Drug Solutions Podcast

External expertise can help companies select the right tools during development.

Adopting Smart Development Strategies

Numerous benefits will eventually lead to large-scale applications in pharmaceutical manufacturing.

Electrochemistry for API Synthesis

BFS technology can help maintain sterility during the biologics manufacturing process.

Improving Sterility Using Blow-Fill-Seal Technology

Standardized risk assessment and analysis protocols facilitate the comparison of processing equipment components.

Analyzing Extractables and Leachables in Single-Use Systems

Biopharma focuses on streamlining biomanufacturing and supply chain issues to drive uptake of cell and gene therapies.

Growth in Cell and Gene Therapy Market

Development and Scalability of ADCs and CGTs

Drug Digest

Grant Playter is the Assistant Editor for 

While the debate between stainless steel and single-use systems (SUS) will continue to rage for the foreseeable future, most would agree that there is a time and place for either approach. Naturally, however, this raises the question: when is it ideal to utilize an SUS approach? What advantages does it confer? How are they being used in the current manufacturing environment?

spoke with SUS experts Nick Johnson, director of Product Management, Biopharma, CPC, Wolfgang Walcher, chief commercial officer, Single Use Support; and Helene Pora, vice-president, Technical Communication & Regulatory Strategy, Pall, to get their perspective on the current benefits of single-use systems.

Can you share your thoughts, broadly speaking, on the merits of single-use systems, consumables, etc., in manufacturing? Is there any aspect that you feel is under or over-emphasized in this discussion?

 Think about the flexibility single-use systems allowed during the pandemic. Manufacturers urgently reallocated new therapy and other capacities to commercial vaccine production. The capability to quickly switch from one kind of production to another is a huge benefit that SUS affords in everyday practice. Single-use technologies (SUT) definitely contribute to speed and efficiency by allowing multiple products to be produced in one manufacturing suite with relative ease.

SUT’s flexibility and sterility also has made it simpler to ‘fail fast’ in clinical trials, too, compared to traditional stainless steel. The impact on bioprocessing from early-stage development through commercial manufacture has been an industry game changer.

 SUS offer a level of flexibility, scalability, and cleanliness that is near impossible to achieve with glass and stainless-steel counterparts. Lines can be repurposed more easily, and there is no need for cleaning and cleaning validation. This saves a great deal of time and money while making the process safer for operators. SUS can also reduce the time to build a plant and lower overall capital expenses. And from an environmental perspective, there is a lower carbon footprint, less water, and less chemicals despite higher solid plastic waste.

Unfortunately, the amount of solid waste is frequently overstated compared to the benefits. In 2020, ISPE released a review showing that SUS is responsible for .01% of all global plastic waste, which is largely driven by consumers. This does not mean that the industry does not see the use of plastic as a problem—we are actively investing in recyclability and overall process impacts—however, it does not deserve the level of criticism it gets.

: Single-use systems are trending for a reason:

They help to improve safety, cost-efficiency, and sustainability in comparison with the use of durable stainless-steel manufacturing facilities.

With single-use assemblies, bioprocess containers, and other sterile consumables operators can transfer liquids in closed systems and as customized options.

They are adaptable to changing requirements of system setups.

Usually, the systems are designed to minimize manual interventions, thus preventing human errors which can result in quarantined or even rejected batches.

The most under-emphasized aspect is probably sustainability. Different life-cycle assessment studies have proven that single-use systems can be more sustainable than stainless-steel solutions (1). However, there is still room for improvement, and we’ll drive innovation to further improve sustainability in the pharmaceutical industry.

What are the costs of using single-use systems, consumables, etc.? What factors should be considered when deciding whether or not to employ them?

 There are different factors that come into play to influence costs of single-use systems because of the wide range of consumables on the market, which offers a wide span of prices.

The answer is strongly dependent on the application/use of single use systems. For example, in API primary packaging the alternative to single use systems is shipping hundreds of kilograms of cryo-vessels worth millions of dollars and causing tons of CO2 [carbon dioxide] emissions; alternatively, SUS, like bags, are low at cost, easy to store, and safe to ship.

For other applications, [such as] sampling or bioprocess containers, it is a question of flexibility, and people forget that stainless-steel multi-use vessels require a high amount of resources—producing, repairing and maintenance, cooling, etc. 

: Ease of use, flexibility, reliable sterility, production efficiency—these are all factors to be considered. Thanks to SUT, it’s economically feasible to manufacture therapies for diseases that affect small patient populations that have the kinds of numbers that might not justify an investment in a traditional stainless-steel operation.

Modular, purpose-built SUS can be optimized for specific processes so they’re ready when needed. The production suite can be changed over quickly to accommodate the next process. There’s no downtime between production runs because SUS don’t require cleaning or equipment requalification in between batches. The ability of SUS to eliminate the risk of cross-contamination between processes is significant. All of this contributes to more streamlined operations.

Also, SUT is the most cost-effective way for manufacturers to make a wide range of drugs from vaccines, to mAbs [monoclonal antibodies], to cell and gene therapies.

SUS are priced more affordably than traditional equipment. However, SUS require bags and connectors that will generate consumable costs over the life of each process. The cost of consumables and security of supply is very important to consider. Working with trusted suppliers that have taken steps to secure sourcing is paramount in today’s market.

It is, of course, important to consider batch size and the number of batches that will be needed per year. With size constraints usually hovering around 2000 L, any high-volume drug would require a parallel processing approach. And whether the plant will be multi-product or single product is also critical.

Though it can be argued that the ability to changeover is only valuable if it is needed, it is always a smart investment. Having the flexibility, even in a single product environment, is a good backup if anything were to go wrong (e.g., clinical failure) along the way to commercialization.

What trends have you seen occurring as it pertains to single-use manufacturing? Do you anticipate them continuing for the foreseeable future, or is the end in sight?

If you looked back a decade ago, the discussion was still, ‘will this work?’ We are so far past that now, and SUS have helped to enable an era of innovation in this industry that is unmatched. We see a diverse range of modalities, which continues to grow, and a move towards more efficacious or even curative products.

