Behind the Headlines Episode 27

Ask the Expert

Small Molecules, APIs, and Excipients—Trends, Challenges, and Opportunities

Drug Digest September 2025

Artificial intelligence, machine learning, and novel instruments are helping drug developers.

Enhancing Bioanalysis and Drug Development with Advanced Tools and Technologies

J.P. Morgan Report Lists Biologics, Obesity, China

Top Trends Reshaping Pharma R&D

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

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The Davos Alzheimer’s Collaborative (DAC), led by the World Economic Forum and the Global CEO Initiative on Alzheimer’s Disease, announced on April 22, 2025 that it has selected the genomic sequencing company PacBio as its technology partner in the launch of a new project, the North African Dementia Registry (NADR) (1).

Other partners, according to a press release, include the Institute of Global Health and Human Ecology (I-GHHE) at The American University in Cairo (AUC), and UCL Queen Square Institute of Neurology at University College London (UCL) (1). The purpose of the project is to develop a high-quality and comprehensive multi-omics dataset that will serve to advance the research community’s understanding of Alzheimer’s disease genetics, and those of other forms of dementia, in diverse populations around the world.

Data generated by the efforts of the collaboration will be made accessible via a worldwide research platform, the Alzheimer’s Disease Data Initiative (1).

The NADR, which desires to address an underrepresentation of North African populations in dementia research, is part of DAC’s goal of investing more than $700 million to accelerate innovation in drug development and healthcare approaches to Alzheimer’s disease (2).

“This collaboration will bolster our understanding of Alzheimer’s disease in a region characterized by remarkable genetic diversity,” Vaibhav Narayan, DAC executive vice-president, said in the press release (1). “Over time, these insights will inform locally relevant prevention and intervention strategies for communities often overlooked in global research efforts.”

“Addressing the global challenge of dementia requires diverse, high-quality datasets. With PacBio’s technology and workflows, we can accelerate our understanding of the genetic architecture of populations in North Africa and uncover novel biomarkers and potential therapeutic targets,” Mie Rizig, PhD, UCL NADR lead and clinical senior research fellow in the Department of Neuromuscular Diseases at UCL Queen Square Institute of Neurology, said in the release (1).

The number of people living with dementia is forecast to as much as triple, to 139 million individuals, by the year 2050 (2). Currently, three out of four people with dementia are not only never treated for it—they aren’t diagnosed.

“With a population exceeding 110 million, Egypt serves as a unique bridge between Africa and the Middle East, offering a rich tapestry of genetic and cultural heritage,” said Mohamed Salama, AUC-NADR lead and professor at AUC’s I-GHHE, in the press release (1). “This collaboration not only promises to benefit the Egyptian population but also aims to advance our collective understanding of dementia in the region and beyond.”

“We are proud to partner with DAC, AUC, and UCL on this important project to advance our understanding of the genetics of Alzheimer’s disease, and hopefully help researchers identify new diagnostic tools and therapeutic solutions,” said Neil Ward, vice-president and general manager of EMEA at PacBio, in the release (1). “Our long-read sequencing technology is uniquely suited to deliver the high-quality genomic data needed to explore the complex genetic landscape of Alzheimer’s disease. This initiative aligns with our commitment to enabling genomic discoveries that improve human health worldwide.”

At the American Society of Gene and Cell Therapy (ASGCT) conference in Baltimore, Md., in May 2024, 

® sat down with Nadia Sellami, PhD, global segment lead for gene and cell therapy at PacBio, about the benefits of long-read sequencing in cell and gene editing (3). That video interview can be viewed in full at 

1. Davos Alzheimer’s Collaborative. Davos Alzheimer’s Collaborative Selects PacBio as Technology Partner for Global Project to Advance Alzheimer’s Disease Research in North Africa. Press Release. April 22, 2025.
2. Comments received via email correspondence on April 22, 2025.
3. Spivey, C. 

The Benefit of Long-Read Sequencing in Gene Therapies.

Articles

The project, the North African Dementia Registry, will unite multiple entities for the purpose of developing a comprehensive dataset to advance the research community’s understanding of Alzheimer’s disease and other dementias in diverse populations.

PacBio Chosen as Tech Partner for Global Alzheimer’s Disease Research Project

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

Industry Outlook 2025: Mergers, Acquisitions, and Funding

According to Erik Wiklund, CEO of Circio, the bio/pharmaceutical industry has seen a trend toward fewer, but larger mergers and acquisitions. During the COVID-19 pandemic, biotechs had ample access to venture capital and public funding; however, since the pandemic, capital has dried up, as valuations have plummeted and investors have lost money. In addition, a looming patent cliff is also straining revenue expectations.

“Both of these forces can converge into larger and later-stage deals, so investors are likely to buy into later-stage de-risked programs with clinical validations, Stage II, Stage III, [with a] clear path to approval, and that's probably where the M&A deals are and will continue to happen,” Wiklund says. “Investors are looking for lower-risk assets with a clear development path closer to the clinic. Unfortunately, for a company like ours, which is building a really exciting new gene therapy technology platform, it has become difficult to fundraise in the current environment. This forces companies like Circio to prioritize asset generation, picking a track and going deep in one single area, rather than to scientifically develop the platform to its full potential which would have been the standard strategy three years ago, where Big Pharma and investors were looking for technology platforms with broad therapeutic potential.”

Click the above video to watch the interview.

