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

Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

TOP NEWS on grunge world map | Image Credit: © Sean K - stock.adobe.com

On the final day of CPHI Milan 2024, Oct. 10, 2024, a panel brought together by Fujifilm Diosynth Biotechnologies debated the numerous paths to “Building the Future Pharma Workforce” (1,2). Moderated by Pushpa Vijayaraghavan, healthcare practice lead at Sathguru Management Consultants, the other contributing panelists were Nagarjun Chakilam, director of Maithri Drugs; Jakub Knurek, business development specialist at Mabion; Morgan Rex, senior quality engineer at ApiJect; and Megan Smyth, senior team leader at Almac Group.

“There's two significant changes that I've really seen in my nine years of being in the industry so far,” Rex said. “The first is that there's a general trend, and this is really relevant in the United States, to bring healthcare out of the hospital in[to] the clinic and bring it directly to the patient as much as possible. And that trend is being driven by this desire to decrease the cost of healthcare while also increasing the access to healthcare, which will increase the adherence of patients to their medicine, which will improve vaccine accessibility—and so that's what we're seeing in the developed world, and … we're creating different formats for drug delivery and injections.”

Accelerating these changes in the industry have been some necessary adjustments in workflow and, in tandem, newly forged technologies resulting from the COVID-19 pandemic.

“So, the way it impacted us is, you know, [to] think about digitizing all the quality processes,” Chakilam said. In the past, quality processes were manual and siloed, according to Chakilam. “But now for us to embrace these new technologies, what we thought was it is more crucial and more important to digitize them first, and not just digitization like transforming from paper to screen or just doing something on the computer, but we want to have all those systems integrated in the back end as well.” Chakilam suggested technology trends be embraced and for the industry to move to implement flow chemistry once digitalization is completed. “Maybe at that point it will be a little bit more easier and more effective.”

“We're really excited about how we can unleash the power of AI [artificial intelligence] in our roles, in our organizations and our industry,” moderator Vijayaraghavan added. “How do we get our human capital, the security that there is still a people-driven future here? And how should people think of staying ahead of this curve and not feeling threatened by it, but, you know, being part of [the] revolution?”

Discussing the rise of women in leadership positions in the pharmaceutical industry, Vijayaraghavan made light of the expert panel consisting of more women than men, a point that was then elaborated on by Knurek.

“In every gender, [to] have that passion for biotech, for improvement that's really challengeable for all companies, how we can search, I think, more about headhunting, talent acquisition from that perspective?” he said.

In any case, Smyth said, the industry is expanding, and job recruitment is hearty. “There's just so many opportunities to be able to do so much in this industry. And you know, we've been building our capabilities towards manufacturing, and yeah, I think I'm really excited,” she said. “It's not going to be without its challenges, because we're doing a lot of these things for the first time, and it's exciting to be an innovator, but it's also going to have the challenges that need to be problem solved. And I think ultimately that's why most of us are in this industry, to be able to improve it and make it better.”

1. Vijayaraghavan, P.; Smyth, M.; Chakilam, N.; Rex, M.; and Knurek, J. Building the Future Pharma Workforce. Presentation at CPHI Milan 2024, Milan, Italy, Oct. 10, 2024.
2. CPHI Milan, Conference Agenda. cphi.com/europe/en/whats-on/agenda (accessed Oct. 10, 2024).

Articles

Five speakers discussed the impact of the COVID-19 pandemic, the rise of artificial intelligence, more women in leadership tracks in the industry, and various emerging technologies.

CPHI Milan 2024: What Does the Future Pharma Workforce Look Like?

CPHI Milan 2024: Heparin and Heparinoids in Pharmaceuticals

 sat down with Joan Bassa, Human Health Business Unit Director at Bioiberica, to talk about the history of heparin, its uses in pharmaceuticals, and what heparinoids have to offer the industry.

“Heparin has been [around] for more than 50 years, [and is] the product of [choice] against thrombosis, that, by the way, is still now one of the most frequent causes of death worldwide. There are other important new applications being researched. For example, there are clinical studies in different phases, some very advanced, on the use of heparin, for example, in malaria, as well as in some respiratory diseases like COPD [chronic obstructive pulmonary disease], or for instance, in facilitating the mechanism of childbirth in certain conditions that could affect the viability of the newborn. These probably are the most remarkable in the in the past few years.”

