs for a short period and pivot to finding and cultivating as many alternate vendors as possible for a given product.”
To hedge risk, she says that the company ended up placing orders with multiple suppliers at a time. “In some cases, we identified smaller manufacturers further upstream (that had been suppliers to our original suppliers), and we even started to switch to raw materials and processes in favor of those that were more widely available during the process-development phase,” Mostafa continues.
“Setting up a robust material requirement planning (MRP) process is one important way for suppliers to meet their pharma customers’ drug-development and manufacturing needs and help to reduce risk,” says Mostafa. For a CDMO with a large early-phase pipeline and a considerable number of complex molecules, determining the full bill of material (BOM) a year ahead can be challenging. “Nonetheless, during the pandemic, we took action to strengthen our MRP process and our tech-transfer workflow to be able to complete 95% of the BOM well ahead of time.”
Similarly, by considerably improving material demand planning and safety stock determination process—while consolidating its own global materials demand database to allow for quicker identification of available inventory within our own network—Mostafa continues, “We have been able to transition to a leaner inventory while still retaining our agility to respond to client needs.”
The reliable supply of APIs, excipients, and critical components (e.g., vials, stoppers, tubing, filters, aseptic bags, specialized temperature-controlled packaging) is subject to disruption at any moment because of workforce shortages, weather events, geopolitical tensions, mechanical failures, fire or flooding, cyberattacks, quality or regulatory issues, transportation issues, and other risk factors that may impact suppliers. To manage risk, producers of biologics (and their third-party CDMO partners) must be imaginative during strategic planning exercises and contracting efforts with suppliers—running many ‘what if’ scenarios to develop an accurate assessment of both obvious and non-obvious sources of risk.
A regular review of best practices that are emerging among competitors, along with increased use of state-of-the-art modeling that can support improved demand forecasting, should be part of any winning risk-reduction strategy. “Biopharmaceutical companies rarely have the luxury of extra time,” says Aust. “Supply chain interruptions create costly and painful consequences for drug manufacturers that are not prepared. Long lead times could delay or interrupt clinical trials, threaten the regulatory filing, and lead to shortages in commercial therapies.”
“One of the challenges many manufacturers have is that they don’t always get transparency from upstream suppliers in terms of where their chemicals are coming from,” says Luchsinger. “A lack of transparency can compound risk because many materials come through multiple layers of the supply chain.”
How many suppliers is enough? While intuitively there is often benefit to be gained from simplifying and streamlining any complex supply chain to reduce the number of players, many experts agree that reliance on a single vendor for mission-critical supplies or components is never wise.
While supplier redundancy certainly makes sense, “many biologics manufacturers are still making the mistake of having one company designated as primary and all others as secondary,” says Luchsinger. “A better practice is to designate two primary suppliers. That way, if there is an issue arises with one supplier, the other can hopefully jump in to make up the temporary shortfall in supply with little to no lag time in the event of two scenarios—either a surge in demand on the part of the drug sponsor, or a supply interruption from one of the suppliers.” Increased use of domestic suppliers can also help to streamline the rigorous documentation that is required by various regulatory bodies worldwide when suppliers have many different countries of origin.
However, adding a secondary source brings its own challenges. “With materials that have unique traits, there may be only one type of supplier approved,” Luchsinger continues. “Approving a second source of supply within the realm of biologics is certainly more challenging compared to basic chemicals, which tend to have a relatively straightforward set of specifications.” Given the complexity, the objective for drug makers should be to identify and qualify new sources of supply and straighten out all of the non-disclosure and other agreements as early as possible, he adds.
Meanwhile, vertical integration is another way that some CDMOs are working to increase overall visibility and reduce the potential for supply chain surprises. For instance, in recent years, science and technology innovator Danaher has acquired both Pall Corp. (a maker of specialized filtration, separation, and purification systems), and Cepheid (a molecular testing and diagnostics company). Danaher also acquired Integrated DNA Technologies (which develops, manufactures, and markets DNA products to support the life sciences industry), and Cytiva (which offers products and solutions that allow for the development and scaling of biomanufacturing operations), and many more, with a goal of keeping under one roof critical suppliers that support steriledrug development.
“When planning for safety stock inventories, drug sponsors must take into account total lead time required, so that items can be replenished in an efficient manner without creating potential disruptions in production,” says Aust. “Since supply planning is a function of demand planning, the need for visibility up and down the supply chain is essential.” He notes that electronic quality management systems (eQMS) from competing vendors can help drug sponsors keep track the status of all raw materials and integrate product demand signals, but also be alerted to audits, deviations, and status updates and more from suppliers and other vendors.
