In the fast-paced world of supply chain management, warehouse efficiency plays a pivotal role in ensuring timely and accurate order fulfillment while minimizing costs. With the rising demands of e-commerce and globalization, businesses are continually seeking innovative ways to optimize their warehouse operations. This article delves into the significance of warehouse efficiency, the challenges faced, the role of technology, and best practices to achieve maximum productivity.

Understanding Warehouse Efficiency

Defining Warehouse Efficiency

Warehouse efficiency refers to the ability of a warehouse to utilize resources effectively and deliver products to customers efficiently. It involves streamlining processes, reducing wastage, and maintaining accuracy in inventory management.

The Importance of Efficient Warehousing

Efficient warehousing is crucial for businesses to stay competitive in today’s market. It ensures swift order processing, minimizes holding costs, and enables faster response to customer demands.

Identifying Challenges in Warehouse Operations

Inventory Management

Maintaining optimal inventory levels while avoiding stockouts and overstock situations can be a complex challenge for warehouse managers.

Order Picking and Packing

Inefficient order picking and packing processes can lead to delays and errors in fulfilling customer orders.

Space Utilization

Limited warehouse space and inefficient use of available space can restrict the storage capacity and lead to operational bottlenecks.

The Role of Technology in Improving Warehouse Efficiency

Warehouse Management Systems (WMS)

A WMS provides real-time visibility into inventory levels, automates order processing, and optimizes warehouse layouts for enhanced efficiency.

Automation and Robotics

Automated systems and robotics streamline repetitive tasks, such as picking, packing, and loading, resulting in increased productivity and reduced human errors.

IoT (Internet of Things) in Warehousing

IoT sensors enable real-time tracking of inventory, monitor equipment health, and offer predictive maintenance insights.

Data Analytics and Artificial Intelligence (AI)

Data-driven insights and AI-powered algorithms help warehouse managers make informed decisions, predict demand patterns, and optimize supply chain operations.

Implementing Best Practices for Enhanced Efficiency

Efficient Layout and Design

An organized and logical warehouse layout improves material flow and reduces the time taken to process orders.

Optimized Inventory Management

Regular audits, ABC analysis, and adopting just-in-time (JIT) inventory practices lead to efficient stock management.

Streamlined Order Fulfillment Process

Integrating order processing, inventory management, and shipping systems streamline the entire fulfillment process.

Employee Training and Engagement

Well-trained and motivated warehouse staff contribute significantly to improved efficiency and reduced errors.

The Benefits of Improving Warehouse Efficiency

Cost Savings

Enhanced efficiency leads to reduced operational costs, better resource utilization, and minimized waste.

Increased Productivity

Automation and streamlined processes result in higher productivity and quicker order processing.

Customer Satisfaction and Loyalty

Efficient warehousing ensures timely deliveries, leading to increased customer satisfaction and loyalty.

Overcoming Challenges and Resistance to Change

Addressing Workforce Concerns

Incorporating technology requires addressing employee concerns and providing training to adapt to new systems.

Emphasizing Long-Term Gains

Promoting the long-term benefits of efficiency improvements helps gain support for technology adoption.

Case Studies: Successful Implementation of Technology and Best Practices

Company A: Automating Order Processing

Company A achieved significant efficiency gains by implementing an automated order processing system, reducing order fulfillment time by 40%.

Company B: IoT Integration for Real-Time Inventory Tracking

By integrating IoT sensors for real-time inventory tracking, Company B improved inventory accuracy and reduced stockouts by 30%.

Company C: Data-Driven Predictive Analytics

Company C leveraged data-driven predictive analytics to optimize inventory levels, resulting in a 25% reduction in carrying costs.

Future Trends in Warehouse Efficiency

Advancements in Automation and Robotics

Advancements in automation and robotics will lead to even greater efficiency gains and reduced reliance on manual labor.

AI-Driven Warehousing

AI will revolutionize warehousing with intelligent decision-making, predictive analysis, and efficient resource allocation.

Sustainable and Green Warehouses

The future will witness the rise of environmentally conscious and sustainable warehouses, focusing on eco-friendly practices.