Erik Wiklund, PhD, is CEO of Circio. He has deep scientific knowledge in RNA and cancer biology, and 13 years of pharma and biotech industry experience in a variety of functions including R&D, finance, and business development. Previous employment includes the radiopharmaceutical company Algeta, which was acquired by Bayer in 2014, Aker Biomarine, and management consulting experience from the Pharma & Health Care practice of McKinsey & Company. Wiklund holds a PhD in Molecular Biology from Aarhus University, Denmark, and the Garvan Institute of Medical Research, Sydney, Australia

Videos

Pharmaceutical Technology® Group spoke with Erik Wiklund, CEO of Circio, about the future of M&A in the bio/pharmaceutical industry and the struggle small biotech companies face raising funds.

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Roche announced on April 22, 2025 that it will be investing $50 billion into its United States footprint between now and 2030, a commitment that is expected to create more than 12,000 jobs—including almost 6500 in construction—and 1000 jobs at new and expanded facilities (1).

The plans that have been announced for those facilities cover eight states in the US, although a location has yet to be disclosed for a proposed 900,000-square-foot manufacturing center to support Roche’s expanding portfolio of next-generation weight loss medicines (1). Sites in California, Indiana, Kentucky, New Jersey, and Oregon will receive expanded and upgraded manufacturing capabilities for innovative medicines and diagnostics; expansion and upgrading of existing pharmaceutical and diagnostics R&D centers in Arizona, California, and Indiana will also be part of the investment.

Additionally in Indiana, there are plans to build a new manufacturing facility for continuous glucose monitoring. A state-of-the-art gene therapy manufacturing facility will be built in Pennsylvania, and a new R&D center is planned in Massachusetts, where Roche said cutting-edge artificial intelligence (AI) research would be conducted, with the facility serving as a hub for the company’s new R&D efforts in the cardiovascular, renal, and metabolism spaces (1).

“Roche is a Swiss company with a strong heritage in more than 130 countries globally. Today’s announced investments underscore our long-standing commitment to research, development, and manufacturing in the US,” Thomas Schinecker, Roche Group CEO, said in the press release (1). “We are proud of our 110-year legacy in the United States which has been a key driver for jobs, innovation, and the creation of intellectual property in the US, across both our Pharmaceutical and Diagnostics divisions. Our investments of $50 billion over the next five years will lay the foundation for our next era of innovation and growth, benefiting patients in the US and around the world.”

Roche said that when the new and expanded manufacturing capacity all comes online, the company will be exporting more medicines from the US than it imports; its diagnostics division already has an export surplus from the US, according to the press release (1). That may be especially relevant given the uncertainty surrounding tariffs being imposed by the US, and reciprocation from other countries, which were 

 at INTERPHEX 2025 in New York City from April 1–3.

“We have seen a few companies that are our customers that are reaching out to look at automated manufacturing stateside, where they had [previously] been producing the parts overseas,” Peter Sarvey, head of sales at Automation NTH, told 

® at the conference (2). “So I think that’s the end result, and the end goal, I’d have to imagine, is to bring that manufacturing back [to the US].”

Some of Roche’s other activity thus far in 2025 was covered 

 series. In that discussion, industry experts included Roche’s unveiling of a new class of next-generation sequencing with its novel sequencing by expansion technology, as part of a larger conversation about new genomics tools (3,4).

Prior to the announcement of the $50 billion investment, Roche’s US footprint included more than 25,000 company employees at 15 R&D centers and 13 manufacturing sites (1).

1. Roche. Roche to Invest USD 50 Billion in Pharmaceuticals and Diagnostics in the United States over the Next Five Years. Press Release. April 22, 2025.
2. Lavery, P. 

Tariff Pause Reinforces Uncertainty Among Biopharma Professionals.

Behind the Headlines Episode 12–Cell and Gene Therapies, New Genomics Tools, and Recent Partnerships.

, March 5, 2025.
4. Roche. Roche Unveils a New Class of Next-Generation Sequencing with its Novel Sequencing by Expansion Technology. Press Release. Feb. 19, 2025.

The commitment will include new, state-of-the-art R&D facilities as well as new or expanded manufacturing sites in multiple states.

Roche to Invest $50 Billion in US Pharmaceuticals and Diagnostics

Industry Outlook 2025: The Impact of Politics on Pharma

The political landscape is evolving and unpredictable at the moment, according to Edwin Stone, CEO of Cellular Origins, and the development of an inward focus by the United States might have a negative impact on the development and manufacturing of emerging treatments. Collaboration when tackling complex biology to treat complex diseases is necessary between the US, Europe, and beyond, says Stone.

“For a long time, I've always been hopeful and optimistic, and frankly, my confidence is a little shaken now that Asia, and particularly China, can be bought into the fold,” Stone says. “There's an awful lot going on in advanced therapies in China that we do not see in Europe or the US, and similarly, vice versa. Unfortunately, it looks like in the immediate term, we may see a backing off on that. Now, what we don't know is how much narrative transfers into reality there. And there is some suggestions, I think, that perhaps actually the reality will be a bit more tempered, some saber rattling and some strong signals early on to get some positioning. And hopefully, actually what we're seeing is a level of pragmatism come into that, because I really am a great believer that for the sort of problems we attack on now, if we work together, we'll have a chance to actually move these things forward and move these things forward a lot quicker. And let's remember this is for the benefits of patients and for people. It is not just about profits.”

Click the video above to watch the full interview.

The PharmTech Group interviewed Edwin Stone, CEO of Cellular Origins, about the impact of the changing political landscape on the pharmaceutical industry.