The technologies needed to support the continuous high growth projections in the industry will rely on SUS in many cases. As we’ve seen through the pandemic, SUS not only enable innovation, but they allow for the type of rapid response needed for vaccines. Undoubtedly, the COVID-19 vaccines would not have been introduced and produced so quickly without SUS.

The growth may not be as high as we have seen throughout the last two years of the pandemic, but it will continue. A new product mix with an emphasis on biologicals and smaller indications will keep that demand growing over time. We also cannot ignore that SUS will be the backbone of existing processes (pending the patient population), creating sustainable demand in those areas.

Additionally, the scope of SUS use is continuing to expand, with more critical applications than ever before like formulation and final filling.

SUS will play a vital role in pharmaceutical and biopharmaceutical manufacturing and supply chain in future. The more personal medicines and low volume high potency medication (e.g., gene therapeutics, mRNA [messenger RNA], small interfering RNA, etc.) is progressing, the more important single use system will be. Challenges [such as] recycling of single-use systems will be solved in the near future and [will], therefore, significantly improve the environmental sustainability and CO2 footprints of systems used.

: Most new and upgraded contract development and manufacturing organizations, contract manufacturing organizations, and biopharma companies are incorporating single-use bioprocessing equipment. That’s the way the industry has been moving and will continue to go.

From a big-picture standpoint, it might take five to seven years from groundbreaking to a qualified facility using stainless steel. In contrast, a SUS-based facility might require two to three years. Then, after a facility is operational, SUS allow biomanufacturers to process multiple drugs simultaneously in one space or make rapid equipment changeovers between production runs without compromising sterility. That push for efficiency and modularity within and across sites is a driver.

There’s strong interest in standardizing SUT, which begins with components purchased from SUS equipment suppliers. The same equipment, standard operating procedures, and a shared supply chain create efficiency. SUS components also will need to work in automated equipment as the industry moves away from reliance on operators toward automatic processes.

Are there any unique use cases for single-use consumables, systems, etc. that you have experienced in the industry?

: The SUS component industry is catching up a bit to create solutions specifically for small-bore tubing in small-volume work—applications [such as] sampling, seed train expansion, analytical processing, buffer/media transfers, and early cell-culture processes involving shaker flasks and rocker tables.

A growing number of companies are now engaged in small-volume (< 10 L) aseptic processes, such as early-stage drug development. You’ll also see very small volumes in cell therapy, for example, where cell availability is limited or media is expensive, and in the development of small-batch autologous therapies.

In the past, making reliable sterile connections in these smaller aseptic processes was typically handled using biosafety cabinets or tube welding. But biosafety cabinets can only handle a limited number of processes at one time. Tube welding is labor intensive, and the equipment is expensive—easily $15,000 or more per welder—and takes up valuable cleanroom space. Small companies with limited resources may not have the capital to purchase tube welders.

Until recently, tube welding was the only option for creating sterile closed systems at small volumes. Now there are single-use aseptic micro-connectors designed to sterilely connect small-bore tubing, so that’s new to the industry. Aseptic connections with new micro connectors can be completed in three steps and up to four times faster than an operator using tube welding, which can require a dozen steps or more to get a successful weld.

Also, in our line of work—connection technologies—there’s never been a genderless connector that can both connect and disconnect tubing using one product in bioprocessing until this past spring. Users appreciate genderless products because they’re more convenient. They eliminate mating complexity, reduce inventory requirements, simplify system design and reduce operator error. That genderless convenience factor was taken up a notch by creating a product that connects and disconnects aseptically without the need for ancillary equipment.

: Initially the use of SUS was focused on providing a solution for media and buffer preparation and handling. Over the last decade, we can now leverage the benefit of SUS throughout the process and even into the final filling applications. The use here is very functional—we only use exactly what we need, which is another part of how we keep the volume of waste minimized.

: There is a broad application of SUS established, so you will find all (even exotic) applications of SUS in the industry.

While the broader effects of the COVID-19 pandemic have lessened in public discourse, the supply chain interruptions it brought on remain a concern. Can you discuss the impact this has had on manufacturing? How would a mass return to the just-in-time (JIT) delivery model shift the current landscape?

The industry wasn’t prepared for such a supply chain challenge. The shortages have jeopardized business continuity of major manufacturing sites apart from COVID-19.

The shortage of SUS has therefore made biopharmaceutical manufacturers reflect on their relationship with suppliers. It has shown that it is crucial to have reliable partners, to plan ahead, and to establish reliable forecasts. Suppliers can react accordingly by building stock and procuring it early. Manufacturers and suppliers need a common understanding and common standards across the industry with respect to equipment and consumable design, as this enhances delivery speed.

A JIT delivery model in the pharmaceutical industry needs suppliers who rethink supplier relationships by offering solutions [such as] supplier agnostic solutions for flexibility or various business continuity measures to allow fast delivery times.

From a supplier perspective, it has driven us to significantly increase our manufacturing footprint and take deeper steps internally to secure our supply chain. Just about a year ago, Danaher announced an investment of $1.5 billion into the Cytiva and Pall lines of business (2). Over $300 million of that has been dedicated to strengthening the SUS line of business. Even as we start to realize some of the benefits of these investments, we remain committed to honing an agile approach to business processes standardization in parallel with our daily activities.

There will be a tradeoff for every approach. JIT will be largely dependent on the capability of biomanufacturers to produce accurate forecasts. While this can be achieved to a certain level with commercial products, it will remain very difficult for clinical manufacturing. Therefore, JIT delivery will be a combination of demand and how much some form of standardization is achieved, together with improved forecasting practices. It will still take some time to reach that level after the pandemic. The goal is really to more reliable and reproducible lead times, regardless of the model.

: From a supply-chain perspective, there’s no question that COVID-19 has disrupted everything from obtaining raw materials used to create components to the ability to ship sterilized equipment in a timely way. This isn’t exclusive to SUS, but it’s had an impact throughout the supply chain.

