Digital Transformation in Pharma Manufacturing

Patent Cliff Deals, Tariff Pressures, and the In Vivo Cell Therapy Bet

Behind the Headlines, Episode 23

ICH Q12 and Post-Approval Changes

Speed, Flexibility Top Large-Molecule Manufacturing Trends

Drug Digest July 2025

Key Insights from Industry Survey Results

Bio/Pharma's Tariff Response

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

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The careful design and development of formulated oral drug products are key to ensuring patient acceptability and compliance for achieving the desired clinical outcomes. Many APIs are extremely bitter or have other aversive attributes that can make developing palatable drug products challenging, notes Nazim Kanji, executive director of pediatric services with Quotient Sciences. Several factors can influence palatability, including the chemical structure of the drug substance and the finished medicinal product formulation, as well as the excipients used. “Undesirable taste is a common problem seen in medicines spanning all therapeutic areas, from antibiotics and painkillers to antihistamines and decongestants,” Kanji notes.

Taste masking of oral dosage forms is, therefore, an essential component of formulation development. A one-size-fits-all approach is not available, however, according to Ashish A. Joshi, pharma technical and business manager with BASF Pharma Solutions. Taste-masking strategies, he observes, must almost always be tailored to various aspects, such as the degree of inherent bitterness of the drug, the type of dosage form, the patient age-group, and whether the final formulation is in a solid or liquid form.

As the percentage of drug substances in development suffering from bitter tastes has increased and many new formulation and delivery strategies have been introduced to increase patient convenience and compliance, taste-masking technology has therefore evolved. In addition to more traditional approaches such as the use of barrier coatings, solid dispersions, and the addition of sweeteners and flavoring agents, formulators are leveraging newer strategies such as liposomes, various forms of complexation, co-crystal and pro-drug formation, emulsification, and microsphere and encapsulation technologies.

As part of developing palatable pediatric and patient-centric drug products such as solutions, suspensions, and orally disintegrating tablets (ODT), several recognized approaches can be taken to mitigate the poor taste of these APIs. “The most common approaches include using a combination of flavors and sweeteners to mask a bitter taste or barrier coatings to prevent the release of API from the drug product into the buccal cavity prior to the dose being swallowed,” comments Kanji.

Some advances in taste-masking technology are improving on these basic approaches. Researchers are, for instance, exploring methods to enhance both the perception and physicochemical stability of long-acting flavors through encapsulation and complexation techniques, according to Joao Marcos Assis, global technical marketing manager at BASF Pharma Solutions. Joshi adds that certain zinc salts have also demonstrated the ability to mask bitter taste effectively.

Improvements in pH-dependent barrier film coatings, meanwhile, have helped to overcome the coating inefficiencies for fine (small particle size) drug substances that require extended processing times due to their large surface areas. For these APIs, additional steps or approaches such as drug granulation to increase particle size or drug layering in inert pellets, can be used, Assis observes.

Lipids and insoluble polymers such as stearic acid, ethyl cellulose, and carnauba wax, when used in combination with surfactants, have also been shown to be promising as effective taste-masking approaches for drug particles. “These hydrophobic materials have low solubility in the mouth, contributing to improved taste-masking properties,” Joshi explains. He does caution, though, that it is important to be aware that use of lipid coatings may result in changes in a drug substance’s release profile, thus potentially impacting drug bioavailability.

Reverse-enteric polymers have become increasingly attractive as taste-masking polymers due to their pH-dependent solubility; they do not dissolve in the mouth at salivary pH, but once exposed to the acidic pH of the stomach, dissolve immediately to release the drug substance.

When these types of polymers are employed, the coating composition and level must be carefully balanced to prevent drug release during the residence time in the buccal cavity (e.g., up to 30 seconds for orally disintegrating tablets) while still allowing adequate drug release in the gastrointestinal tract to ensure that pharmacokinetic (PK) performance is not compromised, according to Kanji. “Realizing this balance can be a challenging prospect and may not be accurately predicted by in vitro dissolution testing,” he observes.

One example noted by Assis is a copolymer of methyl methacrylate (MMA) and diethylaminoethyl methacrylate (DEAEMA), which exhibits a lipophilic characteristic and does not dissolve at neutral to basic pH due to the amino functional group. “This lipophilic quality is very beneficial to the process [because] it reduces the required coating level for taste-masking purposes and provides moisture protection for sensitive drugs,” he observes. With these attributes, the drug substance becomes more suitable for liquid taste-masked formulations, where well-coated particles can be suspended in a neutral pH liquid, enabling the creation of a taste-masked suspension.

In the dry-powder form, water-insoluble matrices have been used effectively in melt-granulation processes, Joshi adds. During extrusion, the polymer covers the drug substance and forms a stable barrier layer once the granules are cooled. “The key advantage of this process is that it does not use any water or solvents and thus achieves efficient taste-masking of a moisture-sensitive drug substance while minimizing its possible degradation due to exposure to an aqueous or organic coating process,” he comments.

Another benefit to melt-granulation is the reduced process time compared to film coating, according to Assis. It can also be implemented as a continuous process, he notes. Reverse-enteric polymers in the dry state may also be suitable for the development of hot-melt extrusion formulations, allowing the production of taste-masked amorphous solid dispersions with improved solubility and taste, Assis remarks.

Using a mixture of water-soluble and insoluble polymers represents another newer strategy. “Tailoring the ratio of a polyvinyl acetate (PVAc)-based water-insoluble polymer and a water-soluble pore former such as a polyvinyl alcohol-polyethylene glycol (PVA-PEG) copolymer in a barrier coating allows efficient taste-masking to be achieved without significantly altering the release profile of the formulation,” Joshi explains.

The assessment and optimization of the polymer coating can be efficiently undertaken by integrating drug product formulation development and manufacturing with clinical testing activities, says Kanji. Quotient Sciences, for instance, uses a proprietary drug-development platform that enables drug products to be manufactured, released, and dosed in healthy subjects in a matter of days so that compositions can be optimized based on emerging clinical data. In addition to PK data, each formulation’s palatability attributes (e.g., bitterness, mouthfeel, grittiness, and aftertaste) can also be assessed as part of the same study, Kanji adds.

Following development of the taste-masked dosage form, confirmation of acceptability is achieved via palatability assessment of the drug product, thereby providing assurance that poor taste will not impact patient acceptability and compliance, Kanji concludes.

Lipid excipients are also being explored as encapsulating agents. One example highlighted by Joshi involves dispersing the drug substance in molten stearic acid or glycerol monostearate followed by atomization in a cold environment using a melt-congealing microencapsulation process. “This approach is particularly useful when the API is both extremely bitter and highly sensitive to moisture because it allows for effective taste-masking without the use of a typical aqueous barrier coating,” he contends.