Artificial intelligence (AI) precision medicine company Sonrai Analytics and next-generation AI technology specialist Paige have announced a strategic partnership that both parties say will allow researchers, pathologists, and clinicians in the bio/pharmaceutical space to harness emerging AI capabilities for R&D of precision medicines (1).

The announcement, made on April 16, 2025, further clarified that Paige’s state-of-the-art foundation models would be integrated with Sonrai’s intuitive cloud-based data analysis and bioinformatics platform (1).

“We are thrilled to partner with Paige to unlock new possibilities for biopharma researchers and clinicians,” Darragh McArt, CEO and founder of Sonrai Analytics, said in a press release (1). “By combining our Sonrai Discovery platform with Paige’s foundation models, we are making AI and machine learning [ML] more accessible, enabling researchers to extract deeper insights from their data and accelerate precision medicine breakthroughs.”

Sonrai Discovery is Sonrai Analytics’ flagship product, which has the aim of expediting identification and development of therapeutic targets through the use of AI, thus improving patient outcomes (1).

"Our goal has always been to build best-in-class AI technology that is accessible to as many users as possible,” Razik Yousfi, CEO and CTO at Paige, said in the press release (1). “Our partnership with Sonrai further drives this vision, providing a wider audience of researchers access to Paige's foundation models through the Sonrai Discovery platform. This will ultimately accelerate pharma research and discovery globally, accelerating the new wave of AI-driven biomarkers in cancer and other diseases.”

AI has been a hot topic for the bio/pharmaceutical industry in the early part of 2025. AI-based computational models will be a part of 

FDA’s new approach to reducing, refining, or replacing animal testing

 in the development of monoclonal antibody therapies (2). Siemens has an agreement in place to 

acquire the life sciences R&D software provider Dotmatics,

 a move that extends Siemens’ AI-powered product lifecycle management portfolio into the life sciences market (3).

In March 2025, survey data released jointly by The Pistoia Alliance and the Copyright Clearance Center suggested that 

agentic AI is identified by pharmaceutical industry leaders

 as the technology that will have the most significant impact on the field in the next two to three years (4).

Alexander Seyf, CEO and co-founder of Autolomous, 

 that AI can and should be used as another tool in the toolbox, but can’t be the solution to everything.

“AI and ML can help us to do the leg work, but the main work is going to need to be done by our own brain, by human beings,” Seyf said in an April 2025 interview (5).

Similarly, at INTERPHEX 2025, Peter Sarvey, head of Sales for Automation NTH, illustrated an example 

 if not take over, processes that were formerly entirely performed by humans.

“There are a lot of inspections that previously were done manually, because it's not a simple pattern match for if this medical device or this pharmaceutical component is a reject,” Sarvey said (6). “Now we can teach the AI what a good part looks like, what a bad part looks like, and then over time, shift that area too, all in the nature of increasing throughput and decreasing yield loss.”

1. Sonrai Analytics. Sonrai and Paige Partner to Bring Advanced Machine Learning Capabilities to Biopharma. Press Release. April 16, 2025.
2. FDA. FDA Announces Plan to Phase Out Animal Testing Requirement for Monoclonal Antibodies and Other Drugs. Press Release. April 10, 2025.
3. Siemens. Siemens Acquires Dotmatics to Extend AI-Powered Software Portfolio to Life Sciences. Press Release. April 2, 2025.
4. The Pistoia Alliance. Life Science Professionals say Agentic AI to Have Most Impact in Next 2-3 Years, but 51% Cite Resistance to Change as Biggest Barrier to Innovation. Press Release. April 3, 2025.
5. Thomas, F. and Haigney, S. 

Industry Outlook 2025: Technology as a Supporting Element.

, April 14, 2025.
6. Lavery, P. and Haigney, S. 

INTERPHEX 2025: AI and Automation in Pharma.

Paige, Sonrai Form Partnership to Harness AI for Precision Medicine R&D

Video interview at DCAT with Frank Romanski, PhD, from Lonza CHI

Inside Lonza CHI’s Innovation Engine: Future-Ready Capsules for Complex Drugs

Frank Romanski, Ph.D., Global VP of Strategic Growth & Revenue Management at Lonza CHI, shares how the company is advancing both product and process innovation to support the next generation of pharmaceutical therapies. From addressing the challenges of biologics and complex formulations to delivering sustainable manufacturing solutions and unmatched service, Lonza CHI is partnering with customers to meet the evolving demands of the pharma industry. Ultimately, Lonza CHI is helping bring smarter, more effective drug delivery systems to life globally.

How Lonza Capsules & Health Ingredients (CHI) is redefining drug delivery with cutting-edge capsule innovation, customer-first service, and a strong commitment to sustainability

Inside Lonza CHI’s Innovation Strategy: Future-Ready Capsules for Complex Drugs

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FDA Commissioner Martin A. Makary, MD, has announced a policy directive that will limit employees of companies regulated by FDA, such as pharmaceutical companies, from serving as official members of FDA advisory committees (1). In a press release on April 17, 2025, the agency said the change was made in an attempt to boost public trust in FDA decisions, and to improve the operations of the committees.

“While [FDA] should be partnering with industry to ensure a user-friendly review process, the scientific evaluation of new products should be independent,” Makary said in the release (1). “Industry employees are welcome to attend FDA advisory committee meetings, along with the rest of the American public, but having industry employees serve as official members of FDA advisory committee members represents a cozy relationship that is concerning to many Americans. In fact, [FDA] has a history of being influenced unduly by corporate interests.”