According to Bassa, heparinoids inhibit blood clots and anti-inflammatory properties, especially in patients who cannot use heparin. Heparinoids can be used in wound healing, ulcers, inflammatory diseases, or in vascular diseases. “Heparinoids can be administered orally in topical gels, for example, or ointments, or depending on the quality and the purity, they can also be injected,” says Bassa. “In the case of heparin, all the heparin, basically is injected. So, these are the main differences. But it's true that more and more, heparinoids are becoming an important product to be used in in these different applications.”

"At Bioiberica, we are committed to the highest manufacturing excellence standards," Bassa says. "Through our vertically integrated supply chain, we give peace of mind to our customers, ensuring the highest quality, safety, and full traceability of our products."

Click the above video to watch the full interview.

 is being held from Oct. 8–10, 2024 in Milan, Italy.

Videos

Pharmaceutical Technology Europe sat down with Joan Bassa, Human Health Business Unit Director at Bioiberica, to talk about the history of heparin, its uses in pharmaceuticals, and what heparinoids have to offer the industry. 

The microbiologist is testing the microbial contamination in the sample under vertical laminar air flow cabinet, concept of microbial laboratory in pharmaceutical industry, selective focus photograph. | Image Credit: ©Sukjai Photo - stock.adobe.com

Submitted: April 14, 2024
Accepted: July 9, 2024

Previously, a silver-based disinfectant composed of a low concentration (approximately 0.015% by weight) of a suspension of silver was sporicidal with a one-minute wet-contact time. The proprietary technology, licensed by the Environmental Protection Agency, for producing the silver particles has been enhanced to produce more consistent numbers and sizes of silver particles in the active raw material. Confirmatory testing has been performed on three manufactured lots to verify the consistency of disinfectant efficacy in accordance with 

United States Pharmacopoeia (USP) 37–National Formulary

 32. Various microorganisms, including molds and bacterial spores, were tested on stainless-steel coupons and demonstrated 2–6 log reductions with one-minute wet-contact times. These evaluations were designed to demonstrate that the enhanced disinfectant had a similar disinfectant efficacy as the previously tested product. Sterility testing suitability on the disinfectant was demonstrated according to the 

. Sterility testing on all three lots of disinfectant was satisfactory.

It was previously reported that a silver-based disinfectant composed of a low concentration (approximately 0.015% by weight) of a suspension of silver was sporicidal with a one-minute wet-contact time (1). The proprietary technology for producing the silver particles has been enhanced to produce more consistent numbers and sizes of silver particles in the active raw material. The new product is licensed by the Environmental Protection Agency (EPA) (EPA Registration Number 96194-1, 10 March 2021). Confirmatory testing has been performed on three recently manufactured lots to verify the consistency of disinfectant efficacy in accordance with the 

 32 (2). Various microorganisms including molds and bacterial spores were tested on stainless-steel coupons and demonstrated 2-6 log reductions with one-minute wet-contact times. These evaluations were designed to demonstrate that the enhanced disinfectant had a similar disinfectant efficacy as the previously tested product. Sterility testing suitability on the disinfectant was demonstrated according to the 

 (3). Sterility testing on all three lots of disinfectant was satisfactory.

The antimicrobial effects of silver (Ag) have been recognized for thousands of years. In ancient times, it was used in water containers (4) and to prevent putrefaction of liquids and foods. In 1884, silver nitrate drops were introduced as a prophylactic treatment for the eyes of newborns, to prevent infections caused by 

 transmitted from infected mothers during childbirth (5). In 1928, the “Katadyn Process” for water purification, based on the use of silver in water at low concentrations, was introduced (6).

The bactericidal efficacy of silver and its associated ions is through the strong binding with disulfide (S—S) and sulfhydryl (—SH) groups found in the proteins of microbial cell walls. Through that binding event, normal metabolic processes 

of the cell are disrupted, leading to cell death (7). There is also evidence that after entering a cell the silver ions displace the hydrogen bonds between adjacent nitrogen molecules of purine and pyrimidine bases which may stabilize the DNA helix and prevent replication of the DNA and, subsequently, division of the cell (8).

