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Dosage Forms: Roundtable on Oral Solid Dosage Trends

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Out-of-the-Box Packaging Advancements

From Theory to Reality: Automating Process Development

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The Importance of Appropriate Supplier Oversight

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Feliza Mirasol is the science editor for 

Andelyn Biosciences, a patient-focused cell and gene therapy contract development and manufacturing organization, announced on Aug. 6, 2024 that it has entered into a license agreement with the Broad Institute of MIT to include MyoAAV plasmids in its AAV Curator Platform, which expands the platform’s offerings.

Under the agreement, Andelyn will have use of the MyoAAV plasmids to perform research and development services for clients who are developing gene therapies. Andelyn will screen potential candidates and perform scale-up and pre-clinical development work to prepare for investigational new drug-enabling studies. The agreement also gives Andelyn permission to sublicense the MyoAAV plasmids to its clients for internal research purposes.

The MyoAAV plasmids were developed by researchers at the Broad Institute of MIT and Harvard. They are a new family of plasmids that produce adeno-associated viruses (AAVs) ten times more efficient in reaching muscle tissue and targeting the liver than wild-type vectors, according to a company press release. “With more precise targeting of muscle tissue, research shows MyoAAV-delivered therapies may require lower dosing,” Andelyn stated in the press release.

Andelyn will utilize its expertise in translational drug development to bring Broad's new class of engineered AAVs to biotech organizations as they target diseases in therapeutic areas with significant unmet need. The company expects that the new AAVs will ultimately reduce the effective dose demand while improving product safety.

“Our license from the Broad Institute furthers our goal of providing the industry access to critical tools and capabilities that facilitate the development of innovative therapies to bring more treatments to more patients. With access to the increased specificity of MyoAAVs, our clients now have the opportunity to maximize efficiency in their gene therapy processes and drive down the cost per patient,” said Matt Niloff, chief commercial officer of Andelyn, in the press release.

In May 2023, Andelyn was selected to manufacture AAV therapies using its Curator Platform under the California Institute for Regenerative Medicine (CIRM) Accelerating Medicines Partnership (AMP) Bespoke Gene Therapy Consortium (BGTC) (1).

CIRM established a partnership with Andelyn to advance BGTC’s goal of developing platforms and standards that will drive the development and delivery of customized or “bespoke” gene therapies for rare diseases. BGTC is focused on developing cures for eight such rare diseases. Andelyn’s role will be to optimize and scale the AAV gene therapy processes for treating congenital hereditary endothelial dystrophy–type 1.

“As a long-standing pioneer in AAV gene therapies and historical connection to the clinic, we have great synergies with the CIRM/BGTC. Andelyn is privileged to work with the CIRM/BGTC on its first AMP established specifically for rare disease and leverage our AAV Curator Platform to help overcome the major obstacles related to developing gene therapies,” Niloff stated in a company press release (1).

1. Andelyn Biosciences. Andelyn Biosciences Selected as Viral Vector Manufacturing Partner for the California Institute for Regenerative Medicine (CIRM) Accelerating Medicines Partnership (AMP) Bespoke Gene Therapy Consortium (BGTC). Press Release, May 23, 2024.

Articles

With the agreement, Andelyin Biosciences will add MyoAAV plasmids developed by Broad Institute of MIT and Harvard to its AAV Curator Platform.

Andelyn Biosciences and Broad Institute of MIT Enter into License Agreement to include MyoAAV Plasmids in AAV Platform

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

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A transmembrane 4 L six family member 1 (TM4SF1)-directed antibody-drug conjugate (ADC) called AGX101 is now being given to patients in a Phase I clinical trial, as announced by Abzena in a press release on Aug. 8, 2024 (1,2). Abzena, a contract development and manufacturing organization (CDMO), is partnering with Angiex, a developer of nuclear-delivered antibody-drug conjugate (ND-ADC) therapies for solid cancers, to conduct the trial (1).

As defined by the two companies, the AGX101 monotherapy targets two different tumor components, its vasculature and cancer cells, and operates via three mechanisms: eliminating tumor blood vessels, killing tumor cells that may be capable of invasion and/or metastasis, and, finally, instructing the immune system to attack the cancer (1).

In preparation for the Phase I trial being run by Angiex, Abzena said it provided linker-payload design and synthesis, bioconjugation, process development, and current good manufacturing practice (CGMP) manufacturing (1). The Phase I study is open-label, with dose escalation and expansion components that are intended to evaluate the safety, pharmacokinetics and pharmacodynamics, and preliminary anti-tumor activity of AGX101.

“We are very excited to have dosed our first patient in our first-in-human study of our novel TM4SF1 ADC, AGX101,” Paul Jaminet, Angiex co-founder and CEO, said in the press release. “Throughout the development of AGX101, Abzena has worked closely with us to achieve successful GMP manufacturing and quality control. We could not have reached this milestone without Abzena’s expertise, cooperation, and support. Both companies have extensive expertise in their respective fields and an aligned mission, and we look forward to continuing our partnership to ensure that AGX101 is available to meet the needs of clinical cancer patients. We are delighted that Abzena shares our vision that no one should die of cancer.”

“The Abzena team is incredibly proud to have helped Angiex achieve this significant milestone,” Abzena CEO Matt Stober added in the release. “Our unique ability to support Angiex with a fully integrated approach allowed us to de-risk and rapidly progress AGX101 into the clinic for patient dosing. We will continue supporting Angiex with our extensive ADC expertise and integrated capabilities to accelerate the development timeline of AGX101, and ultimately get this life-changing treatment to cancer patients faster.”

According to the two companies, the dose escalation portion of the study can assess doses up to 10 mg/kg in the solid tumor patient population, while the dose expansion portion can evaluate treatment at the recommended Phase II dose in multiple indications (1).

