The need to ensure patient safety and drug efficacy in pharmaceuticals is only increasing. With the sudden disruption caused by the COVID-19 pandemic, the Chemistry and Manufacturing Controls (CMC) process has been thrown into the spotlight as critical to drug manufacturing and to pharma regulation in general. But this same pandemic has also altered what many thought to be the future of the industry, and where CMC will go from here is an increasingly uncertain question. Proventa spoke to Jean-Pierre Metabanzoulou, Senior Director, MBA, PhD, CMC & RA at Acasti Pharma, to hear more about his work in CMC and how the field will progress over the next five years. 

Proventa: Tell us about your role within CMC, and which parts of the area you enjoy most?

Jean-Pierre Metabanzoulou: I am actually currently Senior Director of CMC at Acasti. Day to day, I lead a cross-functional internal team of 10 people and external CDMO/CRO resources to ensure anything to do with process development and analysis runs smoothly, and as we’re using QbD, that we have a robust development program. I also ensure we have a strict set of specifications for our processes and that other critical quality attributes are set and in line with what the process can deliver. 

I also deal with the troubleshooting of any program issues, and ensure we have a risk-based system in place to investigate problems thoroughly and ensure they cannot happen again. This is what we call the CAPA system – corrective action, preventative action.

A lot of the enjoyment I find in my role stems from introducing new concepts and innovation. I’m keen on looking at new technologies and new ways of doing things – for example when I joined the team, they were performing continuous manufacturing, but they were missing continuous quality control. I looked at the process and decided that there was an opportunity to include this element. At the time we didn’t have the right internal resources, so we worked with academia to gain access to these. Continuous quality control is not yet implemented because we’re not at the commercial manufacturing stage yet, but we have the elements to include the quality control continuous monitoring. Once the batch is manufactured at the end, the quality testing will be completed at the same time. This is how I envision CMC.

Proventa: Which technologies would you want to implement into CMC, or adopt more to progress the sector?

JPM: What I’m seeing more of, and what the CMC professional must do, is reduce the siloing that occurs in the pharma industry. We have medicinal chemistry experts who design the molecule, and then the development side who take over when the lead is optimised. The drug can then be developed and moved along the clinical pipeline. 

But what we should be doing, as soon as some candidate leads have been identified, is to ensure those currently involved at later stages are brought in earlier, so they can have more input on the molecule’s design. This is vital because in development these people will be familiar with some attributes that medicinal chemistry experts perhaps are not, and so by involving them issues that might come up later can be prevented. So we definitely need to break down these silos!

Right now there’s a lot of innovation and new technology on the discovery side of things, and how professionals there are developing and designing new molecules and validating targets is changing. So this makes it even more important to work as a team. For global companies this can be difficult, but it’s much more achievable for biotechs and smaller companies. So greater collaboration is something the industry desperately needs. 

On the technology side, we’ve talked about it a lot but it’s worth repeating: AI. There’s a lot of data gathered in pharmaceuticals and CMC, but this data is scattered across different systems which don’t interact with one another. There’s an opportunity here, and I’m seeing more and more tools which can be applied to this – but none that are commercial and off the shelf at present that can facilitate the data acquisition and exchanging from early development up to commercialisation. This is vital if we want to understand our processes, improve them, and use the data to feedback into our systems. This will not only improve quality but also reduce costs. 

Proventa: How do you see CMC changing over the next five years?

JPM: The industry is definitely moving towards improving drug quality and greater standardisation. This concept has been around for quite a while, with Process Analytical Technologies (PAT) gaining fame in the early 2000s after it was introduced by the FDA and other regulatory bodies and pharma companies were encouraged to adopt them. PAT standards were introduced to combat batches being recalled and bad product quality within the industry. As a side effect of PAT, the costs also decreased as fewer batches were lost.

We are seeing more and more online testing, meaning you implement some probes on your process that monitor the quality of your product. As soon as you see that there’s a risk, you can make sure you immediately put in measures so the process will be back in control. So this is what we’re looking at also.

In terms of technology, one tech that’s changing things is NIR – Near Infrared Tech. That’s very interesting – it’s very sensitive to the environment. That means we won’t have the same response when you’re testing for a material, as it’s like a fingerprint. Different molecules have different fingerprints. It’s a very interesting technology in the small molecule arena. 

