The traditional centralized manufacturing model has long been the cornerstone of therapeutic production and distribution for pharmaceutical companies.
That’s set to change.
New classes of therapies are treating previously incurable conditions and are on their way to becoming the new standard in healthcare.
Coupled with an era marked by unprecedented technological and scientific advancements, the industry needs to navigate new, fit-for-purpose manufacturing and supply chain models to ensure patient access.
There are early signs that a shift is underway; decentralized manufacturing is starting to challenge the established norms and offer a novel perspective on therapy delivery, all in the pursuit of getting life-changing therapies to the patients who need them.
The good news is that regulatory bodies are keeping pace, in particular, the FDA and MHRA have published draft guidelines that set out definitions of manufacturing models, where and how quality control should be managed, and, in part, how inspections may be carried out.
The MHRA’s guidance centers on point-of-care manufacturing, whereas the FDA has categorized four manufacturing models:
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Centralized
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Distributed
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Decentralized
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Point-of-care
Whilst there are several movements across the cell and gene therapy industry to coordinate, standardize, and progress near-patient manufacturing, we believe that action can be taken now, and patients should not have to wait.
Together, we can improve patient access with the technology and regulatory frameworks we have today.
New Manufacturing Paradigms
There has been a string of substantial delays between the approval and launch of cell and gene therapies. In the past year, we’ve seen approvals from BioMarin (Roctavian) where no patients were treated for a year after regulatory approval1. Bluebird Bio even decided to withdraw Zynteglo from the European market completely after failing to agree on pricing and significant manufacturing delays2.
It's clear that we need to take accountability as an industry for improving the cost and time-to-patient, but how?
These market access and reimbursement bottlenecks are well recognized. However, appropriate infrastructure is a crucial factor in improving patient access that’s not as widely discussed.
Advanced therapies require specialist treatment centers, which are sparsely located and result in a long, complex pathway to treatment for patients. While there is more than just physical infrastructure at play here, near-patient manufacturing models could be a game changer for patient access worldwide.
Fortunately, the regulatory infrastructure is developing, with the FDA providing draft guidance and some fundamental definitions of different types of manufacturing models. The MHRA have settled on ‘point-of-care’ in their draft guidance, stating that ‘The aim is to support increased manufacture of point-of-care products whilst ensuring these products attain the same assurance of safety, quality and efficacy currently in place for more conventional medicinal products.’3
To provide some context and clarity, let’s examine the terminology used, here are the recent FDA definitions of four types of manufacturing models:
1. Centralized
A centralized manufacturing strategy typically consists of a manufacturing facility producing the product and distributing to end users.
- Increased logistical coordination for manufacturing and administration
- No concerns about analytical comparability
- All QC testing performed in the same facility for all products
- Quality oversight is controlled at the centralized facility
2. Distributed
Manufacturing occurs at multiple locations (decentralized facilities) via deployed manufacturing units.
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- Manufacturing may initially take place at a centralized facility.
- Contain a cGMP environment that is similar to that in a traditional manufacturing facility
- Increased manufacturing agility
- Analytical comparability is needed between sites
- Assay bridging is needed for QC testing performed at each site
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Centralized quality oversight
3. Decentralized
Manufacturing occurs at multiple locations (regional facilities). Manufacturing is replicated and geographically dispersed to shorten supply chains and increase supply reliability.
- Increased manufacturing agility
- Analytical comparability is needed between sites
- Assay bridging is needed for QC testing performed at each site
- There is quality oversight at each manufacturing facility and for the overall product
4. Point-of-care
Manufacturing at host sites in close proximity to patient care.
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- Non-traditional cGMP environments
- End-users may not share similar experiences to traditional manufacturing operators at centralized facilities
- Increased manufacturing agility
- Analytical comparability is needed between sites
- Assay bridging is needed for QC testing performed at each site
- Centralized quality oversight
The EU also published updates to the General Pharmaceutical Legislation amendment proposal in 2023, which included their take on regulating decentralized manufacturing. One of the crucial parts of this proposal is that decentralized sites do not need their own marketing authorization. As described in section 1094:
“When the manufacturing or testing steps are decentralized, they should be carried out under the responsibility of the qualified person of an authorized central site. The decentralized sites should not require a separate manufacturing authorization from the one granted to the relevant central site but should be registered by the competent authority of the Member State in which the decentralized site is established”.