The press release did not indicate a timeline for the Phase I study, or when further trials might be scheduled.

1. Abzena. Abzena Supplies Clinical Trial Material for Angiex’s Phase I Study of AGX101, a First-in-Class TM4SF1-directed ADC. Press Release. Aug. 8, 2024.
2. Chen, G.; She, X.; Yin, Y.; et al. Targeting TM4SF1 Exhibits Therapeutic Potential Via Inhibition of Cancer Stem Cells. 

AGX101 targets the cancer cells and vasculature of a tumor, and works to eliminate the tumor blood vessels, kill tumor cells capable of invasion or metastasis, and direct the immune system to attack the cancer.

Abzena, Angiex Collaborate for Phase I Trial of Solid Cancer Tumor Therapy

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 notice dated Aug. 8, 2024 announced FDA’s Fiscal Year 2025 Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality (OPQ) Experiential Learning Site Visit Program (ELSVP) (1,2).

The ELSVP, according to a press release from FDA, allows staff to observe commercial manufacturing and testing operations as well as pilot plants, with the goal of better understanding standard operations of the pharmaceutical industry and how those impact the developmental programs and commercial life cycles of drugs (1). It does not replace or supplement a regulatory inspection.

 notice identified the ELSVP as part of CDER’s commitment to ensuring that safe, effective, and high-quality drugs are available to Americans, in this case by arranging site visits (2). Companies encouraged to participate include those that engage in the development and manufacturing of either APIs, both small and large molecule, or drug products (1).

Groups of no more than 15 OPQ staff typically come to a site to observe operations over a one- to two-day period. There are a number of areas of interest for these staff members, according to FDA, though it is not an exhaustive list (2):

Solutions, suspensions, emulsions, semisolids, and solids

Modified- and immediate-release formulations

Drug-device combination products regulated by CDER (e.g., inhalation products, transdermal systems, implants intended for drug delivery, and pre-filled syringes)

Design, development, manufacturing, and controls:

Engineering controls for aseptic processes

Process analytical technology, measurement systems, and real-time release testing

The selection process gives priority to facilities on the basis of FDA staff training and a facility’s current compliance standing with FDA, among other considerations (1).

Companies that may want to schedule a site visit, or which simply desire more information, are invited to submit a proposal as of Oct. 1, 2024 to 

. Visits will be made within a year of that date, by the close of the next government fiscal year on Sept. 30, 2025 (2).

FDA said proposals should include the following (2):

Facility Establishment Identifier and D-U-N-S numbers, as applicable

maximum number of FDA staff that can be accommodated during a site visit (maximum of 15, on average)

a proposed agenda outlining the learning objectives and associated activities for the site visit

maximum number of site visits a site would be willing to host by the close of the government fiscal year

proposed time frames for each site visit (i.e., month or quarter).

If a site is selected for a visit, FDA will collaborate with the contact person provided on appropriate visiting dates.

1. FDA. FDA Invites Drug Companies to Participate in Site Visitation Program. Press Release. Aug. 7, 2024.
2. FDA. Office of Pharmaceutical Quality Experiential Learning Site Visit Program; Program Announcement. Notice, 

, 89 FR 64938, 64938–64939, Aug. 8, 2024.

The program, for which visits will be scheduled through September 2025, does not replace or supplement a regulatory inspection.

Drug Companies Encouraged by FDA to Participate in FY 2025 Site Visitation Program

US Specialty Formulations (USSF), a provider of pharmaceutical solutions for healthcare, diagnostics, and new drug developers, has begun a $15 million initiative to expand biopharma operations at its Allentown, Pa., facility, according to a July 31, 2024 press release.

USSF has already secured $4.7 million of its $15 million goal. Under the expansion, the company plans to bring in new facility cleanroom suites and state-of-the-art automated packaging and product inspection equipment. The expansion is expected to increase the company’s cleanroom production capacity by more than 2.5 times. The expansion is expected to be completed at the end of 2025. Once done, the company will have the capability to take on substantially larger projects to support growth for new and current clients.

“This expansion is a transformative step for USSF,” said Kyle Flanigan, CEO of USSF, in the press release. “By investing in cutting-edge technology and streamlining our manufacturing processes, we are raising the bar for ourselves and reaffirming our commitment to delivering innovative pharmaceutical solutions that reduce the risk profile of new drug development or contract manufacturing and ultimately improve patient lives. This expansion empowers our dedicated team to serve our partners and clients worldwide more effectively.”

In addition to raising USSF’s cleanroom capacity, the expansion is also expected to significantly boost the local economy by creating jobs and increasing revenue for the Greater Philadelphia region. When completed, USSF will seek to employ more than 100 staff to support the facility.

The company stated in its press release that cleanrooms are required to meet most pharmaceutical manufacturing standards. “They provide a highly controlled environment essential for product quality, safety, and compliance with CGMP [current good manufacturing practice] standards. These rooms provide a sterile environment for the production of injectables, including small molecules, botanicals, and vaccines.”

USSF offers a range of services, including drug R&D, contract manufacturing, private label formulations and packaging, and small-molecule pharmaceuticals. The company has developed the oral vaccine platform, QYNDR, and a self-administered drinkable vaccine, the first, according to the company. This drinkable vaccine completed a Phase I clinical trial in 2023 (1).

QYNDR is a next-generation protein-based oral vaccine (mucosal vaccine) developed to addresses the challenges seen with the current COVID-19 vaccines. According to a company press release, the results of the Phase I clinical trial showed that the vaccine demonstrated longevity and cross-variant protection from multiple COVID-19 strains. In addition, the study may possibly have identified a correlation of protection against the virus and other strains, which is to be further investigated in a Phase II clinical trial (1).