I definitely see silos being reduced over the next five years. Other than that, COVID-19 has of course changed how the industry is collaborating. We see more and more people working as a team, and reaching out to other organisations more than we used to. 

I can see these cross-functional teams continuing post-pandemic. These are very important, and we need the different perspectives of people in separate departments, sciences etcetera. Our work needs experts from early development, pharmacology, CMC, manufacturing, quality control and assurance, all working together to develop processes. We need those different perspectives. By bringing these together, we’ll see improved final results – but this isn’t easy to do! I think it will take time for this to become a norm in the industry. But the more we do it, the easier it will be to break those silos. 

Joshua Neil, Editor
Proventa International

The post The Future of CMC: An Interview with Jean-Pierre Metabanzoulou appeared first on Proventa International.

Chemistry, Manufacturing and Controls (CMC) is a vital part of the drug development process. A CMC strategy gives companies a template for bringing a drug through the early clinical stages all the way to commercial manufacturing. 

The CMC process has a number of benefits for a company: it can reduce development costs and reduce delays, as well as ensuring that the end product is safe and consistent. 

In larger pharmaceutical companies, CMC is not often an issue: enough resources exist to fund sufficient personnel to deal with strategy creation and ensure that no mistakes are made. In contrast smaller companies have a much greater challenge in CMC: their lack of staff or subject experts means that even if they had the resources to conduct CMC duties well, they lack the knowledge to put it into action and create robust strategies to characterise and control a product. 

There are a number of challenges, both process and regulatory, that hamper smaller companies from performing CMC as well as they could. But the solution is simply greater understanding of these issues and being aware of the right procedures and rules to navigate them. Proventa takes a look at how smaller companies can better conduct CMC. 

Current Challenges in Small Pharma CMC

As mentioned above, a major CMC challenge for smaller companies is a lack of technical and subject expertise. Without resources or knowledgeable experts mistakes can easily be made across the CMC template, from failing to spot significant impurities in a product to setting up inadequate formulation recipes. 

Often CMC activities up to phase 2 of a product’s trial will be co-ordinated only by one individual, often alongside other duties. Even should they have the background and experience to understand the complexities of the CMC process, managing it can be extremely difficult. 

This is often exacerbated by timelines that are too short for the necessary development, potentially jeopardising qualification and validation of assays and suppliers, not to mention storage conditions, tech transfer and process validation. 

These challenges are compounded by recent regulatory decisions. This is not helped by the fact that other values like safety and efficacy often overshadow CMC concerns, particularly in small molecule new chemical entities. The FDA’s accelerated review process, which comes as part of the 501(b)(2) approval pathway, allows smaller companies to use CMC shortcuts when approving drugs. This shortcut, however, has in some cases resulted in millions of dollars and huge amounts of times being added on to development timelines due to CMC deficiencies. Over the last few years, the FDA has increasingly sent out complete response letters (CRLs) to manufacturers putting a stop to drug approval until CMC issues are addressed, with 25% of the 33 CRLs sent out between January 2017 and May 2018 focusing specifically on CMC. 

Greater Development Strategies

Developing a clear CMC strategy can be made easier by focusing on a target product profile and understanding what needs to be achieved. This should take into account the therapy method, patient sub-populations, and the drug’s chemical characteristics. It’s also important to look at the product’s cost and any intellectual property issues at play, to understand how a CMC strategy would fit into the larger clinical and regulatory strategy for the product. 

While every development program is different and will require a tailored approach – that can be learned from experience – it is important still to focus on the data generated and understand the potential problems that each program could have. This, naturally, is difficult for companies with limited experience or a lack of understanding around the data, but it is important nonetheless to avoid errors of omission or unforeseen problems. 

This can mean looking out for red flags during analytical development, like changes in a compound under certain conditions, or other changes that result in a polymorph form through solubility differences – differences that can be caused even through minor additions like a new colouring. 

Regulatory Strategies

Certainly with newer companies, it can be difficult to understand what CMC requirements regulators need. While the FDA specifies in 21 CFR 312 that an Investigational New Drug (IND) form requires a clear description of a drug’s manufacture and control, it is hard to know how much information to give and when it should be submitted. 