Masking the taste of highly bitter drug substances in liquid dosage forms (solutions or suspensions) remains a significant challenge. Despite advances, effective taste masking can still be difficult when a drug substance has multiple taste and/or sensorial attributes (e.g., bitter, metallic, burning sensation), according to Kanji. This situation is particularly true for liquid formulations, which typically rely on the use of flavors and sweeteners for taste masking, he notes. Barrier coatings may also lose their effectiveness over the shelf-life of the product due to continuous exposure of the API to water, Joshi adds.

One new solution is to use micelle-forming surfactants, liposomes, or cyclodextrins to protect the drug substance. “For instance, in an aqueous environment,” Joshi comments, “certain surfactants and poloxamers form micelles that can entrap the drug substance, forming transient inclusion complexes, thus shielding it from the tastebuds and effectively masking its taste. This approach, he observes, also has potential for use in other dosage forms, such as gummies.

The use of water-in-oil (W/O) emulsions for taste masking of soluble APIs is another promising approach for liquid formulations, according to Assis. “In this case, the drug substance is effectively encapsulated within the water phase, which is surrounded by the continuous oil phase, preventing it from coming in direct contact with the taste buds and thus masking unpleasant tastes such as bitterness,” he says.

The water-soluble API is dissolved in the aqueous phase. The continuous phase comprises an oil with an acceptable taste profile, with medium-chain triglycerides (MCTs) being of particular interest, as well as surfactants with both low and high hydrophilic–lipophilic balances (HLBs) as the emulsifiers, Assis observes. He notes that polyoxyl 40 hydrogenated castor oil with a high HLB of approximately 14 to 16 is recommended for solutions and suspensions because, unlike other emulsifiers, it has a more pleasant taste. Additionally, glycerol monostearate type II (mono- and di-glycerides) is an excellent alternative as a co-emulsifier due its low HLB value of approximately 3.8.

The water phase is dispersed within the continuous oil phase, and the resulting O/W emulsion has the drug substance “hidden” within the emulsion droplets, which act as a barrier between the API and the taste receptors, Assis says. The oil phase surrounding the water droplets, meanwhile, prevents release of the drug substance while it is in the mouth; release occurs only once emulsification and absorption take place in the gastrointestinal tract.

Solutions for high drug-loading formulations

One important trend in oral dosage drugs is development of high-drug-loading formulations. “High-dose drugs in solids can be very tricky and demand better approaches to improve their taste profiles,” Joshi says. For instance, he notes, traditional barrier coatings can be challenging as long coating processing times are often required to achieve the desired level of masking.

One alternative is to use a dual-granulation coating approach to establish a barrier coating. “In this process,” explains Joshi, “the coating polymer not only covers the API and excipients, but also acts as a binder that enables formation of larger granules. The result is effective taste masking combined with improved flowability and compressibility of the drug product.” It is necessary, though, to use appropriate cushioning agents/plasticizers to maintain the integrity of the polymer following compression into a tablet. Certain methacrylic acid polymers can be effectively used in this application.

Development of additives for oral dosage drugs that block the receptors in the mouth that perceive bitterness has been a goal for many years. Taste buds elicit taste responses using G-protein coupled receptors (GPCR) or ion-channel receptors. Modulating their responses using compounds that block these receptors would be an effective means of eliminating the perception of specific tastes, according to Joshi.

This approach remains challenging, however. Such compounds need to be safe and provide transient and reversible modulation so that a patient’s taste perception is not affected for a long time after consuming the drug, Joshi says. In addition, there are at least 25 different, highly genetically diverse bitter taste receptors, and the drug substance-taste receptor pathway is not always known, Assis observes. Despite these challenges, a few specific compounds referred to as bitter blockers have been developed that interfere with the taste transduction process, at least to some degree, by inhibiting the taste cascade (interrupting the GPCR signal cascade), says Assis.

A few other approaches are also being explored. For instance, the API, which typically exists as a salt of some kind, can be converted into a more palatable compound, such as a prodrug, freebase, or different salt, according to Assis. It is necessary when using this strategy, however, to carefully consider the formulation development time and to assess any potential changes in pharmacokinetics.

Finally, complexing agents like ion-exchange resins and cyclodextrins can be used to prevent interaction of the API with bitter receptors. When using these approaches, Assis emphasizes the importance of considering factors such as the potential for drug-resin dissociation and the amount of cyclodextrin needed, respectively, as these factors may impact dosage size and costs. Cyclodextrin, for instance, can not only be very costly, but also may need to be used in a high quantity to ensure effective complexation with the drug substance at the molecular level.

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology®.

®
Vol. 49, No. 1
January/February 2025
Pages: 17–19

When referring to this article, please cite it as Challener, C.A. Evolving Approaches to Taste Masking. 

Articles

Increasing API and formulation complexity and new delivery strategies are driving innovations in taste-masking.

Evolving Approaches to Taste Masking 

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

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Belgium-based Ardena announced on Feb. 4, 2025 that it had successfully completed the acquisition of a state-of-the-art drug product manufacturing facility from Catalent. The facility is located in Somerset, NJ, in the United States, according to an Ardena press release (1).

Ardena, a pharmaceutical contract development and manufacturing organization (CDMO) and bioanalytical contract research organization, said in the release that the transaction furthers the company’s strategic expansion into North America, enhancing its suite of drug development services—particularly late-stage, small-scale commercial manufacturing of oral drug projects (1).

“This acquisition reflects our ongoing commitment to supporting biopharma innovators at every stage of drug development,” Jeremie Trochu, Ardena CEO, said in the press release. “The addition of the Somerset facility strengthens our ability to provide tailored, high-quality development and manufacturing solutions to our clients, while accelerating the international expansion of our fast-growing bioanalytical business.”

The New Jersey facility is comprised of more than 50,000 square feet of current good manufacturing practice space and is a recognized Center of Excellence for advanced oral dosage forms, according to the release (1).

Ardena intends to open a new bioanalytical lab on the Somerset site, as part of expanding services the company offers in that region in North America. Plans outlined in the press release call for the lab to have a 2500-square-foot capacity and provide advanced analytical testing services for both small and large molecules, including platforms supporting immunochemistry, liquid chromatography coupled to tandem mass spectrometry, flow cytometry, and quantitative polymerase chain reaction (1). There are currently more than 200 workers on staff at the Somerset site.

“We are thrilled to officially welcome the Somerset team into the Ardena family,” Trochu said. “Their deep scientific and technical expertise, their impeccable regulatory track record, and unwavering dedication to excellence align perfectly with our mission of helping clients bring life-changing treatments to patients quickly and efficiently.”