Conclusion

Improving warehouse efficiency is a critical component of modern supply chain management. By leveraging technology and adopting best practices, businesses can achieve higher productivity, cost savings, and customer satisfaction. Embracing these changes and staying ahead of emerging trends will enable warehouses to thrive in the dynamic business landscape.

FAQs

1. What is the significance of warehouse efficiency? Warehouse efficiency ensures timely order fulfillment and minimizes costs, contributing to overall business success.
2. How does technology enhance warehouse efficiency? Technology such as WMS, automation, IoT, and AI streamlines processes, optimizes inventory management, and improves overall productivity.
3. What are some best practices for efficient warehousing? Efficient layout and design, optimized inventory management, streamlined order fulfillment, and employee training are key best practices.
4. How can warehouse managers overcome resistance to change? Addressing workforce concerns and emphasizing the long-term benefits of efficiency improvements can help overcome resistance to change.
5. What are the future trends in warehouse efficiency? Advancements in automation, AI-driven warehousing, and sustainable practices are the future trends to watch for in warehousing.

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While the impact of COVID-19 was significant in every area of the pharmaceutical sector, some of the most pandemic’s most overlooked impacts were within the regulatory space. From study design to submissions, the virus affected every aspect of drug regulation, from trial design and co-ordination to submission of documents and filings. 

Redesigning clinical trials

The impact of COVID-19 required a more prioritised, rapid vaccine development than has ever been seen before. The need to push through an efficacious, easily manufacturable product to combat COVID affected every aspect of the pharma industry, from drug design to trials to manufacturing and regulatory affairs.

Rapid developments in the regulatory space have been critical in speeding up the clinical trial process. The need to ensure patient safety led to a decentralised, fluid approach to clinical trials, which in turn saw an uptick in ways patient data can be harvested. The urgent need for swift approvals meant that standard procedure was modified or relaxed, with regulatory applications for vaccines approved in less than a week. Overall, regulatory changes made during COVID reduced approval timelines by three to four months. 

The increased speed of the drug development process has also meant that companies need more rapid access to regulatory authorities in order to quickly assess clinical trial development plans or changes. In light of the pandemic, grants of pre-investigational new drug (IND) meetings with the FDA were given in under 30 days, with a reduction in the specificity of non-clinical information needed in order to start studies more quickly.

Another major regulatory change to speed up trial completion was the move towards centralised site clearance. This move away from local approvals of each trial site allowed for quicker approval of sites and subsequently a shortened approval timeline, from months to only days. 

Beyond these changes, regulators became more flexible generally regarding trial design and product approval. A more flexible approach was created regarding product registration, rapid review of trials and auditing. Deadlines were extended where necessary. 

Decentralisation

Novel technologies and the need for social distancing saw the rapid uptake of decentralised trials, often taking place in patients’ homes. These trials have been shown to cost at most the same as traditional trials, but with the added benefits of increased patient engagement and retention, greater data collection and overall faster, more flexible study timelines. 

Scaling up decentralisation while maintaining quality will, however, mean the need for much more rigorous compliance given the diversification of data sources and complexity of large-scale studies. Automation is one solution to this increased need for vigilance, with unmanned data capture through wearable devices and automated reporting critical to ensuring accuracy and completeness of translatable submissions.

The new methods of collecting patient data – from wearables like the Apple Watch to electronic forms such as eCOA – were rapidly accepted and incorporated by regulators, and have helped increase patient safety in trials as well as facilitating a more rapid turnaround in trial completion. 

Regulatory submissions

Shortly after the scale of the pandemic became clear, regulatory authorities began granting Emergency Use Authorizations (EUAs) to COVID treatments. This meant that the onus of creating efficiencies to speed up drug approval fell on regulators. In part, this came from innovations in technology and digitalisation.

Regulatory information management (RIM) technology was used widely to reduce reporting activities through automation and machine learning. Other new approaches to reporting could rapidly expand this speed and efficiency, replacing older models of reporting: adoption of electronic Common Technical Documents, use of electronic product labels, reform to the Certificate of a Pharmaceutical Product procedures, and discarding the need for ‘wet signatures’ on documents would all significantly reduce the current time and onerousness of regulatory reporting for a number of countries and businesses. 