“The [P]hase I clinical data showed strong evidence that this oral platform and vaccine is a revolutionary industry disruptor and will become the preferred method of vaccination in the future,” Flanigan said in a press release issued at the time that the Phase I trial was completed. “As we proceed into Phase II and III, we are confident this next-generation vaccine will be more effective than other mucosal vaccines in current development and testing.”

1. US Specialty Formulations. US Specialty Formulations Completes Phase I of Clinical Trials for the Qyndr Vaccine. Press Release, Sept. 7, 2023.

 US Specialty Formulations plans to invest $15 million to expand biopharma operations at its Allentown, Pa.,facility.

US Specialty Formulations to Modernize Biopharma Operations with $15 Million Investment

 is Industry Market Manager Biopharma, Pharma EMEA - Brenntag GmbH.

Benzoyl peroxide powder, chemical compound used in the preparation of cream, lotion or gel in the treatment of acne and mild to moderate forms of dermatitis. | Image Credit: © RHJ - stock.adobe.com

For more than a century, chemically synthesized medicines such as aspirin and paracetamol have helped treat fever, pain, and inflammation (1,2). The constantly improving understanding of the genetic roots of many diseases has led to the development of a new generation of biological active agents (3). The ongoing development of so-called biopharmaceuticals is linked to the establishment of new development processes and new specific challenges in the choice of starting materials. The manufacturing technology for biopharmaceuticals can be divided into upstream and downstream process steps (4). The upstream biopharmaceutical production of APIs refers to the first stages of the production of biopharmaceuticals (5). This includes several processes, including cell line selection, culture media selection, growth parameters, and process optimization to achieve optimal conditions for cell growth and biopharmaceutical production (4). Processes used in the production of biopharmaceuticals rely on diverse basal medium formulations containing more than 50 essential nutrients, such as amino acids, vitamins, trace elements, and additional chemicals. Compared to chemical drugs, biopharmaceuticals are more difficult to produce, and have more than one route of application and unique pharmacokinetics. Their advantages are high selectivity and efficiency, target specificity, and low toxicity. It is especially these advantages that make them particularly interesting for use in personalized medicine (5).

APIs can be produced traditionally (chemically) and have a high degree of stability. Here the molecules are exposed to extreme conditions (high pressures, high temperatures, solvents, etc.). The production of biopharmaceuticals is based on living systems, which only tolerate narrow temperature and pH windows to produce the API. Protein-based biopharmaceuticals are produced using genetically modified cells. Viral vector-based biopharmaceuticals are infectious viruses that can be used to express the desired API recombinant via 

) cells. Patient cell synthesized biopharmaceuticals are typically produced using human cells and transduced via a lentivirus. Figure 1 summarizes the four different starting points for producing APIs (6).

 Four starting points for API production.

The challenge in biopharmaceutical production of ensuring safety and quality

The lessons of the past, in which a few biopharmaceuticals were contaminated, have led to the current best practice, which relies on three pillars: the selection of appropriate starting and raw materials with a low risk of containing adventitious virus; testing of cell banks and in-process materials to ensure they are free from detectable viruses; and finally, the incorporation of steps to remove and inactivate potential undetected adventitious and endogenous viral contaminants during purification of the product (7). Regulatory guidelines are essential for patient safety. There is no “one-size-fits-all” approach for the different types of pharmaceutical drugs. Biopharmaceuticals are absolutely different from classical chemical APIs.

Ensuring that all components of the biopharmaceutical manufacturing process are free of impurities is one of the pillars to produce a high-quality and clean API product.

It is widely acknowledged that risk-assessment strategies play an important role in the successful implementation of manufacturing processes for biopharmaceutical API production. They assist in the establishment of appropriate specifications for raw materials and help ensure the implementation of effective testing approaches. The development of test methods to verify the identity and quality of materials used in biopharmaceutical manufacturing can help to prevent the use of unsuitable raw materials, thereby providing a solid foundation for a successful process. Whereas pharmacopeial standards may not be a 100% perfect solution, they do provide valuable tools for users of these materials. They can save them time and expense that would be required if they were to develop and validate test methods themselves. Raw materials that have been processed under good manufacturing practice (GMP) conditions and meet the requirements set out in compendial monographs have established a certain level of quality. Nevertheless, it is still necessary to prove their suitability for use in the process. For instance, pharmaceutical-grade citric acid is available for use as a cell culture supplement (process step upstream), and its quality could be tested against existing monographs. However, to establish its quality, it may be helpful to also assess the impact of the albumin’s lot-to-lot variability on cell growth, its stability in the process, and possible interactions with other processing components. Many regulatory guidelines indicate that raw materials should be included in the manufacturing strategy, but they do not describe exactly how to do this. The question arises as to why there are still no exact conditions and standards in known guidelines regarding the choice of raw materials in the upstream process. As there is no exact definition of what quality a raw material should have, theoretically any quality of raw material from Table I can be used for production of a biopharmaceutical API.

 General grades and their characteristics (8).

The European Medicines Agency publishes scientific guidelines on human medicines that are harmonized by the International Council for Harmonisation (ICH). The ICH publishes harmonized scientific guidelines for pharmaceuticals, accepted by regulatory authorities and industries in Europe, Japan, and the United States (9,10).

There are two ICH guidelines in the “Specifications” chapter, one for chemical drugs (ICH Q6A) (11) and one for biopharmaceuticals (ICH Q6B) (12). However, none of the ICH guidelines describe what quality a material should have that is to be used in the upstream process to produce an API. In ICQ 7, the decision to select the quality standard is left to the manufacturer of the API.

