Rising to the challenges of modern drug development, while effectively responding to growing pressure to operate more sustainably is dependent on a fresh approach - one where waste is no longer tolerated. According to Almac’s Lyn McNeill, Just in Time Manufacturing is a supply chain strategy that can help Sponsors achieve just that.
Drug development has transformed immeasurably over the past decade. Even before the Covid-19 pandemic and the conflict in Ukraine, which have contributed to raw material shortages and unprecedented supply chain disruption, the pharma sector’s tectonic plates were shifting. With the emergence of high-value, low-yield biologics — coupled with increasing competition — the concept of ‘waste’ has been brought into sharper focus.
In today’s geopolitical climate, where demand outstrips supply, key resources — including APIs, comparators, co-therapies, and clinical packaging materials - are more difficult to come by and more expensive to procure. The cost of raw materials for the pharmaceutical sector has increased by up to 160 per cent and therefore waste can no longer be afforded. And while the commercial impact of waste remains a key driver for sponsors to embrace ways to limit it, pressure to operate more sustainably is emerging as another influencing factor for change.
With growing numbers of sponsors scrutinising clinical trial operations against corporate Environmental, Social, and Governance (ESG) frameworks, sustainability is no longer a buzzword in the background. Instead, sustainability is rapidly becoming a key performance indicator and a mechanism to lower the environmental impact of bringing new drugs to market, ensuring limited resources are ethically utilised to safeguard patient access, and drive more cost-effective operations.
Just in Time (JIT) manufacturing has an important role to play in supporting sponsors to meet these objectives by injecting flexibility into supply chains, preserving precious clinical trial material (CTM), and significantly reducing product waste.
To keep global warming to no more than 1.5°C – as called for in the Paris agreement Paris – emissions must be reduced globally by 45 per cent by 2030, and we must collectively reach net zero by 2050.
Conversely, the pharma industry’s CO2 footprint is set to triple by 2050. If mitigation measures are not widely adopted , the need to urgently and meaningfully seek out opportunities to operate clinical trials more sustainably is clear.
One way to reduce waste arising from clinical trial operations — and deliver enhanced sustainability — is to replace traditional drug production approaches with LEAN methodologies, including JIT.
JIT can range from partial late-stage customisation, where an auxiliary label is added at the time of dispatch, to full late-stage customisation, where drug supply is stored in its primary pack, such as naked vials, ampules & syringes, until there is an actual patient need at a clinical site.
Just in Time Labelling (JTL) is ideal for quick and simple additions to an already clinically labeled kit and is typically best suited to small molecule operations involving wallets and bottles. For biologics, Just in Time Manufacturing (JTM) can help create optimised and adaptive supply chains that promote enhanced product viability and reduced product waste.
With a JTM model, the process of label printing and kit assembly for full late-stage customisation is initiated by drug order forms. This introduces key advantages for sponsors looking to optimise the use of clinical supplies while maintaining viability. Firstly, this approach provides sponsors with the ability to utilise single panel, country-specific labels. Incidentally, this has been proven to decrease study start-up timelines by up to 50 per cent, helping sponsors meet key study milestones faster and more cost-effectively.
Secondly, it empowers sponsors to print study-specific labels with the most current label variables, such as the most recently approved expiry date. This helps to reduce waste and improve bigger-picture efficiency. Finally, by delaying labelling and kit assembly until clinical need arises, supplies remain usable for any country or study, which drastically reduces the risk of costly stock outages that can negatively impact patients and overall trial performance.
A common scenario where JTM’s role in delivering more sustainable clinical supply chains is evident relates to the traditional method of site seeding.
When this is the case, one of two scenarios unfold. In the first, CTM remains on the shelf at the clinical site before being returned, reworked, and redistributed to fulfill anticipated needs elsewhere at a significant cost to the sponsor and the environment. The second scenario involves unused CTM that has already been produced, transported, and stored at the site — within specific temperature ranges that bump up energy demand and environmental impact — being returned to the sponsor for reconciliation and destruction.
In contrast, JTM allows sponsors to prevent the added financial and environmental impact of sites failing to recruit patients. With a JTM approach, drug is only sent to sites once patients are recruited and demand is known. This is achieved by storing bulk inventory that can be packaged and labelled on demand, resulting in highly customised patient kits. This also removes the need to forecast large quantities of bulk drug for packaging, which typically see errors of +50 per cent - 200 per cent. With JTM, drugs do not gather dust on site shelves or require rework, return, or destruction, which contributes to less waste and more sustainable supply chains.
Of course, site seeding is not the only scenario that JTM delivers on its waste limiting potential. It is standard for studies to be changed significantly or stopped all together mid-stream. Whether stemming from emerging study dose information, adverse events, recruitment challenges, regulatory hurdles, protocol design discrepancies, or the addition of new territories, the impact is the same. If supply is produced in bulk utilising a traditional approach, all will require return, reconciliation, rework, or destruction at significant financial and environmental cost.