John M. Lindsay (SM) ACM, is president, Aseptic Solutions, Inc.

®
Vol. 48, No. 10
October 2024
Pages: 27–33

When referring to this article, please cite it as Lindsay, J. M. A Silver-Based Disinfectant—Non-Corrosive, Non-Toxic, Sporicidal: Disinfectant Efficacy Evaluations. 

Various microorganisms, including molds and bacterial spores, were tested on stainless-steel coupons and demonstrated 2–6 log reductions with one-minute wet-contact times.

A Silver-Based Disinfectant—Non-Corrosive, Non-Toxic, Sporicidal: Disinfectant Efficacy Evaluations

AAPS PharmSci 360 2024: Predictive Models for Poorly Soluble Drugs

As a preview of what’s to come at this year’s AAPS PharmSci 360, being held Oct. 20–23, 2024 in Salt Lake City, Utah, 

® sat down with Niloufar Salehi, advisor at Eli Lilly & Company, to discuss the problems associated with the formulation of poorly soluble drugs. Salehi also provided a look at how predictive models and other tools can be used to predict and improve solubility in both small-molecule and biologic drugs.

“There are several predictive tools that are used in order to determine poor solubility at [the] early stage of development,” says Salehi in the interview. “One of those is, for example, in silicon modeling that involves using computer simulations to provide insight on how [a] drug will behave in different media, and that can help scientists to identify the potential solubility issues before going any further. Also, another approach is high-throughput screening, which allows [a] researcher to quickly test the solubility of a large number of compounds, and that's enabled the scientists to identify whether there is any modification required for the further development.”

Salehi will be moderating the Symposium: Accelerated Development of Poorly Soluble Drugs Using Predictive Tool at AAPS PharmSci 360 on Tuesday, Oct. 22, 2024. Presentations include the following:

Biorelevant Media and Relevance in Current Time
Speaker: Sandra Klein, University of Greifswald

 Predictive Tools in Early Drug Product Development
Speaker: Fady Ibrahim, Sanofi

Role of Multi-Compartment Systems for Low-Solubility Weak Base Drug
Speaker: Yasuhiro Tsume, University of Michigan

 Predictive Dissolution Data with Pre-Clinical and Clinical Studies
Speaker: Stephen D. Stamatis, Eli Lilly & Company.

Pharmaceutical Technology sat down with Niloufar Salehi, advisor at Eli Lilly & Company, to talk about the session she is moderating at AAPS PharmSci 360 2024, Symposium: An Accelerated Development of Poorly Soluble Drugs Using Predictive Tool.

CPHI Milan 2024: Pharma Developments in Emerging Markets

 sat down with Rafael Ferrer, interim chief business officer at Acino, to talk about expansion into emerging markets, such as Latin America. Acino has been concentrating recent efforts there, in Africa, and in the Middle East, and Ferrer says the new drug pipeline often doesn’t extend to these areas.

“A large part of what we're trying to do is really be able to bring access to innovative drugs to patients in these geographies today,” Ferrer says. “If you look at the data, more or less, of 100 or so products that have been launched in the last 10 years, let's say novel molecular entities, be it new chemical entities or new biologic entities, only about 10% to about 30% of those ever make their way to emerging markets. So, there's a significant gap in terms of access to novel therapeutic modalities and novel medicines across our geographies. And for us, we see it as a mission to be able to improve access to novel medicines, while at the same time, of course, continuing to provide, you know, high-quality, well-known, well-proven brands, which are a large part of our portfolio.”

Ferrer also talked about the pitfalls of the regulatory landscape when it comes to these markets.

“The regulatory complexities and realities of Brazil are not the same as those of South Africa or the ones in Kuwait or the UAE, right?” he says. “So, we have to take that into consideration. I think [we] at Acino are very well positioned in the sense that not only do we have in-market teams that truly understand the local regulations and are able to work with regulators, with the regulatory bodies, to understand what are the pathways of getting new drugs, new medicines, to market across those markets, but also are really uniquely positioned to be able to execute on that, with the overall support that we have behind the corporation that we built.”

Rafael Ferrer, interim chief business officer at Acino, talked about his company's recent efforts to reach customers in Africa, the Middle East, and most recently, Latin America.