The raw materials used (media, buffer components) may provide the potential for growth of microbiological contaminants. Depending on the source, method of preparation, and the intended use of the API or intermediate, control of bioburden, viral contamination, and/or endotoxins during manufacturing and monitoring of the process at appropriate stages may be necessary

Impurities influence product quality, stability, and efficacy, so their levels need to be minimized (14). The use of pharmacopeial standards can bridge the gap between the lack of guidelines and the minimum requirements of the raw materials for the upstream process, as they can be tools for traceability and compliance. Reference standards can be used as calibrators to ensure that substances are used in a consistent manner, meet the same specifications, and are then transferred to consistent production.

Downstream manufacturing processes remove two types of impurities: product-related, such as unwanted molecular variants, and process-related, such as residues of cell culture components and substrates. These must be reduced to acceptable levels to ensure product safety (15).

Not all methods used in the downstream process lead to the removal of all contaminants that arise during the upstream process. This is one of the reasons why it is important to ensure that the starting materials are of high quality and purity right from the start, to reduce contamination to a minimum. The removal of lipopolysaccharides and endotoxins, for example, is complicated and causes high costs in the downstream process when removing these. It would therefore make sense to choose purely endotoxin-free starting materials, set out in an ICH guideline, to improve this process and minimize the risk (16). Downstream process costs, which currently account for the majority of costs, could be reduced by using higher quality products that do not contain endotoxins from the outset (17). Today, about 80% of the cost to produce and purify a biopharmaceutical active molecule is found in the downstream process section (18).

Quality through strategic partner selection and tailor-made services

Various regulatory guidelines emphasize the importance of including raw materials in manufacturing strategies. However, they often lack specific instructions on how to achieve this. Pharmacopoeia standards can fill this gap by providing compliance tools. For example, reference standards can serve as calibrators to ensure consistent material usage and adherence to specifications, promoting uniform manufacturing practices.

The use of pharmacopoeia standards can mitigate the risks associated with manufacturing products at multiple sites.A careful selection of suppliers ensures that only the highest quality products are used in the upstream biopharmaceutical manufacturing process. Adhering to strict standards and rigorous testing protocols, can also ensure the quality of raw materials. The investment required for manufacturers of starting materials for the biopharmaceutical process to conduct appropriate tests according to pharmacopoeia standards is significant. Due to the absence of explicit guidelines stipulating that upstream materials must adhere to a corresponding standard, and given that quality is often considered secondary during the laboratory development phase, some manufacturers opt not to produce according to these standards. However, to provide assurance in these instances, testing of these raw materials should be done according to pharmacopoeia standards. This ensures that biopharmaceutical API manufacturers receive the quality required by pharmacopoeia standards, facilitating the production of high-quality APIs. Frequently, raw material manufacturers package their products in a manner that suits their own economics but may not be suitable for the end customer. Repackaging supplier-packaged goods to meet the specific requirements of the API manufacturer, offers a customized solution. The development of new biopharmaceutical APIs through the various clinical phases takes time and therefore attention should be paid at the beginning of the development phase to ensure that high quality raw materials are used in order to ensure that the production of the APIs will continue in the coming years, assuming that exact requirements for the origin of the raw materials in the bioprocess are defined at some point.

1. Zahn, P.K.; Sabatowski, R.; Schug, S.A.; Stamer, U.M.; and Pogatzki-Zahn, E.M. Paracetamol für die perioperative Analgesie. 


2. Deutsches Patent und Markenamt. “120 Jahre Aspirin,” n.d.
3. Kesik-Brodacka, M. Progress in Biopharmaceutical Development. 


4. Jozala, A.F.; Geraldes, D.C.; and Tundisi, L.L. Biopharmaceuticals from Microorganisms: From Production to Purification. 


5. Haider, R. Pharmaceutical and Biopharmaceuticals Industries: Revolutionizing Healthcare. 

The Challenge of CMC Regulatory Compliance for Biopharmaceuticals

, 3rd ed.; Springer Nature, Switzerland, 2019. DOI: 


7. Barone, P.W.; Wiebe, M.E.; Leung, J.C.; et al. Viral Contamination in Biologic Manufacture and Implications for Emerging Therapies. 


8. Schieving, A. The Most Common Grades of Reagents and Chemicals. 

, Feb. 27, 2018.
9. European Medicines Agency. ICH: Quality. 

 (accessed June 18, 2024).
10. Ohno, Y. ICH Guidelines—Implementation of the 3Rs (Refinement, Reduction, and Replacement): Incorporating Best Scientific Practices into the Regulatory Process. 

Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

Good Manufacturing Practice for Active Pharmaceutical Ingredients

, Step 5 version (2000).
14. Oshinbolu, S.; Wilson, L.J.; Lewis, W.; Shah, R.; and Bracewell, D.G. Measurement of Impurities to Support Process Development and Manufacture of Biopharmaceuticals. 


15. Shukla, A.A.; Jiang, C.; Ma, J.; et al. Demonstration of Robust Host Cell Protein Clearance in Biopharmaceutical Downstream Processes. 


16. Melo, C.C.; Fux, A.C.; Himly, M.; et al. Recovering What Matters: High Protein Recovery after Endotoxin Removal from LPS-Contaminated Formulations Using Novel Anti-Lipid A Antibody Microparticle Conjugates. 


17. McNulty, M.J.; Berliner, A.J.; Negulescu, P.G.; et al. Evaluating the Cost of Pharmaceutical Purification for a Long-Duration Space Exploration Medical Foundry. 


18. Almeida, C.; Pedro, A.Q.; Tavares, A.P.M.; Neves, M.C.; and Freire, M.G. Ionic-Liquid-Based Approaches to Improve Biopharmaceuticals Downstream Processing and Formulation. 