As Makary mentioned, the new policy will not preclude any employees of FDA-regulated companies from attending, or presenting their views, at committee meetings—or even continuing to be selected to serve as representative members when required by statute (1).

Seeing as FDA uses its advisory committees to obtain independent advice and recommendations from experts in areas such as scientific, technical, and other policy decisions, exceptions will be made to the new policy in cases where an individual’s scientific expertise is of unique use to an FDA committee. However, Makary said, such exceptions will be rare, and are contingent on the employee strictly complying with applicable ethics requirements (1).

“Public trust in the healthcare-industrial complex is at an all-time low,” Makary said. “We need to restore impeccable integrity to the process and avoid potential conflicts of interest.”

Previously, on April 10, FDA announced it intended to 

 in the development of monoclonal antibody therapies and other drugs, in favor of “human-relevant” methods the agency said are more effective, including the integration of artificial intelligence-based computational models in some cases (2).

Makary’s swearing in as FDA commissioner

 on April 1, after a bipartisan vote in the United States Senate (3). The confirmation came among changing tides at the agency, just one day after 

 who had previously been director of FDA’s Center for Biologics Evaluation and Research (CBER) (4). Patrizia Cavazzoni, the previous director of FDA’s Center for Drug Evaluation and Research (CDER), 

 at the same time that prior FDA Commissioner Robert Califf was also stepping down (3,5).

1. FDA. FDA Commissioner Makary Announces New Policy on Individuals Serving on FDA Advisory Committees. Press Release. April 17, 2025.
2. FDA. FDA Announces Plan to Phase Out Animal Testing Requirement for Monoclonal Antibodies and Other Drugs. Press Release. April 10, 2025.
3. FDA. Martin A. Makary, MD, MPH, Sworn in as FDA Commissioner. Press Release. April 1, 2025.
4. Marks, P. 

Letter to Sara Brenner, MD, MPH Acting Commissioner of Food and Drugs US Food and Drug Administration

.
5. CDER Trade Press. CDER Director Patrizia Cavazzoni to Retire from FDA. Email Correspondence. Jan. 10, 2025.

The policy announced by Commissioner Martin A. Makary, MD, will not preclude employees of regulated companies from presenting their views to committees, and rare exceptions will be allowed.

FDA Announces New Policy on Advisory Committee Members

The United States Centers for Disease Control and Prevention (CDC)’s Advisory Committee on Immunization Practices (ACIP) has recommended Bavarian Nordic’s recombinant vaccine for the prevention of disease caused by chikungunya virus (1). Bavarian Nordic, which is based in Denmark, reported the recommendation of the virus-like particle (VLP)-based, single-dose injection (brand name Vimkunya) on April 16, 2025.

 in February 2025 for use in individuals age 12 and older, the same group for which ACIP’s recommendation was made (1,2). It had also been 

 by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency at CHMP’s January 2025 meeting (3).

ACIP has recommended the vaccine for those, again, age 12 and older, who may be traveling to a country or territory where there is a chikungunya outbreak (1). It also may be considered for persons who are traveling or residing in a locale without an outbreak, but where there is elevated risk for US travelers if their stay is planned for an extended length of time.

“ACIP’s recommendation of our chikungunya vaccine for Americans aged 12 and older is a big step forward to expanding access to this vaccine in the United States,” Paul Chaplin, president and CEO of Bavarian Nordic, said in a company press release (1). “Chikungunya is an emerging public health threat around the world, and today’s decision is another milestone in our mission to protect more people from this virus.”

The disease known as chikungunya is mosquito-borne and is caused by the virus of the same name (1). It has been identified in more than 110 countries in the past two decades, including numerous travel destinations in Asia, Africa, and the Americas, and evidence of transmission has been observed in more than 50 countries since 2020. Bavarian Nordic characterizes outbreaks as often large and unpredictable.

Symptoms usually include fever, rash, fatigue, headache and often, according to Bavarian Nordic, severe, incapacitating joint pain (1). While most patients recover in one to two weeks, up to 40% of those with the disease have the chance of developing months- or yearslong chronic arthritis. Worldwide chikungunya cases were reported to have increased by more than 20% in 2024 over 2023, equating to approximately 620,000 diagnoses. However, Bavarian Nordic said data has suggested that case numbers are “severely” underreported, with many misdiagnosed as dengue fever (1).

ACIP’s recommendation is pending final approval by the director of the CDC, and by the US Department of Health and Human Services. The Bavarian Nordic vaccine is supplied in a single-dose, 1-mL glass pre-filled syringe, with a dose volume of 0.8 mL (1).

1. Bavarian Nordic. Bavarian Nordic’s Chikungunya Vaccine Receives Recommendation from US CDC’s Advisory Committee on Immunization Practices (ACIP). Press Release. March 16, 2025.
2. Bavarian Nordic. Bavarian Nordic Receives U.S. FDA Approval of Chikungunya Vaccine for Persons Aged 12 and Older. Press Release. Feb. 14, 2025.
3. EMA. Meeting Highlights from the Committee for Medicinal Products for Human Use (CHMP) 27-30 January 2025. Press Release. Jan. 31, 2025.

The recombinant vaccine, under the brand name Vimkunya, is recommended for persons age 12 and older who are traveling to a country or territory where there is a chikungunya outbreak.

Bavarian Nordic Chikungunya Vaccine Recommended by CDC's ACIP

Nishant B. Thakar, RPh, PharmD is assistant professor Clinical Sciences, Roosevelt University College of Science, Health, and Pharmacy.