Supply-chain considerations are especially important when selecting suppliers of single-use assemblies. That’s because no supplier of single-use assemblies manufactures all of the products used in that assembly. For example, the manufacturer of a single-use mixer bag probably sourced the aseptic connectors, tubing, tubing clamps, T or Y connectors, filter capsules, etc., from other companies. Each of those component suppliers has a supply chain that may comprise sub-component suppliers, external assemblers, raw material suppliers, contract manufacturers, and so on. You can see that the SUS supply chain is multi-tiered and complex; the ability of the SUS manufacturer to supply product is 100% dependent upon the robustness of the entire supply chain.

Enhancing sustainability in the pharma industry

Cytiva, “Cytiva and Pall Corporation investing 1.5 billion USD over two years to meet growing demand for biotechnology solutions,” Press Release, July 27, 2021.

Grant Playter is the Assistant Editor at 

Articles

Experts outline the benefits of single-use consumables relative to traditional approaches.

Weighing the Benefits of Single-Use Consumables

Editor of Pharmaceutical Technology Europe

According to research, post-pandemic R&D growth is healthy in the pharma industry with the number of drugs in the R&D pipeline now exceeding 20,000 in 2022—which represents an expansion rate of 8.22% from 2021 (1). This heightened spending into researching novel chemical modalities and substances can be absorbed by some pharma companies as an internal cost; however, development of a suitable and ultimately successful formulation strategy to advance a molecule to commercialization can benefit from external expertise. As such, it has also been projected that the expanding R&D pipeline will be a driver for the formulation development outsourcing market (2).

“An outsourcing partner should have a good understanding of CMC [chemistry, manufacturing, and controls] perspectives with the developer’s interests in mind, which enables the developer to have a sharp vision of potential scenarios to develop for first-in-human (FIH) trials, but also considers factors that will influence filings and the product’s commercial success,” says Thierry-Thien K Nguyen, director of Product Development, Catalent Biologics. “In addition, an outsourcing partner should collaborate with customers to develop PrOACT (identify problems, objectives, alternatives, consequences, and trade-offs) and enable customers to make the most informed decisions to reduce risk and increase the program’s chances of success.”

To support optimal formulation strategies, not only must outsourcing partners invest in building a resource pool with the right skill set, but they must also provide continuous training development programs and bring in the right infrastructure, adds Anil Kane, PhD, senior director, global technical scientific affairs, pharma services, Thermo Fisher Scientific. “Employing the right tools (modeling, simulation, predictive) at the right stage of pre-clinical, clinical or late-stage development is important and has a huge potential for application, interpretation, and science-based decision making in adopting smart formulation strategies,” he says.

A tool that is aiding in early development is computer-based predictive modeling, reveals Kane. “This predictive modeling avoids trial-and-error-based search of the right solution to solve the complex technology and excipient selection process, thus helping to reduce the time and investment in early clinical development,” he specifies. “An algorithm-based in-house developed software can predict technologies that will offer a higher probability of success among several options such as micronization, amorphous solid dispersions (spray drying or hot melt extrusion), lipid-based delivery, complexation, and others.”

“During formulation and process development, at an early preclinical/clinical stage, an in-depth understanding of material properties and their impact on formulation and process is critical,” Kane continues. It is possible to simulate the behavior of bulk materials in oral solid dosage forms using discrete element modeling (DEM)/compaction simulation tools, he explains. “The use of these tools mitigates formulation/process challenges early in development and helps speed up process development and troubleshooting,” Kane says.

Additionally, Kane emphasizes that modeling has found further use in aiding the design of formulation strategies for immediate-release and controlled/extended-release oral solid dosage forms through physiologically based pharmacokinetics modeling. “Predicting animal/FIH doses, 

 correlation (IVIVC), food effects, bioequivalence, pharmacokinetic/pharmacodynamic (PK/PD), and so on, using software has helped in the assessment of formulation impact on PK, compartmental PK analysis of animal data, evaluation of animal bioavailability, and defining an FIH clinical dosing strategy,” Kane states.

Focusing on large molecules, Nguyen points out that there have been several innovations that have significantly impacted formulation strategies during recent years. In addition to predictive models using artificial intelligence (AI) and machine learning (ML), Nguyen highlights high-purity, parenteral-grade excipients in cryopreservation media for autologous and allogeneic cell therapies; novel excipients for use in vaccines, viral therapies, and high-concentration biologics formulations; lipid nanoparticle components and associated manufacturing technology for encapsulation; and continuous sterile freeze-drying technology, as key innovations.

However, each of these innovations faces several challenges, such as toxicology/pharmacology and pharmacovigilance data requirements for novel excipients before they can be widely adopted, Nguyen stresses. “Some innovations are more acceptable, such as lipid nanoparticles (LNP) in messenger RNA/LNP formulations,” he says. “To overcome these challenges and enable technology adoption, those aspects identified using a quality-by-design (QbD) approach need to be addressed in order that patient-centric requirements are satisfied, and a clear understanding of product quality attributes and associated process parameters is demonstrated.”

There has been much advancement in the field of information technology recently, confirms Nguyen, such as the implementation of AI- and ML-based techniques in a variety of industries. “However, the pharmaceutical industry has been slower than others to adopt AI- and ML-based techniques, perhaps because of the lack of clear regulations, a paucity of funding for research into these fields, and a scarcity of reputable quality training programs,” he notes.

Yet, Nguyen continues, when digitalization is implemented both thoroughly and properly into formulation development strategies, it is possible to improve cost and time efficiencies in drug product formulation and process development. If applied correctly, it is possible to enable past information on formulations, APIs, and processing conditions to be amassed; allow the creation of a large common library to teach/train new ML algorithms; support the creation of algorithms that predict how similar molecules/entities would behave

in given formulation environments; and will provide the potential for quicker access to data and greater processing power, which would make the formulation candidate selection more efficient, he specifies.

“Finally, with a predictive AI model, minimal data sets could more accurately anticipate a molecule’s stability,” Nguyen adds. “For formulation in a traditional manufacturing site, digitalization benefits could be realized in the next few years, which have already been explored in both academia and industry. For personalized medicine, bedside and 

 formulation, and in combination with wearable devices, there is still some way to go, but the future is exciting.”

