The COVID-19 pandemic put a spotlight on how the bio/pharmaceutical industry and regulators can work together to bring life-saving therapies to the market fast to safeguard and improve public health. The lessons learned from the pandemic should be evaluated and possibly applied to how regulators approve medicines and how manufacturers produce and deliver them to patients that need them.

Pandemic-related vaccines and treatments are not the only medicines that may be ushered quickly through approval and production processes. There are medications needed for a variety of diseases and conditions that are considered rare, unmet needs. Orphan drugs are one example. FDA defines an orphan disease as affecting fewer than 200,000 people in the United States. “Some diseases have patient populations of fewer than a hundred. Collectively, however, they affect as many as 25 million Americans, according to the National Institutes of Health (NIH), and that makes the diseases—and finding treatments for them—a serious public health concern,” according to the agency (1).

Regulatory agencies recognize the need for treatments for these conditions and have policies in place to ensure treatments are available for patients. FDA’s Fast Track designation process facilitates the development of medicines to treat serious conditions and/or fill unmet needs. The process also expedites the review of these drugs. Unmet medical need is defined by FDA as “providing a therapy where none exists or providing a therapy which may be potentially better than available therapy.” The process includes early and frequent communication between FDA and the sponsor company so therapies can be approved quickly (2).

In Europe, the European Medicines Agency (EMA) uses their priority medicines (PRIME) scheme to enhance development of medicines to fill unmet needs. The agency gives early and proactive support to PRIME drug sponsors so that robust data can be generated about the benefits and risks of medicines in development (3).

“In response to COVID-19, the Government of Canada wanted to build domestic capacity for rapid mRNA [messenger RNA] vaccine production to meet future potential outbreaks of infectious disease. As a modality, mRNA addresses a much broader range of diseases than only COVID-19. Some of these drug or vaccine candidates may be appropriate for an expedited approval process. For example, the science and technology are in place to use mRNA for therapeutic vaccines and other therapies to treat diseases like cancer and orphan conditions. We also have customers looking at mRNA vaccines for flu and other infectious diseases,” says Peter Ercoli, chief operating officer, Biologics, BIOVECTRA.

With the new interest in potentially shortening time to market for medicines using the lessons learned in the pandemic, industry and regulators may be looking to fast track large-molecule drugs. Biologics, however, are often more complex than their small-molecule counterparts and, therefore, may have specific quality considerations that make fast tracking these drugs more difficult. “As large organic molecules, biologics are inherently more complex and variable than small molecule drugs, creating challenges to manufacturing and quality control,” says Ercoli. “One roadblock is the need to understand a variety of processing methods that differ for each biologic modality.”

Roadblocks to expediting biologics, according to Steven L. Walfish of Statistical Outsourcing Services, include 12 months of real-time stability, analytical method validation, and licensing of manufacturing facilities. Biologics rushed to market also require more risk-based quality control in the development stage, says Walfish. “Companies must determine which quality control tests are vital to ensuring quality versus running all tests because the regulatory landscape expects it.”

Expediting most biologics may not be as viable as the COVID-19 vaccines, according to Ercoli. “Given the critical nature of the COVID-19 pandemic, for which there were no existing viable treatments, scaled up production and regulatory approval of mRNA vaccines occurred in only six to nine months. This was a special case in which expedited approval meant focusing the entire world’s resources and attention on it. Getting other drugs manufactured, tested, and through regulatory agencies will continue to take years, not months, unfortunately. We may be able to shave a few months off that timeline for a rare disease treatment that gets fast-track designation,” he says.

Manufacturers must ensure, however, to not sacrifice quality control when speeding up production, says Ercoli. “Process development and manufacturing of biologics is complex, including development of cell lines, fermentation, and downstream purification of proteins or mRNA.” Robust processes may decrease the time to market, but regulatory guidance must be followed, according to Ercoli. “Taking what we learnt from the COVID vaccine approval process, we need to ensure quality control is adequate at each stage of development, manufacturing, and post-approval. Then, we can take what we learnt from the COVID vaccine approval process and apply it to other biologics in the future.”

Quality by design and historical knowledge should be used during development, according to Walfish. “Tasks that are usually performed later in the product life cycle can be moved up to earlier stages,” he states.

Quality considerations during manufacturing

Consistency of manufacturing is necessary for commercial readiness of a biologic, explains Vincent Villegas, senior director, Government Affairs and Strategic Initiatives at Jubilant HollisterStier. Qualification of equipment, facilities, and utilities must be guaranteed as well as the reproducibility of the process. “There must also be a continuous process verification that includes a control strategy, ongoing assurance the process is in control, and that there is statistical analysis and proactive improvement to the process,” stresses Villegas.

Adequate chemistry, manufacturing, and controls (CMC) information is a challenge, according to Melissa El Khouri, head of Quality, BioCina, “in particular for comparability assessments and stability programs, to support the approval of the biologic.” El Khouri recommends using a phase-appropriate and risk-based approach. “[One should] consider the type of product (microbial, plasmid, mRNA), the characteristics of the molecule, the clinical phase of the program, and the quality control data available to support changes and impact on the critical quality attributes of the manufacturing process,” she says. Artificial intelligence and machine learning may also be used to understand process variability quickly and determine how it impacts product quality, “in line with support and approvals required from the applicable regulatory bodies,” according to El Khouri.

Walfish stresses that manufacturing of expedited biologics includes making more risk-based decisions so that time is not wasted on methods that do not add information to the process. “Most organizations have orthogonal methods to confirm results of methods,” he says.

Contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs) play an integral role in expediting therapies to market, including the ability to offer facilities and expertise. Contract organizations, and the sponsors who utilize them, should use sound scientific approaches to ensure safe products, according to Villegas. “The CMO should develop a continually improving process in conjunction with pharmaceutical quality systems that meet or exceed GMP [good manufacturing practice] requirements. CMOs should not underestimate the complexities during scale-up and tech transfers and should utilize all tools available to them to ensure a smooth process. It is a collaborative effort with multiple divisions within the organization for a successful technology transfer and final manufactured product,” he says.