In October 2024, Ardena announced a strategic investment in two sites in the Netherlands: a brand-new bioanalytical laboratory at its Pivot Park facility, located in the city of Oss, as well as added capacity and new good laboratory practice capabilities at its Bioanalytical Center of Excellence in Assen (2). Meanwhile, at the beginning of 2025, Catalent was 

 as one of five CDMOs to watch in the year ahead (3).

Ardena’s acquisition of the Catalent site is the latest of several developments with facilities in New Jersey. In November 2024, 

Avantor opened a new, flagship Innovation Center

 in Bridgewater, NJ, a 60,000-square-foot, state-of-the-art R&D space (4). Previous to that, in July 2024, BeiGene opened an $800 million biologics manufacturing facility at the Princeton West Innovation Campus, in Hopewell, NJ, intended to be that company’s flagship facility in the US. The Hopewell site also houses a clinical R&D center (5).

The new bioanalytical lab being opened by Ardena at the Somerset site is expected to be operational by the third quarter of 2025, according to the Ardena press release (1).

1. Ardena. Ardena Completes Acquisition of Advanced Drug Product Manufacturing Facility from Catalent and Expands Bioanalytical Services in North America. Press Release. Feb. 6, 2025.
2. Ardena. Ardena Expands Bioanalytical Services in Europe. Press Release. Oct. 29, 2024.
3. Bigica, A. 

, Jan. 2, 2025.
4. Avantor. Avantor Opens New Bridgewater Innovation Center Focused on Solving Life Science’s Biggest Challenges. Press Release. Nov. 14, 2024.
5. BeiGene. BeiGene Opens Flagship US Biologics Manufacturing and Clinical R&D Facility, Continues Global Expansion to Deliver Medicines to More Patients Around the World. Press Release. July 23, 2024.

A new bioanalytical lab being opened by Ardena at the site is expected to be operational by the third quarter of 2025.

Ardena Acquires Catalent Drug Product Manufacturing Facility in New Jersey

Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

Leroy (Lee) Hood, MD, PhD discusses the potential impact of precision medicine, moving towards a more preventive health model, and the role of AI in health information.

Lee Hood on Precision Medicine and Shifting Towards Prevention

Leroy (Lee) Hood, MD, PhD, has developed a long list of paradigm-shifting scientific instruments that have made possible major advances in the biological and medical sciences.

We had a chance to speak with Hood at the 

 World Conference in Santa Clara, CA, where he discussed the practicalities of turning a disease care system into a health maintenance system and also his plans to develop a new peptide information-based pharmaceutical company.

"Data-driven health is at an enormous turning point, and it's going to trigger, I think, within less than a five-year period, the ability to analyze literally millions of people with regard to their genome and [transcriptome], and from that derive the optimization of wellness, healthy aging, and even the ability to detect and reverse diseases early,” Hood told 

Hood went on to talk about the real-world adoption of preventive medicine versus treatment of chronic disease, suggesting that uptake will likely need to come from an economic point-of-view, given that there would potentially be an enormous amount of savings by avoiding chronic disease.

Hood is president and co-founder of the Institute for Systems Biology. He is also senior vice president and chief science officer of Providence St. Joseph Health. He is one of only 15 individuals elected to all three US National Academies—the National Academy of Science, the National Academy of Engineering, and the National Academy of Medicine. Hood played a key role in founding or co-founding 15 different biotechnology companies, including Amgen, Applied Biosystems, Rosetta, and Arivale. Hood was the recipient of the 1987 Albert Lasker Basic Medical Research Award for translating the genetics of antibody diversity into explicit molecular terms.

Videos

Hood, a pioneer of systems biology and systems medicine, shared his personal interest in starting a new peptide-based, informational-driven pharmaceutical company that would address wellness and longevity.

Systems Biology Pioneer Lee Hood Talks Precision Medicine, AI in Health, and the Next Paradigm Shift 

 is senior director, Business Development and Alliance Management, TPU (Tjoapack US).

Pile of colorful medicine pills and capsules in blister packs | Image Credit: © ImageFlow - stock.adobe.com

The global biologics market is currently experiencing considerable growth, and it is set for even greater expansion in the near future. In 2022, the market was valued at $461.74 billion and is projected to reach $817.48 billion by 2032, growing at a compound annual growth rate (CAGR) of 8.5% (1). This growth is fueled by several factors, including an aging global population, increasing prevalence of chronic diseases, and advancements in biotechnology, including innovations in monoclonal antibodies and cell and gene therapies. In recent years, supportive regulatory frameworks in many countries have also helped accelerate the development and approval of biologics.

Current and future market trends in biologics packaging

The expansion of the biologics space has influenced growth in the packaging market, with continued innovation and favorable market conditions bound to propel this area’s further expansion. The following are some of the key trends driving this market:

 spoke with Mark Staiger, PhD, head of strategy at Schott Pharma, and Stefan Verheyden, global vice president, sales, pharma & biopharma solutions—injectables at Gerresheimer, about the outlook for pharma packaging in 2025.

What drug modalities is the market most focused on?

 The market is heavily focusing on GLP-1 agonists, [messenger] RNA-based drugs, and antibody-drug conjugates (ADCs). Significant investment and development are also seen in cell and gene therapies, CAR-Ts [chimeric antigen receptor T-cell therapies], and RNA [interference]. Personalized medicines are gaining traction, with companies like BioNTech making substantial progress.

 Almost half of newly approved drugs by FDA, EMA [European Medicines Agency] or other regulatory authorities are biologics. Depending on the therapeutic area and the route of administration, biologic drugs present several challenges to effective delivery, including the potential for elevated viscosity with increased concentration, larger volumes, and the sensitive nature of the biomolecules. The pharmaceutical primary packaging and the respective drug delivery devices must address these challenges and ensure drug stability through storage and transport as well as safe, precise drug delivery with patients’ comfort in mind. Our biologics customers often require smaller batch sizes and packaging solutions matching their high-end requirements, de-risking of fill/finish operations, and a significantly shortened time-to-market—all that, while ensuring patients’ safety.

What innovations or trends are you following when it comes to delivery formats?

 Finding new, innovative routes of administration with patients’ comfort in mind is an ongoing topic in the pharma industry. For the majority of our biologic customers, we still see injectables as the preferred route of administration. A clear trend toward drug delivery devices that enable home treatment, such as pens, auto-injectors, or on-body drug delivery devices is therefore noticeable.