Advances in analytics and digitalization are being leveraged by many Big Pharma companies to improve drug development productivity, asserts Kane. Approaches to increase productivity or success rates in drug design that are adopted by researchers, medicinal chemists, and pharmaceutical experts include big data, AI, ML, neural networks, quantitative structure-activity relationship modeling, and others, he states.

“The traditional approach to drug formulation development relies on iterative trial and error, requiring a large number of resource-intensive and time-consuming 

 experiments,” Kane says. “ML-directed drug formulation development offers unparalleled opportunities to fast-track development efforts, uncover new materials and innovative formulations, and generate new knowledge in drug formulation science (3).”

At the dosage form level, advancements are allowing for more comprehensive data collection. For example, digital pills that feature ingestible sensors in an oral drug delivery dosage form will revolutionize diagnostics, clinical monitoring, data collection, and data analytics in the healthcare industry, Kane emphasizes. “Smart medicines involve a target applied directly to the medicine via a coating or ink, and a sensing device (a cell-phone application) is used to read the medicine and convert the signal into a digital format in a matter of seconds. With smart medicines, every dose becomes a basis for patient communication, engagement, and data generation,” he says. “The transition to smart medicines offers an enormous source of value creation to the pharmaceutical industry.”

It is important, however, to ensure the quality of the data being collected, warned Nguyen. When collecting data that will be used to build a library and then to train machines, for example, the data should conform to ALCOA+ [attributable, legible, contemporaneous, original, accurate, and additionally that it is complete, consistent, enduring, and available] guidance and should be unbiased, he explains.

“Good input and good process shall yield good output, otherwise, with less representative data the predictive model would misrepresent, and unintentionally skew toward an unwanted design space,” Nguyen says.

“Continuous manufacturing (CM) continues to be of interest for specific products by the emerging, mid-size and Big Pharma companies for one or more of the well-documented and proven reasons—reduced API usage from early to mid-stage development to commercialization, robust simplified formulation, scale-up efficiencies, speed to clinic and to market, supply chain flexibility, reduced cycle time, and potential reduced overall cost of supply while having a greater assurance of quality,” Kane asserts. “A CM process certainly changes the formulation strategies, as there will be far more controls and checks at critical processes as compared to a batch process that utilizes multi-unit operations. Selection of excipients and a process needs to be aligned with the continuous manufacturing equipment design and scale.”

Process analytical technology (PAT) tools, such as near infrared and Raman spectroscopy, are integral for continuous manufacturing programs, continues Kane. Additionally, to be able to expand the continuous solid dose program and bring customer programs to commercialization, it has been beneficial at Thermo Fisher Scientific to use real-time release—for finished product release testing—as well as predictive models and in-suite tools to support the required testing, he adds.

“Advanced continuous manufacturing approaches are often considered for mAbs [monoclonal antibodies], therapeutic proteins, or other biologics that are compatible with such a process,” states Nguyen. “[Advanced CM] is more challenging to adapt for cell therapies and less-standard modalities made through complex, smaller-scale processes.”

Across the board, however, demonstrating homogeneity in bulk drug substance and assurance of dose uniformity are key aspects of formulation and fill/finish, Nguyen points out. “From this perspective, CM and process intensification, while making much advancement in terms of drug substance upstream (cell culture) and downstream processing (purification), still faces such challenges that it is often decoupled from fill/finish operations. As a result, at the end of the process, bulk drug substance containers need to be stored and handled within the correct conditions and shipped to fill/finish sites to process as batches upon demand,” he says.

“For a product that requires only a single formulation and single strength, formulation considerations could be built in during the ultrafiltration/diafiltration (UF/DF) step and the finishing step to create formulated bulk material,” Nguyen continues. “Upon receiving at the fill/finish site, it would require pooling, blending, filtration, aseptic filling, and packing.”

When considering the quality requirements, as is the same with batch processing, the framework of CM should start with a patient-centric design, the target product profile, followed by CMC target profile, Nguyen states. “At each unit operation, risk needs to be evaluated, and the learnings carried over to the next steps to understand what can be further removed, polished, controlled, mitigated, or monitored,” he says. “Understanding the endpoint and requirements would help developers anticipate what shall be considered upfront to avoid costly correction or redevelopment later in a product’s lifecycle. Moving from early phase to late phase, as product and process knowledge are accumulated, the presumptive attributes and process parameters would be further refined as critical versus non-critical, or key versus non-key for a product and its process.”

“Digitization of operations, use of augmented and virtual reality, AI and ML, increased use of robotics, and using connected data systems to drive better quality and business decisions need to be actively pursued in many parts of the business,” asserts Kane.

Through digitization, it is possible to reduce the number of conditions that need to be performed in the design of experiment within formulation, Nguyen adds. “If a reliable predictive model can be built using a high-quality, diverse, and unbiased database, then that will drastically help improve formulation strategies in terms of time, cost, and likelihood of success, and would contribute to bringing drugs to patients more quickly.”

“Therefore, expertise and experience in utilization of the modeling tools is critical to bring speed and efficiency to clinical programs,” Kane summarizes. “In late-stage clinical studies, it is critical to adopt sound, science-based risk-assessment and risk-mitigation strategies to optimize formulations and process of manufacture.”

1. I. Lloyd, “Pharma R&D Annual Review 2022: Navigating the Landscape,” White Paper, Citeline Informa Pharma Intelligence (March 2022).
2. Research and Markets, 

Global Formulation Development Outsourcing Market Size, Share and Trends Analysis Report by Service (Preformulation, Formulation Development), by Formulation (Oral, Injectable), by Therapeutic Area, by Region, and Segment Forecasts, 2022–2030

, Market Report (June 2022).
3. P. Bannigan et al., 

Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.


Vol. 46, No. 10
October 2022
Pages: 16–19

When referring to this article, please cite it as F. Thomas, “Adopting Smart Development Strategies,” 

External expertise is beneficial in helping companies select the right tools at the right stages of development to ensure success.

