The need to respond to the emerging healthcare needs of a rapidly aging global population, refine existing treatments and discover new ones that improve, extend or save the lives of patients has prompted a monumental shift in drug development.
 
Over the last decade alone, the industry has transitioned from largely single arm, single country studies of small molecule pharmaceuticals, towards truly global trials. Indeed, the number of countries serving as study locations outside of the United States has more than doubled in the space of 10 years.¹
 
Globalization is not the only driving force for industry transformation. As the sector invests in delivering targeted and effective therapeutics that negate the need for invasive surgery and the negative side-effects associated with small molecule drugs, the emergence of biologics has been both rapid and disruptive in equal measure. Representing another huge contributor to change, sales revenue for commercialized biologics tipped $232 billion in 2017—a 70% increase compared with 2011.² Growth that shows no sign of abating, as analysts predict biologics will account for a quarter of the entire pharmaceutical market by 2020.³ 
 
While these developments are incredibly positive for global human health, they represent significant challenges for clinical trial sponsors keen to ensure the right drug is delivered to the right place, at the right time and under the correct temperature parameters. Upholding this ideal standard in the face of growing supply chain scale and complexity is easier said than done. Yet the risk of failing to rise to the challenge puts both patients and profits at risk.
 
Although several manufacturing and supply chain strategies have been developed to manage these new-era challenges with greater control and flexibility the adoption rate has failed to keep pace due, in part, to a lack of understanding. Instead, many sponsors continue to rely on less than optimal methods of managing the production, packaging, labeling, storage and distribution of study drugs and, in doing so, introduce unnecessary risk and cost.
 
Just in Time Manufacturing (JTM) is a prime example of this. Although the approach ticks several boxes for sponsors looking to maintain operational efficiencies, reduce risk and optimize costs while running complex, personalized or large-scale studies, it is often by-passed in favor of better-known, albeit less appropriate, models. This is largely attributable to several preconceived notions that surround JTM, which cause many sponsors to shy away from embracing an approach that has the potential to deliver tangible value. 
 
What is Just in Time Manufacturing?
 
Before exploring the misconceptions that shroud JTM in the drug development sector, it’s important to understand its definition, purpose and place within the bigger picture of modern clinical supply chain management. 
 
Developed by Toyota Motor Corporation in post WWII Japan, the Just in Time method was created as a means of “making only what is needed, when it is needed, and in the amount needed.”⁴
 
In the drug development sector, JTM is defined as the full late stage customization of clinical kits, which can be used in isolation or as part of a wider LEAN initiative—a systematic and strategic approach that maximizes value by removing or minimizing waste from processes. JTM makes it possible for stock materials, such as bottles, wallet cards, vials, ampules and pre-filled syringes, to be packaged and labeled just prior to shipment in order to effectively meet varying global need, once demand is known.
 
JTM is an alternative method to standard batch manufacturing; a technique where drugs are packaged and labeled before being added to inventory over several workstations to produce set demand.
 
Until recently, batch manufacturing has been the default setting for sponsors. This is owed to its ability to readily accommodate the less certain demand forecasts synonymous with clinical trials compared with commercial drug production, which benefits from a continuous manufacturing strategy. With batch manufacturing, operations can start and stop to meet varying needs and, depending upon the exact scenario, facilitate reduced overheads, as one production line can be used to produce multiple products, and the savings passed on to sponsors.
 
However, in the modern clinical trials landscape, batch manufacturing can present numerous disadvantages. When dealing with biologics for example, the shorter shelf life heightens the risk of fully assembled kits surpassing expiry dates, while waiting to fulfil notoriously unpredictable enrollment demand from clinical sites. The fact that sponsors are dealing with highly expensive, limited supply also makes batch manufacturing risky business for some biologics-based trials.
 
For many studies involving expensive products, like gene therapies, rare or orphan disease, oncology and immunotherapy; for patient-centric trials that necessitate patient specific labeling and kit configuration; for trials operating a pooled supply strategy; and for trials involving drugs with short stability and a need for frequent re-testing, JTM can represent a better-fit solution.
 