The future of pharma regulation 

The major changes witnessed during the pandemic were created in an extreme situation, and it is without doubt that their extremity will be reduced as the world returns to normal. Nevertheless, many of the lessons learnt during the COVID-19 crisis will continue to be preserved, from swifter pre-IND meeting times to safer drug trial practices. 

Real-world evidence (RWE) will be a major regulatory force in the coming years, with real-time access and analysis of data providing a huge boon to drug research – as long as regulators can fully standardise datasets and analytics, as a lack of careful monitoring can lead to potential risks in the procedure. 

The technology that has been pioneered during the pandemic will continue to grow and develop as COVID-19 recedes into memory. Cloud technology will allow greater connectivity between teams and reduced siloing, on top of speeding up regulatory submission significantly, as soon as it is taken up by regulatory agencies globally. AI, automation and machine learning will speed up document completion and regulatory submission, and move the industry towards higher-value innovations. 

Joshua Neil, Editor
Proventa International

The post COVID’s Impact on Innovations in Regulatory Affairs appeared first on Proventa International.

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.

Cell and Gene Therapies (CGTs), experimental technologies to treat or cure diseases using the body’s cells, have been on the ascendant for some time now. As promising as they are, CGTs have consistently moved forward faster than regulatory agencies can keep up: despite the first CGT products only receiving approval in 2017, new types of CAR-T therapies are already being examined. 

The European Medicines Agency (EMA) in Europe and Food and Drug Administration (FDA) in the USA are responsible for the regulation of CGTs. Since the first CGT approvals, applications in the space have been skyrocketing. In 2018 the regulators saw around 500 active gene therapy applications.

Despite this, CGT treatments are still a more risky proposition than other, more established therapies. One of the first in vivo gene therapies, Roche’s Luxturna, can create a short-term immune response in the liver that must be treated by steroids. Questions still exist around giving a patient with previous exposure to AAV viruses a further dose through gene therapy. Similarly studies such as Sangamo’s 2018 trials have failed to demonstrate clinical benefit for patients.

In light of these issues regulatory agencies are constantly changing and adapting to the new environment. New guidance is constantly being produced, with the EMA and FDA working more closely together to ‘avoid digressions between the two’. 

Standardisation and Other Issues

One of the major issues within CGT today is the lack of standardisation in processes. A major regulatory concern are the manufacturing processes involved when creating CGT medicines, and how changes could affect the product’s safety and efficacy. 

Creating CGTs is an extremely complex process. Due to the need to use biological materials, manufacturing must ensure very high quality throughout the production. This in turn requires expensive equipment and technical expertise, something many labs – especially smaller companies – lack. While companies often turn to contract manufacturing organisations (CMOs) to provide these functions, they are now considerably overburdened by the number of therapies heading towards trials. 

This issue is made worse by organisations’ need to change and update their processes for greater returns, which strains the ability to keep their products consistent and efficacious. 

Current and Future Regulation 

The USA and EU have markedly different regimes for overseeing the approval of CGTs. The U.S.’ FDA oversees its clinical trials, while the EMA in Europe does not. For a CGT clinical trial to occur in Europe, approval must be received from a competent authority and ethics committee in the Member State, as well as approval to use a genetically modified organism. 

Despite this, the two organisations use similar data-heavy approaches to assessing safety and efficacy of drugs, often working together through teleconferences. 

Since 2017, when Luxturna was first approved by the FDA, regulatory standards and guidelines have evolved at a rapid pace. In August 2018, the U.S. National Institutes of Health ruled that gene therapies no longer needed a regulatory review before the start of clinical trials could begin, eliminating duplicative oversight with the FDA. From that point, the Recombinant DNA Advisory Committee focused on emerging biotechnology issues. It was in this year that the FDA published six proposed new guidelines on gene therapy, with two more published in 2019. 

The EMA also updated its frameworks in 2018, changings its guidance on design, manufacture, characterisation and testing of delivery mechanisms. 

This is a rapidly-changing field, made swifter by the efforts of trial sponsors within the area. Generally, CGT sponsors work with regulators from the earliest stages of development, sometimes even during preclinical development. The talks with regulators on how to design the drug programme allows for easier approval when the drug is set for manufacture. 

Despite this, concerns have been expressed that the agencies lack the necessary expertise to fully deal with the influx of new therapies sent to them for approval. With estimates suggesting that by 2021 over a thousand CGTs will be expecting regulatory approval, this seems a genuine concern that so far has no solution. 