 There is a noticeable shift toward subcutaneous administration, including large-volume injections, and ready-to-use (RTU) manufacturing. The number of biologics is steadily increasing, necessitating injectable formats. There is a continuous rise in demand for prefillable syringes (PFS), with a shift from vials to PFS and new approvals driving this trend.

Pharma companies seem to be transforming when it comes to packaging. What trends have you observed in areas including automation, smart packaging, regulatory compliance, and maintaining sterility?

 We see a clear trend in the industry toward deploying RTU or what Gerresheimer calls ‘ready-to-fill’ (RTF) formats in vials and cartridges, as we did some years ago with syringes. RTU/RTF packaging, like any pharmaceutical packaging, must meet rigorous standards. Pharma companies can mitigate the risk of contamination, maintain the highest quality, and thus ensure patient safety when deploying RTU/RTF packaging. And they can rely on robust validation and seamless regulatory approval of the primary packaging through comprehensive documentation and data packages. Industrialization at scale and highly automated processes are very important aspects for the whole industry. This includes primary packing and drug delivery systems like Gerresheimer is offering today. We have been using artificial intelligence (AI) technology in our own Gx G3 inspection systems for quality control for a number of years already, and we are constantly upgrading our automation and smart factory capabilities. Connected ‘smart’ packaging is certainly a very interesting trend in the industry and Gerresheimer offers a number of innovative solutions in this field.

 Automation is enhancing efficiency and reducing human error in packaging processes. Maintaining sterility is critical, especially with the rise of complex biologics and personalized medicines.

What major learnings from 2024 are going to help shape the year ahead?

 The rise of biologics will drive change in the industry. Beside the big pharma players, there are now a number of new, smaller players in the market with highly sophisticated drugs in the pipeline. We have one of the broadest portfolios in the industry: containment solutions in glass and plastics, as well as drug delivery devices, including our own intellectual property (IP) devices. And we amended our portfolio even further with the acquisition of Bormioli Pharma.

 The industry has learned the importance of supply chain resilience and localization to mitigate disruptions. There is a stronger emphasis on sustainability and eco-friendly packaging solutions. The need for digital transformation and data-driven decision-making has been highlighted, driving investments in AI and machine learning.

Increased demand for biosimilars and biobetters

. Biosimilars are expected to gain significant market share due to their lower cost than original biologics. The biosimilar market in the United States has experienced rapid growth, with 61 biosimilars approved across 17 unique biological molecules as of September 2024, and the global biosimilar market is estimated to reach $43.8 billion by the end of 2024 (2,3). Biobetters, which offer improved efficacy or safety profiles compared to original treatments, are also emerging as a promising trend. The biobetters market worldwide was valued at $65.7 billion in 2024 and is projected to reach $113.78 billion by 2031, growing at a CAGR of 8.2% (4). This rising demand is driving the need for specialized packaging solutions that ensure the stability of these products so that their efficacy is protected. By collaborating with experienced packaging partners, biosimilar and biobetter developers can leverage packaging as a strategic tool to enhance product differentiation, patient convenience, and overall success in this market.

. Advancements in genomics and proteomics are enabling the development of personalized biologics tailored to each patient’s genetic makeup. These treatments cater to niche patient groups with specific genetic or molecular markers, resulting in smaller batch sizes and increased complexity. Manufacturing and packaging need to adapt to handle smaller production runs efficiently, while logistics and supply chain management become more intricate due to diverse product variations. This is why these innovative therapies require flexible packaging and tailored solutions to accommodate diverse formats, fill volumes, and delivery devices to match specific patient needs. Packaging partners help biopharma companies use packaging as a strategic tool to support the successful development of personalized therapies.

Diversification of formulation approaches for a patient-centric approach

. Traditionally, biologics are often administered through injections, which can be inconvenient and painful for patients. To address this issue, researchers have been working on oral solid dosage (OSD) biologic formulations. They can be easily self-administered at home, eliminating the need for frequent visits to healthcare facilities for injections, saving time and reducing healthcare costs. Patients can take oral biologics anytime, anywhere, making integrating medication into their daily routines easier. OSD biologics can be designed with specialized delivery systems that protect the drug from degradation in the digestive system and enhance its absorption into the bloodstream. They can also be formulated for controlled release, delivering the medication gradually over time. This can lead to improved efficacy and reduced dosage frequency, helping minimize side effects and maintain a consistent therapeutic effect.
However, as the digestive system is a hostile environment for many biologics, not all are suitable for oral delivery. For those formulations, pre-filled syringes (PFS) and autoinjectors offer a user-friendly, safe, and convenient way of administration.

. The development of PFS and autoinjectors has simplified the injection process, making it easier for patients to self-administer biologics at home. Autoinjectors are designed for intuitive use, often requiring a single step to deliver the medication. This eliminates the complexity of traditional injections, which involve multiple steps like preparing the syringe, measuring the dose, and administering the injections. Autoinjectors feature ergonomic designs and clear instructions, making them easy to handle and operate, even for patients with limited dexterity or those unfamiliar with injections. The needle is hidden from view, and the injection is automated, which eliminates hesitation and anticipation that can contribute to needle-related anxiety and fear for patients uncomfortable with needles. Autoinjectors empower patients to self-administer their medication at home, reducing reliance on healthcare professionals and increasing independence.

Biologics development and packaging challenges and strategies

The complex nature of biologics, especially in OSD forms, PFS, and autoinjectors, presents unique challenges in their development, packaging, distribution, and delivery. Thankfully, ongoing innovations pave the way for more cost-effective production and patient-friendly administration, helping overcome these hurdles:

Biologics must remain stable during transport and storage, which is challenging due to their sensitivity to temperature, humidity, and light. Using materials with improved barrier properties, compatibility, and stability can enhance biologics’ performance and shelf life.

As PFS and autoinjectors require piercing the skin and bypassing the body’s natural defense systems, they must remain sterile right up to the point of administration to safeguard patient health.

Delivery systems face the same patient safety risks as other drug formats, especially regarding counterfeiting and tampering. Counterfeit drugs pose a danger to patients and undermine the security of the entire pharmaceutical supply chain. Regulations are in place to combat these threats, and packaging must adhere to these standards.

This is where secondary packaging comes in, providing additional protection and maximizing patient safety. In addition to aesthetics and helping with storage and transportation needs, secondary packaging helps preserve medicine integrity, enhance user convenience, and promote compliance and adherence. The right secondary packaging can include extra items like alcohol swabs, replacement needles, and clear instructions, making the process smoother for patients. With more people self-administering medications at home, child-resistant packaging becomes crucial to prevent accidental exposure and protect vulnerable patient groups, such as children or people with additional needs. Packaging partners, such as contract packaging organizations (CPOs) offering comprehensive services encompassing every aspect of the packaging process, can help ensure that biologics are safe and effective when administered.