Varanya Chaiyaperm, RPh, PharmD is clinical assistant professor, University of Illinois College of Pharmacy.

compounding pharmacist at work 2 | Image Credit: ©Nadia -stock.adobe.com

Drug calculations for the formulation of dosage forms and associated preparations are key activities in pharmaceutical compounding. Calculations determine the amount of drug identified in the request for compounding. Correct drug calculations for compounded preparations are essential; if drug calculations are incorrect, resulting preparations will be incorrect—potentially with significant therapeutic and technical consequences.

This paper is the first in a series of discussions that address drug calculations and related topics for small-molecule compounding. Series discussions are applicable to essentially all compounding in 503A pharmacies, 503B outsourcing facilities, pharma industry R&D including clinical drugs, non-product laboratory preparations, and other applications. Series discussions will reflect academic teaching and compounding practice experiences. Textbooks traditionally provide the foundation for calculations (1–3); content in this paper addresses workplace applications and potential hazards (i.e., what might go wrong?) (4). Concepts that are often omitted, confused, or otherwise misunderstood that affect the accuracy of calculations are described. Topics address small-molecule compounding; large-molecule biologic drugs are not compounded (5,6).

Part one in the series addresses terminology, regulations, and labeling respective drug types. Subsequent topics will include numeric calculations, moisture, material losses, and related topics that build on prior publications (7,8). Drug calculations begin with the medication order—individual prescription, hospital order, 503B outsourcing batch, pharma clinical supply request, research formulations, or other request for a compounded preparation. The medication order identifies the desired active moiety by proprietary or generic name along with the duration of treatment. Types of drugs used in compounding are identified. Compounding personnel must select an appropriate drug for compounding—there may be multiple choices—and calculate its amount. Drug selection must integrate patient considerations, physicochemical properties, material handling, and other applicable considerations. After drug selection, calculations are executed; each drug requires different calculations. Post calculations, labeling must clearly define the compounded preparation. 

 shows an overview of calculations-related activities from medication order initiation through final dosage form dispensing and/or shipping; specific part one discussion topics are highlighted in red.

 Drug calculations process. (Figure courtesy of the authors)

 Drugs are known by a variety of terms depending on regulatory agency, country, site vernacular, and other considerations. Some of the more familiar terms include API, active substance, drug substance, bulk drug, bulk drug substance, active, bulk, and so on. “API” terms are more common in pharma industry (e.g., International Council for Harmonisation (ICH) Q7A 

Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients

 [9]); “bulks” language is common in compounding discussions (e.g., Bulk Drug Substances Used in Compounding Under Section 503A of the US Food, Drug and Cosmetic Act (FD&C Act) [10]; Bulk Drug Substances Used in Compounding Under Section 503B of the FD&C Act [11]).

. The active moiety is the part of the drug responsible for pharmacologic activity. In theory, the active moiety excludes molecule portions such as esters, counterions, complexes, chelates, clathrates, and waters of hydration that do not contribute to drug activity. The active moiety is contained within the drug molecule

it may be part or all of the molecule (e.g., diazepam is generally considered to be the active moiety and active drug in Valium). The distinction between active moiety and active drug is critical for understanding calculations and labeling in salt drugs.

. This discussion identifies several drug types relevant to compounding calculations; these are categorized per chemical structure as non-salt drugs and salt drugs. Non-salt drugs are also termed free acids or free bases; non-salt drugs have covalent and other non-ionic bonds. For compounding purposes, the active moiety of a non-salt drug comprises the entire drug molecule (i.e., active moiety is same as active drug).

Salt drugs are molecules with ionic bonds. Salt drugs are easily recognized by name (e.g., sodium drug, potassium drug, drug hydrochloride, drug acetate, and others that include counterions). Some non-salt drugs may be confused as salts (e.g., clindamycin phosphate is an ester; clindamycin palmitate hydrochloride is a salt of an ester). Reviewing the molecule structure is essential to determine the drug type. Some drugs may be available as either non-salt (covalent) molecules or as salts (e.g., phenobarbital and sodium phenobarbital; codeine and codeine phosphate), and either may be used in compounding with appropriate evaluation; their respective properties (i.e., pharmacologic and physicochemical) must be considered.

 Another type of salt drug, policy-exception salts, has also been identified. These molecules are specified in the 

/FDA salt policy and are dosed differently than salt molecules. Policy-exception salts require different calculations and labeling than salt drugs that comply with policy. Recognizing salt molecule structures is also important in electrolyte calculations.

. Peptides may be small-molecule drugs or biologics depending on their amino acid chain length (<40 amino acids are small molecules; >40 amino acids are biologic proteins). Peptides have covalent bonds between amino acids as well as ionizable groups and salts. FDA is currently reviewing data to definitively classify peptides within compounding bulk lists (12,13).

 This discussion also identifies several drug forms relevant to compounding calculations. Forms describe the concentration of drug moiety in the drug. Forms may be bulk solids assumed to be essentially 100% potent or pure; pharma industry and 503B outsourcing facilities commonly use bulk drugs for compounding. Forms may also be drugs at some concentration in solid or liquid mixtures; 503A hospital and community pharmacies are more likely to use drug mixtures (e.g., commercial sterile IV additives and commercial tablets) as drug sources for individual unit compounding. Commercial products used in compounding also contain functional formulation ingredients (filler, binder, coating, flavor, color, etc.) (14).