“A CDMO that has handled hundreds of different processing methods and biologics has the ability to anticipate potential issues, smoothing the path to validation and regulatory approval of a new molecule,” says Ercoli. And he stresses that CDMOs must understand if a sponsor needs full CMC development or if processes need to be replicated and scaled up to productions. “The foundation of what a CDMO does is technology transfer of a customer’s existing process, followed by scale-up. It’s the ability to bring in a new product, evaluate the robustness of the process, scale up production, and transfer it to commercial manufacturing. The key to ensuring quality is to do it right the first time. We never want to be in the position of sending something back to development and saying, ‘This doesn’t work, we need to start again from scratch.’”

Villegas agrees that tech transfer is essential “to achieve product realization during vital situations when CMOs are more than likely utilized to mass produce these products. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach, and ongoing continual improvement so that the product is safe, effective, and consistently manufactured for patients.”

El Khouri offers three ways CDMOs can assist sponsors to expedite a biologic to market: efficiency of operations and phase-appropriate approaches to timelines; effective communication between sponsor and CDMO; and providing regulatory expertise. “A CDMO should offer end-to-end services, new technologies, and strong quality expertise; foster a collaborative approach to partnerships with their sponsors; and encourage early conversations with regulators and sponsors,” says El Khouri.

“In terms of quality, there are no shortcuts whether the process is expedited or not,” says Ercoli. “A good quality system is the most robust business process. One tempting shortcut is to try to generate quality data faster by cutting back on the number of test batches or on stability testing. Usually, that just means having to do it all again because the statistical significance of the data isn’t sufficient to ensure the drug is safe and effective.”

While the regulations for expedited drugs are the same as drugs that go through the traditional approval process, according to Ercoli, regulations for biologics differ from those for solid dosage drugs. “Chemical synthesis of solid dose drugs is a less variable process than the production of biologics. As biologics are derived from living organisms, they have inherent variability, are more prone to degradation, and require a greater degree of product characterization to ensure quality control. Sourcing high-quality raw materials, analyzing critical quality attributes of the drug substance, and stability testing are some of the areas where the regulations differ,” he summarizes.

FDA. Orphan Products: Hope for People with Rare Diseases. 

EMA. Human Regulatory. PRIME: Priority Medicines. 


Vol. 36, No. 12
December 2023
Pages: 10–14

When referring to this article, please cite it as Haigney, S. Reducing Time Not Quality for Biologics Approvals. 

Articles

Cover Story

Biologics have specific quality considerations that make fast tracking these drugs more difficult.

Reducing Time Not Quality for Biologics Approvals

Autologous cell therapies begin with collection of patient cells via apheresis. The properties and quality of these cells can vary significantly from patient to patient and as the result of different collection conditions/methods. Variability in cellular starting materials introduces significant challenges to standardization, and the variability in these materials may be compounded several-fold as downstream manipulations are performed for manufacturing of the final drug product.

“It is entirely possible,” comments Priya Baraniak, chief business officer of OrganaBio, “that a manufacturing process will work with a very high yield, meeting all critical quality attributes (CQAs) and release specifications for one patient’s cells and fail miserably for another. In the case of autologous therapies, this is a very high cost to bear for any one individual’s drug product. In addition, success vs. failure is quite literally a life-or-death situation; there are no additional chances for many of these patients.”

Some actions can be taken to minimize this variability, but not all of it can be controlled. Manufacturing processes therefore must be designed to accommodate the remaining raw material variability to ensure production of high-quality, safe, and efficacious cell therapies.

The level of variability for cellular raw materials used to produce cell therapies depends on several factors, including the target disease. The most obvious variability, according to Akihiro Ko, CEO and cofounder of Elixirgen Therapeutics, is the disease severity and the condition of each patient. “Genetic and epigenetic factors in addition to the general health of the patient, stage of the disease, underlying health of the patient including medications, medical conditions, and environmental factors contribute to the overall quality of autologous cell transplant,” agrees Cynthia Pussinen, CEO of Sernova.

Traditionally, chimeric antigen receptor (CAR) T autologous cell therapies have only been approved as last-line treatments. By the time a patient is enrolled in a trial or approved to receive a commercial product, their disease is well-advanced and they have already received prior treatments. “Prior treatment of the patient before apheresis can affect the quality, quantity, and functionality of the cells collected from the patient,” states Baraniak. “Chemotherapy, radiation, and/or administration of other drug substances such as immunotherapies as first-, second-, and/or third-line therapies have significant impacts on patient cells and their suitability for genetic modification and clinical-scale expansion,” she remarks.

The collection efficiency of leukapheresis products may be impacted by various patient-specific factors such as patient disease state, place in treatment protocol, age, pre-apheresis CD3+ cell counts, hematocrit level, and platelet level, adds Dalip Sethi, commercial leader for cell therapy technologies North America at Terumo Blood and Cell Technologies.

“Ultimately,” Ko concludes, “it is difficult to collect the same quantity and quality of cells from different patients.”

Patient-to-patient differences are, however, just the first source of variability. Both differences in material collection and therapy manufacturing processes can have significant impacts on cell counts and quality, observes David Smith, vice-president of development with BioCentriq. In fact, Pussinen contends, even the cells obtained from the same individual can vary if extracted at different time points (e.g., aging, disease progression) and different sources/locations.

Compounding this issue is the fact that not all apheresis protocols are the same and not all apheresis nurses receive the same type and level of training. “Hospitals and treatment centers have different processes for collecting, processing, and freezing cells for autologous use, which can contribute significantly to variability,” Pussinen says.