When it comes to kicking the tires with critical suppliers and third-party CDMOs, biologics manufacturers should carry out regular audits and inspections. “The goal is to verify their quality systems, to be sure they have their own contingency planning in place, and to ensure that all quality systems are robust,” says Aust. Importantly, when partnering with key suppliers or a CDMO, Aust recommends drug sponsors establish three critical documents—a Business Continuity Plan (which specifies the supplier’s own business-interruption plans), a master service agreement (which specifies all agreed-upon terms and conditions), and a quality agreement (which is a legal document that outlines when the
supplier or contractor must report a certain deviation, how long that company have to deliver a batch, and how often the drug company can go onsite to carry out its own GMP qualification and quality testing).
When it comes to CGTs, the downstream supply chain that connects these highly personalized therapies with patients is fraught with peril and calls for the right mix of high-tech and high-touch support considerations. For instance, there is zero tolerance for failure in any one of the discrete, yet tightly intertwined steps required to produce autologous (“vein-to-vein”) CGT products that are customized for a single patient using blood or tissue extracted from them as the first step of the process.
Each step requires tight coordination and handoffs among parties, all the while working to ensure proper temperature-controlled packaging and swift transportation to reduce delays and temperature excursions that could spoil the high-value product.
When it comes to allogeneic (“off-the-shelf”) CGT products, even greater logistical planning is required. This involves scheduling the collection of the starting materials from the designated donor, delivery to the manufacturing site and then interim storage and distribution to multiple, geographically disparate patients—each of whom must also be scheduled to receive their therapy infusions in different clinical settings. Each step involves specialized packaging and shipping requirements, with robust chain-of-custody and chain-of-identity documentation. With allogenic CGTs, there is also a need to plan for multiple interim temperature-controlled storage, time- and temperature-sensitive transit legs to reach each of the multiple, geographically diverse recipients.
Advanced monitoring and tracking systems that track individual shipments to the individual vial and individual patient and provide user-friendly dashboards to all stakeholders en route help to increase real-time visibility into location, temperature, time in transit, and more. Today’s state-of-the-art data-analytics capabilities help stakeholders to coax actionable insights from the real-time data and identify weak links and potential vulnerabilities with enough time to act upon them.
Just as important is the rise in the use of outsourcing of critical functions. The right third-party partners bring to bear their own specialized expertise and infrastructure to provide end-to-end coordination of services for every dose and every patient. This option is especially useful for smaller companies that lack the financial resources and managerial and tactical bandwidth to manage all of the complexity on their own.
“Working with a specialized service provider to deliver dedicated case-management services for complex supply chains—to take advantage of their scale and scope, as well as established relationships with multiple premium couriers so sponsors don’t have to navigate this—can reduce strain on the pharma company’s limited internal resources, and enables greater program scalability, as the number of indications, patients, and clinical settings continues to add complexity to the overall picture,” says Trish Demko, director of case management services for Catalent Clinical Development and Supply.
When the service provider takes responsibility for the downstream supply chain for CGT products, “we will have already identified multiple backup plans ahead of time and have the infrastructure in place that enables a quick pivot when any situation arises.” She continues, “We’re doing the heavy lifting—managing all steps from scheduling of starting material collection to delivery of the finished therapy for infusion—so pharma and biotech companies don’t have to navigate this on their own and can instead continue to focus on the science and ongoing innovation while still knowing that the product is in good hands at all times.”
By leveraging this specialized service, customers retain complete visibility at all times, knowing that a dedicated case manager is always on call 24/7 for emergency response and issue resolution. “This service is critical because many pharma and biotech companies may not have sufficient resources, experience or long-term relationships with courier services to confidently manage these complex logistics on their own—and may not be comfortable managing these shipments given the potential impact on the patient if the therapy is not received in time,” says Demko.
“Outsourcing supply chain management to an experienced service provider can provide peace of mind,” Demko adds. The goal is to expect the unexpected and then plan accordingly.
Suzanne Shelley is a contributing editor to BioPharm International.
Vol. 36, No. 4
When referring to this article, please cite it as Shelley, S. Reducing Vulnerabilities in Upstream and Downstream Supply Chains. BioPharm International 2023 36 (4).