CPHI Milan 2024: The Usefulness of Fully Connected Continuous Manufacturing

As part of its CPHI Milan 2024 coverage, 

 sat down with Himanshu Gadgil, PhD, CEO of Enzene Biosciences, to discuss the concept of fully connected continuous manufacturing (FCCM) and its unique role in automating an entire biologics operation.

“It's a straight-through process which starts from upstream all the way to purified bulk,” Gadgil said in the interview. “And, you know, because there are no hold steps or hold tanks where the process falls or pauses, you know, it's like Netflix without ads, in a sense, right? So, once you have that, it is easier to bring in process analytical tools, it is easier to automate the whole process and start dynamically controlling it.”

Gadgil also talked about the cost-effectiveness of FCCM, especially in terms of equity for biotech companies that may not normally be able to afford these types of services.

“When you do continuous capture, you're continuously bringing it out from this unstable matrix and into a stable buffer,” Gadgil said. “A lot of the newer modalities, such as bi-specific, tri-specific molecules, often tend to be human-engineered. And what I have observed in so many years of doing bioprocess is anything that is human engineered also seems to have some kind of instability associated with it. So, for such kind of molecules, you really don't have an alternative. So, the cost advantage, of course, is huge. I mean, it can be almost a 90% reduction.”

Enzene Biosciences CEO Himanshu Gadgil talked about fully connected continuous manufacturing's role in providing equity for biotech companies that may not normally be able to afford such services.

Feliza Mirasol is the science editor for 

Nicolas Camper, senior director—Bioconjugation Chemistry, Abzena, discussed new advancements in ADC technologies, including the role of complex chemistries.

CPHI Milan 2024: New Developments in ADC Technologies

*Editor's note: updated on March 3, 2025 to fix typographical error.

spoke with Nicolas Camper, senior director—Bioconjugation Chemistry at Abzena during CPHI Milan. Camper discussed the advancements in conjugation and linker technologies in antibody-drug conjugate (ADC) development and manufacturing. 

Nicolas Camper, Senior Director—Bioconjugation Chemistry, Abzena. Image courtesy of Abzena.

“There have been a lot of new developments in terms of conjugation and linker technologies. There is a definitive move towards site-specific conjugation technologies and away from stochastic conjugation approaches that allows [us] to prepare better-defined antibody-[drug] conjugates,” Camper said.

Another new development that has been observed over the past few years is that linkers are becoming more sophisticated. “Quite often, when you conjugate cytotoxic drugs, they are quite hydrophobic, and that can impact the performance of your ADC. So, there has been a lot of effort put into developing more hydrophilic linkers,” he noted.

Finally, another noticeable advancement in this area has been the development of branch linkers. Branch linkers give some options to prepare ADCs and modulate the drug loading, Camper explained. “[T]hat is something relatively new and should have an impact on the performance of ADCs and ultimately result in better ADCs and more programs,” he stated.

In his role at Abzena, Camper has scientific oversight of the group’s R&D activities focusing on ADC design and developability for external clients. His responsibilities involve technical management of pre-clinical ADC development projects from discovery stage to lead candidate selection. The group has expertise in synthetic chemistry, assembling linker-payloads, conjugation of the linker-payload to various types of protein carriers (primarily antibodies), and analysis of these bioconjugates.

Attendees can visit Abzena at Booth 18H11. CPHI Milan is being held from Oct. 8–10, 2024 in Milan, Italy.

CPHI Milan 2024: Improving Efficiency and Reducing Costs for Oral Solid Dosage Forms

 caught up with Michelle Logan, vice president of the drug product division at Thermo Fisher Scientific, at CPHI Milan to discuss the oral solid dosage (OSD) forms market, its key trends and challenges, the affordability of these drugs within the market, and how OSD developers and manufacturers can drive those costs down and improve efficiencies in their processes at the same time.

“We are really focused around expanding capability and the early development side of things, so we can start earlier on with our customers and transition them through successfully all the way to commercialization,” Logan said in the interview. “So, you'll see that as some of our main offerings and focus, as we continue to expand and support capacity in this space.”

Logan said the digital space is an area Thermo Fisher has identified as wanting to increasingly use to its advantage.

“I think when you think about our commercial capacity that we have, the more we can leverage digital to drive initiatives improvements like line functionality, the better it is for our customers,” she said. “At the end of the day, that's really around the automation side of things ... our oral solid dose customers are leveraging routinely with us to help save from a cost perspective.”