Biopharmaceutical production faces the challenge of ensuring the quality of raw materials due to a lack of specific guidelines. By implementing effective risk assessment strategies and working with reliable, selected solution providers, biopharmaceutical manufacturers can minimize these challenges and improve product quality.

The Quest for Quality: Challenges and Strategies in Raw Material Selection for Biopharmaceuticals

FDA has reopened the comment period for a June 14, 2024 Proposed Administrative Order concerning over-the-counter (OTC) monograph drugs that contain acetaminophen. The order (No. OTC000035), “Amending Over-the-Counter Monograph M013: Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use,” would, if approved, eventually require the addition of a warning label to such OTC products, alerting consumers that the use of acetaminophen can cause severe skin reactions (1).

Comments will be accepted beginning Aug. 8, 2024, continuing through Sept. 27, 2024.

“Today’s actions represent important milestones in FDA’s implementation of new authorities provided by Congress as part of OTC Monograph Reform,” said Theresa Michele, MD, director of the Office of Nonprescription Drugs in FDA’s Center for Drug Evaluation and Research (CDER), in a press release (2). “Today’s proposed order helps to ensure the safety and effectiveness of OTC drugs in our marketplace.”

FDA determined the risk of acetaminophen skin reaction to be “rare but serious” based on what the agency said was a “comprehensive scientific review of available data” (2). The warning language to be used would be the same, which follows below, as recommended in a 2017 final Guidance for Industry entitled 

Recommended Warning for Over-the-Counter Acetaminophen-Containing Drug Products and Labeling Statements Regarding Serious Skin Reactions

 Acetaminophen may cause severe skin reactions. Symptoms may include:

If a skin reaction occurs, stop use and seek medical help right away

The link between acetaminophen and skin reactions, at least as far as FDA is concerned, dates back to 2013, when a Drug Safety Communication identified the reactions as indicative of Stevens-Johnson Syndrome, toxic epidermal necrolysis, or acute generalized exanthematous pustulosis, all of which the agency said can be fatal (4). In addition to the risk factors listed above, FDA said at the time the reactions could also include “detachment of the upper surface of the skin.”

Those who develop a skin rash or reaction after using acetaminophen or another pain reliever or fever reducer are advised to discontinue use of the drug immediately, and to seek medical attention (4). Healthcare professionals are also instructed to assess these risks when evaluating patients, even though acetaminophen is commonly available as an OTC drug that does not require a prescription.

 announcing the reopening of the comment period for more information, and said that due to technical difficulties, comments cannot be submitted in the OTC Monographs@FDA portal. Instead, these must be sent using docket number FDA-2024-N-2422 

in the portal available at Regulations.gov

Amending Over-the-Counter Monograph M013: Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use

 (OTC Monographs@FDA, August 2024).
2. FDA. FDA Issues Agency-Initiated Proposed Order Regarding OTC Monograph Drugs Containing Acetaminophen. Press Release. Aug. 7, 2024.
3. FDA, 

Guidance for Industry, Recommended Warning for Over-the-Counter Acetaminophen-Containing Drug Products and Labeling Statements Regarding Serious Skin Reactions

Drug Safety Communication: FDA Warns of Rare But Serious Skin Reactions with the Pain Reliever/Fever Reducer Acetaminophen

The reopening of comments addresses the addition of a warning to consumers that acetaminophen may cause skin irritation characterized by reddening, blisters, and rashes.

FDA Order on OTC Monograph Drugs Containing Acetaminophen Gets Renewed Comment Period

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

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Decreasing the cost and time of drug development while advancing differentiated therapies with improved efficacy and safety is a priority for drug makers. Automation of activities across all aspects of drug development and manufacturing can help achieve these goals. Indeed, “automation can help the API industry with improved safety, productivity, product quality, and optimized costs, making it an essential tool for the industry to remain competitive and meet regulatory requirements,” states Raghavendar Rao Morthala, chief scientific officer, Navin Molecular. These benefits can be realized at all stages of development as well as across development and manufacturing.

Many applications for automation in API development and manufacturing

Automation in many forms has, in fact, been used for API development and manufacturing for many decades, according to Morthala. He points to examples such as electronic lab notebooks and electronic batch manufacturing records, statistical software for design-of-experiment studies employed in process optimization efforts, control systems for API manufacture in both batch and continuous mode, and inventory management and material movement solutions.

“Automation is used extensively in API synthesis,” emphasizes David Ford, senior director of chemistry at Snapdragon Chemistry, a Cambrex company. “While batch manufacturing processes are primarily executed under direction of a human following a batch record, automation is used for temperature and flow control (reagent dosing), as well as for safety interlocks. Continuous flow manufacturing processes use automation more extensively, as automation can be used for reliable start-up and shut-down of the reactor, clean-in-place operations to recover from a clog, and to divert reactor effluent to waste if the quality is expected to be poor,” he explains.

The above forms of automation, Ford says, make work more convenient, but an operator is still required to be present to initiate operations and complete the batch record. “In contrast, automation in the R&D lab can be used to run processes completely without operator intervention,” he observes. In this context, Ford explains, whether batch or flow processes, all steps including reagent charges, sampling, on-line or off-line liquid chromatography, and storage of product for further analysis can be automated.

Such automation tools can also be coupled with statistically powered experimental design or auto-optimization algorithms. “This type of automation can accelerate tasks that can be labor-intensive, such as process optimization and process characterization. Automation can, in addition, free a process development chemist or engineer to research more broadly in the literature or execute more high-level analysis of the data,” Ford comments.

In addition to accelerating physical experiments, literature search engines are available that continuously update comprehensive databases of identified and potential chemical substances, chemical transformations, and newer methodologies. “Using these automated systems, research scientists can quickly identify desired organic transformations and optimum reaction conditions, as well as gain insights into reactant and product properties and raw material sourcing options,” says Morthala.