Automation as a Solution

Before the industrialisation of CGTs can fully commence, a number of issues must be addressed. Processes must be made more efficient and more cost-effective, and standardised in such a way that regulation becomes less burdensome or stringent. 

Automation is one way to address these problems, and open the door to greater commercialisation of CGTs. Providing greater control over bioprocesses via more efficient and fast readouts, automating CGT manufacturing can easily lead to the optimisation the sector so desperately needs. 

Automation would immediately remove human error and the variation caused by manual handling. It would also allow for the precise determination of process parameters and timings to be saved, and the for integration of process analytics, which would eliminate the subjectivity of which processing decisions are currently based. This would allow for better processing rules. 

With full automation of a process, greater understanding will be had of how individual processes affect cell quality. The optimisation that comes about through these various positives means that manufacturing costs will be hugely reduced. 

From here, the introduction of AI and Machine Learning to these automated processes could improve their efficiency and ability to handle more complex tasks, as well as to perceive cell quality better through a learning feedback loop. 

Conclusion

For CGTs, the regulatory field has advanced in leaps and bounds over the last three years, becoming increasingly more effective and targeted with each new guidance update. It is clear that sponsors and manufacturers have no issue with the direction that regulatory agencies are going in: only that their budgets and means are not equipped to deal with the scale of the CGT revolution to come. 

Automation is the tool of the near future that can change this. With the ability to standardise processes to a regulatorily satisfactory manner, remove human error and increase efficiencies across the manufacturing chain, automation would immediately increase the ability of regulators to work with CGTs and approve life-saving therapies. Companies are certainly implementing small-scale automation in their companies: but it is clear that full automation of CGT manufacturing cannot come fast enough. 

Joshua Neil, Editor
Proventa International

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

The post Solving Regulatory Issues in Cell and Gene Therapies appeared first on Proventa International.

The COVID-19 pandemic proved how ill-equipped the world was for a virus of that scale and potency. In the first months of the pandemic, businesses across all sectors scrambled to prepare their processes and supply chains for the coming disruption, caught unawares by the sudden and enormous changes.

Naturally, one of the sectors most affected by COVID-19 was the pharmaceutical industry, and within pharma biomanufacturing had the potential to be hit hardest. Reliant not only on global travel and well-planned timelines, biomanufacturing also deals with products central to solving the pandemic threat: vaccines.

It is inevitable that change at this scale will revolutionise the field. But how will biomanufacturing shift in the years after COVID has faded from the headlines? Ahead of its Biomanufacturing Strategy Meeting this October, Proventa finds out more.

Transport and Supply

Almost every industry’s transport and supply chains have suffered during the COVID-19 pandemic, including in biomanufacturing, where tight timescales and sensitive payloads are commonplace. Though the impact has largely been less critical than was feared, drug shortage worries and the problem of export embargoes have meant that managing the supply chain has been a greater worry than ever. 

During the height of the pandemic, air traffic to and within the United States was heavily disrupted: according to one report almost 50% of flights were cancelled between mid-March and April 2020. As a large percentage of cell therapy products travel via commercial airways, these cancellations had a significant effect on the sector’s supply chain, exacerbated by the potential for couriers to be unable to travel internationally, either due to health reasons or border restrictions. 

A key contributor to this challenge is the fact that many pharma companies have concentrated their manufacturing centres in one or two places, often either in China or in India – two countries where considerable lockdowns were or are imposed and much of the workforce unable to work. 

Over the coming years, it is expected that this problem will be dealt with by moving manufacturing to less-impacted markets, avoiding critical delays when a major manufacturing country is hit with export difficulties. Spreading factories across a few countries will avoid this risk, though in the short term it will cause greater difficulties due to the tight regulations and need for precise capabilities involved in setting up a factory. 

This will certainly increase complexity within the supply chain. Paired with extra regulatory burdens on working with partners, it is important that pharma companies work to digitise their supply chain as soon as possible, to ensure track and trace, monitoring and licensing requirements are sufficiently met. 