Pramote Cholayudth previously was the managing director of the Professional Conference Center, Ltd. He currently is a validation consultant to Biolab Co., Ltd., in Thailand. He is the founder and manager of PM consult, cpramote2000@yahoo.com.

Two typical tests for oral solid dosage forms are dissolution and content uniformity. In continued process verification (CPV), there must be some kind of evaluation such that the validity of the two test data within the same CPV batch is demonstrated. One such evaluation tool is control charting using F data (i.e., F chart) to demonstrate that the consistency between dissolution and CU data is under statistical control.

Submitted: July 25, 2022
Accepted: Aug. 19, 2022

Pramote Cholayudth, cpramote2000@yahoo.com, is the founder and manager of PM Consult. He is an industrial pharmacist with more than 40 years of experience. He is a guest speaker on process validation to industrial pharmaceutical scientists organized by Thailand’s FDA.


Volume 46, Number 10
October 2022
Pages: 44–47

When referring to this article, please cite it as P. Cholayudth, " Application of F Charts in Continued Process Verification of OSD Forms," 

This article introduces a control chart technique using F statistic for continued process verification of oral solid dosage forms.

Application of F Charts in Continued Process Verification of OSD Forms

Traditional drug development is costly and time-consuming, with many hours, days, and years spent researching and developing novel chemical entities that, for the most part, will likely fail to get to the commercial finishing line. Repurposing a drug can offer companies an approach to drug development that is much more time- and cost-efficient and offers a higher chance of success. According to research, 30% of repurposed drugs gain approval, which is three times higher than the rate for new drugs (1).

There are three main strategies to repurposing a drug product: determining a novel therapeutic indication for an already known drug (repositioning); developing a new formulation of a drug product (reformulation); and combining two or more drugs that were already being used as single drug products (combination) (2). Despite the various benefits of repurposing existing drug products can offer, each strategy also has certain challenges to overcome that can act as a deterrent to developers.

“Reformulation can be used very effectively to develop improved medicines and treatment options for patients,” confirms Jan Jezek, chief scientific officer of Arecor. “For example, creative formulation can be used to improve the pharmacodynamics and pharmacokinetics of a drug.” Highlighting a specific case of creative formulation, Jezek points to the development of a novel formulation of insulin that has is being developed by Arecor, which accelerates the drug’s absorption post-injection, leading to improved glycemic control.

“Another example benefit of reformulation is to convert a lyophilized powder medicine to stable liquid ready-to-use (RTU) product formats, which are becoming increasingly important to enable fast, safe, and effective treatment of patients,” Jezek continues. “Innovative formulation approaches can also lead to improvement in stability of small- and large-molecule products and enable their use outside the cold chain, which can significantly improve convenience of use.”

Balasubramaniam Jagdish, assistant vice-president, Formulation Development, Bengaluru Site, Recipharm, emphasizes that reformulation can be performed for several key reasons. “[Reformulation] can allow developers to improve the performance and patient centricity of an existing drug. For example, it may be done to create a version of an existing drug that is more convenient and easier to use for the patient, increasing quality of life or boosting adherence and, in turn, therapy success,” he says.

Additionally, Jagdish remarks that reformulation can be used to enhance solubility, to improve absorption, or to boost the stability of a drug product formulation. “In all cases, reformulation can save a considerable amount of time and financial resource compared with the discovery and development of an entirely new chemical entity,” he states.

Moreover, it is possible to use reformulation as a way of extending the line of an older drug product, Jagdish points out. “[Reformulation] offers an opportunity to change an excipient or evolve the manufacturing process to deliver marginal gains in performance or ensure compliance with new regulatory requirements,” he says. “Regardless of the reasons for the reformulation, assessment of the regulatory implications of reformulation is essential.”

First and foremost, Jagdish stresses that it is critical for companies to be aware of the regulatory requirements of the target geography of the reformulated drug product. “There is considerable variation in the regimes in each country, so pharmaceutical companies should evaluate their compliance needs on a case-by-case basis,” he says. “For example, the US Food and Drug Administration (FDA) has published its guidance for industry on Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route, which can help companies understand the regulatory requirements in the [United States]” (3).

For Jezek, considering the formulation excipients and whether those being used in the reformulated product are indeed approved for the intended use—administration route and desired dosage regimen—is critical. “[Whether or not the excipients are considered novel] impacts the complexity of development as it is necessary to justify the use of the excipients and to demonstrate the safety of the excipients required. Novel excipients will carry a higher regulatory and development burden,” he specifies.

When approaching a reformulation strategy for a drug product, developers should define the target product profile at the outset, Jezek continues. “In other words, the formulation scientist needs to understand the desired stability and other requirements that the products must meet, such as specific impurity levels, to be approved by the regulatory authorities,” he says.

Reformulating an existing drug product can be a time- and cost-effective way of rejuvenating a product line while also making a therapeutic more patient-friendly. To find out more about how external expertise can help sponsor companies achieve success in reformulation strategies, 

 spoke with Jan Jezek, chief scientific officer of Arecor, and Balasubramaniam Jagdish, assistant vice-president, Formulation Development, Bengaluru Site, Recipharm.

 How might companies benefit from using a partner for reformulation tasks?

 An innovative formulation technology company, such as Arecor, can use its expertise, know-how, and technology to develop novel formulations of therapeutic medicines with enhanced properties, enabled by the formulation, which would otherwise not be possible. These enhancements can improve treatment options and outcomes for patients. The technology can be applied to a variety of new products in development to maximize their benefit for patients. However, the reformulation technology can also be applied to existing marketed products as part of life cycle management.

 Reformulations are often considered by big-brand pharmaceutical companies as a strategy for enhancing the lifecycle management of their patented product and to delay generic entry as far as possible. These companies often have many lead molecules to work upon, meaning it can be hard to find the capacity required for reformulation in-house. Working with a contract development and manufacturing organization (CDMO) partner can help them find that additional resource, enabling them to manage multiple reformulations simultaneously while freeing in-house capacity to focus on innovation.

