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. 

Articles

Development

Sustainability of small-molecule API manufacturing ensures continued success.

Improving the Sustainability of API Manufacturing with Recycling Technologies

Advances in equipment and control systems for three-dimensional printing (3DP) are creating new opportunities to use this alternative manufacturing method for solid dosage drugs. Printers—which are available in good manufacturing practice (GMP) versions—use various additive manufacturing methods to build layer upon layer, which allows precise placement of multiple ingredients within a dose. This customization offers advantages for modified and controlled release, personalized medicine, and point-of-care manufacturing, such as in hospital pharmacies.

“3DP’s material placement turns geometry into a dosing parameter,” explains Sharon Flank, CEO of technology company InfraTrac. “It can use layer thickness, shape, and differential material properties to create complex versions of controlled-release particles.” For example, 3DP can create “upstairs and downstairs layers for a polypill of two or more APIs, or an outer layer and multiple inner layers for precision control of release. Shape manipulation can control release in a way no tablet will ever do,” Flank says. Although 3DP is not as fast as conventional tableting, it can be used to meet the needs of a smaller target patient population that was previously underserved. Custom modifications can be quickly performed via software that controls material placement, compared to conventional tableting that would require tooling changes, Flank explains.

Using 3DP, dosage shapes can go beyond tablets, Flank adds. InfraTrac is working with Stephen Hoag’s Applied Pharmaceutics Lab at the University of Maryland School of Pharmacy on extrusion-based 3DP techniques to create orodispersible films, such as a pediatric rifapentine dose to treat tuberculosis. Outside of oral dosage, the researchers are designing long-acting implants with internal compartments for subdoses.

One example of using 3DP to meet a patient need is Aprecia’s levetiracetam, a high-drug load, rapidly disintegrating design for patients with difficulty swallowing that was approved by FDA in 2015. Made using the company’s 3D-printed ZipDose technology, it was the first drug to be approved using 3DP. It is made with an open-bed, binder-jetting method. More recently, Aprecia has developed its Z-Form 3DP platform integrated with process analytical technology (PAT) that prints doses directly in their primary packaging. The company worked with Battelle to develop the new technology platform for the development and production of dosage forms with a range of functionalities, including the ability to 3D print customized tablets or those with multiple APIs (1).

Triastek is using its Melt Extrusion Deposition (MED) 3DP process for microstructured drug delivery platforms that it has designed for modified release, colon targeting, gastric retention, solubility enhancement, and for improving oral bioavailability of peptides. The company has five drug products in clinical development (in the United States, China, or both) that use these platforms, including its most recent, a 3D-printed drug product designed for extended release and absorption of drugs in the upper gastrointestinal tract that received investigational new drug (IND) clearance from FDA in early 2024 (2).

In July 2024, Triastek announced a collaboration with BioNTech to develop oral delivery forms of RNA therapeutics using 3DP. The researchers aim to use multilayer and multi-compartment tablet designs to minimize degradation in the gastrointestinal tract and deliver the dose to where it can be absorbed optimally (3).

In addition to serving smaller patient populations, the flexible, small volumes enabled by 3D printing are useful in formulation development and clinical manufacturing.

“In clinical and preclinical trial supply, a nimble, small-scale production system could save a lot of time and therefore money,” says Flank. “Whether the final doses are produced via 3DP or conventionally, it is clearly helpful to be able to test several different formulations in a single day or even hour.”

Triastek is working with Boehringer Ingelheim to quickly create multiple prototypes of a new chemical entity and examine dose designs and drug release behavior using its 3DP technology (4). The company says its formulation-by-design approach can accelerate early drug development.

Small 3D printers can be useful for point-of-care manufacturing in a hospital pharmacy or potentially for remote locations, such as battlefields or space travel. A GMP-ready printer from FABRX, the M3DIMAKER, is now available with either one or three printheads and with printhead attachments for different extrusion printing methods—fused deposition modeling, semi-solid extrusion, and direct powder extrusion (DPE).

“We are working with hospitals and healthcare providers to implement our 3D-printing solutions directly into clinical settings, allowing for on-site production of personalized medications,” says Alvaro Goyanes, director and co-founder of FABRX. The United Kingdom-based company also launched a US-based company, FABRX US, in 2024, and is working with InfraTrac and Hoag’s lab on PAT for quality control.

The researchers, funded by the National Institute of Standards and Technology (NIST) through a Small Business Innovation Research program, are working on a predictive model that uses a near infrared (NIR) spectrometer incorporated into the drug printer, in this case the FABRX M3DIMAKER2, says Flank. The lab initially used a Viavi MicroNIR spectrometer and is also testing a Sentronic instrument. “Preliminary results show how NIR can validate and even quantitate API, detect out-of-specification moisture, and reject certain mis-printed doses,” reports Flank. “A robust model should facilitate point-of-care customization by creating pass/fail quality parameters that allow the pharmacist to manage doses and flavorings while delivering GMP product.”

