Opinion SOLVING SCALE-UP AND MANUFACTURING CHALLENGES IN CELL AND GENE THERAPIES

we address the challenges in manufacturing processes that remain.

The industry needs to continue to find efficiencies and optimise manufacturing to deploy cell and gene therapies economically and at a scale that can make a difference for patients globally. Across the board, we need to implement improvements in raw material inputs and drive innovations in manufacturing technology to deploy gene therapies economically and at scale.

For example, adherent cell culture systems are inefficient. Given the magnitude of the therapy being delivered to the patient, it is clear the industry does not have the ability to produce enough to satisfy growing demand.

Either something must change with the process itself or massive manufacturing capacity will need to be built to sustain current production methods, which will make it difficult to make these therapies more affordable for wider patient populations.

Importance Of Process Standardisation

Equally important is the need for process standardisation to improve scalability. Variables and failure modes must be taken out of the process — this is where innovations in process technology can make a real difference.

Production systems can be standardised and closed so they are less exposed to failure modes. Processes can be minimised to drive cost efficiencies and, perhaps, better clinical outcomes.

We can employ better workflow technologies, such as single-use sterile fluid transfer. It is also probable that fill/finish requirements will be different for cell and viral products, so improved excipient technologies will play a large part in better patient experience and response.

WHAT ARE SOME APPROACHES THE INDUSTRY CAN PURSUE TO ADVANCE OPTIMISATION?

There are two major pathways to process optimisation: First, we must anticipate innovation and optimisation coming from advances in academia. Second, we expect step changes in process improvements from contract development and manufacturing organisations (CDMOs) and other producers. This can be done with close monitoring and, where relevant, partnering with these organisations early on.

Developing partnerships with providers as soon as possible should increase process efficiency and minimise later missteps, even on joint approaches to regulators. In raw materials, specifically, manufacturers are receiving more requests for cGMP grades of materials that have never needed to be made at scale or to cGMP specifications before. Even if these are available at the correct analytical grade, there is considerable raw material expense associated with components such as plasmid DNA. The requirement for biological activity to be retained limits the use of harsh purification methods and adds a special sensitivity, so that potentially harmful or adventitious agents cannot be introduced through the raw material supply chain.

This is an area that greatly benefits from close partnerships between manufacturers and their raw material suppliers, to better understand the requirements for cGMP materials and use them early in the therapy development and manufacturing process. Additionally, partnering helps with tracking and measuring a raw material supplier’s quality system, to ensure consistency over time. The importance of collaborations and quality agreements with raw materials suppliers cannot be understated.

New Solutions To Improve Manufacturability

In areas such as cell culture components, production chemicals, single-use technologies, sterile fluid transfer, excipients and the technology surrounding those process components, there is value in trying new solutions to address improving the manufacturability of cell and gene therapies.

Even at the early stages of trials, we can better understand the variability that comes from research data and use it to correlate with clinical and process outcomes. Taking out manual steps as early as possible is important, as well as creating closed systems using sterile fluid transfer technologies to eliminate process risk.

Hopefully, one outcome of these efforts will be to find scalable ways to address costs for cell and gene therapies, which are still exorbitant. Ultimately, these drugs must be developed in a more cost-effective manner. That is an area where technology providers and suppliers can play a significant role by closing and automating systems and by understanding the contribution of labour, overhead and possible economies of scale from reducing processes.

With the amount of strong research into developing, understanding and characterising drug targets, and figuring out how to make these in production-level volumes, this will be a constantly changing landscape. And there will be many parts to patient treatment options going forward.

Cell and gene therapy has the potential to change patient outcomes for the better as treatments and therapies evolve, adding one more healing tool to monoclonals and biologics. As with other treatments that moved from theoretical possibilities to real results, the industry is developing a clearer and more complete understanding of the issues that need to be addressed to drive better patient outcomes. Through collaborative partnerships among researchers, manufacturers and suppliers, the industry as a whole has the opportunity to move science forward.

Throughout the drug authorisation process and right across the marketing authorisation lifecycle, licence holders are responsible for ensuring the continuous monitoring of the safety profile of a medicinal product. This includes accountability for all third parties and contractors with a potential impact on that safety profile. Relevant suppliers could include anyone from local distributors or qualified persons to IT system partners, security providers and even auditors themselves.

Disruption and turbulence in the global life sciences market are adding to that complexity, with changes to the line-up of suppliers and service providers, all of which affect the vendor records and controls that companies must maintain to ensure end-to-end quality. Where control slips, there is a real risk of problems and if these are exposed during inspections, this could lead to fines or even product withdrawal from affected markets.

So how can marketing license holders take back control?

IDENTIFY THE IMPACT THAT THIRD PARTIES HAVE ON THE CURRENT SAFETY SYSTEM

It’s important to start by identifying ALL suppliers with a potential bearing on a product’s safety profile, however tenuous. Once a definitive list has been compiled, each supplier can be reviewed for potential risk/ safety impact and appropriate due diligence.

Each third party can then be assessed for potential safety profile impact, the current supply/contract status and any monitoring, and required next steps.

THIRD-PARTY VARIABLES:

Maintaining A Robust Safety Profile Through Tighter Supplier Controls

how much impact that vendor will have on the safety profile based on the services it is going to provide.

Once the new partner has been classified, the associated risk level must be assessed through a process of due diligence. The objective here is to gather and review all relevant information to facilitate an informed, riskbased decision as to whether your organisation should enter into a contractual relationship. Performing an audit or riskbased questionnaire on all critical and significant third parties is the suggested best practice.

Extend The Same Vigilance Throughout The Lifecycle Of The Agreement

Arriello’s director of auditing and quality assurance, Helen Lowe, considers how drug companies can ensure quality without boundaries and build new confidence in their end-to-end safety profile.

CONSIDER THE AUTHORITIES’ PERSPECTIVE & HOW IT’S EVOLVING

As the life sciences ecosystem continues to change in shape and makeup, and as globalisation is counterbalanced by supplier consolidation and supply chain restructuring, regulators are expected to issue firmer guidance on vendor management controls sooner rather than later.

In the meantime, robust vendor management is an expectation under EU GxP requirements. So if drug developers or license holders fall short, they could risk their reputations as well as significant fines and ultimately product withdrawals.

IDENTIFY & ADOPT BEST PRACTICE

A robust vendor management system (VMS) is every bit as important as a robust quality management system (QMS). Ultimately, it should form an integral part of the QMS, and awareness, training and buy-in to vendor management practices should be formalised with appropriate communication and training.

Perform Initial Due Diligence

When considering new third parties, it’s important that the R&D, MAH, CRO or service provider organisation assesses

From a post-marketing perspective, under GVP Module IV.B.1. (Pharmacovigilance audit and its objective), there must be ongoing due diligence and assessment, alongside an audit program based on risk. This should reflect evolving factors such as changes to legislation and guidance, or a major restructuring of the PV system (e.g. following an acquisition).

All license holders should have all responsibilities clearly documented in an appropriate agreement, to avoid misunderstandings around relative responsibilities. Across the lifetime of the contract, it will be important to review any contractual changes made. Regular testing of the contact details to ensure they are still valid and correct offers one simple way to uncover changes that may not have been identified otherwise through a routine process.