Vaccines under COVID-19

Naturally, vaccines are the area most directly affected by the COVID-19 pandemic. The rush to produce a solution to the virus has driven pharma companies to unprecedented speed in vaccine research: but it is not only the speed of the development that will change post-COVID but how the industry looks at vaccine creation more widely. 

Traditional vaccines, made in eggs or from blood plasma, lack the swift creation and simplicity that is needed today. The industry has turned from these older forms to more modern developments including recombinant antigen-, DNA- and mRNA-based solutions which are not only safer but can respond rapidly to future pandemics with high rates of mortality. 

The changes made during COVID will also enable pharma experts to re-examine other products that in the past have seemed too expensive to run. Such vaccines would use established bioprocess operations that have already been thoroughly tested across a number of modalities, but have so far been too expensive to consider over current vaccine production methods.

The pandemic has changed the cost-risk-benefit balance of vaccines, however: now, area professionals are working ceaselessly to create new biomanufacturing operations that can make more advanced and cost-effective vaccines in large quantities. This will continue as these fields continue to receive additional resources, creating new vaccine possibilities in the wake of the virus. 

In which direction the vaccine field goes will depend somewhat on which of the potential COVID-19 vaccines proves effective; but it is also certain that this period in history has changed how stockholders view the importance of vaccine creation. It is also inevitable that the speed with which these vaccines have been made will not be a passing trend: with the knowledge that vaccines can go from initial stages to phase 3 in under a year, a new standard will be set that future vaccines will be held up to. 

Cell Therapies

The cell therapy space has also been dramatically altered by the onset of COVID-19. Autologous cell therapies, which collect cells directly from the patient rather than from a healthy third party, have naturally been impacted by the need for social distancing. Beyond the difficulty of patients visiting apheresis centres, there is also the difficulty of undertaking treatment regimes which weaken immune systems. 

Beyond this, the supply chain for cell therapies has been particularly interrupted by COVID, depending as it does on strict timeframes for delivery of cells to centralised manufacturing facilities. Due to the variable nature of supply in the pandemic, more patients than ever are opting to delay their therapies where possible to ensure greater safety, with companies like Eli Lilly and Pfizer announcing delays to their trials for patient safety reasons. 

To counter these difficulties, the future will see a broader base of cell donors from which to draw. This will create greater resilience in the supply chain, removing the need for companies to rely on a small number of ‘super donors’ from which cells are sourced. 

Another change that could ensure greater industry robustness is greater use of cryopreservation. Storing cell material will allow patients to have access to therapies even during times of disruption, as well as potentially allowing for cell collection nearer to the patient themselves, thus cutting down the potential for interruptions to the process. While uncertainties still exist around the implications of freezing cells for therapy, the process offers a potential solution to the severe disruptions pandemics can cause in cell therapies. 

Business Decisions 

Beyond area-specific changes that will follow in the years to come, there are a number of business-specific modifications that companies should or will be adopting to prevent future difficulties during a pandemic.

The first of these will be patient-centric: in line with the current trend in the sector, focusing considerably more on the patient’s thoughts and feelings is critical for companies facing the public, particularly those dealing with trials. Understanding how patients are dealing with the pandemic, their difficulties and in what way they feel safe undertaking trials is key to maintaining a working trial during times of crisis. 

This also applies to stakeholders. Understanding what healthcare providers need and when they are able to engage further in the business chain is vital to working together. 

This change has seen, and will continue to see, a rapid positive change in the use of digital equipment for more hybridised trials. The use of econsent and eCOA software to digitally sign patients up and increase understanding, as well as the use of wearable technology, video discussions and social media can all increase patient compliance and retention without the need to breach social distancing measures or put lives at risk. A survey conducted in April 2020 pointed to a 6x increase in patient engagement remotely across a number of specialties and geographies. 

Conclusion

The impact of COVID-19 will not disappear alongside the virus. Whether or not the wider world will be changed by this virus, as many have suggested it might be, is unknowable. But it is certain that biomanufacturing will never go back to what it was before the creation of the COVID-19 vaccine. In terms of supply chain planning, vaccine creation and business decision-making, the pandemic of 2019 has pushed the field into new and exciting territories, from which it will not return. 

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 Biomanufacturing Strategy Meeting 2020.

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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.