These ingredients must be evaluated before use; they may cause undesirable effects on patients (e.g., allergic reactions, lactose intolerance), be restricted by religious beliefs (15), or have incompatible physicochemical properties. Part two in this series will address numeric bulk drug calculations; part three will address numeric drug mixture calculations.

 The atomic mass (atomic weight) is the mass of an individual element expressed in atomic mass units (amu) or daltons (Da) (e.g., sodium = 22.99 amu). Atomic masses represent protons and neutrons in the atom structure; the atomic number represents protons; atomic mass decimals represent atom isotopes. The molecular mass (molecular weight) (MW) of a compound is the combined masses of individual elements, hydrates, solvates, and other molecule components (e.g., sodium chloride MW = Na + Cl = 58.44 amu). The active moiety molecular mass may be calculated based on the atomic weights of the individual elements in the active moiety. Also relevant is the number of active moiety components in the drug molecule (e.g., divalproex sodium contains two valproic acid active moieties). The molecular masses of the active moiety and drug are correlated to their respective gravimetric weights by calculating moles (mols) and millimoles (mmols). A mole is the weight in grams of the drug molecular mass (e.g., 58.44 grams = 1 mole of NaCl; 58.44 mg = 1 mmol of NaCl). Understanding moles is important to determine equivalent dosages of different drug salts.

 The most relevant drug name in compounding is the non-proprietary name. The non-proprietary name is the generic name of the drug; diazepam is a non-proprietary name. Non-proprietary names are approved by country regulatory agencies and the World Health Organization (WHO) and usually include a drug-name stem; (e.g., -caine [local anesthetics], -olone [steroids], and many others) (16). Proprietary drug names are commercial marketing names; Valium is a proprietary name.

 Pharmaceutical alternatives are drugs that have the same active moiety but are a different molecule (i.e., different salts or esters). Metronidazole is an active moiety; metronidazole hydrochloride and metronidazole benzoate are pharmaceutical alternatives. The same moles of pharmaceutical alternatives have the same pharmacologic effect (e.g., same moles of codeine, codeine sulfate, and codeine phosphate have different gravimetric weights but same pharmacologic effect). Pharmaceutical alternatives used for compounding must be approved drugs—not unapproved synthetic salts. Different drug salts may have different properties (solubility, pKa, lipophilicity, hygroscopicity, others [17]); substituting pharmaceutical alternatives requires evaluation of respective physicochemical properties. Pharmaceutical alternative dosages are determined using molarity calculations. Prodrugs are related but are different chemical compounds; prodrugs per se are not pharmaceutical alternatives; prodrugs are compounds that convert to an active moiety drug in the body.

Several other similar terms may be confused or misused when discussing pharmaceutical alternatives. Pharmaceutical equivalents are generic drugs—same drug, same dose, same route of administration, but different appearance. Therapeutic equivalents are the same as pharmaceutical equivalents (generic drugs) that have been tested for bioequivalence. Therapeutic alternatives, therapeutic interchange, and therapeutic substitution are related terms associated with drug substitution with same clinical effects as authorized through a hospital formulary (18).

There are numerous regulatory documents addressing product naming, dosage, and labeling for commercial products that are relevant to compounding (19,20). Respective 503A and 503B bulk drug lists identify approved drugs. Specific compounded dosage form labeling requirements are exempt from FD&C regulations identified in Section 503 (21). 503B compounded preparations must state “This is a compounded preparation” or similar wording (22). Selection, naming, and labeling of compounded dosage forms containing non-salt (covalent) active moieties/drugs is straightforward (23–25); non-salt active moieties are generally identical to their drug. Selection, naming, and labeling of compounded dosage forms containing active moieties that are salt molecules is more complex.

is the basis for FDA guidance (27,28) on calculating and naming salt drugs. The FDA guidance states:

“1. When a drug in a drug product is a salt, the drug product monograph title will contain the name of the active moiety (or neutral form) and not the name of the salt (e.g., ‘newdrug tablets’—not ‘newdrug hydrochloride tablets’).

2. The strength also will be expressed in terms of the active moiety (e.g., ‘100 mg newdrug’) rather than the salt strength equivalent (e.g., ‘123.7 mg newdrug hydrochloride’).

3. If the name and strength of a drug product are expressed in terms of the active moiety, the full name and full strength (or proportion, if CDER [Center for Drug Evaluation and Research] has determined proportion is more appropriate) of the drug (e.g., salt) will appear elsewhere on the drug product label and labeling.

4. The USP Salt Policy provides for exceptions to the ‘active moiety’ naming approach when the name of the salt conveys vital information from a clinical perspective. In these cases, the drug product monograph title will include the name of the salt, and the strength of the drug product also is expressed in terms of the salt form (drug).

5. USP does not anticipate changing existing monograph titles unless necessary for safety. USP and FDA have agreed to coordinate regarding any necessary retrospective name changes.”

FDA expects that new chemical entities that are salts will be named using the active moiety in accordance with the USP Salt Policy described above. However, the FDA guidance also identifies exceptions (#4 above) to this approach. Therapeutic and historic reasons are cited as justification for exceptions. Many historic drugs were dosed according to their drug weights including counterions (e.g., atropine sulfate, codeine phosphate, morphine sulfate). The following are salt drug policy-exceptions per FDA guidance (28):

Drug is a simple salt and administration is therapeutically important (e.g., lithium carbonate, iron sulfate and other intravenous iron, calcium gluconate and other calcium salts, potassium chloride, magnesium sulfate, and other common intravenous additives).