Different collection devices are used at different collection sites, according to Smith. Citrate-based anticoagulants are most common, but others are used that can have different effects on the collected material. The concentration of coagulant can also vary due to the need to halt collection due to problems with different patients, reducing the total collection volume from the typical 15 to 18 liters.

If incubation is required before transplant, then factors related to cell culture and storage will contribute to the variations, adds Pussinen. Cryopreservation media, freezing and thawing methods, and post-thaw recovery also feed into raw material variations. Quality-control factors also matter, she notes, because different facilities might have different regulatory or quality controls in place. Equally important, according to Smith, is the amount of time that passes from apheresis to manufacturing, which often differs depending on the locations of the collection and manufacturing sites.

Another complication noted by Smith and Baraniak is the use of consistent, healthy donor material during process development, as often cells from patients suffering from certain diseases are not available. “Risk is then incurred when moving to manufacturing using cells from unhealthy patients,” Baraniak says.

In addition, Baraniak notes that therapeutic developers have long had a bias for identifying donors/cells that work in their processes and sticking with those particular cells for all their process development and tech-transfer purposes. “Best practice,” she believes, “should include intentional introduction of donor/cellular starting material variability into processes in order to collect data sufficient for understanding which CQAs are truly indicative of manufacturing outcomes.”

Variability in cellular starting materials, if not controlled, can have implications for both upstream and downstream manufacturing operations. Impacts can be caused by differences in viability, growth, functionality during cell expansion, which all impact yield. More generally, manufactures can have difficulty reproducibly manufacturing their products and may fail to meet regulatory standards. Combined, therefore, cellular raw material variability can at a minimum increase the time and cost for product development, and in the worst case potentially influence safety and dosing and thus ultimately clinical outcomes.

For Pussinen, therefore, the “process is the product”. “If we change anything in the process, we run the risk—or benefit—of changing the resultant product into an effectively new and different product with a different analytical and quality profile,” she contends.

Some steps can be taken to introduce controls. Proper eligibility criteria ideally minimize the variability of patient-derived cellular raw materials, according to Ko. He adds that automation of collection processes can have a measurable impact, while consistency in the management of materials from collection to transport to processing must be an integral part of how these materials are handled.

Therapy developers can, Smith observes, put limitations on the patient populations they are targeting. They can also specify the use of a certain apheresis collection device to increase collection consistency and select specific shipping containers and logistic service providers to ensure control of material transport. Large biopharmaceutical companies have, in some cases, established specific protocols and provided training for apheresis nurses. This solution will not be tenable once large numbers of therapies are on the market, however, says Smith, as nurses cannot be expected to use highly specific protocols for each different therapy.

The best overall strategy, emphasizes Pussinen, is to use a risk-based approach that allows definition of the most critical starting materials and thus CQAs. In addition, to overcome lab-to-lab variability across processing sites, she would like to see standardized protocols implemented for cell collection, isolation, profiling, banking, quality control, and other processing, including cell expansion.

Sethi agrees that emphasis should be placed on standardized operator training across sites, better understanding of collection devices and methods involved, and optimization of collection methods to the specific target cell population. For instance, the collection process should be optimized to collect the required amount of target cells while reducing the amount of non-target cells such as granulocytes and platelets. Similarly, post-collection handling and logistics for transporting the raw material should be standardized as much as possible.

In the manufacturing environment, flexibility is needed, however, to accommodate incoming variable raw materials while still meeting good manufacturing practice (GMP) requirements, Sethi says. “In most cases, purification of specific cells is a requirement to generate the cell therapy product. For a cellular drug, the quality of drug products is always the top priority for therapy manufacturers. In addition to the purification and modification steps, the cell expansion platforms should allow enough flexibility to accommodate potentially different growth kinetics of variable raw materials,” he explains.

Flexibility can be challenging to achieve given the need to establish robust, tightly controlled processes, but Pussinen highlights a few strategies for incorporating flexibility into cellular therapy biomanufacturing processes. For instance, multiple cell sources could be used, such as isolating autologous mesenchymal cells from bone marrow and peripheral blood. Parallel processing in which multiple batches are run simultaneously can, according to Pussinen, reduce the impact of raw material fluctuations on overall production. In-process quality checks to support quicker and more-informed decision making can be valuable as well, as can modular process design with freezing of materials at various stages. Pussinen also points to the use of flexible and detailed standard operating procedures (SOPs) that include instructions on how to deal with different scenarios that might arise due to starting material variability as being beneficial.

In fact, cell therapy developers try to limit variability through stringent patient inclusion and exclusion criteria for clinical-trial participation and drug-product eligibility, according to Baraniak. They also, she says, try to minimize variability by setting as many specifications as reasonably possible around the collection, processing, manufacturing, and storage of these materials.

“Optimization for cell collection, standardization of training and post-collection methods, and flexible automated systems that are designed to accommodate variable growth kinetics can improve the overall cell therapy manufacturing process,” Sethi summarizes.

Process analytics play a critical role in the management of raw material variability. For instance, Ko highlights the measurement of cell count and viability as necessary for adjusting the dose of the final cell therapy product.

A multivariate, comprehensive approach to the development of in-process testing plans, assays, and the overall analytical testing strategy is necessary to understand the numerous important product characteristics, Pussinen observes. “Using a hybrid or analytical matrix/toolbox approach will help developers in more completely understanding their product,” she adds.

Specifically, Pussinen mentions the use of standard panels to reflect the typical range of values attributed to cell products, including viability, purity, potency, concentration, in-vitro functionality, and characterization/profiling. However, she emphasizes that several factors should be taken into account, such as the specific cell type, stage of the cell, stage of the manufacturing process, and the intended therapeutic application.

For some applications, those acceptable ranges for different values will be determined by preclinical or early phases of clinical trials, according to Ko. In addition, typically, there will be go/no-go criteria for many of these acceptable ranges. “If values fall outside of those ranges, it may not be possible to pursue the treatment,” he explains.