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Over the last few years, stem cell clinics and direct-to-consumer gene and cellular therapies have proliferated hugely, promising cures for a range of diseases from macular degeneration to multiple sclerosis. The treatments have been condemned by many in the health field, with allusions made to “modern snake oil” and preying on the hopes of those who have nowhere else to turn to alleviate their conditions. 

In its statement Google noted that it had seen a rise in “bad actors” offering dangerous treatments, and said that such “deceptive treatments” had no place on its platform. The new policy, set out on its website, will prohibit all adverts for treatments which have no “established biomedical or scientific basis”. The ban, in effect from October, will affect all of Google’s ad services, including YouTube adverts and those the company serves to third-party sites. 

Google’s actions against such companies are only slightly behind first steps taken by regulators worldwide. It was not until June 2019 that the FDA won its first lawsuit against Florida-based U.S. Stem Cell, whose treatments had allegedly blinded at least four patients. While the FDA’s court success was heralded as a big win for patient safety and ensuring satisfactory regulation of stem cell companies, the slow response of the regulator meant that US Stem Cell remained active for four years after the first reports of blindness made the news, halting its injections into eyes but continuing to deliver the treatment to those with spinal injuries, Parkinson’s disease and other chronic disorders.

The regulator has struggled with this problem before: oftentimes, its guidelines have been criticised as overly reactive, as in mid-2009 when a number of pharmaceutical companies received written warnings about sponsored links on Google that had been in place since September the previous year. 

It is easy to understand why this difficulty remains: the FDA and other global regulators are complex machines, battling legal systems and often their own regulations, facing court cases that can take years to complete. Google, on the other hand, has free reign to impose within its own jurisdiction whatever policies it feels it needs to enforce. 

Andrew Ittleman, a lawyer representing several stem cell clients, argued that the recent advertisement decision has placed Google in the role of a “quasi regulator”, creating rulings that will damage legitimate companies along with potentially unethical ones. While it is doubtful that too many in the life sciences sector share this particular sentiment, the comment does bring to the fore a point with some merit: that Google, with its vast influence and huge responsibility, is often thrust into a regulatory role that has implications for the whole sector.

This is not the first time Google has acted as arbiter over what should and should not be seen on its platforms: in July this year, Google-owned YouTube moved to reduce misleading claims by certain healthcare companies after the Wall Street Journal covered a report on the proliferation of fake cancer-cure claims spreading on the site. 

Such actions have in cases proved controversial. Google’s handling of claims of homophobic harassment was criticised after it allowed a controversial YouTuber’s videos to stay up, citing that no policies had been violated. 

In the latest case, Google also received some censure by refusing to reveal how it will specifically determine which adverts should be disallowed, leading the American Medical Association (AMA) to speak out on the company’s transparency. AMA president Patrice Harris argued that Google should share “the process they use to vet advertisements and what evidentiary standard they use for determining which treatments are appropriate to advertise.”

Despite these complaints, and warnings that stem cell and gene therapy companies will simply move to other sites or circumvent the rules, it is clear that Google’s actions will have a major impact for many: in 2019, Google is set to earn 36.2% of digital media spend, though growing competitors such as Amazon will restrict this monopoly in future. In the pharmaceutical industry, the giant is just as prevalent, with health queries making up 5% of all Google searches – a rate of 3,150 “health and wellness” searches a second. 

With its autonomous decisions on what may or may not constitute unethical practices in pharmaceutical advertising, and with the heavy repercussions dished out to companies who break one of its rules – with the potential to completely lose a (if not the) major source of exposure and customer outreach available, Google has found itself on the forefront of a potentially grey area of technicalities, both around nomenclature and ethicality. While the company does adhere strictly to national regulations around both company morality and advertisement, companies are generally advised to also pay attention to Google’s own specific guidelines for marketing on the platform – created entirely by Google alone. 

Overall, anything that can be done to extend stricter regulation over dangerous companies should be lauded, as Google’s new efforts have been. But it is a fine line between punishing unethical companies and restricting innovation and growth. For many in the space, cell and gene therapies are the future, promising huge rewards and genuine benefit for many, so long as they are carefully researched and ethically achieved. Hopefully Google’s efforts will promote a better and more cautious use of research to help people rather than hurt them.

Joshua Neil, Editor
Proventa International

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