It is important, cautions Jens Schmidt, process expert and high-throughput experimentation (HTE) manager at Lonza, to apply phase-appropriate automation techniques to ensure highly effective use of the technology across the entire lifecycle of a project. In the initial phase of a project, according to Schmidt, automation is particularly potent and extensively utilized in process development, commonly in the form of HTE.

“This technique facilitates the miniaturization and parallelization of chemical reactions, allowing for the rapid testing of a broad spectrum of reagents, solvents, catalysts, and conditions. It enables the assessment of various routes, thereby increasing the likelihood of identifying optimal conditions early in the project’s timeline,” he explains.

For example, Ford highlights the use of automation for screening of reagents, catalysts, or solvents to find beneficial combinations and automated workflows for measuring solubility and partitioning in liquid-liquid extraction to investigate isolation strategies for intermediates and APIs. “Such a screening approach can enable identification of useful combinations that would escape attention if experiments are performed manually because a much larger number of combinations can be screened in an automated context,” he notes.

As a project matures, HTE continues to play a crucial role, albeit in a slightly different capacity. The main goal is to aid in process optimization and characterization, thereby enhancing process robustness, notes Schmidt. He adds that automation during this phase also encompasses the standardization and automated execution of individual experiments, with the objective of delivering reliable and high-quality data.

“Upon reaching the commercial stage, automated experiment execution or HTE supports a diverse range of activities, including the optimization of established processes and the enhancement of process understanding,” Schmidt comments. Automation also contributes to the attainment of sustainability goals, the securing of supply chains, and the resolution of unforeseen issues. Of course, automation of large-scale manufacturing is a significant aspect that warrants consideration due to the numerous advantages it affords.

“Automation is transforming the landscape of API development and manufacturing. By automating tasks like route exploration, reaction optimization, and data analysis, researchers can significantly accelerate the identification of optimal synthetic pathways and fine-tune processes for maximum efficiency. These benefits translate to faster development times, reduced errors, and more consistent API production. For drug developers, that means reduced risk and uncertainty in API development, enabling a greater focus on clinical trials and regulatory approvals,” Schmidt concludes.

Using automation in synthetic route development

The concept of automated multicriteria evaluation of new process routes, combined with route development, is based on data mining, according to Morthala. “There is an increasing prevalence of chemical processes being developed based on automated experiments that make use of data science, which can provide multiple numeric criteria for scientists to reach a balanced decision on the suitability of a novel synthetic route,” he says.

Information generated via data mining can be used for chemical route development and evaluation, including planning of hypothetical synthetic routes, Morthala contends. Such efforts can take into consideration not only process conditions, but environmental indicators, such as energy consumption, E-factor values, solvent scores, reaction reliabilities, and route efficiencies allowing for multi-criteria environmental sustainability evaluations, he observes. “This type of automated workflow is based on deep data mining and algorithmic decision-support tools to enable multi-criteria decision making,” he says.

Small-molecule APIs are becoming more and more complex, and the resulting longer synthetic pathways pose challenges for process chemists to develop efficient API manufacturing processes. Overcoming these challenges is crucial to avoid delays in investigational new drug applications and expenses in transitioning new drug candidates from early development to commercial production, according to Simon Wagschal, associate director of advanced chemistry technologies, Lonza Small Molecules. “As the industry faces new drug candidates requiring over 20 synthetic steps on average, AI [artificial intelligence]-enabled predictive route design technologies have become essential for creating efficient retrosynthetic routes,” he says.

Indeed, AI-enabled API development tools are already being used by several R&D companies for the identification of optimized synthetic routes, according to Raghavendar Rao Morthala, chief scientific officer, Navin Molecular. “An AI platform has the potential to design and synthesize APIs in a matter of weeks or months, compared to the years it can take using conventional methods,” he says.

Currently, however, the application of AI to API synthetic route design is in its early stages, contends David Ford, senior director of chemistry at Snapdragon Chemistry, a Cambrex company. Synthetic route design by AI is used primarily at the brainstorming stage of route development, he says, with identified options narrowed down by humans. “Given the importance of the choice of a route or routes and the quantity of resources used to pursue them, the role of the synthetic chemist remains central in route design,” he states.

Wagschal adds that AI tools have traditionally been used for early-phase discovery, often generating routes not suitable for commercial-scale production.

Other exciting applications for AI in process development, Ford says, lie in its ability to manage knowledge. “Recent advances in large language models have made it possible to index and explore diverse sets of documents like weekly updates, PowerPoint presentations, technical reports, batch records, and campaign summaries,” he explains. These AI models allow for the content to be searched semantically, based on the meaning of the search, instead of by keywords.

“Given the volume of information trapped in these documents, it is very likely that work is forgotten, and hard lessons then need to be re-learned,” Ford observes. “We see great opportunity in helping researchers make connections between their work and the work that has been done in the past,” he notes. Generative AI models may also prove useful for preparing first drafts of templated documents like standard operating procedures, qualification protocols, and batch records, according to Ford.

Lonza, meanwhile, is one company not deterred by the limitations of early AI programs developed for scouting of synthetic routes for small-molecule APIs. “The introduction of computer-aided synthesis planning (CASP) technologies with route prediction capabilities has significantly influenced the route selection process,” says Wagschal.

Nearly all CASP tools employ a form of machine learning called Monte Carlo Tree Search to rapidly prioritize computationally predicted synthetic routes, Wagschal explains. This heuristic search method evaluates the likelihood of reaction success at each step of the proposed pathway, from starting materials through intermediates to the final API. The prioritized routes are then reviewed and refined by process chemists. “This approach, guided by our experts, has increased the number of potential strategies and led to more efficient API synthesis routes,” he states.