Process analytical technologies that provide real-time data can help achieve tighter process control through more timely feed rate adjustments and other modifications and thus avoid such situations, according to Pussinen. Process control with comprehensive data documentation, she believes, helps with identifying and tracking variability.

Developing standardized analytics can be challenging, however. “The cell and gene therapy industry is working diligently in the analytical development space on assay development and variability, assay controls, sample handling along with statistical hurdles associated with working on small numbers of manufacturing runs, patients, etc.,” says Pussinen.

One issue is lack of broadly accessible data, according to Baraniak. She suggests that “addition of data to a Biomedical Data Commons and using evolving data analysis techniques and software—perhaps even artificial intelligence (AI)—could really move the needle on better understanding patient variability and correlations to manufacturing success and clinical outcomes.”

While cell and gene therapy products may never be fully characterized, developers must have a solid understanding of their products and how they perform through the process. Consequently, the analytical and process development work along with the subsequent manufacturing process are crucial in defining the end product, according to Pussinen.

An effective manufacturing process can be viewed, according to Smith, as a funnel through which variability is reduced step by step, resulting in a therapeutic product with the desired quality attributes. It is essential, in fact, because many cell therapies represent the last chance of survival for the patients that receive them. “Manufacturers must be prepared to generate effective therapies from whatever patient material is collected,” Smith comments.

A typical first process step is to wash platelets from the apheresis material, as they are “sticky” and can cause problems in later steps. “Because washing can remove over 99% of platelets, the washing step removes any variability in platelet content,” Smith notes. Typically as long as there is a sufficient number of the desired cell type in the apheresis material, it doesn’t matter how many other cells are present or what types they are, as they will be removed in the cell selection step.

Issues that are more challenging to manage relate to the impact of the collection environment (anticoagulant type and concentration, for instance), storage and shipment conditions (time, temperature, shear, etc.), and early processing steps on cell quality, according to Smith. “Some cells are more sensitive to these issues. Monocytes, for instance, are quite finnicky and their quality can be impacted if they are manipulated too much, which can make them hard to select, grow, and differentiate,” he says.

Much depends on the protocol and the cell population being treated, adds Ko. “Less time can be spent on purification if you are able to treat many cells. It may be critical to do the purification process upfront, however, so that a relatively uniform cell population can be genetically modified,” he continues.

Given that process development typically proceeds with healthy donor cells and consistent apheresis material and focuses on minimizing process variability, it is inevitable that once a process is implemented using patient-derived raw materials, there will be process deviations. “The reality is that in autologous cell therapy manufacturing, deviations are expected,” Smith observes.

Any change from the standard operating procedure, such as adding a second wash step because a particular patient’s apheresis material contains ten times the normal quantity of platelets, must be written up as a deviation. Leaving cells that do not grow sufficiently in the allotted time for a few more days is another.

“Operators must leverage their past experience and assessment of the potential risks of any changes that must be made to accommodate raw material variation before making these types of decisions,” Smith adds. Some companies, he says, provide decision trees to help operators determine the appropriate actions to take based on what they are observing in a given process.

A key advance in autologous cell therapy manufacturing has been the introduction of automated processes, states Ko, as it has led to a drastic reduction in variability and therefore enabled the production of products with more uniform quality and efficacy. He points to automation of cell culture as an example. Ko also cites another benefit of automation as being the potential reduction of stress in the workplace for the technical staff handling precious patient cells.

Elixirgen Therapeutics found that automating its process for production of a cell therapy to treat patients with telomere biology disorders provided much greater consistency in both their process and product. For its Phase I/II clinical trial, cells were selected and treated with the company’s vector in a functionally closed tubing system using the CliniMACS Prodigy (Miltenyi Biotec).

“The elimination of manual manipulations meant elimination of the risk of contamination as well as the risk of human error. This system can also be leveraged for decentralized manufacturing solutions, which additionally eliminates time spent on transportation and risks associated with the freeze-thaw process (loss of cells and reduced cell health/viability), as well as other related issues,” Ko states.

The end goal of cell therapy development, whether autologous or allogeneic, is to get safe and effective treatments to patients. The numerous cell therapy products on the market were, despite the challenges posed by raw material variability, in many cases commercialized more rapidly than most biopharmaceutical products have been in the past, according to Smith.

That success can be attributed, in part, to the leeway regulators have granted cell therapy developers to manage that variability, insists Smith. “FDA has not reduced its expectations for safety, but has been accepting of deviations from set protocols as long as appropriate risk assessments are conducted and the changes shown to not affect safety,” he explains. “The regulators have recognized the need for flexibility given the variability associated with patient-derived materials. They have also seen the value in the funnel approach during manufacturing to remove that variability. They should be given more credit for making it possible to bring these novel and highly individualized therapies to patients in need,” Smith concludes.

It is vital to the long-term success of cell therapies, including driving down their cost to increase patient access, that manufacturing processes are robust enough to account for inherent variability in patient’s cellular starting materials. “The best approach to achieving this goal is to engineer failure in early; fail hard and fast, and apply those learnings to the next program,” states Baraniak.

Doing work upfront will pay off in the end, agrees Pussinen. “Expect variations in autologous transplants. Leverage risk-based assessments, AI, quality-by-design, and modeling. Gain an in-depth understanding of the variations in each specific product, implement quality controls, and apply flexible methods for cell processing. Understand the targeted conditions and patients, and learn what clinicians and commercial colleagues find meaningful and impactful.Meet early and often with the regulators. In essence, be as prepared as possible.”

Cynthia A. Challener, PhD, is a contributing editor to 


Vol. 36, No. 12
December 2023
Pages: 16–19

When referring to this article, please cite it as Challener, C.A. Managing Raw Material Variability for Autologous Cell Therapies. 