For generic companies, reformulation gives them an advantage in terms of 505 b(2) filing. [FDA] 505 b2 approvals give additional exclusivity to a product. When applied to a reformulated drug, it can help to prevent generic entry until the expiry of the filing. As such, they keep development in-house, provided they have the internal capacity and infrastructure. However, if the generic company is reformulating to change excipient or manufacturing process, they may well prefer to outsource to a CDMO to provide the necessary expertise and infrastructure so they can concentrate on other projects.

After defining the target product profile, the developer needs to understand the degradation pathways that can potentially impact the stability of the drug product during storage, Jezek adds. Appropriate methods must be established so that any degradation pathways can be measured and understood. “Such methods are often referred to as stability‑indicating methods,” he notes.

“The last challenge, which is most critical for successful reformulation, is to be able to select the right combination of inactive ingredients that will collectively interact with the small- or large-molecule drug in a way that reduces the degradation rate and thus enables the desired product profile,” Jezek confirms.

According to Jagdish, the challenges that pharmaceutical companies need to overcome when approaching a reformulation project depend upon the type of reformulation they are undertaking. “For example, when developing a new formulation of a drug for the same indication, achieving bioequivalence for the new formulation with the existing one poses a significant challenge, because it is no longer a like-for-like comparison,” he asserts.

“Reformulation can also be considered to reduce the size of the dose of a medication, to improve safety profile and patient compliance,” Jagdish continues. “Again, in this case, there is a need to demonstrate that the efficacy of the lower dose is equivalent to that of the already clinically proven and approved higher dose.”

Providing another example, Jagdish points out that when developing a fixed-dose combination therapy from two independently approved drugs, demonstration of the bioequivalence can also be tricky. “Here, in addition to maintaining bioequivalence with the two existing single-dose products, companies have to ensure the compatibility of the two drugs when in the same formulation,” he says.

When reformulating large molecules, Jagdish emphasizes that additional challenges—when compared with those facing small-molecule formulators—need to be addressed. Challenges such as solubility, absorption, and stability, he specifies.

Because large molecules are commonly administered via intravenous injection, it can be desirable and more patient-friendly to reformulate a drug product to be administered in an alternative way. “Often the focus of a change in the route of administration for a biological medicine is to enable a change from a time-intensive intravenous administration to a single subcutaneous injection,” Jezek confirms. “This [change] requires developing a highly concentrated formulation of the product that can be delivered via a small volume in a single injection.”

However, by reducing the volume of injectable product, the viscosity can become problematic. “Challenges that need to be overcome in developing these high concentration formulations is high viscosity (which can make the product too difficult to inject) as well as the propensity of proteins to aggregate (resulting in the formation of particles, which are unacceptable in pharmaceutical compositions),” Jezek explains. “In addition, proteins are subject to chemical degradation such as hydrolytic cleavage or oxidation. Innovative approaches to formulation design are often required to overcome these challenges.”

Yet, there are relatively easier reformulation routes, such as updating the excipients or the manufacturing process to extend the product’s line, Jagdish states. “Reformulation in these cases often simply involve step changes in the production process or the preparation of ingredients to enhance product quality or to improve manufacturing efficiency,” he specifies. “New ingredients are not generally involved, reducing the number of challenges that need to be overcome.”

1. N. Sommerford, “Drug Repurposing Basics,” Blog, IQVIA, May 12, 2022.
2. S. Murteira, et al., 

Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route


Vol. 46, No. 10
October 2022
Pages: 30–31

There are many benefits of employing a reformulation strategy, but companies must also overcome a variety of challenges too.

Reformulating Success

Jennifer Markarian is manufacturing editor of BioPharm International.

The National Institute for Bioprocessing Research and Training (NIBRT) assessed the extractables and leachables (E&L) in 34 single-use bags used for cell cultivation in biopharmaceutical manufacturing; the bags were from different manufacturers and represented eight different types of multilayer films (1). Bags were extracted according to the BioPhorum Operations Group guidelines (2), and the extracts were analyzed using high-resolution mass spectrometry (HRMS) methods. NIBRT researchers found that polymer type and manufacturing date were the largest contributors to the different E&L profiles found in the different bags. The researchers noted that the types of additives or manufacturing processes for the plastic bags could change, which could change the nature of E&L.

NIBRT researchers have also implemented a method based on accelerated solvent extraction (ASE) and HRMS for plastic raw material extractables characterization, which is a crucial first step in assessing suitability for an intended use (3). The use of ASE for material selection follows industry best practices for conducting controlled extraction studies.

3. N. Dorival-García et al., Talanta 219, 121198 (2020).

Extractables and leachables (E&L) must be analyzed for any product-contact material to determine the risk of leachable compounds contaminating a drug product. Container-closure systems, which contact the drug product during long-term storage, are often higher risk than process equipment, which has a short product-contact time. Processing equipment is not exempt, however. As polymer single-use systems (SUS) are increasingly being used in 
biopharmaceutical manufacturing, there is a growing need to analyze E&L of this equipment. Industry organizations and consortiums have worked
to standardize analysis protocols that can be used throughout the supply chain. Standard methods facilitate comparison between suppliers.

BioPhorum, for example, first published a standardized extractables protocol in 2014, which was updated in 2020 (1). Because the organization was previously known as BioPhorum Operations Group (BPOG), the protocol is often called the BPOG protocol. SUS suppliers can use the protocol to measure the extractables in representative components. The purpose of the extractables testing information package, says BioPhorum, is “to allow the SUS end-user to rigorously estimate the types and amounts of leachables that could be generated by the SUS component during its intended use” (1).

Another set of standard methods was recently published in the 

General Chapter <665> Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products was published in 2022 (2), but the date for it to come into effect was postponed to 2026. 

 accompanying procedural chapter <1665> became official on May 1, 2022 (3).

 documents is the use of risk assessment for end-users to determine the risk level of a component in a particular process. The analysis method depends on this risk level.

The International Council for Harmonisation (ICH) is working on a document related to E&L testing. A final concept paper for ICH Q3E was published in 2020 (4). Industry experts say that questions about how this upcoming ICH guidance will align with the USP and BioPhorum documents are yet to be answered.