To overcome the limitations of early AI-based models for route development with respect to commercial practicality, Lonza has combined leading AI-powered predictive route design models with proprietary supply-chain data, including raw material costs, availability, and detailed supply chain intelligence, according to Wagschal. “This integrated technology allows process chemists to quickly identify not just the shortest pathways, but also the most commercially viable ones by considering real-world supply chain constraints. These advanced AI solutions provide a holistic view that streamlines route scouting and accelerates the transition from research and development to robust manufacturing processes, resulting in significant time and cost savings in developing complex APIs,” Wagschal concludes.

There are challenges to using automation tools for API development, though. Automation systems require substantial investment in hardware, software, and infrastructure, and thus can be expensive to commission, Morthala observes.

Access to relevant, high-quality data is also important, Morthala adds. For automated route development in particular, wide implementation of automated development and evaluation methodologies requires recognition of the value of reaction data currently being held in the cheminformatics community by the wider chemistry and chemical engineering community and publication of that data in a manner that ensures it is accurate and available electronically. “If this state can be achieved, it will be possible to leverage automation for process development on a wider scale,” contends Morthala.

One of the biggest challenges to benefitting from automation in API development in Ford’s opinion is that any automation tools need to at least perform as well as the highly trained and experienced process development scientists and engineers currently executing much of this work manually. “These experts have developed very efficient ways of doing their work and can easily adjust to accommodate a very wide range of process conditions, something that is difficult to achieve in an automated platform. Given that challenge, the key to succeeding in using automation is to identify areas where automation will have a fighting chance of adding value,” he comments.

Beyond having access to the right data and tailoring automation strategies to the specific stage of the project lifecycle, best practice for using automation in API development activities is to take a holistic approach. “First and foremost,” underscores Schmidt, “is to define clear objectives that allow for prioritization of tasks and processes that will most benefit from automation.”

It is also important, according to Schmidt, to ensure that automated workflows are reliable and thoroughly understood. Applying appropriate analytical techniques and where possible integrating advanced analytical tools into automation solutions will enable monitoring and optimization of processes. “Finally,” Schmidt observes, “promoting interdisciplinary collaboration to leverage diverse expertise and ensure cohesive integration of automation solutions, including those for data handling and treatment, across different phases of API synthesis will allow for full realization of the benefits of automation.” 

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

®
Vol. 48, No. 8
August 2024
Pages: 14–17

When referring to this article, please cite it as Challener, C.A. Automating Development of Small-Molecule APIs. 

A holistic approach to automation can provide benefits at all stages of development and manufacturing.

Automating Development of Small-Molecule APIs

Successful biomanufacturing processes not only provide the desired product in high yield and purity, they provide consistent results whether implemented in the lab or the production plant. For many monoclonal antibody (mAb) products, processes must consistently perform at scales ranging from hundreds of milliliters to thousands of liters. Lack of scalability can result in significant project delays and added cost due to the need for further optimization. Developing scalable processes from the outset is therefore the most effective approach to ensuring the smooth advancement of mAb projects through development to commercialization.

The main technical challenges faced during the scaling of upstream mAb processes include variations in cell densities, cell viabilities, and product concentration, as well as potential offsets in product quality attributes, according to a spokesperson from Boehringer Ingelheim. These attributes can be impacted by the bioreactor design, process parameters such as temperature and oxygen transfer, media composition, supplement and feed strategies, and numerous other factors. Obtaining process understanding is therefore essential to establishing robust, scalable processes.

“Addressing these scale-up considerations in upstream mAb process development ultimately comes down to the timeline, budget, and priority of the developer,” says Leslie Wolfe, site head and vice-president (VP) of process development at KBI Biopharma. She notes that it is imperative to fully understand what knowledge exists and what is needed as part of the scope to help support effective process design. Because time and cost are often the most important drivers during early phase development, there may be a necessary trade-off in the form of reduced process knowledge and understanding of the design space. “One potential consequence,” observes Lorenz Hasler, VP of global manufacturing, science, and technology at KBI Biopharma, “may be reduced knowledge of key inputs to process design regarding quality attributes and process performance and underestimation of considerations as they relate to commercial manufacturing equipment.”

Benefits of established platform processes

An important consideration for mammalian upstream processes for mAb production, notes Hasler, is that the potentially critical respective key scale-up factors are comparable between processes. “Process knowledge and expertise can therefore be leveraged between processes. Because potential key parameters and equipment limitations can be taken into consideration upfront, potential scale-up issues can be reduced,” he explains. Risk analysis tools, Hasler adds, can then be used to screen and understand other potential process variables specific to the mAb candidate and thereby mitigate potential process risk at scale.

The best approach to ensuring scalability of mAb production is to use a platform process rather than focusing on individual project variations, observes the spokesperson from Boehringer Ingelheim. Taking this approach, it is possible to manage challenges to scalability using standard equipment (bioreactors).

Wolfe agrees that working with an established and scalable platform is key to mitigating the risks associated with scaling up. She notes that such a platform is typically developed through iterative application, which helps in establishing critical process knowledge.

“This knowledge and understanding form the foundation for establishing a process control and monitoring strategy tailored to each unit operation, leading to a potentially robust and reliable scale-up approach,” says Hasler. Platform processes may also speed up development activities because process development, and facility-fit assessments can leverage process knowledge and understanding, he adds. These platforms also help balance the timeline-versus-process-knowledge conundrum for programs with aggressive development timelines.