Visit Thermo Fisher Scientific at Booth 7B18. 

Michelle Logan, vice president of the drug product division for Thermo Fisher Scientific, talked about expanding capability to better serve customers in the OSD market.

Communication between the manufacturing plant and retail stores. | Image Credit: © Cagkan - © Cagkan - stock.adobe.com

In a joint statement on Oct. 8, 2024, Colorcon, a specialty excipients company, and LOTTE Fine Chemical, a specialty chemical company, announced they were partnering to develop and manufacture drug and dietary supplement products using LOTTE’s AnyCoat Hypromellose products. Through the partnership, Colorcon will have exclusive representation of LOTTE’s AnyCoat-C Hypromellose polymers, used in solution/suspension, controlled-release, and immediate-release formulations; and AnyCoat-P Hypromellose Phthalate polymers, used for enteric coating to deliver a drug safely into the intestines.

“Colorcon is proud to announce our partnership with LOTTE Fine Chemical as we continue to support the formulation development needs of our customers around the world,” stated Kurt Fegely, vice-president of Excipient Technologies for Colorcon, in the press release (1). “LOTTE has been a leader in the specialty chemical industry for more than six decades and they have continued to innovate and evolve during that time. This partnership combines an impressive product portfolio for immediate, delayed, and controlled release with a global network of technical innovation and service that will accelerate formulation development, helping our customers compete in an increasingly competitive market.”

“This agreement is significant in that it represents a long-term collaboration in the pharmaceutical cellulose ether market between recognized market leaders. Through this relationship with Colorcon, an organization with proven expertise and leadership in the pharmaceutical industry, we will be able to deliver the most optimized value to our global customers,” Kim Yong-seok, chief executive officer for LOTTE Fine Chemical, added in the release.

“We are excited to bring together LOTTE Fine Chemical’s expertise in cellulose ether chemistry—and their commitment to high quality manufacturing—with Colorcon’s 60+ years of dedication to service excellence, supply reliability, and technical applications support,” said Simon Tasker, chief executive officer for Colorcon (1). “Our combined offering positions us to bring enhanced value to our customers and is a clear demonstration of our commitment to the global pharmaceutical and nutraceutical industries.”

 recently spoke with Ali Rajabi-Siahboomi, vice-president and chief innovation officer at Colorcon, about the evolution of coating design and how it has impacted investment, as well as innovations in packaging for oral solid dosage products (2). Coating design for solid dosage products has evolved from sugar coating to film coating to solvent-based and then to aqueous coating over the years, according to Rajabi-Siahboomi.

“But the development of this robust and optimized formulation that we've had, and the umbrella of open dry system, has made it much easier to have the right film coating, but at the same time, apply it much more efficiently and take that on board with the increasing population,” he says. “Therefore, there is an increasing demand on making sure that the tablets coming into the market are coated.”

PharmTech.com/view/cphi-milan-2024-evolution-of-coating-design to watch the interview with Ali Rajabi-Siahboomi

Colorcon is showcasing its products at Booth 6D58 at CPHI Milan, which is being held from Oct. 8–10, 2024 in Milan, Italy.

Colorcon. Colorcon and LOTTE Fine Chemical Announce Global Partnership to Support the Development and Manufacture of Pharmaceutical and Dietary Supplement Formulations Using the AnyCoat Hypromellose Product Family. Press Release. Oct. 8, 2024.

Thomas, F. CPHI Milan 2024: Evolution of Coating Design. 

Through the global partnership, Colorcon will exclusively represent LOTTE’s AnyCoat Hypromellose products.

Colorcon and LOTTE Fine Chemical Announce Partnership

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

Improving the sustainability of small-molecule API manufacturing is essential to ensuring the continued success of the pharmaceutical industry. For most APIs, however, evaluating the global warming potential along the whole value chain or lifecycle is difficult. The greatest contributor to the carbon footprint of API manufacturing operations is the use of solvents, reagents, and precious metal catalysts, for which significant restrictions on recycling and reuse can exist. The major argument against reuse and recycling is based on product and application safety, according to Michael Nonnenmacher, director global business development differentiating technologies with Evonik.