Scientific evidence demonstrates the salt form affects the absorption, distribution, metabolism, and excretion (ADME) that influences product selection.

Clinically significant amounts of cations (sodium, potassium, magnesium, calcium) accompany the active moiety of a drug product related to the daily electrolyte intake in special populations (e.g., sodium in cardiac treatment and potassium in renal treatment).

There is significant evidence-based safety concern that the counter-ion part of the salt could cause acid-base disturbances; hepatic, renal, or other organ damage; or hypersensitivity reactions.

The name of the salt is necessary to maintain consistency with other dosage forms of the same drug (salt). For example, drug products approved before 2013 with the salt in its established name and dosage based on the salt form would not change naming for a new dosage form with the same salt drug.

The USP Salt Policy should not be applied if there are relevant, documented safety reasons in a closely related product.

Compounded dosage forms are exempt from commercial product labeling requirements. 503A compounded dosage form labeling is also governed by state pharmacy regulations. Accurate compounded product labeling requires attention to detail (i.e., labeling “codeine” is not the same as labeling “codeine phosphate”).

The labeling of covalent compounded preparations is straightforward. Covalent active moieties are often the drugs in compounded dosage forms. The stated amount of drug must clearly identify the name and drug amount (e.g., Diazepam 10 mg tablets). Approved commercial product labeling containing the compounded drug may be checked to verify equivalence of active moiety and drug in labeling.

FDA guidance documents illustrate labeling of dosage forms containing salt drugs. The following examples illustrate the compounding dilemma involving salt drugs—are salt drugs labeled according to their active moiety or bulk drug? 

illustrates a salt drug label with active moiety as drug name. This label represents product in compliance with the drug salt policy (i.e., active moiety is the focus of compounding and associated calculations; ionic non-active counterions are in secondary labeling). Labeling of this type would have been approved after USP salt policy was implemented. Note active moiety on primary label and the drug (larger number) on side panel of label. Naming and labeling of salt drugs is applicable to compounded dosage forms.

Salt drug dosage form label–active moiety drug name. Note active moiety on primary label; side panel provides bulk drug calculation

 illustrates a policy-exception salt drug label with drug notation on the primary label and active moiety calculation in the side panel (i.e., opposite of 

). This label demonstrates labeling for a pre-2013 approved salt drug product—the entire salt drug amount (Olddrug palmitate) is dosed as the active moiety per USP salt-guidance exceptions. This approach is applied to compounded dosage forms involving drugs identified as exceptions to the salt policy.

Policy-exception salt drug dosage form label–bulk drug name. Note bulk drug name on primary label; side panel provides active moiety calculation. (Figure courtesy of the authors).

Several considerations are potential hazards to drugs selection, calculations, and labeling in compounded dosage forms. Understanding drug chemistry is fundamental. Misunderstanding of the USP salt policy causing dosage errors and labeling errors is an obvious problem. Labeling on approved commercial products may not be consistent with examples described previously.

Compounding personnel involved with the selection of drugs for compounding must have a good understanding of basic drug chemistry; molecular masses, moles, structures, and associated topics are relevant in compounding calculations. Selection of a drug is critical; molecule physicochemical properties may be relevant to compounding (e.g., valproic acid is an insoluble oil and divalproex sodium is a water-soluble solid). The choice of drug and evaluation thereof must be based on technical judgment. Regulations addressing drugs in compounding are also noteworthy; FDA has cautioned regarding use of semaglutide (Ozempic), semaglutide sodium, and semaglutide acetate; the aforementioned salt forms are not FDA-approved (29,30). FDA has also reminded compounding organizations to utilize sterile drugs when compounding sterile dosage forms (31).

 Drug information and labeling may be confusing, inconsistent, or have unusual formats; approved labeling may have been formatted before the USP salt policy became official. Practitioners may incorrectly assume differences between active moieties and drugs are inconsequential; drug dosage errors in salt drugs will depend on the respective molecule masses of active moiety and counterion. Worst-case molecule structure affecting dosing would be a small molecular weight active moiety and a large inactive counterion (sulfate, phosphate, mesylate, etc.). Depending on drug properties, even small-molecule counterions (hydrogen, sodium, potassium) may be significant; the phenytoin package insert cautions that phenytoin and sodium phenytoin have an 8% difference in dosage effects (32). Even when clinical effects are calculated to be minimal; calculations will be incorrect if the counterion molecular weight is overlooked.

 Drug overdoses occur when a drug exception is erroneously calculated to provide the active moiety amount as directed by the USP salt policy (i.e., salt policy is followed when it is not appropriate). For example, if codeine 30 mg was ordered and codeine phosphate drug amount was calculated as a new drug, the codeine phosphate calculated value (40 mg) would be 33% high. Codeine analgesic dosage historically has utilized 30 mg codeine phosphate or codeine sulfate—not codeine base (33,34).

. Drug underdoses occur when the drug is utilized as the active moiety without calculating the equivalent active moiety amount. For example, if clopidogrel 75 mg was ordered for compounding, but clopidogrel bisulfate was used, the clopidogrel active moiety dose (58 mg) would be 23% low.

Individual compounded dosage forms must be correctly labeled reflecting the active moiety and drug content. Labeling “codeine” when dosage and content is “codeine phosphate” is not accurate. Label space limitations may encourage labeling shortcuts that are inaccurate and incorrect. The Institute for Safe Medication Practices (ISMP) has identified labeling problems in compounded dosage forms and has recommended increased FDA guidance on compounded dosage form labeling (35). Drug shortages causing purchase of uncommon concentrations (e.g., heparin) have contributed to errors including fatalities 

 when personnel do not recognize concentration changes and do not recalculate drug amounts.