Development

Preparing for variability and flexible processing are necessary for success.

Managing Raw Material Variability for Autologous Cell Therapies

Innovative biopharmaceutical treatments change the lives of patients every day. As biopharma manufacturers bring transformational treatments to market, they face a confluence of challenges, from speed-to-market pressure and higher demand for novel therapeutics to regulatory compliance and increasing focus on sustainable practices.

In the face of these complex challenges, new solutions can help biopharmaceutical manufacturers find new opportunities. Digital transformation allows businesses to use smart, connected devices and then harness the collected intelligence to optimize manufacturing, improve and streamline quality control (QC) and compliance, and reduce resource use.

High-volume, high-data industries, such as oil and consumer goods, were early adopters of digitalization solutions because most sensors were already in place, lowering their initial investment cost. Finding, for example, small savings of $0.05 per unit across 10 million units would result in savings of $500,000, enabling a clear path to a favorable return. Annual savings of 5–30% have commonly been reported. 

The biopharma industry, in general, has been slower to adopt because biopharma companies did not have the sheer number of data-collecting sensors and instruments that higher-volume goods manufacturers have. Nor did biopharma companies produce the type of high-volume outputs where a savings of $0.05 per unit could scale to yield major savings. In addition, early digitalization technologies lacked the data control and integrity required for life sciences products. In 2019, 40% of biopharma labs in one study had not begun to use digital solutions, and just 37% were piloting new offerings (1).

The COVID-19 pandemic—as well as other challenges, such as supply chain and labor issues—combined with improvement in data integrity helped to drive the move toward digitalization. In 2022, 91% of biopharma labs reported acting toward digital transformation, and 69% reported they were piloting, scaling up, or in a phase of wide-scale adoption (1). While in some labs, manual or paper-based processes remain, the industry is taking significant steps toward capitalizing on the opportunities digitalization offers. The following are some ways digitalization can help biopharma companies improve business operations.

Biopharma companies run very complex processes. As a result, it can be very difficult to examine every single variable in a particular process. Digitalization enables companies to collect large datasets, then use technology to analyze that data, calculate conclusions, and recommend improvements. Digitalization technologies also greatly reduce reliance on manual record keeping. By digitizing, and even automating, information such as batch records or equipment use logs, companies can reduce manual data transfers and decrease the risk of human error.

Smart technology’s ability to provide real-time data also increases efficiency by identifying processes that have drifted outside set parameters. For example, if a certain pH is required for a specific chemistry, an alarm can sound on a lab worker’s mobile phone or personal computer (PC) to alert them that a correction is needed before the batch is put at risk.

Likewise, digitalization technologies can also improve scheduling. When systems for equipment, maintenance work orders, labs, employee schedules, and electronic batch records are digitally connected, an intelligent scheduling system optimizes a production schedule over a specified period, such as two weeks or a month. Likewise, a scheduling system can create better balance between manufacturing and QC. Because it typically takes less time to manufacture a product than it does to test one, the technology could identify optimum ways to move a sample and track all its inputs throughout the workflow, increasing efficiency and shortening test time.

A single batch record can be long and complex, involving significant paperwork and leaving opportunity for human error. Even transposing a number incorrectly or writing the wrong lot number in the wrong place can impact manufacturing. Digitizing these records virtually eliminates those quality concerns.

It also creates manufacturing efficiency because a worker can spend less time on documentation to capture each step. When it is time to review and release the batch record, it can be done electronically, validating and guaranteeing the record contains the correct data. Improving QC systems also supports the need to comply with strict regulatory requirements.

As with companies across many industries, biopharma manufacturers are challenging themselves to meet ambitious sustainability goals. Whether it is sensors that adjust equipment such as dehumidifiers for energy efficiency or digitizing records to reduce paper use, smart technologies can play a significant role in conserving resources. In addition, the ability to optimize processes through digitalization prevents the batch failures that result in scrapped product and wasted resources.

Special PCs and smart programmable logic controllers (PLCs) are installed at the “edge” of the network to collect, process, and provide context to plant floor data, then send that data to the cloud for analytics. For a biopharma facility, this could be a device that sits in the purification area, connected to the PLC that controls the process. This edge device will collect data from the PLC and assign meaning to that data, including which plant, which area, which line, and which equipment the data are coming from. That contextualized data can be transmitted to the cloud for analytics leading to improvement of that purification process. Optimized recipe parameters could be sent to the edge device, then to the PLC for a better purification run on the next batch.

Smart sensors can have a significant impact on a biopharma plant floor. For temperature-dependent process variables, smart temperature sensors can be connected directly to another device such as an anti-foam pump so that anti-foam is added proportional to the temperature profile that effects foaming, while also sending data to the cloud. Software can historize and analyze the data, recognizing patterns and issues within the datasets—and it does so significantly faster and with much more pattern-recognition capability than humans. The software could even order more anti-foam when needed. Sensor technology can be used to collect various data points, including pressure, turbidity, humidity, flow, and more.

Sensors connected to digitalization technologies can also provide essential real-time monitoring. This allows biopharma manufacturers to keep processes more effectively on track, especially when working with variables, such as total organic carbon, that are difficult-to-measure outside of the process in the lab. For inventory, smart shelves with embedded sensors can detect when materials on the shelves drop below a predefined number. When connected to an inventory management tool, smart shelves can initiate timely stocking and improve inventory visibility.

This technology uses cameras or sensors to identify or inspect critical information. In recent years, vision systems have become affordable and much easier to use, providing biopharma manufacturers with significant opportunities to improve production.

For example, a vision system added to a filling line can inspect product labels to ensure lot numbers and expiration dates are correct. The system can also identify labels that are incorrectly placed or are marred by smears or smudges. A vision system can also be used to determine if a bottle cap is cross-threaded. For instance, one camera with two different inspection criteria (height of cap in view vs. expected height can detect front-to-back variance, levelness can detect left-to-right variance) can identify a cross-threaded cap and immediately reject what could become a leaky cap in the field.

