What keeps Joseph Makowiecki excited is the recurrent need for multilayered connectivity in bioprocess development and manufacturing, particularly when it comes to new therapeutic modalities, flexible platforms, and multiproduct facilities.
“Connectivity is critical across the value chain,” says Makowiecki. “Silos stop progress and hamper acceleration of new lifesaving drugs to patients who are waiting at the end of the line.”
Makowiecki champions single-use, automated, flexible, and deployable biomanufacturing platforms. He also facilitates downstream process development, scaling, cGMP manufacturing, technical transfer, contract manufacturing services, and the manufacture of multiple vaccine and biotherapeutic products.
In an exclusive interview with GEN, Makowiecki says the top method-based advances in biomanufacturing are process development and manufacturing of new therapeutic modalities, digital connectivity, and patient-specific therapeutic workflows.
“You’re going to see evolution of new therapeutic modalities like autologous and allogeneic cell therapies, viral vectors, pDNA, mRNA, and oligonucleotides. mRNA therapies, for example, will grow and evolve especially for infectious diseases and cancer vaccines, and eventually for personalized therapies,” he said. In the aftermath of the first two mRNA based COVID-19 vaccines that were developed and brought to market in record time, the development of new therapeutic modalities will become mainstream, Makowiecki believes.
For Makowiecki, digital connectivity relies upon the use of “intuitive and plug-and-play automation, coupled with standardized and simplified manufacturing execution systems.” The digital ecosystem of integrated process development that will bring future therapies to the market will focus on process modeling, safe and secure cloud-based artificial intelligence (AI), and limited, but focused, empirical testing, believes Makowiecki, and will determine how well processes and products are understood, optimized, and controlled. This will dramatically improve speed and quality while significantly lowering the risks as therapies progress through developmental phases.
The unmistakable trend toward patient-specific medicines includes both personalized and individualized medicine, which though often used synonymously, are distinct, Makowiecki points out. “Personalized medicine involves finding the right, off-the-shelf drug specific for the patient whereas individualized medicine involves creating and manufacturing a new drug specific for the patient.”
Small-scale drug development and manufacturing challenges
With increased emphasis on personalized and individualized medicine, biopharma must pivot from traditional mass manufacturing towards small-scale, modular, and flexible manufacturing.
“Small-scale manufacturing enables and accelerates life-giving therapies to patients,” says Makowiecki. “Advances in new cell lines, improvements in product titers, potencies, and overall process recoveries are driving down the scales required for manufacturing.”
This trend poses a new set of challenges. “It’s a relatively new space,” says Makowiecki. Most technologies, equipment, and consumables on the market today were designed for large-scale manufacturing of monoclonal antibodies or recombinant proteins. “Technologies that fit into small-scale cGMP manufacturing don’t exist in most cases.”
Small-scale equipment, even when available, is designed for process development and in most cases are not single use or cGMP-complaint. “There are clean and reuse challenges with this equipment as most are designed with threaded fittings that are not suitable for cGMP manufacturing,” says Makowiecki. “High cost of goods also comes into play with smaller scales as you’re not getting the benefits of economy of scale often achieved with larger scale biomanufacturing.” He believes small-scale, single-use, cGMP-compliant equipment will soon become more mainstream.
Single-use equipment is convenient
Over the past decade, single-use technologies have made significant headway in replacing traditional stainless-steel equipment. When a process cycle is run, steel systems must be cleaned and tested before reuse.
“Cleaning and testing equipment takes time, people, and money,” says Makowiecki. “Most single-use components are made from plastics. It’s the layer that’s in direct contact with process buffers and solutions, cells, or the drug product.” Once a manufacturing unit operation or batch is run, single-use components are typically discarded, eliminating the need for cleaning and quality control (QC).
“Single use reduces time and increases flexibility. It’s easier to convert between unit operations and products. It limits risks of cross-contamination and makes it a lot easier to develop and manufacture your processes and products,” says Makowiecki.
Most developers have multiple products in their development pipeline. Compared to a fixed stainless-steel platform, single use accommodates multiproduct manufacturing with greater flexibility.
“The benefit of single-use technologies is speed. It’s a way of accelerating many molecules to market. Over the past 15 years, it’s had a huge impact on how we accelerate lifesaving molecules to patients,” says Makowiecki.