Working with regulators early on is a vital step in CMC that smaller companies can leave out or think they lack the time for. But hiring an individual for later trial stages, preferably with an advanced degree and experience both of management and integration, and being able to consult regulators on any issues which arrive is vital for a smooth transition through different stages without any major setbacks. It will also clarify any vagaries companies find when filling in INDs or other forms. 

Similarly, it is important for a company to write their new drug applications (NDAs) in a clear, coherent structure. Particularly, critical information must be clearly presented and easy to find. Without this, progress can stall as regulators fail to find the information they need within the time limit.  

Other areas in CMC to be explored early in development and relayed carefully to regulators include safety assessments; transition from early- to late-phase commercial and clinical dosage forms; and analytical testing methods. 

Conclusion

To a smaller company, CMC can seem like an area that is both less vital than others but also a worrying complexity that would take an inordinate amount of energy to understand and complete.

But taking the first step of understanding where to look and what to do can do wonders for the CMC abilities of a company. With that small knowledge, pharma organisations can begin to seek out the necessary talent they need to get started, collate the rules and regulations that overarch this area, and work more closely with expert regulators and CMOs to fill in the details they lack and become more proficient with the complex area of CMC. 

To ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s online Biomanufacturing Strategy Meeting 2020.

Joshua Neil, Editor
Proventa International

The post Better CMC Organisation in Small Pharma Drug Development appeared first on Proventa International.

Safety is one of the most important aspects of drug development. The need for a drug to be efficacious, consistent and non-harmful to humans is vital for its success. And where a treatment is new, highly variable, and can involve introducing viral vectors into the human body, safety must be ensured more than ever. 

The chemistry, manufacturing and controls (CMC) processes are key to ensuring at every stage that a drug is safe and effective. But given the novelty and variability of cell and gene therapies, what challenges does CMC face in this field? 

Ahead of our CMC / Regulatory Affairs online Strategy Meeting on 2/3 June, we looked more at the challenges of CMC in cell and gene therapies.

Cell and Gene Therapies

Cell and gene therapies (CGTs) are two distinct but overlapping treatments in modern medicine, whose potential is only now beginning to be fully explored. In both cases, cells are extracted either from a patient (autologous approach) or from a healthy donor (allogeneic approach). They are then altered to contain a corrected or modified version of the damaged genes, and returned to the patient’s body. There they will propagate and hopefully solve the issue. As a result of this method, CGTs have the potential to be extremely long-lasting solutions. Some require only one or two treatments in a lifetime. 

So far, CGTs have been used primarily to treat rare and currently untreatable diseases, such as motor neuron disease and some types of cancer. Their efficacy can be excellent: One treatment for B-cell acute lymphoblastic leukaemia showed an 83% remission rate after three months. 

As with any new treatment, a number of difficulties have arisen around the development and manufacture of CGTs. These range from development to manufacture, and include: 

– design of facilities, as the single-use and highly bespoke nature of CGTs reduces a number of standard processes to redundancy

– a much more complex supply train, in which a number of biological elements must be tracked, monitored and kept safe at the same time

– additional training for healthcare staff, who must learn new CGT methods and techniques

– the development of new payment models to deal with the high cost of CGTs and their more specialised targets

The Regulatory Challenge for CMC

But it is in the CMC arena that CGT is facing one of its most difficult challenges. The area’s natural need for flexibility and adaptability could potentially be solved by a strong risk-based CMC framework. But this is only recently appearing, both in the U.S. and within the European Union. In addition to this, the grant of breakthrough and ‘Regenerative Medicine Advanced Therapy’ status to a number of CGTs means that any CMC development process is sped up, causing further issues.

The newness of CGT is not, however, an excuse for reduced CMC compliance. The FDA has stated that by phase 2 of a CGT study there is increasing expectation for product characterisation and compliance with cGMPs. For licensure, full compliance with all applicable regulations is required. The FDA expectations for late-stage product development include having:

– sufficient manufacturing experience to narrow acceptance limits

– a controlled manufacturing process and planning for future scale-up

– a biologically relevant potency assay

The FDA released CMC guidelines for CGT manufacturing in January 2020. This covers CMC expectations for both early-stage and late-stage product development, as well as accelerating product developments through the FDA. 