The Extractables and Leachables Safety Information Exchange (ELSIE) Consortium, made up of 33 biopharma/medical device companies, is also active in this area and aims to provide expert input to efforts such as 

new chapter and the in-progress ICH Q3E, through working groups and formal commenting processes as well as white papers, workshops, and other public meetings. “ELSIE provides a collaborative environment where member companies can discuss and benchmark the approaches that companies are taking,” explains Lee Nagao, senior director of science, regulation, and policy at the ELSIE Secretariat. Harmonized guidelines or compendial chapters are crucial, because without them, “regulatory expectations can vary depending on the health authority and the experience of the specific [biologics license application] reviewer,” says Nagao.

Standardized protocols help in setting baselines and comparing differences. For end-users of SUS, standard protocols facilitate “like-for-like assessments between each supplier’s single-use technology (SUT)
products and components,” says Dan Rosen, vice-president and general manager of bioproduction at Thermo Fisher Scientific.

Extractables testing of the materials or components is used to identify which leachables might come from the material under standard conditions and in a simulation study. A challenge, however, is that different leachables could be formed during sterilization, storage, or use.

“Key challenges in characterizing E&Ls include identifying unknown molecules that arise during primary sterilization of the SUT products,” says Rosen.

The response of materials to commonly used gamma irradiation is generally well established, but due to limitations in capacity for gamma-radiation sterilization, X-ray sterilization is being considered as an alternative (5). Current theories suggest that the E&L profile should be similar after X-ray or gamma sterilization, but it is important to perform extractables testing, says the Bio-Process Systems Alliance (BPSA).

BPSA published a guide for E&L in cell and gene therapies (CGT) in July 2020 (6) to support companies developing manufacturing lines for scale up or scale out. “Since CGT was a new modality, the drug developers were almost exclusively using single-use components for economic, safety, and technical performance. This [situation] led to a need for BPSA to help coordinate a guide to assist developers on appropriate choice of materials and components for their process development,” says Brendan Lucey, chair of BPSA’s CGT Committee. CGT processes differ from other biopharma manufacturing using SUS because in classical biopharma, process-related impurities, including process-equipment related leachables, are removed in the downstream purification process. In CGT processes, however, there may be washing steps, but not the same kind of downstream purification. Because of this process set-up and the variety of contact surfaces and contact times, E&L testing to assess and then control leachables is crucial, concluded BPSA (6). The type of polymers used in SUS for CGT manufacturing also differs from classical biopharmaceutical manufacturing. In particular, the report noted that polyvinyl chloride (PVC) polymer may be used in transfer bags and tubing sets in CGT collection, processing, and storage. Because flexible PVC typically contains plasticizers and other additives that are not present in other polymers used in SUS, leachables from these additives should be considered (6).

The rapid pace of change in guidelines has required a quick response by contract labs to create experiment designs that are compliant, says Dujuan Lu, manager and global lead of extractable and leachable testing at SGS Health Science. SGS labs are following the 

 <1665> procedures, because these have been official since May 2022, but the postponement of 

 <665>’s official date is helpful for the industry, Lu says. “The transition period gives pharma/biopharma manufacturers time to requalify as needed. We are seeing lots of activity now because clients want to be ready for 2026,” she explains.

 and BioPhorum protocols, says Lu, who explains that the two differ slightly in recommended solvents for acid and base conditions. Lu points out that 

 considers the different solvents for acid conditions to be equivalent; for the base conditions, 

 recommends choosing the alkaline solvent depending on the specific process pH value.

Design of extraction studies for single-use components is complicated by multi-component assemblies and complex geometries. “The recommended ratio of surface area to volume is 6 cm2/mL. Calculating the surface area is straightforward for a tube or a bag, but can be challenging for a connector or valve, for example,” explains Lu. In designing an extraction study for single-use filters, both the housing and the membrane must be evaluated. “The procedure depends on the shape. For a capsule filter, for example, we can fill the filter with solvent and cap the ends. For a smaller filter, we might need to remove the membrane and submerge it in solvent,” explains Lu.

Because many different polymeric materials are used to construct single-use components, the extractable profile is complex and multiple analytical techniques are needed to identify and quantify the compounds, says Lu. She explains that volatile organic compounds can be measured with headspace gas chromatography (HS-GC) coupled with high-resolution mass spectrometry (HRMS) or flame ionization detection (FID). Semi-volatile organic compounds can be measured with direct sample injection in GC-HRMS/FID. Non-volatile organic compounds can be measured with ultra high-performance liquid chromatography (UHPLC) coupled with HRMS and a photodiode-array detector. “Unknown identifications are crucial for the extractables testing, so high-resolution mass spectrometers are recommended for both GC and LC testing,” says Lu. She adds that elemental impurities can be measured with inductively coupled plasma-mass spectrometry.

Calculating the analytical evaluation threshold (AET) for processing equipment is another challenge. “The AET is set up based on the toxicology concerns; above [the AET], analytes need to be identified and quantified for health risk assessment,” explains Lu. “The instrument detection limits need to be at, or lower than, the AET to make sure all compounds above the AET can be detected. The process equipment AET is typically calculated based on the final product AET by applying the dilution factor during the process. The difference between the batch size and the extraction stoichiometry during the extractable study will be considered during the calculation.”

To perform risk assessment, it is crucial to have a good understanding of the manufacturing process. “[Understanding] any clearance, concentration, or dilution steps [is] critical, particularly to help narrow down the number of materials requiring in-depth characterization,” says Nagao.

Questions remain, says Nagao, about what point in the process a risk assessment should begin, how to define component risk, and what the minimum data would be to qualify low-risk components. “For example, gaskets, seals, or connectors used upstream of a [filtration] step will be inherently low risk and unlikely to contribute significantly to the leachables profile. Is it necessary, then, to fully characterize the extractables profile? This [type of question] is where a harmonized guidance that is implemented across the globe, perhaps based on risk-management principles, would be helpful,” Nagao suggests.