Advanced analytic tools for digitalization

Connected devices, such as sensors and vision systems, generate massive datasets when combined with integration of data collected from laboratory information management systems (LIMS) and more. Advanced tools such as artificial intelligence (AI) and machine learning (ML) assess and analyze the data for deep-dive insights, finding patterns and interrelationships or detecting process deviations that would be virtually impossible for a human to detect. These predictive analytics allow manufacturers to make necessary corrections or adjustments before the point of product failure.

The technology can also optimize the manufacturing process to save time, energy, and resources. For example, AI and ML have the potential to optimize a specific process beyond the capabilities of base digitalization technology, such as a manufacturing execution system.

The rise of the single-use (SU) system has proven to be a game-changer in biopharma, and digitalization used in its production has demonstrated benefits to biopharma manufacturers as well as SU suppliers. In the past, bulk material—typically delivered to biopharma manufacturers in pails, drums, or super sacks—required quality assurance testing upon receipt before being subdivided and used in production. Now, materials are delivered in pre-weighed, single-use packages supplied with e-delivery of material documentation.

Because the material in that single-use product is only used for a given production run, the package’s traceable e-data can be automatically incorporated into upstream or downstream operations. The packaging also may allow for quick, nondestructive identification, such as Raman identification, which provides a rich dataset of raw material variability.

By working with SU suppliers, biopharma manufacturers can leverage a supplier’s available datasets without the need to build the database itself. The time savings can be significant. In one case study (conducted internally by Avantor), a manufacturer reduced the process of receiving and preparing production materials from 30 hours to nine.

Some SU suppliers are incorporating transformational technologies into their own processes. By moving beyond data aggregation to more connected operations, SU suppliers can automate data-driven decisions to efficiently advance their own production processes to meet biopharmamanufacturers’ needs.

SU technology production requires the assembly of multiple types of tubing, connectors, sensors, and other components. Other factors impact manufacturing too, including the need to maintain production in cleanroom conditions by technicians wearing personal protective equipment. On-time production and delivery rely on these environments being fully stocked.

Tools such as smart buttons provide a single point of contact for onsite support teams to provide QC inspections or engineering support from outside the cleanroom. Use of smart shelves minimize stockouts and inventory discrepancies. Combined with AI and ML systems, this transforms human-driven inventory management to a data-driven process that generates savings and efficiencies in SU production and QC.

Smart technologies will continue to create opportunities for the biopharma industry. Consider digital twins, a modeling technology that uses AI or ML to virtually test improvements and outcomes. More common in high-volume, high-data industries, digital twins can improve biopharma manufacturing processes. In addition, results from digital twin modeling can identify projects that should be prioritized or rank projects in the order of their ability to deliver the best overall quality, productivity, or customer satisfaction-related improvements. This would allow manufacturers to best determine where to invest capital.

As technology improves, machine learning has the potential to further optimize processes through prescriptive analytics that go beyond predicting what will happen and make recommendations, as well as predict their potential outcomes (see 

). For example, prescriptive analytics could identify if an agitator runs faster at the beginning of a batch, it will produce a specified improved yield. Furthermore, the system could then automatically issue a management of change order that, after human review and approval, would then change the agitator’s setting.

Augmented reality (AR) appeared several years ago with the creation of a mobile app that allows users to move around in the real world and interact with AR-generated content. This technology can help support biopharma manufacturer workforce development by being utilized to train operators. For steps that are easier to explain with a video rather than a batch record, the operator can point their phone camera or tablet at the equipment to overlay a graphic that demonstrates how to perform the next step. Thus, AR can serve as a 3D standard operating procedure that helps reduce the risk of human error and, ultimately, save time during production.

Digital transformation technologies allow manufacturers to ensure the product is the process. By optimizing manufacturing, improving and streamlining QC and compliance, and decreasing resource use, the end product will be better—and a life-changing treatment can get to the patient faster.

1. Elicker, J.; Maixner, D.; Fish, M.; Heavey, B. Driving Digitalization at Scale in the Lab. 

www.accenture.com/us-en/insights/life-sciences/digital-labs

Mark Featherston is director, quality, strategic programs and global lab services, and John D. Fisher is director, engineering, global ops; both at Avantor.


Volume 36, No. 12
December 2023
Pages: 22–27

When referring to this article, please cite it as Featherston, M.; Fisher, J. D. Revolutionizing Biomanufacturing: The Digitalization Advantage. 

Manufacturing

Digital transformation allows for smarter and connected biomanufacturing operations.

Revolutionizing Biomanufacturing: The Digitalization Advantage

While every drug molecule is unique and brings its own fragile chemical makeup to the production process, one element is consistent across the board: the importance of stability from start to finish. Stability testing is a highly important part of the production and commercialization process because it allows a contract development and manufacturing organization (CDMO) and drug developer to note what production processes, packaging, and shipping options will maintain the drug’s delicate chemical composition without jeopardizing quality.

When a drug developer partners with a CDMO, whether in Phase I, II, III, or beyond, it is not only recommended, but vital for the CDMO to conduct stability studies. This testing must take place in every phase of development, often more than once per phase, and should be integrated into the predetermined timeline. These studies do take time. Therefore, it must be accounted for early on in the process to prevent a delay in achieving commercialization. Injectable drug molecules naturally evolve as they are developed. Stability studies offer a proven method to test the drug ingredients’ quality as it is subject to external conditions such as environment, temperature, humidity, light, and more. Looking beyond the production timeline, stability studies bring added value in determining retest dates, shelf-life, expiration dates, packaging, storage, and shipping conditions.

Without sufficient stability studies, a drug product is failing to meet regulatory requirements and will inevitably never reach the patients who rely on it.