Cost-effective biologics packaging solutions

The complexity of production and need for specialized facilities and equipment contribute to the current high cost of biologics. Working with a specialist CPO with experience in biologics offers advantages especially with diverse delivery methods. Specialized CPOs have expertise and infrastructure to handle biologics with care, ensuring integrity and efficacy. They can provide packaging solutions for biologics like pre-filled syringes, vials, and autoinjectors with appropriate temperature control and protection measures. CPOs are also well-versed in regulatory requirements and have established quality systems to ensure compliance, reducing risk of regulatory hurdles or delays. They can provide comprehensive validation documentation and support for packaging processes to ensure traceability and accountability.

Specialist CPOs also tend to stay abreast of all of the latest innovations in biologics packaging, such as drug delivery systems, and connected packaging technologies. Leveraging the knowledge of partners with expertise in innovative solutions can significantly reduce the cost of life-saving biologics, making them more accessible to healthcare systems as well as patients.

 (2022 to 2032). FMI–Future Market Insights, October 2022.
2. Samsung Bioepis. 

; 7th edition; Samsung Bioepis, September 2024.
3. Jha, S. N. 

(2024 to 2034). Fact.MR, June 2024.
4. Persistence Market Research. 

, Share, and Growth Forecast for 2024–2031. Persistence Market Research, September 2024.

Joe Compton is senior director, Business Development and Alliance Management, TPU (Tjoapack US).

®
Vol. 49, No. 1
January/February 2025
Pages: 23–25

When referring to this article, please cite it as Compton, J. Meeting Secondary Packaging Challenges of Innovative Delivery Systems for Biologics. 

Rapid market growth in biologics is helping the packaging market expand as well, but the complex nature of biologics and the desire for personalized therapies present unique hurdles to make packaging solutions cost-effective and safe for patients.

Meeting Secondary Packaging Challenges of Innovative Delivery Systems for Biologics

medical ampoules on a white background | Image Credit: ©vipman4 - stock.adobe.com

Demand for biosimilars is predicted to be expanding at a compound annual growth rate of nearly 18% from $9.4 billion in 2023 to $66.9 billion in 2028 (1). This strong growth reflects both higher acceptance and adoption rates and increasing numbers of approvals in multiple regions. By mid-2024, 40 biosimilars had been approved by FDA in the United States, with 25 products launched to the market. While this growth is attracting new entrants, hurdles to developing cost-effective and competitive biosimilars remain. In addition to the need to clearly demonstrate biosimilarity to reference branded products, manufacturing complexity, including scaling challenges, must be overcome.

Developing a biosimilar starts with characterization of the reference product. That information is used to develop a cell line capable of producing the desired product with comparable post-translational modifications and other important product quality attributes. Process development and optimization, including upstream cell culture and downstream purification comes next. Comprehensive product characterization, formulation development, fill/finish, final product release, and packaging round out the activities.

Successful scaling of upstream, downstream, and fill/finish operations while ensuring high yields of high-quality product that is comparable to the reference molecule requires consideration of many factors. The best approach is to use a holistic strategy that takes these factors into account from the outset.

Biosimilars approved to date are largely recombinant proteins and monoclonal antibodies. The past decade has witnessed a rapid rise in approvals of more complex modalities, such as bi- and tri-specific antibodies, fusion proteins, antibody-drug conjugates, and cell and gene therapies. In a recent analysis, the Boston Consulting Group estimated that new modalities represented $168 billion in pipeline value in 2024, an increase of 14% from 2023 (2). Many products in these new drug classes will soon lose patent protection, according to Patrick Meyer, global head of business development and alliance management at Rentschler Biopharma.

“These modalities present greater challenges in development, manufacturing, and analytics compared to conventional antibodies. They often necessitate advanced cell-line development techniques, additional downstream processing steps, and sophisticated formulation and analytical methods,” Meyer says. This greater complexity means that developing scalable processes is often more difficult. Importantly, the different modalities often have specific manufacturing requirements and thus require tailored and customized development, optimization, and scaling solutions.

Meyer therefore anticipates the growing diversity of modalities will further drive the need for contract development and manufacturing organizations (CDMOs) with the willingness and flexibility to adapt to new modalities and markets.

Although it may not seem like a specific scaling challenge, Meyer argues that the need to demonstrate biosimilarity is indeed a scaling challenge because of the nature of biologics. “Ensuring biosimilarity is a multifaceted challenge because biological systems are inherently variable, and thus achieving comparability with the reference product requires addressing several important aspects throughout the development and approval process,” he observes. One crucial success factor in biosimilar process scaling, therefore, is maintaining cell growth and productivity without introducing variability when transitioning from small-scale to large-scale bioreactors.

Achieving product and process consistency from batch to batch and across scales is a notable challenge as well. Realizing this goal must start at the cell-line development stage, where all differences from the reference product must be minimized, according to Meyer. Development of highly controlled processes is then essential to ensure stringent product quality as processes move through development phases and scale-up to commercial production. “Application of advanced analytical techniques that enable comprehensive comparison of the biosimilar’s critical quality attributes (CQAs) to those of the reference product is key,” he says. Biosimilar developers therefore must have experience and expertise in the analysis of biologics and access to well-equipped, state-of-the-art analytical labs.

Successful scale-up of biosimilar manufacturing processes also requires access to a stable supply chain affording consistent supply of high-quality raw materials and up-to-date knowledge of regulatory requirements, Meyer notes. Process scaling must also be practically achievable with reasonable process economics without compromising product quality.

Fortunately, the biopharmaceutical industry is, although conservative, also highly innovative, with constant investment in new technologies geared to improving productivity and quality while reducing risk and cost. Biosimilar developers have benefited from many recent advances.

Notable examples highlighted by Meyer include single-use bioreactors, which reduce the risk of cross-contamination across all scales; process analytical technology, which allows for real-time monitoring and control of critical process for streamlined scale-up and consistent performance from lab to commercial production; and innovations in cell-line development such as clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing and high-throughput screening, which have led to more productive and robust cell lines that, in turn, support streamlined scaling.

Of course, introduction of new technologies inevitably brings new sets of challenges. For instance, new technologies cannot be integrated into complex biomanufacturing frameworks without a transition period, according to Meyer, which can include, among other things, reconfiguration of systems and processes and significant training of personnel.

The implementation of new technology also brings about new challenges regarding data management and security, Meyer comments. “As biopharmaceutical manufacturing becomes more automated and digitized, it is the responsibility of CDMOs to ensure the safe and compliant handling of client and product data,” he contends.