A final emerging approach that cannot be ignored is hospital-based therapeutics, particularly for CAR-Ts. While controversial, several institutions are seeing success and timely, cost-effective treatment of their patients.
The hospital exemption policy5 in Europe has given the Hospital Clínic de Barcelona an effective pathway to develop its own CAR-T products that are reimbursed by the national healthcare system and a third of the cost of commercially available CAR-Ts. So far, around 300 patients have been treated6.
Israel is another noteworthy region that is taking this route. By keeping the manufacturing and delivery at the hospital, complex logistics are avoided, and processing has been reduced to 10 days7. This is hugely significant for patients who have run out of treatment options and are in a critical condition.
Another interesting case is at the City of Hope Hospital in California, who is not only developing CAR-T therapies, including for underserved indications like ovarian cancer8, but is also moving CAR-T infusions into an outpatient setting9, further improving access and options for patients.
There are still many questions around reimbursement and widespread adoption and infrastructure. Indeed, what will the implications be for commercial therapy developers? What is the willingness to pay for a hospital vs commercially produced CAR? Looking towards the future state, we could be comparing a hospital-based CAR vs a commercial, allogeneic CAR – what will the cost differential be, and which is more likely to be reimbursed?
What is undeniable, however, is the drive to elevate patient access and outcomes.
Making Near-Patient Manufacturing a Reality Today
So, there are several alternatives to the centralized manufacturing model, and we envision a world in which they can co-exist in some capacity and where patients are the ultimate beneficiaries.
Some of the bottlenecks standing in the way of realizing decentralized manufacturing and other models include quality oversight, comparability between sites, technology innovation, standardization, enough expertise and talent, digital capabilities, and a reliance on paper.
However, we believe that the tech and infrastructure that exist today can deliver robust, quality-driven decentralized manufacturing for cell and gene therapies.
Pursuing perfection in technological innovation isn't a prerequisite for advancing decentralized manufacturing. The industry could benefit from embracing currently available platforms and regulatory frameworks to make this a reality sooner. By doing so, we'll gather valuable insights to guide the scalable model and pave the way for long-term success. This mission was the driving force behind the Title21 and Germfree partnership announced in October 2023.
Integrating modular and mobile cleanroom facilities with adaptable, scalable software solutions creates a robust foundation for decentralized manufacturing. This integration enables various sites to operate under a unified system, promoting uniformity and regulatory compliance across multiple locations.
The big concern around quality oversight is also addressed through this partnership:
- Standardization of processes: Title21's quality management system enables standardized processes, and protocols can be implemented across various decentralized sites. As such, every manufacturing location adheres to the same high-quality standards and regulatory compliance.
- The Title21 operating system enables remote monitoring and control of manufacturing operations, which, when combined with Germfree’s remote monitoring and facility management services, ensures cleanroom performance meets specified standards. Additionally, this synergy allows multiple sites to function cohesively as a networked system.
- Utilizing modular or mobile facilities to standardize the manufacturing environment effectively clones the operational setting, significantly reducing variability across different sites. This approach streamlines the qualification process for facilities, equipment, and manufacturing procedures. Standard Operating Procedures (SOPs) can be uniformly applied across all locations, ensuring comprehensive control over operations. Moreover, centralized quality oversight becomes more manageable when each site adheres to the same processes, procedures, and systems.
Together, these capabilities allow centralized oversight of decentralized operations, ensuring that quality and performance standards are maintained across all sites.
In conclusion, affordability of and patient access to cell and gene therapies is a global issue that requires innovation in terms of manufacturing models, regulatory frameworks, technologies, and, possibly, mindsets.
We have the capabilities to make decentralized manufacturing today through collaboration and leveraging the infrastructure and software currently at our disposal; together we are greater than the sum of our parts. Patients cannot wait and need these life-changing treatments as soon as possible.
Have a question? Contact us at info@title21.com.
For more information about the manufacturing definitions set by the FDA, download our infographic for FDA Definitions for CGT Manufacturing Models.
4https://eur-lex.europa.eu/resource.html?uri=cellar:bfcb9e00-e437-11ed-a05c-01aa75ed71a1.0001.02/DOC_1&format=PDF (section 109)
5https://health.ec.europa.eu/system/files/2016-11/pharm600_hospital_exemption_0.pdf
6https://www.statnews.com/2023/12/19/car-t-therapy-spain-hospital/
7https://www.labiotech.eu/interview/in-house-car-t-cell-therapy/