“Integrating PAT and advanced testing capabilities into our machines addresses a critical need for real-time quality control and assurance in 3D-printed pharmaceuticals,” adds Goyanes. “This integration ensures that every product meets stringent quality standards, enhancing the reliability and safety of the medications produced.”

Goyanes points out that the development of effective cleaning protocols for printheads is essential to maintain equipment performance and prevent cross-contamination. FABRX introduced a new DPE printhead cleaner in July 2024 to improve the cleaning process. The company continues to work on technologies to meet other user needs it has identified, including development of modular and scalable 3D printing systems that can be easily adapted to different production volumes and requirements, Goyanes says.

Another technology designed for 3D-printing of personalized medicine in compounding pharmacies is the Pharma Kit from CurifyLabs. The platform includes GMP-manufactured excipient bases (called Pharma Inks); a desktop-sized automated Pharma Printer; software containing a library of validated formulae of Pharma Inks with APIs that guides the user; and integrated, automated quality control tools.

“Our goal was to modernize and bring automation to compounding and hospital pharmacies to make safer products and save time,” says Niklas Sandler, founder and CTO at CurifyLabs.

The developers automated as much of the workflow as possible, including weighing, mixing, dispensing, and packaging, explains Sandler. The built-in quality control tools include NIR to test blend homogeneity and a weigh scale to measure every tablet. The library of premanufactured excipient bases that have been optimized for the printing process and the formulations that have been validated are crucial to the system, says Sandler.

“We did all the validation work up front so that it would be easy and quick for pharmacists to follow the validated process. The technology can be used to produce a wide range of dosage forms, such as tablets and suppositories, and to dispense liquids accurately. The Pharma Kit is used in several markets in Europe,” Sandler adds.

“Both Europe and North America are witnessing a growing adoption of 3D printing in the pharmaceutical industry,” Goyanes suggests. In 2023, Goyanes and others launched the Pharmaceutical 3D Printing Initiative, an international consortium to facilitate collaboration between academic institutions, healthcare providers, regulatory agencies, and industry players. Other partnerships with universities and hospitals aim to train the next generation of scientists and engineers in 3D printing technologies. “These collaborations are crucial for advancing the field and ensuring that our solutions are continually evolving to meet the dynamic needs of the healthcare industry,” Goyanes concludes.

Aprecia. Aprecia and Battelle Are Impacting the Pharmaceutical Industry Through 3D Printing Innovation. Press Release, Nov. 15, 2023.

Triastek. Triastek’s 3D Printed Gastric Retention Product T22 Receives FDA Clearance of IND Application. Press Release, Jan. 31, 2024.

Triastek. Triastek Announces Research Collaboration and Platform Technology License Agreement with BioNTech to Advance 3D Printed Oral RNA Therapeutics. Press Release, July 23, 2024.

Triastek. Triastek Announces Collaboration with Boehringer Ingelheim to Advance and Accelerate Research and Development of Innovative Pharmaceutical Products with MED 3D Printing Technology. Press Release, March 17, 2023.

Jennifer Markarian is a contributing editor to 


Vol. 48, No. 10
October 2024
Pages: 22–23

When referring to this article, please cite it as Markarian, J. Exploring 3D Printing for Solid Dosage Drugs. 

Manufacturing

As a GMP manufacturing method, 3D printing offers benefits for modified release and personalized dosages. 

Exploring 3D Printing for Solid Dosage Drugs

It’s an election year in the United States, and it’s not just the cost of groceries that Americans are concerned with. The cost of medications has been a long-standing debate in the US government. How the Republican and Democrat presidential candidates might appeal to voters on this topic is starting to be seen. But will pharmaceutical companies take a hit?

In the past, according to Allison Gatlin of 

, the previous administration under Donald Trump proposed an approach whereby the Medicare prices for drugs given in doctor’s offices are linked to an international pricing index. There was also a plan to pass rebates to Medicare enrollees that would go to insurers and pharmacy benefit managers (1). If Trump is elected for a second term, it is possible that he could seek to implement the use of international price referencing for prescription drug costs, which had failed to get approval during his first term in office (2).

The current Administration, which includes Democrat presidential nominee, Vice President Kamala Harris, is jumping into the ring by announcing lower prices for the first 10 drugs selected for Medicare price negotiation (3). Medicare can negotiate prescription drug prices as part of the power given to it by the Inflation Reduction Act, which was signed into law by President Biden in August 2022.

Harris has also backed a draft guidance to allow federal agencies to exercise “march-in rights” (4). This guidance, if approved, would mean that federal contractors could retain the rights to patents for innovations developed with federal financial backing. Essentially, this is aimed at enabling greater competition within a specified market, such as healthcare.