Navigating testing throughout product lifestyle

As any drug developer or CDMO will know, creating an entirely new drug poses its own unique challenges, one of which is securing regulatory approval from several authorities in different markets. Submissions for approval to these authorities must contain data from stability testing for the drug substance and drug product. As a result, stability assessments will be performed in nearly every development phase to evaluate a drug product’s overall stability in various instances.

Stability testing begins in early development phases. This is completed by analyzing technical batches and clinical samples to support the identification of proper formulation, primary packaging, and production processes that are best suited to maintain the drug formulation’s quality. Later, testing continues but changes its focus to the generation of expiration dates and obtaining market authorization. Stability studies must be done throughout the full development lifecycle. Should testing show a drop in quality at any point, the problem must be immediately addressed to prevent delays in the production and
commercialization process (1).

A CDMO will bring different study types to the development process (e.g., real-time, accelerated, intermediate, and photostability studies). Real-time testing looks at a product under intended temperature, humidity, and packaging storage conditions. Accelerated testing gathers supportive data through estimations of long-term testing outcomes and evaluations of short, temporary excursions from label storage conditions. Intermediate testing is performed between long-term and accelerated studies when accelerated studies show potential for significant change after six months (2).

Once a product launches, stability testing does not stop. Follow-up studies should be conducted regularly and additionally after post-approval changes. Some might consider stability testing to be one of the most essential elements of a drug product’s entire lifecycle, as it supports the drug and the health of the patients.

Identifying the right stability testing for each drug product

Drug products can vary extensively, from small-molecule to large-molecule, complex, highly sensitive, vaccines vs. oral, biotechnologically produced, and more. Therefore, the stability testing conducted for every drug product must differ accordingly. As each drug product evolves, its testing must adapt to address all quality needs.

Consider biologics, for example. These drug products experienced a boom in clinical development in recent years when the global pandemic required a vaccine for treatment. Injectables are delivered through a small, concentrated volume of liquid. Therefore, its potential stability issues are unique to this format and can range from aggregation, viscosity, and thermal degradation. While small-molecule drugs are often more straightforward to test for quality, large-molecule drugs can be much more complicated and require deeper bioanalytical testing methods. Regardless of a drug molecule’s size, testing must be uniquely designed to evaluate all key elements of a one-of-a-kind biologic.

As drug products differ in their formulation, packaging, delivery, and treatment method, so too does the most suitable stability testing approach. A CDMO and drug developer must select stability programs that align with its company philosophy, product type, and regulatory requirements. Customer expectations may also vary and play a role in the testing done by a CDMO.

Above all else, the stability program for a given drug will base itself on the regulatory needs for that product. Selecting stability testing should remain fluid and, on a case-by-case basis with several factors in mind.

Meeting regulatory expectations and requirements

When a drug undergoes regulatory evaluation, it will not simply receive a “yes” or “no” during its stability testing. Instead, it sets parameters that guide the development program with quality assurances in mind. While regulators will likely outline drug stability requirements in good manufacturing practice (GMP) guidelines, these programs will include more than the baseline expiration date (3). It will also require written stability studies outlining sample sizes, test frequency, storage needs, validated test methods, and specifications. With these qualifiers in mind, CDMOs and pharma customers will implement the unique stability testing program often enough to maintain quality throughout the process. This testing must be done within the product’s container that it will go to market in.

Luckily, the industry has seen synergy across multiple regulatory authorities and guidelines for stability testing. In fact, the International Council for Harmonisation (ICH) pharmaceutical stability guidelines are now considered a globally accepted standard (4). By following the ICH’s recommendations for amount and type of drug stability data needed per drug substance type, drug developers will be prepared to earn regulatory approval on any new drug product. ICH guidelines, particularly Q1A–Q1F, have measurably improved the overall quality of pharmaceutical drug products on the market, both in small- and large-molecule formats. While this does not mean that every drug product will require the same testing, it does set a precedent that can be adhered to across the board. For example, biologics are notoriously more sensitive so they will require a variety of complex analytical tests including, for example, potency testing.

While stability testing can be done by pharmaceutical and biotech companies, its growing demand is a result of a rising complexity of global regulatory requirements. Many choose to work with an outsourcing partner, or CDMO, to take advantage of their stability testing expertise. It is unlikely that a customer has this level of expertise in-house, but it is often available to leverage when working with an external partner. Besides the knowledge-base, CDMOs often bring added analytical equipment and qualified storage capabilities that would be a cost-add to a customer’s own internal repertoire.

Full-service CDMOs allow a customer to bring production, release, and stability testing together within the oversight of one quality management system. By entrusting the comprehensive stability testing process to one partner, a drug developer mitigates the need for additional organization, coordination, and logistic activities. This saves both cost and capacity for other drug development projects. In addition, changes can be addressed more seamlessly when both production and stability testing are with one company.

This outsourcing method opens pharmaceutical and biotech company capacities for product development, leaving an experienced CDMO to manage stability studies.

Across the industry, some trends are consistent, ranging from increased complexity of drug molecules, shortened timeframes for development and delivery, and decreased batch sizes. There is also a shift to greater collaboration between pharma and biotech companies, CDMOs, and regulatory bodies. By working together to create guidance for stability testing based on risk assessment, drug developers can get ahead of regulatory expectations and establish new testing criteria to address quality expectations.

As stability testing and regulatory approval become increasingly intertwined, the value customers place on it is growing and becoming a high-value service provided by CDMOs. As more customers engage CDMOs for stability testing support, there is also an increase in the related requirements placed on outside partners.

The current landscape and future forecasts of the stability testing market indicate a need for global standardization and improved approaches. As this becomes reality, CDMOs will have greater adaptability to provide streamlined testing with better quality results generated.

Thomas, F. Stability Testing: The Crucial Development Step. BioPharm Intern. 2020 33 (3) 2020.

Vetter. Stability Testing & Storage. Vetter-Pharma.com; 2023.