To get around the sparsity of firm CMC frameworks, greater awareness of the current situation and better communication must occur. All parties must take care to share knowledge as early in the process as possible, to determine where quality/clinical connections are, and how to manage potential risks as they occur. 

More information on CMC requirements for CGT IND applications can be found here. 

Manufacturing Challenges for CMC in CGT

Across manufacturing, CGT faces issues that hinder CMC. An incomplete understanding of some therapies’ mechanism of action means data is limited. This in turn makes it more difficult to link clinical outcomes to critical quality attributes and process control parameters.

Additionally, the inherent variability of starting materials, changing from patient to patient, can affect process performance and efficacy of the final product. Other problems in manufacturing include:

– The need for segregating products in facilities, and the numerous inherent safety risks of viral vectors and (often-manual) work during manufacturing

– The short shelf-life of sampling, which can impact release testing strategies

– Accelerated approval pathways negatively impacting manufacturing timescales and process design

– Difficulty during comparability exercises based on lack of data 

Facility-specific safety challenges can be solved by giving significant thought to facility design, staff training and chain of custody procedures for any manual steps in the process. For those processes which do not need manual work, closed systems and automation are highly recommended to reduce cost, increase safety and limit error. 

Regarding comparability, one solution is to create process development and technology transfer procedures suitably early in production as a vital part of the life-cycle. Creating suitable analytical methods to assess batches of products can allow comparability of a product before and after changes to a batch. 

Other Challenges for CMC in CGT

Legislation and guidance are not the only area pharma companies must be aware of. Selection of raw materials is a particular challenge when such a degree of variability exists in extracted biologics. Poor or unlucky selection will become a particular problem later in the process, reducing efficacy or potentially harming the patient. To combat this issue, high-grade materials should be ascertained and used. 

This issue is further compounded by the lack of clarity surrounding the terminology for ‘‘raw materials’. In the U.S., raw materials can include starting materials, ingredients, reagents, processing aids and many other ingredients. There is a disparity between the United States and stedEurope around what exactly ‘ancillary materials’ covers as a term. 

Beyond this, a number of other challenges exist around raw materials, including the potential variability and risk of using animal-derived materials, the use of Research Use Only materials such as growth factors that are labelled ‘not for clinical use, for research purposes only’, and the lack of simple characterisation tests for many raw materials. With every challenge, a risk-based approach to assessing and using raw materials is suggested, as detailed in USP Chapter 1043  and European Pharmacopoeia General Chapter 5.2.12.

Another challenge is the need for versatility where novel products are being created. The diversity of CGTs means that often, standard practices and processes will not work – for example, some viral vectors are too large or sensitive for terminal sterile filtration, a necessary part of purification. To surmount such an issue, companies must determine the best possible alternative, using risk- and science-based justifications for new control strategies. 

Seeking Regulatory Approval

Regulator feedback on product development strategies is enormously helpful for winning product approval. Pre-IND meetings can be a source of understanding and collaboration that can hugely improve CMC efforts early on in the development process. Where guidance does not cover certain issues, regulators can assist companies who show that they are aware of potential gaps in knowledge and are eager to address them. 

Analytical methodology is a useful area to receive feedback on, especially where a CGT’s mechanism of action may not be fully understood. Companies must take all possible chances to ensure methodologies are sufficient for the current stage of development, and that if the mechanism of action isn’t known that surrogate assays can be utilised for further insight. Regulators can help with this by recommending particular attributes to evaluate. 

Keep an eye out for Proventa International’s upcoming Biomanufacturing White Paper, looking at the challenges surrounding CGT Manufacturing and their possible solutions. 

Joshua Neil, Editor
Proventa International

To ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s online Clinical Operations, Supply Chain & Pharmacovigilance Strategy Meeting 2020.

The post The Challenges of CMC in Cell and Gene Therapies appeared first on Proventa International.

As is increasingly known in the pharmaceutical industry, the rise in both trial costs and drug failures has seen a corresponding increase in the need for tight regulations and stricter procedures, to ensure the few successes are not further compromised. In the past, even drugs that reach manufacturing stages fail in particular climates and temperatures through unforeseen difficulties.

In addition, these falling returns means “acceptable loss” in a product batch is shrinking. This means greater attention must be paid to the status of drugs in transit, and continuous improvement in technologies and processes is vital. As the problems mount, cold chain processes have stepped in to help.