Overall, Meyer concludes, it is essential to balance the benefits and challenges of innovative technologies to realize the successful and sustainable scale-up of biosimilar manufacturing processes.

Adopt a holistic strategy and platform processes

Given the multiple steps involved in biosimilar process development and scale-up, planning is essential and, according to Meyer, should take into account several key factors: process consistency and robustness, analytical excellence, and regulatory compliance.

At Rentschler Biopharma, success in biosimilar development hinges on providing robust processes that deliver material of highly comparable quality to the reference product, and doing so in a manner that supports submission timelines and ensures reliability, according to Meyer. That is achieved by taking a holistic approach and considering multiple factors from the outset of a biosimilar development project, including cell-line development, analytical needs, and regulatory compliance.

Establishing state-of-the-art cell lines that ensure biosimilarity early on and provide consistent performance across scales, including high titers to lower overall cost of goods, is crucial for biosimilar market success, observes Meyer. Use of state-of-the-art analytical techniques for thorough characterization and real-time monitoring of CQAs also supports successful process development and scaling. Rentschler Biopharma leverages these approaches combined with a quality-by-design approach, which enables early identification of CQAs and process parameters, leading to greater process understanding and the ability to develop robust, scalable processes. Meanwhile, use of scalable bioreactor systems, including multiple 2000-L and 3000-L bioreactors, makes it possible for Rentschler Biopharma to optimize conditions for large-scale production.

Staying abreast of regulatory changes is also crucial to ensure ongoing compliance. Rentschler Biopharma has a dedicated regulatory affairs team with extensive experience in biosimilar development that engages with regulatory authorities early on in the development process and maintains open communication to align on expectations and requirements, according to Meyer. “By anticipating additional data requests from regulators, we prepare comprehensive data packages in advance,” he adds.

Access to modular and flexible manufacturing facilities is also essential to ensuring easy scale-up of biosimilar processes given that each molecule has unique attributes and often requires custom solutions to ensure consistent performance across scales. With its sites in Laupheim, Germany, and Milford, Massachusetts, in the United States, which leverage similar equipment and manufacturing platforms across lab to commercial scale, for instance, Meyer notes that Rentschler Biopharma can provide tailored development and manufacturing support for many different biosimilar candidates from early to late-stage through commercialization.

MarketsandMarkets. Biosimilars Market by Drug Class (Drug Class (Monoclonal Antibodies (Adalimumab, Infliximab, Rituximab, Trastuzumab), Insulin, Erythropoietin, Anticoagulants. rhGH), Indication, Region–Global Forecast to 2028. Marketandmarkets.com (accessed Dec. 23, 2024). 

https://www.marketsandmarkets.com/Market-Reports/biosimilars-40.html

Chen, L.; Bush, B.; Brochu, M.; and King, G. New Drug Modalities 2024, Boston Consulting Group. BCG.com. Sept. 24, 2024. 

https://www.bcg.com/publications/2024/new-drug-modalities-report

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

®
Vol. 49, No. 1
January/February 2025
Pages: 20–22

When referring to this article, please cite it as Challener, C.A. Overcoming Biosimilar Scaling Challenges. 

Process consistency and robustness, analytical excellence, and regulatory compliance are essential in the scale-up of biosimilars.

Overcoming Biosimilar Scaling Challenges

Jabil, a St. Petersburg, Fla.-based company specializing in parenteral drug delivery and engineering, manufacturing, and supply chain solutions, announced it has successfully completed an acquisition of the contract development and manufacturing organization (CDMO) Pharmaceutics International, Inc. (Pii), which offers services in early stage, clinical, and commercial volume aseptic filling, lyophilization, and oral solid dose manufacturing (1).

A Feb. 4, 2025 press release from Jabil said the acquisition, which includes a 360,000-square-foot footprint across four sites on a Hunt Valley, Md. campus, would enhance Jabil’s development and commercial production of auto-injectors, pen injectors, inhalers, and on-body pumps (1).

“Jabil is very pleased to announce this acquisition. With our shared commitment to creating the best solutions possible for patients around the world, we believe the addition of Pii’s capabilities, supported by over 300 team members, is a perfect fit for Jabil and our customers,” James O’Gorman, vice president, Pharmaceutical Solutions at Jabil, said in the press release. “The convergence of Jabil’s and Pii’s complementary capabilities will bolster Jabil's customer offering and support business growth potential as we enter the CDMO market.”

“This acquisition marks an exciting new chapter for Pii,” John Fowler, Pii president and CEO, said in the release. “We look forward to leveraging Jabil’s extensive expertise to accelerate our mission of delivering best-in-class drug development and manufacturing solutions to our customers and ultimately the patients we serve.”

Pii had announced, in November 2024, a $3.6 million investment into its prefilled syringe services, specifically boosting the company’s advanced labeling, automated visual inspection, and fill/finish technology (2). The branded syringe labeler intended as part of the investment was, as of that announcement, to be fully operational in the first or early second half of 2025, but the press release from Jabil did not specify the status of that project.

Pii’s state-of-the-art good manufacturing practice facilities contain, according to the press release, more than 70 manufacturing rooms—among them containment suites to handle high-potency compounds and hormones, dedicated suites for oral products, specifically soft gels, and an aseptic facility for injectables (1).

“As the pace of healthcare innovation accelerates, pharmaceutical companies need partners who can help them scale rapidly with a focus on quality and safety,” said Mike Mahaz, senior vice president of Global Business Units, Healthcare, at Jabil, said in the release. “Jabil and Pii’s combined capabilities can provide end-to-end support for pharmaceutical customers, offering one safe, trusted pair of hands to simplify their entire supply chain.”

In developments related to parenterals, in December 2024, Eli Lilly and Company (Lilly) announced plans to expand a manufacturing facility in Kenosha County, Wis., that it had purchased earlier in 2024 (3). The $3 billion investment in that site is intended to extend Lilly’s global parenteral product manufacturing network to meet growing demand for its diabetes and obesity therapies, as well as future pipeline medicines across therapeutic areas. Lilly said at the time that it expected to add 750 highly skilled jobs to a current, approximately 100-person workforce at the Kenosha County location.

Meanwhile, elsewhere in Maryland, Taiwan-based Bora Pharmaceuticals has expanded its North American footprint by purchasing, in June 2024, an 87,000-square-foot sterile manufacturing facility previously owned by Emergent BioSolutions, at a price of $30 million (4). Emergent, in turn, entered into a six-year commercial partnership with Hikma Pharmaceuticals, beginning in January 2025, for the sale of 8 mg naloxone hydrochloride nasal spray in the United States and Canada (5).