BioPhorum Best Practices Guide for Extractables Testing of Polymeric Single-Use Components Used in Biopharmaceutical Manufacturing 

2. USP, General Chapter <665>, “Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products,” 

3. USP, General Chapter <1665>, “Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products,” 

Final Concept Paper ICH Q3E: Guideline for Extractables and Leachables

X-Ray Sterilization of Single-Use Bioprocess Equipment, Part 1: Industry Need, Requirements, and Risk Evaluation

Extractables/Leachables Considerations for Cell & Gene Therapy Drug Production Development

Jennifer Markarian is manufacturing reporter for 


Vol. 46, No. 9
October 2022
Pages: 48-51

When referring to this article, please cite it as J. Markarian, "Analyzing Extractables and Leachables in Single-Use Systems," 

Standardized risk assessment and analysis protocols facilitate the comparison of processing equipment components. 

Blow-fill-seal (BFS) technology presents several advantages over other aseptic techniques, such as flexibility in packaging design, the ability to ensure a high level of sterility assurance, and maintaining low costs (1). In addition, the use of BFS technology limits human involvement, which further improves the level of sterility assurance by removing a significant contamination factor from the process entirely. The technology enhances the ability to form the container and closure during the packaging process, which allows for a more custom design of the container. BFS technology can thus be used to meet specific needs and improve container ease-of-use (1). In order to learn more on the logistics, benefits, and potential drawbacks of BFS technology, 

spoke with Waiken Wong, PhD, manager of development engineering at Woodstock Sterile Solutions, an Illinois-based provider of sterile development and commercial solutions.

Can you please explain what BFS packaging technology is and how it applies to bio/pharmaceutical manufacturing?

 Blow-fill-seal packaging technology is a method where the container is formed, filled with product, and then sealed in a sterile environment. What comes out is a fully sterile finished product. It’s a good presentation for many drugs, including biopharmaceuticals. Sterility is critical for biologics and many other drugs because it prevents microbial contaminants in products.

 What benefits does BFS packaging technology offer, compared to traditional glass vial manufacturing?

There is far less human intervention when BFS packaging [is employed], and humans are the biggest cause of contamination. Contamination can have a negative impact on microbial sterility. Because the BFS process happens completely inside the cabinet of the machine, there is little chance for external contamination and problems with sterility. With BFS, the environment inside the cabinet of the machine is continually monitored for viable and non-viable particulate, and there is a constant, positive pressure shower of high-efficiency particulate air (HEPA)-filtered air that covers the filling section of the BFS machine. With those controls in place, along with the automation of the BFS machine, the operator doesn’t have to be in the room. It is designed to operate on its own, without any human intervention. An additional benefit is that there are fewer components compared to glass vials, so you don’t have to deal with stoppers, crimp tops, and other closures. There are no equivalent cleaning steps to the ones glass vials need to go through. There are also no equivalent treatment steps to the ones glass vials need to go through, such as depyrogenation. Raw resin is used; it goes directly into the BFS machine and is molded directly. So, there are fewer components, fewer steps in the actual manufacturing process, and there is far less human interaction.

Can you explain cold temperature BFS and its benefits compared to regular BFS?

 Cold temperature BFS requires implementing a combination of techniques all together in one manufacturing process to help control the amount of heat that is imparted onto a drug product. During the typical BFS process, there is naturally quite a bit of heat, because raw resin is being melted to make bottles. The bottles themselves also need to be warm throughout the process so that the containers can be sealed shut in the final step. There is latent heat, but Woodstock Sterile Solutions has found ways to control that heat so that biomolecules can survive with no impact through the manufacturing process. With a cold BFS process, there are additional drug products that you can package, since you do not have to worry about drugs that are thermally sensitive. Many biomolecules are heat sensitive, and there are many proteins that can denature or degrade with heat, so traditionally, the biopharma industry has stayed away from BFS and stuck with glass—a tried-and-true option. Having this collection of manufacturing steps expands what is possible for drug products in blow-fill-seal.

What are some key considerations when implementing BFS technology?

One important consideration is understanding the drug product’s compatibility/interactions with plastic. Before opting for BFS, there needs to be an understanding of how the product interacts with plastic—if there are concerns about adsorption or absorption, for example. Additionally, plastic containers are permeable in a way that glass is not, and it is critical to understand if that will have an impact on the product throughout its shelf life. That being said, there are ways to counter permeation, whether it is water vapor moving out or oxygen moving in, in order to maintain the quality of the product inside. Lastly, although BFS can be used to fill liquids that are highly viscous, if the product is more ointment-like, then it will be difficult to fill using BFS. That makes it harder to push through the piping and other parts of the system, but the technology can handle a wide range of viscosities.

What are the drawbacks of using BFS technology, if any?

The permeability mentioned earlier is one challenge, as are the material interactions I noted. Also, there are challenges with heat and thermally sensitive products, but those can be addressed using cold BFS.

What are the regulatory and compliance considerations when using BFS, if any?

 FDA considers BFS as an advanced aseptic manufacturing technique, recognizing its ability to produce sterile drug products reliably while also ensuring a high level of quality for patients. The industry is held to the same standards, as all drug packaging technologies are, to ensure product safety and quality.

Pharmaceutical Technology, Pharmaceutical Technology Europe


Vol. 46, No. 9
October 2022
Pages: 37, 51

When referring to this article, please cite it as A. Leon, "Improving Sterility Using Blow-Fill-Seal Technology," 

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Electrochemistry offers many strategic advantages for increasing the sustainability and efficiency of small-molecule synthesis. It also has the potential to enable the creation of molecules not accessible using more traditional chemistry. As a consequence, interest in this technology is increasing in both academia and industry. Three researchers having a strong impact in this area through their independent work and collaborations with industry include Phil Baran of The Scripps Research Institute (1), Siegfried Waldvogel of Johannes Gutenberg University in Mainz, Germany (2), and Song Lin at Cornell University (vide infra).While its use in medicinal chemistry and drug discovery has been increasing, implementing these reactions at large scale under good manufacturing practice (GMP) conditions has been challenging.