Offering a regulated, strictly monitored solution to temperature and humidity difficulties in manufacture and shipping, cold chain allows sensitive compounds to move across continents without loss of or damage to product through heat, humidity or other natural conditions.

The boom in the cold chain market, alongside increased regulator focus, has spurred on a leap in innovation and ingenuity. But it’s a necessity, too: the International Air Transport Association estimates that the pharma sector loses around $2.5-$12 billion every year due to temperature problems in transit. We decided to look at some of the most recent innovations in the important sector, and what is being done to improve the process. 

What Is ‘Cold Chain’?

“Cold chain” or “temperature controlled” shipping refers to the entire process of protecting, storing and transporting pharmaceutical products under a specified temperature range. The process utilises cooling systems to ensure maintenance of temperature restrictions at all times, alongside product integrity and humidity. In the pharma sector, cold chain processes adhere to Good Manufacturing Practices (GMP), a series of standards enforced by regulatory bodies. This means they must allow no negative impacts on safety, quality or efficacy of drugs. 

Cold chain provides enormous benefits for companies working within the pharma space. Vaccines, for instance, are now transportable to any country in the world, as are many other types of biological product. Most of these are in the early or development stages, and are temperature-sensitive. Should these become compromised during transport – as has occurred several times in the past – they can lose efficacy or even harm patients.

The cold chain industry has grown rapidly in the last few years. Changes in the pharma sector have directly driven this. Pharmaceutical products requiring refrigerated storage and transport are worth around $320 billion to the industry, and are set to rise by 70% between 2015 and 2021. Managing these products costs around $14 billion, with the value of such shipped products growing at around 10% annually. 

Biopharma cold chain logistics are one of the biggest drivers of cold-chain innovation, too: while non-cold chain logistics are worth almost $80 billion, by 2021 cold chain biopharma sales are set to top $396 billion. 

Globalisation

A number of innovations have been posited recently to deal with the increasing globalisation of manufacture and shipping. These can ensure temperature remains controlled at every single point from start to finish of the cold chain operation. The most comprehensive of these are ‘pharma corridors’, linking a number of locations via strict temperature controls.

Emirates’ cargo unit, SkyCargo, has already created a number of these corridors. Linked locations include Amsterdam, Cairo, Dublin, Luxembourg, Rome and Singapore. They operate under uniform standards that either meet or better the EU’s GDP rules, or IATA’s CEIV-Pharma guidelines.

Packaging and Shipping Integrity

Packaging has been a major focus of recent cold chain innovation. Moving away from older solutions such as dry ice, newer processes feature active temperature management, re-usability and improved cleaning procedures to ensure no cross-contamination. 

Improving cleanliness can be a difficulty when packaging materials vary so strongly in integrity and reaction to cleaning liquids. Pulsed xenon-based ultraviolet light (PX-UV) disinfection has been recently employed as a solution. This has been shown to result in some cases in a 5-log CFU reduction of superbugs on spiked plates. Currently, Cryoport is developing this technology for its cryogenic and C3 shippers. 

Companies have unveiled several new innovations recently in the area of protecting shipments from harm. These systems for the most part simply improve current systems, or provide a higher fine-tuning of requirements. Softbox, for instance, has released a number of new parcel shipping systems including Tempcell ECO and Silverpod MAX. 

The former technology is a shipper made from recyclable corrugated paper materials. The shipper is able to control different temperature ranges from 0 – 30 degrees Celsius products. The latter is a high-performance shipper incorporating phase change materials and can maintain up to 96 hours of thermal protection. It can also enhance thermal performance and uses next-generation recyclable coolants. 

Unveiled at the IQPC Temperature Controlled Logistics conference in January 2019, even newer styles of shipper are geared largely to ensuring unbroken cold chain regulation anywhere. One cold chain product allowed for 48-hour cooled delivery even without temperature-controlled vehicles. Another, a compact shipper, allowed fully-cooled last-mile delivery of a product to a patient’s home. 

Data and Informatics

To ensure consistency and accuracy during shipping, data loggers for tracking package information are becoming increasingly accurate and holistic. While newer trackers can sense temperature, location, orientation, humidity, pressure and other measures, many use lithium metal or lithium ion batteries. These are classed as dangerous goods, and must meet a number of regulations when shipped by plane. Because this limitation may restrict the application of trackers in the future, alternative power sources are being eagerly sought.