1. Jabil. Jabil Acquires Pharmaceutics International, Inc. Press Release. Feb. 4, 2025.
2. Pii Expands Prefilled Syringe Services with $3.6M Investment in Capacity and Technology Upgrades. Press Release. Nov. 19, 2024.
3. Eli Lilly and Company. Lilly Announces $3 Billion Expansion of its Recently Acquired Manufacturing Facility in Wisconsin. Press Release. Dec. 5, 2024.
4. Bora Pharmaceuticals. Bora Pharmaceuticals Expands North American Footprint with Agreement to Acquire First Sterile Manufacturing Facility. Press Release. June 20, 2024.
5. Hikma Pharmaceuticals. Hikma Announces Exclusive Commercial Partnership with Emergent BioSolutions for Kloxxado (naloxone HCl) Nasal Spray 8 mg. Press Release. Jan. 14, 2025.

The transaction is expected to enhance Jabil’s development and commercial production of auto-injectors, pen injectors, inhalers, and on-body pumps.

Jabil Completes Acquisition of Pharmaceutics International, Inc.

Monitoring and course correction. Keep the process under observation and control. Calibration. | Image credit: ©Andrii Yalanskyi – Stock.Adobe.com

Accurate and timely analytics are essential to successful development and manufacturing of biopharmaceutical products, whether they are small-molecule drugs, recombinant proteins or antibodies, or novel modalities such as cell and gene therapies. The correct choice of analytical technologies for process monitoring and optimization during process development can reduce timelines and risk while increasing the ability to develop robust, readily scalable processes. Outsourcing of analytics to contract research organizations (CROs) with state-of-the-art capabilities, meanwhile, can help drug developers realize these goals in a cost-effective manner.

Business and technical drivers for analytical outsourcing

Outsourcing of analytics and testing often occurs for a combination of business and biological reasons, according to Alex Sargent, director of process development for cell and gene therapy at Charles River Laboratories, particularly in the case of complex, novel modalities. “For instance, it may be more cost-effective and efficient to outsource routine testing rather than investing in the space, equipment, and personnel needed to run a limited number of assays, making it more practical to rely on external providers,” he explains.

In addition to providing more cost-efficient and scalable solutions, CROs can also offer faster turnaround times to adapt to the needs of client projects as they advance from early development to commercialization, notes Jincui Huang, senior vice-president and head of the analytical sciences and clinical quality control department at WuXi Biologics.

Outsourcing analytics to CROs is also driven by the need for specialized expertise and advanced capabilities, Huang observes. “Many biotech companies recognize that developing and maintaining in-house systems for comprehensive analytics for process monitoring and optimization can be resource-intensive. By partnering with CROs, biotech and biopharma gain access to advanced technologies and methodologies that may not be available internally,” she says.

As an example, Sargent highlights bioinformatics and DNA/RNA sequencing for cell and gene therapies as technologies often accessed by developers through strategic partnerships with CROs.

The increase in outsourcing of biologics production for both drug substances and drug products to contract development and manufacturing organizations (CDMOs) is also leading to more analytics outsourcing, according to Elliott Franco, vice-president of lab operations at Alcami. “Many CDMOs have become true experts in process development and gain deep understanding of each process they work on through establishment of comprehensive analytical capabilities. That expertise allows for easy correlation of data trends to process parameters and thus efficient optimization of processes to maximize reliability and robustness,” he comments.

Increasing automation with room for improvement

Driven by the demand for greater efficiency and robustness in biologics development, automation in analytics is becoming increasingly prevalent among leading CROs. Areas of application can include, according to Huang, sampling, real-time monitoring, and data analysis.

Integrated automated sampling systems, Huang says, allow for collection of samples from both continuous and traditional fed-batch processes in real time without interrupting the processes. Inline process analytical technology (PAT) tools such as Raman spectroscopy and bio-capacitance measurement, meanwhile, when applied in upstream processes, offer real-time, high-frequency, and non-invasive analysis of the cell-culture process through corresponding chemometric algorithms, she observes. In downstream processing, online liquid chromatography with robotic systems offers high-throughput and near-real-time analysis for monitoring of product quality attributes during purification steps, according to Huang.

The ability to follow process milestones (protein concentration, cell densities, critical impurities, etc.) with online sampling/testing capabilities provides the type of data needed to truly understand critical process parameters, Franco agrees.

Advanced digital tools, meanwhile, are transforming the way analytical data are analyzed and used. “Digitalized auto-integration/analysis and predictive modeling help us develop methods in a more efficient way and identify potential risks earlier while continuously improving assay accuracy by analyzing historical and real-time data,” Huang explains.

Additional improvements in automated testing are still needed, however, particularly with respect to process development and optimization for newer modalities such as cell and gene therapies, Sargent contends. “The state of automation in analytics within the cell and gene therapy sector has room to grow, especially when compared to manufacturing,” she states.

In the past few years, there has been a surge of new technologies and platforms for the automated manufacturing of cell and gene therapies that have the potential to streamline operations, expand access, and significantly reduce costs, particularly for autologous therapies, Sargent notes. He believes, however, that, although equally important, automating analytics for process monitoring and testing during development and commercial production has been more challenging. “When talking about autologous cell therapies, for instance, there are thousands of independent batches generated every year, all of which require analytics for quality control and release. To effectively reduce the costs of these life-saving therapies, prioritizing the automation of testing will be critical,” he asserts.

Many benefits of automating outsourced analytics

There are, in fact, many ways in which automation of analytics at outsourcing partners can benefit biologic drug developers. “Automated analytics capabilities provide customers with several significant advantages, particularly when offered by service providers with robust experience in PAT and other automatic analytics technologies,” Huang says.

Specific benefits highlighted by Sargent include faster, more cost-efficient, and more accurate analytics compared to manual techniques. “Removing human error and bias can improve robustness and reproducibility, and outsourcing testing to a partner with automated capabilities can really help someone scale up or scale out their clinical or commercial program,” he remarks.

“In addition to allowing drug developers to avoid the need to make significant capital investments in expensive and complex technologies, automated solutions at CROs often speed up process development and scale-up while also enhancing the robustness of large-scale production by leveraging the CRO’s technical expertise and comprehensive data analytics capabilities,” Huang agrees. This support helps clients make informed decisions, optimize their processes, and ultimately achieve higher yields and better product quality.

“Overall,” concludes Franco, “use of automated analytics typically ensures that processes are well characterized and less likely to encounter failures to meet specifications with access to better and more comprehensive process data.”

There are some challenges to establishing comprehensive automated analytics capabilities, even for CROs serving large numbers of clients. “In general,” summarizes Franco, “establishing automation is costly and requires significant expertise at the interface of manufacturing, process development, and analytical development.”