Contrastingly, with JTM, only the clinical supplies that have been distributed are lost. The rest remains unpackaged and unlabelled in inventory and can be utilised in another configuration for the same or a different study altogether.
This is particularly pertinent for biologics and next generation cell and gene therapies (CGT) that require precise handling and extremely limited time out of conditions. These compounds require significant energy to manufacture, transport, and store at ultra-low and even cryogenic temperature ranges. JTM can help to offset some of this environmental impact by extending the lifecycle of the drug and mitigating product waste that would have a substantial impact on both ESG credentials and a sponsor’s bottom line.
As these compounds are more expensive to manufacture and have extremely limited stability, product conservation is paramount. Advanced therapeutics especially are high value commodities, with the cost for manufacturing one batch of CGT product typically varying between US$500,000 and US$1m. Considering the proportion of the batch that will need to be allocated for samples, stability testing and so forth, the number of units that can be utilised for clinical trial use is already low; resulting in little margin for error. As such, a traditional production approach – that necessitates time out of conditions to manually rework products (that have been pre-packaged and labelled) in the event of a mid-study change - threatens product integrity and sustainability objectives.
However, by harnessing JTM, sponsors can better conserve high cost, low yield, low stability, energy intensive supply by eliminating the need to remove naked vials etc. from appropriate conditions to rework it. Instead, sponsors can manage changes, such as expiry updates, within systems and without ever physically touching the bulk drug product. This increases the longevity of the drug’s lifespan, promotes enhanced product integrity, and removes the need to exert additional energy reworking an entire batch.
The limited stability, high value, low yield nature of large molecule compounds also goes hand in hand with unpredictable recruitment, especially where next generations CGTs are concerned. Being patient-specific and primarily used to target rare diseases or last-lines of therapy, CGT serve smaller patient populations due to low disease prevalence and/or strict eligibility criteria. This serves to cloud visibility for forecasting and heightens the risk of product waste. Limited stability and short expiry dates combine with unpredictable recruitment to create a perfect storm where inefficiency, risk and waste can escalate. And with the increase in CGT trials, more sponsors will need to develop effective mitigations to address the associated issues and ensure sustainable, cost-effective supply chain practice prevails.
Despite the added complexity of bringing all drug compounds to market in a post-pandemic clinical trials’ landscape, drug development continues to boom. There are now more ongoing clinical trials than ever before, with the number of initiated trials increasing by 59 per cent from 2012 to 2021.
However, while JTM is well established in other sectors, pharma has taken longer to embrace its potential. This is owed in part to misconceptions surrounding costs, with many sponsors assuming it to be a more expensive method of assuring supply to patients compared with traditional approaches. This supposes that running smaller operations more frequently chips away at economies of scale yet fails to acknowledge the bigger picture. While initial overheads of JTM can be higher than traditional manufacturing approaches, the financial and environmental savings delivered via a substantial reduction in product waste soon justify the investment. As does JTM’s ability to expedite key study milestones, promotes increased supply chain agility, and reduces the need (and financial burden and environmental impact) for accountability and destruction activity.
Another important consideration to bear in mind when weighing up the merits of JTM in relation to waste reduction is that it does not have to be all or nothing, and it is not just capable of adding value to small studies. Many sponsors are now harnessing JTM at the start of a study when demand is less predictable, and the location of patients remains unclear. Then, once enrolment stabilises and demand is less of an unknown, switching to traditional production approaches becomes feasible. Likewise, a hybrid model featuring both JTM, and a traditional approach is also an option. This can be ideal in trials with multiple arms, where some treatments lend themselves better to JTM than others, in terms of high unit price and availability.
Drug development will continue to evolve and the push for more sustainable supply chain operations is only going to increase, along with the commercial and ethical pressure to mitigate waste in a competitive market. While JTM by no means represents the silver bullet in the quest to establish carbon neutral operations, it does have proven potential to drastically reduce waste and support sponsors to uphold their responsibility to patients and profit margins.
References:
1 https://www.resilinc.com/wp-content/uploads/2023/01/Resilinc_Special_Report_Healthcare_v2_November.pdf
2 https://www.weforum.org/agenda/2022/11/pharmaceutical-industry-reduce-climate-impact/#:~:text=While%20it%20may%20not%20get,by%202050%20if%20left%20unchecked.
3 https://www.clinicaltrialsarena.com/features/sustainable-clinical-trial-supply-chains/
Lyn McNeill is the Just in Time Manufacturing Solutions Manager at Almac Clinical Services in Northern Ireland. Lyn joined Almac in 2016 and has transitioned through roles in IRT and business Project Management before taking on responsibility for service implementation, stakeholder engagement and development of Almac's Just in Time service suite in August 2021.