 Compounding personnel must be wary of inconsistent, confusing, or non-standard formats in labeling (

) that do not follow the FDA format described above. For example, metoprolol tartrate (Lopressor) is an immediate-release beta blocker that is dosed twice daily; metoprolol succinate (Toprol XL) is an extended-release metoprolol preparation formulated for once-daily dosage. Secondary labeling on metoprolol succinate products (37–39) references metoprolol tartrate to aid in transitioning patient dosage. Potassium phosphates injection (policy-exception drug) is labeled as phosphorus mmol/mL and potassium mEq/mL on the primary label and mg/mL amounts of potassium phosphate monobasic and potassium phosphate dibasic equivalent amounts of potassium and phosphate on the side panel (40,41). Succinylcholine labeling may be inconsistent or different format (e.g., same concentration products may be labeled as total drug mg/vial (42–44). These labels were likely approved before the salt policy was implemented and have not been updated.

Part one of this series addresses pharmaceutical principles including terminology, regulations, and dosage form labeling in compounded preparations. Types of drugs are identified. Non-salt (covalent) drugs and salt (ionic) drugs are primary groups; certain salt drugs are further grouped as policy-exception salts. Policy-exception salts are dosed as non-salt drugs including their molecule counterions; labeling must identify the equivalent active drug amounts. Forms of drugs are also identified. Drug formsmay be solids or liquids; they may be bulk drugs or drugs in mixtures; mixtures may include solutions, mixtures of solids, and commercial products (e.g., tablets). 

 summarizes the drug types, dosage rationale, forms, active moiety identification, primary labeling, and secondary labeling. The USP salt policy, historical precedent, and identified exceptions are the bases for these requirements; note significant labeling differences between salt drugs and policy-exception salts. Problems associated with the above are identified. Effects resulting from misunderstanding of drug salt principles may include overdosing or underdosing of dosage form active moiety. Mislabeling of dosage form content is also possible; attention to detail is critical. Labeling may have variations for a variety of reasons. Careful reading of commercial product labeling with good understanding of principles is mandatory for compounded product applications.

503A pharmacy labeling is also regulated by state agencies.

 edition. Wolters Kluwer/Lippincott, Williams, & Wilkins, Philadelphia, PA, 2013.

 edition. John Wiley & Sons, Hoboken NJ, 2017.

Pharmaceutical Compounding Calculations in The Art, Science, and Technology of Pharmaceutical Compounding

 ed. American Pharmacists Association, Washington, D.C., 2020.

https://database.ich.org/sites/default/files/ICH_Q9%28R1%29_Guideline_Step4_2023_0126_0.pdf

ASHP. Compounding Frequently Asked Questions. ASHP.org. September 2016. 

https://www.ashp.org/-/media/assets/advocacy-issues/docs/compounding-guidances-frequently-asked-questions.ashx?la=en

FDA. Compounding and the FDA. Questions and Answers. FDA.gov. Nov. 15, 2024. 

https://www.fda.gov/drugs/human-drug-compounding/compounding-and-fda-questions-and-answers

Pluta, P.L. Compounding Overview: Primary Considerations in the Workplace. 

https://www.pharmtech.com/view/compounding-overview-primary-considerations-in-the-workplace

Pluta, P.L.; Mancini, A.M.; Thakar, N.B.; and Chaiyaperm, V. Pharmaceutical Compounding Calculations in the Workplace Environment. 

https://www.pharmtech.com/view/pharmaceutical-compounding-calculations-in-a-workplace-environment

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q7a-good-manufacturing-practice-guidance-active-pharmaceutical-ingredients

FDA. Bulk Drugs Used in Compounding Under Section 503A of the FD&C Act. FDA.gov. Sept. 26, 2024. 

https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding-under-section-503a-fdc-act

FDA. Bulk Drugs Used in Compounding Under Section 503B of the FD&C Act. 

https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding-under-section-503b-fdc-act

Alliance for Pharmacy Compounding. Understanding Law and Regulation Governing the Compounding of Peptide Products, March 1, 2024. 

https://join.a4pc.org/hubfs/PDFs/APC-Peptides-Statement-March-1-2024.pdf?hsLang=en

FDA. Bulk Drug Substances Nominated for Use in Compounding under Section 503A of the Federal Food, Drug, & Cosmetic Acid, 9-20-23. 

503A Categories Update for September 2023

Pravastatin Pharmaceutical Compositions Having Good Stability. US patent 5180589A, 1991. 

https://patents.google.com/patent/US5180589A/en

Khokhar, W. A Dein, S.L. Qureshi, M.S., Hameed, I., Ali, M.M., Abbast, Y.; and Sood, R. When Taking Medicine May Be a Sin; Dietary Requirements and Food Laws in Psychotropic Prescribing. BJPsych Advances, Cambridge University Press, V21, #6,2 January 2018. 

https://www.cambridge.org/core/journals/bjpsych-advances/article/when-taking-medication-may-be-a-sin-dietary-requirements-and-food-laws-in-psychotropic-prescribing/5E1A5178CD8AEF2915B852316CFEE305

The Use of Stems in the Selection of International Non-Proprietary Names (INN) for Pharmaceutical Substances 2018

https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/stembook-2018.pdf?sfvrsn=32a51b3c_6&download=true

Calculating the amount of drug needed for compounding requires different considerations for respective drug types and forms.

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