One might worry about the effect of plastic waste on the environment, but Makowiecki says, “The biotech and biopharma industry represents only a small percentage of the total single-use plastics usage and disposal space. Despite this, there’s tremendous biotech and biopharma industry focus on single-use life cycle management, sustainability, and green manufacturing.”
Based on numerous lifecycle assessment studies, Makowiecki says, “Single-use technologies have less of an impact on the environment than stainless steel. The manufacturing of stainless steel leaves a significant carbon footprint.” In addition, there’s significant water and power usage in cleaning and testing stainless steel equipment and systems used for cGMP manufacturing.
Almost every manufacturer, developer, and supplier has focused sustainability programs. Many developers use recycling programs or repurpose plastics in energy production. Another decade down the road, biodegradable plastics made from plant-based products might solve this issue altogether.
Workforce and regulatory challenges with new therapeutic modality manufacturing
An underestimated challenge in new therapeutic modality manufacturing relates to workforce issues. “Many new processes, for example autologous cell therapies, are quite small, complicated, inconsistent, and inefficient, and due to the lifesaving criticality of the product, much of the manufacturing is performed by high level scientists,” says Makowiecki. “That’s not a sustainable manufacturing solution from a cost, workforce hiring, training, and retention perspective. This is where increased automation and digital solutions are needed to create a more sustainable manufacturing ecosystem.”
Problems in workforce management arise not only in training operators, but also in retaining scientists in manufacturing. “High level scientists don’t necessarily want to be operators performing cGMP manufacturing. They want to be working on and thinking about process development and optimization and the next evolution of products and processes,” says Makowiecki. “Despite these workforce challenges, biopharma, educational institutions, and government agencies have made significant progress in improving workforce development.”
Unlike traditional biologics, new therapeutic product modalities are supported by limited development and regulatory data, experience, and expertise for both developers and regulatory agencies. “New therapeutic product modality developers and regulatory agencies are learning, sharing, and improving together,” Makowiecki says. “The FDA is really stepping up to these challenges. They have launched programs like INTERACT (INitial Targeted Engagement for Regulatory Advice on CBER ProducTs) where they consult with developers of new therapeutic modalities.”
INTREACT is an informal non-binding consultation where sponsors can discuss innovative investigational products with FDA’s Center for Biologics Evaluation and Research (CBER) at early stages of development.
Customization versus flexible standardization
Smaller, flexible manufacturing facilities must at times be set up closer to the patient within tight deadlines, requiring significant technical recalibrations. This creates a tug-of-war between customization and standardization.
“With customization comes increased complexity, cost, risk, and time. We must move away from customization and leverage standard platforms. Standard platform designs can still be flexible and adaptable,” Makowiecki says. “Standardization provides the benefits of a similar ecosystem which makes it easier to transfer processes, procedures, equipment, and consumables, and makes it easier and faster to replicate manufacturing platforms and facilities because everything is based upon a pre-populated, standard, and repeatable design.”
Most aspects of customization require comparability studies and revalidation, adding to the cost and time of the operation, whereas standardization enables efficient transfer of processes between sites. When speed is of the essence, as is the case for most new therapeutic products, standard platforms accelerate production, lower risk, and improve patient survival.
In helping establish modular manufacturing facilities, Makowiecki finds misconceptions involving flexibility and standardization. “Some think a standardized platform cannot be flexible and accommodate their process needs. That’s just not accurate. Standardized platforms are designed with flexibility in mind and can be configured to accommodate many different processes.” The speed at which several COVID-19 vaccines were developed, scaled, and distributed would not have been possible without leveraging elements of standardization.
Connecting analytical assays to modular trends
Quality control analysis is critical and cannot be underestimated in maintaining product quality and cGMP compliance while adapting to multi-site and decentralized manufacturing, however, Makowiecki sees adaptations and utilization of newer and faster product in-process and release assays. “At the end of the day, quality is king, and these new and high-speed assays need to sufficiently convince regulators of the safety, identity, strength, and purity of the drug,” says Makowiecki.
Some QC assays are also moving closer to the manufacturing floor. Whereas in-line analysis places a probe or sensor in a process vessel or conduit for direct, continuous, and real-time measurements, at-line and off-line analysis mostly involves manual sampling followed by discontinuous and disconnected measurements. Product quality attributes can change between sampling and the availability of the results, rendering direct feedback and process control unfeasible with at-line and off-line testing. Moving QC testing in-line improves process and product control, increasing manufacturing-QC connectivity.