Cost is often the first challenge when implementing automation for process monitoring and optimization, as the upfront investment to implement new analytical technologies in a process workflow can be significant, Sargent observes. “When transitioning from manual methods to automated systems, it is essential to demonstrate that the new method delivers equivalent readouts and results. For therapeutics developers, particularly those in advanced clinical or regulatory phases, implementing such changes may be impractical or even infeasible, despite potential improvements in throughput or robustness. It thus falls on the CRO to identify clients well-suited to automation and new technologies, particularly early-stage developers or those looking to transition to new platforms,” he comments.

Another issue highlighted by Huang that CROs must be able to overcome is the need to integrate new automation technologies with client-specific practices, as many clients use specific and diverse systems that require harmonization with automated platforms. Use of many different platforms, meanwhile, creates a need to consolidate data from multiple sources into a cohesive format for analysis, which can be complex, she notes. It is also essential to ensure automated systems meet stringent compliance standards, which requires robust validation. In addition, training staff and adapting workflows to incorporate automation can take time.

One strategy for overcoming these challenges, according to Huang, is through investment in advanced infrastructure, development of proprietary integration frameworks, and having a commitment to operational excellence.

Several exciting advances in automation and analytical technologies are increasing CRO capabilities in the field. First, Huang points to high-throughput automated platforms leveraging robotic systems capable of executing multiple assays simultaneously, which are improving productivity and reducing turnaround times.Many of these systems are designed to be end-to-end platforms, she adds. “The use [of] multiple robotic arms or automated guided vehicles to connect different modules can provide seamless end-to-end automation, from sample management, to analysis and reporting,” she explains. Bioreactors with embedded sensors and integrated advanced analytical systems, meanwhile, enable continuous monitoring of critical process parameters. “These innovations are critical for improving efficiency, scalability, and precision in biologics development,” Huang states.

In cell and gene therapy, the rapid advance of next-generation sequencing technologies and bioinformatics is, according to Sargent, having a transformative impact. Rather than years, hundreds of genomes can be sequenced in a week. Similar advances in transcriptomics, proteomics, and other comprehensive assays are equally important, he observes.

Across all biologics, Sargent believes that the implementation of machine learning and artificial intelligence (AI) in process monitoring and analytics systems is tremendously important. “We are only at the beginning of what AI can do in analytics and process monitoring, and the potential for how it may transform this space cannot be ignored,” Sargent remarks.

While automation in analytics is providing many benefits, limitations remain for CROs looking to maximize the opportunities that can be realized for their customers. Lack of standardization between different vendor systems remains a major issue in this regard, says Huang. “Industry efforts are required to establish open-source standards from software to hardware perspectives,” she notes. That should include development of next-generation technologies for effectively managing and interpreting the overwhelming amount of data generated by automated systems.

Huang would also like to see the development of modular automation solutions, which she believes could help smaller CROs overcome the challenge of high upfront expenditures currently associated with existing automated analytics systems.

Sargent emphasizes the need for more end-to-end analytics solutions for process monitoring. As an example, he points to flow cytometry, which is an essential tool in the cell and gene therapy space. “New advances in cytometers have improved throughput, removed human subjectivity, and automated crucial analysis workflows, but sample prep and staining remain laborious, manual tasks. Having an end-to-end automated solution for sample collection, storage, preparation, testing, and analysis will be key for future development, both for CROs and their customers,” Sargent says.

Automation of potency assays, including testing and analysis, is also needed. “These assays can be a major challenge using existing technologies. Automation and innovative methods/techniques will therefore likely prove critical to enabling a deeper understanding of biology and cellular responses, which will benefit everyone in the field, from academic researchers to drug developers and their outsourcing partners,” he concludes.

®
Vol. 49, No. 1
January/February 2025
Pages: 26–28

When referring to this article, please cite it as Challener, C.A. Outsourcing Analytics for Process Monitoring and Optimization. 

Developers save money and time while accessing expertise.

Outsourcing Analytics for Process Monitoring and Optimization

Movement towards the intended goal. Moving forward, step by step. Labor and aspiration. Motivation, self-development. Business strategic planning, risk management. New opportunities. Achieve. | Image Credit: ©Andrii Yalanskyi – Stock.Adobe.com

The development and production of biologics can be a complex process. And the manufacture of biopharmaceuticals requires that processes be developed and validated so that product specifications can be met to create a safe and effective biologic drug. Steps can be taken at each stage of the development and manufacturing of biologics to ensure processes are optimized for the best results.

Sponsor companies often look to contract development and manufacturing organizations (CDMOs) to help with process development of these products. The following article provides advice and insight from experts and bio/pharma CDMOs on how process development can be optimized.

A scalable production system is necessary when considering how to optimize upstream processes, according to Daniel Giroux, vice-president of Biologics Development at Abzena. Typical large-scale systems range from using 500- to 2000-L bioreactors, and the scale can prevent experiments. “If you have a single, 2000-L reactor, you can’t run multiple experiments for optimization,” says Giroux. A small-scale system will be needed in which growth and production parameters of the larger-scale system can be reproduced.

After the small-scale model is created, a design-of-experiment (DoE) approach can be used to identify parameters that may impact the titer or the product quality. “You create a statistical experiment where you’re varying those parameters in combination and singly. And then you execute that experiment in parallel bioreactor systems, so a small-scale reactor where you have many of them,” Giroux explains. Statistical tools can then be used to pull data from DoEs and models to optimize input parameters to achieve maximal titers.

Process intensification is another approach Giroux points to, where higher cell densities are used at inoculation to increase the area under the cell density versus culture time curve. “You want your cell density to be high for a longer period of time,” Giroux says. “And by starting at a higher cell density, it lets you do that, and you basically get 50 to 100% more titer in an intensified fed batch process. That means, though, that you have to develop a perfusion process for your penultimate reactor, your last seed reactor, so that you can actually have enough cells to inoculate your production systems at these higher densities.”

According to Paul Mugford, director, Biologics Process Development at BIOVECTRA, media optimization is an important part of upstream processing, especially in microbial fermentation. Media should be formulated to support optimal growth and productivity of the microorganism, says Mugford, which includes optimizing carbon and nitrogen sources, trace metals, vitamins, and other supplements. “All media components, of course, have to be animal free,” says Mugford. “And we also choose to start our process development with representative materials that will be used at large scale. These are raw materials that meet all the required GMP [good manufacturing practice] requirements, so there’s no issues transferring from small to large scale with respect to materials.”

The optimization of processes for the development and manufacture of biopharmaceuticals is pivotal for producing quality products. 

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