So what’s preventing more sponsors from considering the merits of JTM?
 
Identifying the false economy of the ‘default setting’
 
The answer is JTM remains a relatively new concept for drug development and fear of the unknown creates mistrust and misinformation.
 
Perhaps the most common industry misconception surrounding JTM is that it is always the more expensive method of assuring supply to sites and patients. Justification for this perception focuses on the fact that JTM requires sponsors to run smaller operations more frequently, rather than fewer but much larger batch manufacturing operations, which many assume removes the economies of scale advantage.
 
At face value, this makes perfect sense. However, it’s important to examine the bigger picture of an on-demand approach to the clinical supply chain and identify the false economy that, depending on study design, manifests as a result of selecting the default setting during a study’s planning phase.
 
The initial overheads associated with implementing JTM may sometimes be higher, compared with a standard batch manufacturing approach. However, the scales soon tip back into JTM’s favor with the cost savings that can be realized in waste reduction, shortened timelines, minimized overage and far fewer returns—and therefore significantly lower investment in accountability and destruction activity.
 
Drilling down into the concept of waste, it is clear to establish a link between implementing JTM and reducing waste in the clinical supply chain. For instance, it is estimated that 50 percent of clinical sites fail to recruit patients in line with estimates.⁵ If sponsors are utilizing a batch manufacturing approach, a significant quantity of seeding stock is likely to remain unused and either require replacement, due to expiration, or destruction due to unrealized demand.
 
Equally, using batch manufacturing techniques, unpredictable or inaccurate enrollment projections can quickly lead to production overage and the unnecessary cost that comes with producing too much supply for too little (actual) demand.
 
Contrastingly, the full late stage customization of clinical supplies supports variable demand and patient-specific requirements, while mitigating the risk of IMP exceeding its expiration date, while awaiting distribution. The approach also removes the need to pre-package supplies before a study commences and facilitates pooled supply across protocols. Waste management becomes even more vital when considering the expensive nature of biologics and the industry-wide supply shortage of many commercial comparator products.
 
The shortened timelines associated with JTM also offer bigger picture cost efficiencies, with a JTM approach reducing the average timeline of study start-up up, the cycle time necessary to be distribution ready, by up to 50% for initial supplies and by up to 60% for new or reconfigured supplies, which may include addition of new countries or new kit types, compared with a standard batch manufacturing approach.⁶ Arguably, this cultivates enhanced patient centricity and overall experience; mitigating missed patient visits and supporting retention, while reducing the expense that comes with replacing patients.
 
Finally, because clinical supplies are only customized and distributed to fulfil a precise and immediate need, sites are left with far less product that needs to be returned and destroyed, either at the end of a trial or in the event of a patient drop out. This incurs significant savings in courier costs, administration time and the expense of physically transporting and incinerating product.
 
Basing suitability on study size or technology utilization
 
Another common misconception about JTM is its suitability for particular studies over others.
 
Some sponsors believe that JTM is only an appropriate choice for smaller trials, due to the fewer operations associated with small, phase I studies.
 
It is correct that JTM can help facilitate drug supply for smaller studies, including trials involving treatments designed around niche patient groups and disease types that typically deal with limited supply. Although patient populations may be smaller, forecasting supply and demand can be more difficult, due to the reduced patient pool that comes with developing highly targeted medicines.
 
Couple this with the lack of stability data and need for end-to-end cold chain management  that comes as part of the package with small trials involving biologics drugs and it’s clear to see how an on-demand supply strategy can alleviate some of the pressure sponsors of these trials face, while simultaneously mitigating risks and controlling costs.
 
Many sponsors also believe that JTM is only relevant for smaller trials that don’t utilize interactive response technology (IRT) to manage key study components, like screening, randomization, dosing, drug supply and inventory management, patient tracking and clinical outcome assessments. The assumption is that JTM can provide the flexibility needed to maintain patient access to vital medication, without introducing unnecessary cost in the absence of technology that uses study data to establish the optimal balance of inventory to minimize supply costs and maximize successful patient resupply.
 