The ability to recycle and/or reuse these materials, however, enables measurable resource savings and carbon footprint reduction. “For multi-step syntheses, it is likely that hundreds of kilos of raw materials are used to produce a single kilogram of final product. It is still common practice to incinerate most of the waste generated from these raw materials, oftentimes resulting in tons of carbon dioxide (CO2) per kilo product. The possibility to recover some of these materials or replace them with greener alternatives would enable a tremendous reduction of the process carbon footprint and improve the overall sustainability of these operations,” Nonnenmacher states.

Solvent and catalyst recycling offers several significant advantages. In contrast to incineration or other forms of disposal, which generate substantial amounts of CO

, catalyst and solvent recycling allow repurposing in the same process or in different applications with minimal energy expenditure, according to Niklaus Künzle, senior director, global head of process technology and innovation for small molecules at Lonza. In addition to the reduced direct CO

 emissions, this approach also necessitates less production of raw materials, resulting in further substantial savings in both energy and CO

Solvent recovery is the most practiced recycling solution in established large-scale processes. “For API manufacturing, the use of recycled solvent is mostly restricted to the same process and a limited number of cycles, and a thorough risk assessment to mitigate potential impurity formation and accumulation in the process is needed,” Nonnenmacher says. “Since the discovery of nitrosamine impurities, which are potent carcinogens, stemming from solvent degradation, recovery is under a lot of scrutiny, but it should still be considered in cases where it will result in no process risk,” he adds. In cases where it is not appropriate to use recycled solvent in the API production process, Nonnenmacher observes that it is possible to find other fine-chemical applications where they are suitable.

Recycling of expensive palladium, platinum, rhodium, and other precious metal catalysts helps not only to reduce costs, but the carbon footprint associated with the mining and refining operations necessary to obtain the metals, notes Nonnenmacher. While solvent recycling is often performed in-house, the transformation of used catalysts back into active species is typically performed externally by specialized companies, according to Künzle.

In addition, although filtration of heterogeneous catalysts from process wastes is typically easy, separation of dissolved homogeneous catalysts from oftentimes dilute solutions requires more specialized technologies, comments Nonnenmacher. “Evonik has established an efficient process for the concentration of precious metal-containing organic waste streams using membrane cross filtration. This approach enables the sustainable recovery of the metal at the refinery, and thus contributes to resource saving and carbon footprint reduction,” he says.

The best strategy for realizing the greatest benefits from recycling during API manufacturing is to, according to Nonnenmacher, apply the principles of green chemistry early on during process development. “In this manner, it is possible to implement eco-friendly and more sustainable raw material and API manufacturing processes,” he notes. Key considerations highlighted by Nonnenmacher include avoiding the use of large volumes of especially hazardous organic solvents that cannot be recycled, applying process intensification approaches, and controlling the atom economy for waste reduction.

“Beyond these approaches, the introduction of recycling concepts or reuse options into processes right from the beginning can facilitate acceptance by regulatory authorities,” Nonnenmacher contends. Performance of process and product life-cycle analyses to generate important sustainability metrics such as process mass intensity and E-factor values when a candidate is in clinical development can, he says, help pharmaceutical firms and API makers visualize and understand potential adverse steps in the synthesis early enough, allowing manufacturers to implement more sustainable solutions.

Of course, one of the best approaches to improving sustainability is to avoid the use of problematic processes and materials. “Ideally, the most elegant solution is to minimize or completely eliminate the use of solvents,” Künzle states. Lonza therefore strives to implement process improvements in collaboration with drug developers during the early development phase. “These process improvements aim to reduce the number of used solvents, decrease dilution, and enhance the process yield. Selection of process solvents is also optimized by considering solvents and mixtures that are feasible to recover from process waste streams,” he explains.

Recycling compounds from a complex mixture requires efficient separation techniques, such as rectification and membrane separation. Continuous liquid-liquid or liquid-solid separation may also be employed, according to Nonnenmacher. The adsorption to scavengers or filter aids can be efficient for catalysts as well. Immobilizing catalysts such as enzymes by attaching them to a solid substrate also facilitates recovery and reuse, he says.

For solvents specifically, distillation, extraction, adsorption, and membrane separation techniques, according to Künzle. “Often,” he notes, “multiple technologies must be combined to ensure the purity required for recycling these materials back into API processes.”