The rollout of 5G-enabled sensors will soon allow stakeholders to see more data, in real time. It could also allow for greater vehicle-to-vehicle communications, a particularly vital technology as the world moves towards driverless systems.

Targeted Therapies and Specific Temperature Demands

Over the last few years, the increase in varied new medicines – such as biologics or personalised medicines – has led to broader temperature needs. Requirements range from ‘body temperature’ to ultra-frozen products at below -80 degrees Celsius. 

The commonly-used packaging choice, semi-active packaging, is both economical and useful for short hauls. it is not self-regulating, however, and is often one-use, leading to environmental damage. 

Newer solutions offer a great deal practicality, with an increase in cost. Most offer long-term temperature control, containing specific engineering to ensure a stable storage environment. Such innovations, including phase-change materials, offer five to seven times more efficacy than older alternatives. 

In terms of advanced monitoring and data-logging, companies are increasingly adding GPS technologies and tracking equipment to newer shipping devices. These often feature shutdown mechanisms to enable safe flights, and provide real-time information on a package’s temperature, humidity and location. 

Such innovations include the LOG-IC 360 Bluetooth Data Logger. This gives accurate readings on product temperature and humidity up to 300 feet from the product, with a temperature range of -20 to 70 degrees celsius. It also retrieves and stores relevant data on when and for how long the package was not in range of acceptable requirements. 

Personnel

The key to solving the cold chain problem does not come down to technology alone. Given the increasing complexity and specificity of pharmaceutical companies’ demands, logistics organisations are increasingly having to become specialists themselves. Many shipping companies are becoming more proficient at tailoring specific selections for individual companies or products, rather than the more generic approach of selling set shipping packages. 

This extra agility extends to the entire breadth of a shipping companies’ processes. Pharma companies are increasingly expecting multiple options for transport route and technology in case of natural disaster or disruption in the supply chain. 

Staff roles, too, are changing. Good practices are needed across the hundreds of staff and workers required to run the cold chain process, all of whom must understand the package needs and correct procedures for ensuring requirements are never breached. 

Regulators are stepping in to ensure this compliance is met. The IATA now promotes its own accredited scheme for companies in healthcare. CEIV Pharma has a voluntary certification scheme for staff to “improve competency, operational and technical preparedness” within the supply chain. 

Joshua Neil, Editor
Proventa International

The post Trending Innovations in Cold Chain Processes appeared first on Proventa International.

SUT uses 

Uses for SUTs are widespread. Upstream, the increasing volume of single-use bioreactors (SUBs) allows for low initial costs and fast commercial turn-around, with similar sizes of SUB for both clinical and commercial meaning less need for scale-up and fewer batches. These SUBs have considerable utility in the biomanufacturing space, most notably in creating niche therapies and monoclonal antibodies with more limited production requirements, as well as the commercial production of vaccines that can be swiftly deployed as needed. 

Downstream processes, while historically benefiting less from SUT technologies due to the limited accuracy and sensitivity of single-use sensors and reduced importance of purity, still benefit from their implementation. Particularly in filtration systems, buffer preparation systems and sampling systems, SUTs offer swifter implementation over reusable equipment. As more accurate sensors are developed and capacity demands can be more easily met, downstream SUT use will only increase. 

In drug product operations, sterilisation and ensuring no cross-contamination is a difficult task that requires consistent security from end-to-end. Sterile equipment is an important part of this process, historically performed through heat and recycling of equipment. SUTs such as bag chambers and filter capsules remove the need for equipment re-use and subsequently the risk of contamination or break-down that imposes. Pre-assembled and sterilised SUTs have been used to create a fill operation needing no class-A laminar flow, though appropriate risk-analyses are needed to ensure no unwanted interactions occur with the drug product during the process. 

Finally, SUTs have an additional benefit in allowing some companies to keep their manufacturing capacity in-house, due to the reduced size of facility needed and lower capital requirements. 

Benefits 

SUTs offer a huge range of benefits to biomanufacturing companies, reflected in the demand the industry has shown for the technology’s integration. First, SUTs are cheap. Less stainless steel equipment is needed in the manufacture, and the related costs of installing and cleaning them are greatly reduced. Companies can save up to 50% of general costs, including labour, water, utilities and consumables, with SUTs over stainless steel. A 2008 study also found that SUTs require 87% less water and 29% less energy to run than stainless steel equipment, reducing environmental burden as well. 