Relying on platform processes to ensure scalability must be pursued with some caution, however. “Conditions and predictions to perform a process at scale or commercial process for any new drug substance or drug product still need to be demonstrated at laboratory or pilot scale,” Hasler states. Additional information may also be needed to support the requirements of specific mAb-based candidates. When necessary, for instance, Boehringer Ingelheim uses computational fluid dynamics and process modeling, including detailed equipment characterization, to ensure smooth scale-up.

To ensure scalability for upstream mAb processes, designing an efficient process complemented with an effective process control approach is critical and should be tackled during early process development, according to Hasler.

For Boehringer Ingelheim, a critical aspect of its scalability approach for mAb processes is the selection of a robust clone during early development. The chosen clone, says the company’s spokesperson, should not only fit the platform, but also exhibit robustness in relation to classical scaling parameters.

Even when a platform process is employed, Hasler recommends generating process knowledge for a specific mAb candidate using design-of-experiment studies, which help in defining the relationships and multivariate interactions between various process parameters and resulting outputs. He notes that it is also crucial to develop compelling analytical methods to support these small-scale studies. Demonstrating scalability of upstream mAb processes at an intermediate scale is beneficial as well, according to Wolfe, as doing so helps to de-risk scale-up to manufacturing.

Finally, Hasler comments that for mAbs with expedited approval designations, the shortened development timelines may lead to a reduced approach to process design and, therefore, reduced process knowledge and understanding. To balance the potentially reduced process development activities, he suggests that a detailed gap identification and subsequent risk evaluation may support potential scale-up considerations and success.

Consistent scale-up through platform approach

Platform processes not only streamline the development of scalable processes, they also make it possible to use a consistent approach to scale-up across all mAb-related projects. That is the case at Boehringer Ingelheim. “We do not test different scale-up strategies for our projects, as our scale-up strategy is not influenced by the specific product being expressed. Whether the product is a standard IgG1 [immunoglobulin G1] antibody or a trispecific molecule, the scale-up strategy generally remains the same,” says the spokesperson from Boehringer Ingelheim.

While general scale-up strategies also apply to more complex or advanced antibody-based therapeutics, Wolfe observes that appropriate risk assessments should be conducted and considered with more complex therapeutic targets to ensure sufficient knowledge is available. “Using this approach ensures the target product quality profile is achieved from the defined process,” she concludes.

®
Vol. 48, No. 8
August 2024
Pages: 18–20

When referring to this article, please cite it as Challener, C.A. Considering Process Scaling for Monoclonal Antibodies During Early Phase Development. 

Platform processes and effective risk assessments help overcome time and cost challenges.

Considering Process Scaling for Monoclonal Antibodies During Early Phase Development

BioIVT has launched new cleanroom manufacturing space in Winchester, Va. A research partner and biospecimen solutions provider for drug and diagnostic development, the company partnered with Germfree, a provider of modular cleanroom infrastructure and services, to build the space, according to an Aug. 1, 2024 company press release.

The cleanroom comprises design and solutions from Germfree that boost BioIVT’s capabilities in cell and gene therapy (CGT) development. The integration of cleanroom processes will include BioIVT’s good manufacturing practice (GMP)-compliant raw materials for supporting CGTs, including Human AB serum.

“This facility will play a significant role in our expanding portfolio of GMP-compliant products,” said Parijat Jain, vice-president of Cell & Gene Therapy at BioIVT, in a company press release. “The cleanroom was designed in collaboration with Germfree, relying on their extensive expertise to build a facility that will support client-specific manufacturing requirements and configured for high-volume production enabling product use in late-stage clinical and commercial manufacturing. We continue to evolve and strengthen our support for the development of CGT research, and our future-ready cleanroom will provide expanded capabilities and access to developers.”

The new space is purpose built to support workflows for excipient and ancillary material bioprocessing. The cleanroom ensures quality and regulatory compliance and includes the following features:

qualified in accordance with FDA requirements

FDA-current GMP, International Organization for Standardization, ion selective electrode, Center for Disease Control–Biosafety in Microbiological and Biomedical Laboratories, and American Society for Testing and Materials tested

heating, ventilation, and air conditioning controls systems

high efficiency particulate air filtration.

"We at Germfree are honored to contribute to BioIVT's groundbreaking manufacturing space by providing our modular cleanroom technology,” said Kevin Kyle, CEO, Germfree, in the press release. “This new facility reflects BioIVT's dedication to advancing biospecimen solutions and scientific research, and the company’s deep experience in helping manufacturers build cutting-edge facilities. We are excited to support their mission and look forward to the innovative achievements that will benefit the life sciences and pharmaceutical industries, fostering advancements in research and development."

The cleanroom addition is the latest in a series of expansions BioIVT has pushed forward. In February 2024, the company increased its capacity for delivering readily available fresh, standard, and mobilized human leukopaks (1). The additional capacity further builds the company’s ability to scale its network of diverse and highly characterized cell donors. Earlier in October 2023, BioIVT expanded its biospecimen portfolio with the launch of its new Center for NeuroExcellence. Through this center, BioIVT can offer neurology researchers a single source from which they can obtain supplies, from controls to difficult-to-collect biofluid samples from populations with neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (2).

1. BioIVT. BioIVT Announces Expansive Fresh Leukopak Capability in Europe. Press Release, Feb. 22, 2024.
2. BioIVT. BioIVT Expands its Biospecimen Portfolio in Support of Neuroscience Research. Press Release, Oct. 27, 2023.

BioIVT opened new cleanroom manufacturing space, using Germfree’s technology to boost its capabilities for cell and gene therapy development.

Partners BioIVT and Germfree Open New Cleanroom Manufacturing Space at US Site

The new additions to the company’s equipment at its early phase clinical manufacturing facility in Oregon will allow for cleaning, filling, capping, and sealing, and also detecting defects in drug products.

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