Nonnenmacher also emphasizes that both increasing cost constraints and sustainability ambitions are driving the development of more efficient processing techniques for separation, as well as more selective processes that result in waste mixtures that are less difficult to separate.

Recycling, whether of solvents or catalysts, is often not an easy task given the complex solutions used in API manufacturing. “Extracting valuable materials from complex process mixtures can be a significant challenge, especially when aiming to restore them to a high-purity starting quality with minimal energy consumption and at minimal cost,” says Künzle.

Another major challenge for implementing recycling solutions at both clinical and commercial scale is that recycling is usually not attractive enough for small campaigns, according to Nonnenmacher. “It is considered a given that waste is sent to incineration and, therefore, oftentimes from a cost and effort perspective, recycling strategies are not a priority,” he adds. In addition, especially for smaller API manufacturing sites that are not fully self-sustained, there are significant logistical constraints given that recycling requires significant site infrastructure. “Even if waste streams are shipped offsite for recovery, a minimum buffer capacity separate from other wastes needs to be available,” Nonnenmacher observes.

Another factor that impacts recycling opportunities is regulatory considerations. The recycling of solvents in API manufacturing may come with potential impurity accumulation and is therefore scrutinized by regulating authorities, especially when considering environmental- and health-critical solvents, according to Nonnenmacher.

For example, Nonnenmacher points to the decomposition of dimethyl formamide (DMF) to dimethylamine and the potential for subsequent formation and accumulation of the carcinogen N-nitrosodimethylamine, which makes DMF recycling almost prohibitive.

When developing a solvent recycling process, notes Künzle, it is therefore crucial to ensure that no by-products accumulate in the solvents, which involves extensive laboratory and pilot testing and continuous analysis. In addition, whenever recycling of less critical solvents is possible from a risk perspective, Nonnemacher once again emphasizes the importance of establishing any recycling concepts during early development and into validation and using a defined, limited number of cycles before final disposal. “As part of the process, the recycling concept needs to be filed and accepted by the authorities,” he notes.

A risk-based approach to recycling is also required for materials other than solvents. “In most cases, waste streams from API manufacturing must be incinerated due to the potential risk of pharmaceuticals or other contaminants leaking into the environment,” observes Nonnenmacher. However, he does comment that recycling of metals that in principle undergo complete reset to their original state is handled outside of the process and not questioned by regulatory agencies.

Regardless of the material or technology, the best strategy is to integrate recycling considerations into regulatory filing activities from the very beginning, Künzle concludes.

Recognition of the importance of increasing the sustainability of pharmaceutical manufacturing operations is driving investment in many new technologies and solutions, including those for recycling. “Current and future innovation in many fields will contribute to the sustainability of API manufacturing and recycling of process components. Those innovations may come from established fields like from physical separations, or from research areas less obviously related, such as more in-depth process development supported by artificial intelligence resulting in more efficient production methods and cleaner off-streams, which would be easier to recycle,” Nonnenmacher comments.

Lonza, for instance, is working to enhance its entire infrastructure to enable the realization of additional recycling solutions, according to Künzle. One example is the expansion of pervaporation capacities in Switzerland, which allow the company to process challenging mixtures with minimal energy expenditure. Lonza is also applying new oxidation and enzymatic technologies for wastewater treatment that involve significantly reduced energy consumption.

Evonik, meanwhile, is leveraging fundamentally different approaches to how pharmaceutical chemistry is performed. One example is the Chemistry in Water platform the company is developing and using for the manufacture of active ingredients. “This technology allows significant reduction of organic solvent consumption, oftentimes combined with offering superior reaction performance, such as in the field of cross-coupling reactions,” Nonnenmacher says.

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

®
Vol. 48, No. 10
October 2024
Pages: 18–20, 33

When referring to this article, please cite it as Challener, C.A. Improving the Sustainability of API Manufacturing with Recycling Technologies. 

Sustainability of small-molecule API manufacturing ensures continued success.

Featured Content

Digital Transformation in Pharma Manufacturing

Behind the Headlines, Episode 23

ICH Q12 and Post-Approval Changes

Drug Digest July 2025

Bio/Pharma's Tariff Response