World Health Organization. Annex 2, TRS No 999. WHO Good Manufacturing Practices for Biological Products (WHO, 2016).

ICH. Q1A(R2) Stability Testing of New Drug Substances and Products (ICH, 2003).

Karin Kottig, PhD, is head of Contract Service Analytics, Vetter Development Service.

®
Vol. 36, No. 12
December 2023
Pages: 30–32

When referring to this article, please cite it as Kottig, K. Stability Studies: An Essential Step for Quality Management in Drug Development. 

Analytics

Sufficient stability studies show a drug product meets regulatory requirements, therefore ensuring the drug reaches the patients who rely on it.

Stability Studies: An Essential Step for Quality Management in Drug Development

Pharmaceuticals are entering a transition into a far more complex era of patient therapies, and patient segmentation. It will not be an easy process. It’s an evolution long in the making and welcomed for not only improved treatment outcomes, but also for increasingly realistic “cures”. In such a tightly regulated space, where large financial investments are also required, many unwilling stakeholders will be swept along with this rising tide of new medicines. Who would have seriously considered larger-scale three-dimensional printing of medicines five years ago, or marrying messenger RNA delivery methods with chimeric antigen receptor therapies for reconfigurable patient specific antigen profiles, within the same patient, over the span of a month?

To keep this surging tide heading into workable spaces without swamping all systems, international bodies, such as the International Council for Harmonisation and the World Health Organization, are going to have to be relied on to perform much of the heavy lifting. New financial cooperation models, some of which were trial ran during the COVID-19 pandemic, must also be implemented for consolidated gains to remain real.

With these advances rolling in at a more rapid pace than ever before, our coverage of the pharmaceutical space must also evolve. This year, we have increased our coverage of the daily news, to provide insight at a greater pace. The brand has also rededicated to video coverage, to provide insight from the experts on the frontlines of these advances. Along with these changes, we have amped up our conference coverage, to provide key advances and learnings from major meetings throughout the year, like our coverage from the 11th International mRNA Health Conference and CPHI Barcelona. All these latest insights can be read at 

As we eye up trends and opportunities for 2024, we are truly excited for the fruits of the future. There is so much awaiting us, and we can be guaranteed that the new medicines about to be manufactured, stored, delivered, and received will be more efficacious than ever and worth the efforts. And that is something worth holding on to, something to be proud of.

Mike Hennessy Jr. is the President and CEO of 

When referring to this article, please cite it as Hennessy, M. The Dislocation of Progress. 

From the Publisher

Pharmaceuticals are entering a transition into a far more complex era of patient therapies, and patient segmentation.

The Dislocation of Progress

Q: My company is a contract manufacturer. Our final product inspection process consistently delays timely release of the manufactured products to our clients. Is there a best process/practice for performing final
product inspection?

A: This is not a new problem for the industry. To me, some of the issue is the fact that we call the specific activity of the overall physical product evaluation the “final product inspection.” In my opinion, the physical product evaluation should start at the beginning: the receipt of the individual components (stoppers, vials, labels, etc.) that are used in manufacturing. Each component should pass an incoming quality inspection with defined acceptable quality limits (AQL) and clear directions for rejection of the component should it exceed the AQL. The specific elements to be looked at on incoming inspection will vary depending on the component.

Let’s assume your company manufactures sterile injectable products and the major component you will use in manufacturing is a glass vial. The first step in the process is to perform an incoming inspection of the glass vials. The number of vials to inspect from the shipment will depend on the number of vials contained in the shipment. The sample size to be inspected should be recorded in the appropriate standard operating procedure (SOP). The specific defects to be inspected should also be included in the SOP. When evaluating these defects, most companies employ definitions of critical, major, and minor to the reject/accept criteria. In the case of vials, critical might be defined as likely to cause harm to the patient; major might be defined as leads to impairment to the patient; and minor would be defined as cosmetic defect causing no threat to the patient. Defining the acceptance criteria upfront may save you a lot of time at the end of the process.

Once the vial is accepted, it will be used in the manufacturing process. Defects that exist in the vial after initial acceptance may be detected during this step of the process. Many manufacturing lines have automatic sensors that detect vial imperfections and eliminate the vial from the batch before it is sent for labeling. It is important for the line operators to be trained to recognize when there is an increase in rejected vials because this could mean that the incoming inspection did not pick up the vial defect. Again, if the defect can be detected and categorized at this process stage, it will save time at the product release stage.

The last stage for potential vial inspection before labeling would be visual inspection of the stoppered vial. Some companies perform this step manually with trained visual inspectors while others utilize visual inspection equipment to perform the final inspection of the vial before labeling. Companies using vial inspectors typically focus those inspectors on looking for particulates in the vial, but they should also be trained to recognize vial defects. Regardless of which inspection format is used, there should be SOPs and AQLs governing the inspection process.

Final product inspection results should be included as part of your batch release documentation, so it is important to have repeatable, defined process/processes in place at all stages of the manufacturing process that is/are suitable for the product being inspected. The more time you spend upfront in the component inspection process, the more efficient your final inspection and batch release process will be to ensure timely product release to your clients.

Susan J. Schniepp is distinguished fellow at Nelson Laboratories, LLC.

When referring to this article, please cite it as Schniepp, S. Final Product Inspection: Making the Most of Your Processes. 

Ask The Expert

Final product inspection results should be included as part of the batch release documentation, says Susan J. Schniepp, distinguished fellow at Nelson Laboratories, LLC.

BioPharm International, December 2023

Reducing Time Not Quality for Biologics Approvals

Managing Raw Material Variability for Autologous Cell Therapies

Revolutionizing Biomanufacturing: The Digitalization Advantage

Stability Studies: An Essential Step for Quality Management in Drug Development

The Dislocation of Progress

Final Product Inspection: Making the Most of Your Processes