However, this is not the first time that market competition has been assessed in the US. In fact, this year sees the 40th anniversary of the Drug Price Competition and Patent Term Restoration Act of 1984, which was created to increase market competition between generic-drug companies and pharmaceutical companies. This Act, according to Darby Kozak, PhD, deputy director for the Center for Drug Evaluation and Research, Office of Generic Drugs, in FDA, resulted in a growth in the generic-drug market, with generic drugs increasing from 19% of the market in 1984 to 90% in 2024 (5).

Whichever way the pendulum swings in November 2024, the bio/pharma industry should probably brace itself for an impact.

1. Gatlin, A. 2024 Election: Drug Prices Remain a ‘Hot Topic’. Can Pharma Stocks Withstand the Pressure? 

2. Cohen, J.P. Trump Plans to Rescind Funds for IRA Law’s Climate Provisions, but May Keep Drug Price Measures. 

FACT SHEET: Biden-Harris Administration Announces New, Lower Prices for First Ten Drugs Selected for Medicare Price Negotiation to Lower Costs for Millions of Americans. 

March-In Rights Under the Bayh-Dole Act: Draft Guidance. 

5. FDA. 40th Anniversary of the Generic Drug Approval Pathway. CDER Conversations. 

, Sept. 23, 2024 (accessed Sept. 25, 2024). 

Mike Hennessy Jr is President and CEO of MJH Life Sciences®.

When referring to this article, please cite it as Hennessy, M. Drug Prices on Debate. 

From the CEO

How the Republican and Democrat presidential candidates might appeal to voters on this topic is starting to be seen. 

Drug Prices on Debate

Q: I work for a 503B compounding organization. A customer has asked us to manufacture a drug product that includes a food-grade component because it is less expensive than the compendial-grade material. Is this an acceptable substitution?

A: No. Substituting a food-grade material when a compendial material is available is not acceptable. US 21 United States Code (USC) 351 states that a drug is considered adulterated if it “purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standard set forth in such compendium” (1). This section of the USC goes on to state, “No drug defined in an official compendium shall be deemed to be adulterated under this paragraph because it differs from the standard of strength, quality, or purity therefore set forth in such compendium, if its difference in strength, quality, or purity from such standard is plainly stated on its label.”

This is supported in the language contained in the General Notices of the 

] are recognized in the laws and regulations of many countries throughout the world.” It also states, “In the United States under the Federal Food, Drug, and Cosmetic Act (FDCA), both 

 are recognized as official compendia. A drug with a name recognized in 

 must comply with compendial identity standards or be deemed adulterated, misbranded, or both. See, e.g., FDCA § 501(b) and 502(e)(3)(b); also US Food and Drug Administration (FDA) regulations, 21 

] § 299.5(a&b). To avoid being deemed adulterated, such drugs must also comply with compendial standards for strength, quality, and purity, unless labeled to show all respects in which the drug differs. See, e.g., FDCA § 501(b) and 21 

 § 299.5(c).”The General Notices goes on to state, “Compounded preparations, including drug products compounded by outsourcing facilities, may also be subject to applicable monographs” (2).

However, there may be situations where there is no compendial standard for the material you are being asked to use in the formulation. In that case, you need to perform an assessment that would allow you to introduce the material. However, before you go through the activity of introducing a non-compendial material into your facility, it is advisable to check to see if the material in question is supported by monograph requirements contained in either the European or Japanese pharmacopoeias. If neither of those compendia contain a monograph, the following questions may help you determine if the material in question is safe to bring into your facility:

How are you going to accept this material and bring it into your facility?

Because it is food grade, are there additional specifications you need to have based on the intended use of the finished drug product?

Are there additional tests you need to conduct? If so, then talk to the supplier. You must work with supplier to establish the conditions, criteria, specifications, under which you will accept this material and make sure the additional criteria are included on the Certificate of Analysis.

Determine what type of additional training needs to be conducted so you are assured you can perform the test methods for the new material.

Determine if the cleaning procedures are effective. Is there cross-contamination to consider for the new component?

Having a robust quality management system will help you to answer these questions. You should be able to understand the risks and how to obtain information on how to sample/store the material. All of this will be in your quality management system which will allow you to have a risk management plan.

21 USC 351: Adulterated Drugs and Devices. Title 21 Food and Drugs. Updated Sept. 16, 2024.

Susan J. Schniepp is a distinguished fellow at Regulatory Compliance Associates.

When referring to this article, please cite it as Schniepp, S.J. Using Compendial-Grade Materials for 503B Compounding Facilities.Pharmaceutical Technology 

Ask the Expert

Substituting a compendial-grade material with a food-grade material is not acceptable, says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates. 

Pharmaceutical Technology, October 2024

Improving the Sustainability of API Manufacturing with Recycling Technologies

Exploring 3D Printing for Solid Dosage Drugs

Drug Prices on Debate

Using Compendial-Grade Materials for 503B Compounding Facilities