It is true that JTM can bolster the efficiency of small, phase I studies, especially those that do not utilize IRT systems. That said, just because JTM solves problems for smaller studies, doesn’t mean it can’t play a leading role in streamlining operations for larger, technology-enabled trials as well. 
 
JTM can play an integral role in larger studies as part of the overall packaging and labeling strategy. Sponsors can incorporate JTM during the early part of a study, during active enrollment, when global demand is unpredictable and the rate of recruitment can be delayed beyond initial “period of use date.” Once target recruitment has been attained the sponsor can shift back into the batch manufacturing model to support remaining treatment cycles. This hybrid approach can assist sponsors with conservation of IMP, and mitigation of rework operations. In addition, since JTM has been developed to release product to the IRTs utilizing the same medidata points as they use today, studies are able to leverage this hybridized approach with their technology vendor.
 
Limiting JTM application by therapeutic area and/or drug type
 
Along with JTM’s compatibility with larger studies, many sponsors are also quick to dismiss JTM based on the therapeutic area a trial relates to. A common misconception about JTM is that it is only a good fit for cell and gene therapy studies, due to the patient-centric nature of an on-demand supply strategy that sees kits being produced to accommodate patient-specific parameters, such as age and weight. Whereas JTM clearly offers benefits to cell and gene therapy trials by customizing supplies to achieve optimal supply chain results, it is, by no means, limited to this therapeutic area.
 
In reality, JTM operations can accommodate and add value to not just any trial size but also for any therapeutic area. The premise of JTM is its ability to respond quickly to shifting demand while preserving drug product. Therefore any study that faces enrollment challenges or limitations with drug availability, such as oncology, immunotherapy, investigator initiated trials, just to name a few, could greatly benefit from this approach.
 
Breaking the cycle of misinformation
 
As the industry continues to evolve, key drivers are emerging that will push sponsors closer to JTM. The costs involved with producing biologics and the associated short stability, which makes assigning expiration dates well in advance of a traditional manufacturing operation incredible difficult, is a primary one.
 
Other drivers include the need to work within conditions to preserve inventory, adopt industry best practice in relation to patient centricity and respond quickly and effectively to change. Corporate Social Responsibility is another motivator for some sponsors, that recognize waste and inefficiency doesn’t just impact patients and P&L, but the planet too and therefore want to implement measures that reduce a clinical trial’s carbon footprint.
 
Although a significant proportion of sponsors continue to view JTM as a foreign, unfamiliar way of operating, in response to these key drivers, the drug development sector is beginning to warm up to the possibilities an on-demand supply chain presents. Consequently, perceptions are slowly changing.
 
Greater awareness is needed to bridge the gap between new-era challenges and helping sponsors select best-fit solutions like JTM further. This awareness will translate into increased confidence and accuracy when sponsors are specifying the most appropriate manufacturing methods to meet the precise supply needs of their clinical trials. Through better engagement and understanding across the industry, perceptions can be challenged, and attitudes changed, so that flexible supply chains can be designed to not only benefit sponsors but their patients too.
 
References
1. International Journal of Clinical Trials da Silva RE et al. Int J Clin Trials. 2016 Feb;3(1):1-8
2. https://www.iqvia.com/-/media/iqvia/pdfs/nemea/uk/disruption_and_maturity_the_next_phase_of_biologics.pdf
3. https://www2.deloitte.com/content/dam/Deloitte/global/Documents/Life-Sciences-Health-Care/gx-lshc-ls-outlook-2018.pdf
4. https://marketrealist.com/2016/05/toyotas-just-time-method-critical-success/
5. Source: Tufts CSDD, n=15,965 sites participating in 153 global phase II and III clinical trials
6. Almac statistics
 
Natalie Balanovsky is the Just In Time Manufacturing Solutions Manager at Almac Clinical Services in Souderton, PA, responsible for stakeholder engagement, implementation, and the development of Almac’s Just In Time service suite. Natalie has previously held other roles at Almac including global project leader and project manager of distribution, managing Phase 1 though 4 clinical trials of various size, and complexity. She has over 15 years of professional experience within project management, business development, GMP operations, and quality compliance for various industries including pharmaceutical, financial and b2b.