One of the major benefits offered by SUTs is their flexibility: the ease with which manufacturers can change process needs is vital for professionals in a rapidly-changing industry. Companies can also use the technology to accommodate multiple drugs in one manufacturing suite, vital for switching processes swiftly to accommodate more drugs in a portfolio. 

Because it can be pre-sterilised by the supplier, SUTs also benefit from increased safety over alternative processes. Reduced cross-contamination can also reduce downtimes and wastage. 

In short, the benefits of SUTs are:

• Increasing manufacturing and process flexibility 
• Eliminating cleaning and sterilisation requirements, and the need for cleaning chemicals
• Reducing storage requirements
• Lowering downtime of processes
• Cost benefits from reducing size, maintenance and consumables
  

Challenges

While around 90% of biomanufacturing companies are already using SUTs to some extent, there are a number of associated risks and challenges that remain when using the technology. The biggest problem in the area is the need to demonstrate safety of extractables and process-derived leachables from fluid-contact plastics, when the FDA has not set out the acceptable limits for either compound. 

One of the main challenges when working with SUTs is the need to create an entire process step to integrate individual SUTs with one another. While often cheap to make and requiring little storage space, SUTs still pose a more difficult implementation than reusable equipment does, due to the time needed to assess extractables data and qualify modified disposable equipment.

Standardisation is also a considerable challenge in SUTs. Often, suppliers’ components are singular and cannot be interchanged, with the lack of interoperability ensuring manufacturers must only use one supplier. This has the knock-on effect of increasing supply chain security concerns and inventory costs. 

Finally, automation is difficult to implement in SUTs, due to its manual nature. Despite this, automation efficiencies are possible by ensuring suppliers deliver prevalidated and tested manufacturing control system software alongside the equipment. 

Solutions

While these challenges are problematic for manufacturers, solutions to many do exist. Regarding the issue of demonstrating leachable and extractable safety where limited guidelines exist, several organisations have published standardised consensus recommendations, with a standard for extractable testing of plastic process equipment published by the US Pharmacopeia.

To overcome the requirement for a complete process step, some manufacturers are offering more immediately-effective SUTs to ensure easier adoption and swifter turnaround. At their most complete, such SUTs would feature configurable pre-application tested assemblies, validation packages and technical support. The ability to quickly set up SUTs in limited space will also have a knock-on effect on costs associated with installation. Linked to this, greater flexibility can be achieved by increased moveability of modular hardware, allowing for more processes to be undertaken. 

To remove issues around change management and extensive assessment, manufacturers and SUT suppliers should ensure rigorous change management procedures are in place so disposable equipment constantly meets application specifications. 

Regarding standardisation issues, a number of major associations including the Bioprocess Systems Alliance (BPSA) and the International Organization for Standardization are in talks to create standards for the use of SUTs, looking at standardisation of extractables and integrity testing to product characteristics and specifications to increase interoperability. The most notable ongoing regulatory operations include an ASTM operation to standardise the determination and characterisation of extractables from single-use materials, and a joint ASTM-BPSA-American Society of Mechanical Engineers project on system integrity testing issues.

Many of the above groups have published technical documents and guidelines on these subjects already, including a BPSA quality assurance template for establishing an agreement between a single-use supplier and biopharmaceutical manufacturer on quality consistency and quality test reference matrices from the same company. 

Other solutions often are a matter of due diligence. Manufacturers and other SUT users must ensure that suppliers’ processes are validated and that data showing the reliability and safety of the product, and on the consistency of supply, exists. 

Despite the fact that challenges still remain and solutions have not yet been found for all, SUTs promise big improvements across the biopharma board, from reduced environmental impact and storage takeup to improved flexibility and project turnaround. Understanding potential solutions to the challenges remaining will allow companies to make best use of SUTs within their business. 

To ensure you remain up-to-date on the latest in biomanufacturing, sign up for Proventa International’s Biomanufacturing Strategy Meeting 2019, hosted on 8th October in Zurich, Switzerland. 

Joshua Neil, Editor
Proventa International

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