“Sensor-based analytics improve connectivity to the manufacturing process and enable real-time analysis and control. Many developers still rely upon off-line analysis, where you produce your material, take a sample, and bring it to the QC lab for analysis. Off-line analysis prevents real-time process changes,” Makowiecki says. “Due to the complexity and the criticality of the manufacturing processes, many new therapies will need to rely upon in-line connectivity to enable real-time analysis and decision making.”
Developing analytical assays requires evolving connections between existing and emerging knowledge. This becomes even more important with new modalities, where limited volumes of the product are available for QC testing, and analytical assays must be developed simultaneously with process development.
“Analytical development and process development go hand in hand,” says Makowiecki. “Continuous in-line measurements rely upon analytical sensors that are not just measuring critical process parameters but quality attributes to get a snapshot of your product as it’s being manufactured.”
New therapeutic products that must be produced in a compressed timeline—sometimes within a month or a week—require even greater connectivity to facilitate quick, informed decisions that enable the success of the batch and ensure safety, quality, and integrity of the product.
Makowiecki says, “Moving forward, automation and digital connectivity will be critical in improving process efficiency and product quality. These collect and aggregate all process and product data, transfer data to a secure cloud-based system, analyze the data, and return meaningful information, so operators can make the right process decisions, at the right time.”
In addition, tracking and trending protocols ensure end-to-end process execution, logistics, and distribution. “You must know what came in, what’s going on, what’s going out, has it been tested and released, where is it located, how do I get it to the patient, and am I giving the patient the right drug. The ecosystem needs connectivity to analytics, manufacturing, and distribution to get accurate data in a fraction of the time that it takes today,” says Makowiecki.
Fixed to flexible, large to small, and batch to continuous manufacturing transitions require process intensification which involves enhancing manufacturing platforms and facilities to increase output, decrease scales, or pivot toward a desired product or multiple products.
“Perfusion bioreactors and systems, run in concentrated fed batch mode, where you’re concentrating the cells along with the product in the bioreactor, true perfusion mode, where your product is continuously being removed from the bioreactor and either collected or further processed or combinations of both are examples of upstream process intensification and key elements to continuous manufacturing,” says Makowiecki.
Makowiecki sees a lot of semi-continuous manufacturing which mostly includes upstream perfusion and downstream batch processing, indicating that many developers are investigating and investing in continuous manufacturing. Some are still trying to understand its feasibility and worth, while others are trying to determine how to design new continuous manufacturing suites and facilities or modify existing batch-focused ones.
Makowiecki says, “There are still technology gaps in continuous manufacturing, such as sensors and durable and cost-effective consumables, as well as regulatory gaps such as clear strategies on process scale-up, scale-down, and process validation. Many of these gaps are currently being addressed by developers in this space.”
Although advances in upstream process intensification have been greater, the downstream has been slowly catching up. “Many continuous chromatography systems as well as high flow rate and high-capacity chromatography resins membranes and monoliths are already available in the market. Recently we have seen the emergence of new rapid cycle chromatography devices including Cytiva’s Fibro™ that create new options for downstream process intensification. We are also seeing advances in tangential flow filtration (TFF). Single-pass TFF devices and systems including Pall’s Cadence™ Single-Pass TFF modules and systems allow direct flow-through concentration with no recirculation of product. It’s taken some time, but downstream process intensification is well positioned for the future,” says Makowiecki.
It is important for companies like Cytiva to provide customers with soup to nuts solutions, Makowiecki believes. “At Cytiva, we go far beyond just providing a piece of equipment. We provide the connected ecosystem: from equipment to education, from how to run and analyze the process to how to design and operate your facility.”
Through combined implementation of pre-designed and standardized platforms, multi-layered automation and digital connectivity, equipment, and consumables, and supporting services, Makowiecki aims to provide holistic solutions that place companies on a fast track to cGMP manufacturing readiness.
In addition to traditional mAbs, Cytiva is evolving its products and services to accommodate new product modalities. Makowiecki says, “We are in this new product modality space with products, services, platforms, and facilities to accommodate cell therapy, viral vector, pDNA, mRNA, and oligonucleotide process development and manufacturing. We have sold multiple end-to-end cGMP manufacturing platforms for all the above product modalities and are adapting and evolving with the industry.”
The winds of change in biomanufacturing are certainly blowing toward small-scale, continuous processing while the industry walks the tightrope between customization of new therapeutic modalities and the practicalities of standard platforms. Throughout these layers of change, connectivity remains key.