® Group interfaced with nearly a dozen companies at the annual INTERPHEX conference in New York City on April 1 and 2, 2025, and while one of the overarching topics may have been the tariff policies of United States President Donald Trump’s administration—in which there were new developments during the event—many of the interviewees over those two days were eager to share their businesses’ latest innovations in manufacturing and how those might fit into the industry at large.

Most people interviewed did have at least one eye on what the Trump administration’s decisions might mean in terms of outsourcing, as best expressed by David Loula, global product director at ITT Engineered Valves.

“If you are procuring components [from] or some of your supply chain is based, for example, in China, you’ve seen a recent increase in tariffs on components coming out of China that has a direct impact on our costs, and it’s something that we have to decide as to whether we’re going to pass those costs along to our customer base, or we’re going to eat those costs ourselves,” Loula said. “You don’t always know if the steel components that you’re buying have metals that were sourced in one of the target countries. So that one’s a little trickier to figure out, but we’re working closely with our supply chain to identify which of those items might have direct impact on our cost position.”

Beyond those concerns, however, three main manufacturing themes emerged: safety, sustainability, and the rise of artificial intelligence (AI) and automation.

Joe Bobacher, regional sales manager for OPW Engineered Systems in Hamilton, Ohio, spoke to PharmTech Group about preventing spills in the manufacturing process, which all companies would like to ideally avoid in order to not lose product, but also to prevent anything corrosive from leaking into the environment.

“As safety evolves throughout manufacturing process facilities where you have fluid transfer, spill prevention is very important,” Bobacher said (2). “So, we find that companies are looking to reduce the amount of spills at a site because a lot of facilities and processes have that fluid transfer and the products that we supply.”

One category that has increased in popularity in recent years is single-use equipment, technologies, or entire systems, a trend noted by Todd Andrews, global director of Applications and Business Development for the Biopharma business at CPC.

When it comes to safety, Andrews said single use used to be a “wild wild West” where everyone wanted a customized solution. This was a complex problem, he said, and stressed the supply chain because manufacturers were often stuck making different assemblies for the different demands of their various customers. But these suppliers have since adapted.

“What we’re seeing now is a lot of forward-thinking end users trying to break up—we call it ‘break up the octopus’,” Andrews said. “Instead of this giant tubing assembly, how do you break it up into the common subassemblies? And you almost can treat it like a Lego, where you may have a ‘T’ or a cross and you can basically customize at the point of use, instead of customizing with the OEM [original equipment manufacturer]. And if you’re an OEM supplying this, this adds a lot more efficiency, because now, instead of making lower volumes of multiple part numbers, you can make higher volumes of lower part numbers.”

Pharmaceutical Technology®/Pharmaceutical Technology® Europe/BioPharm International

When referring to this article, please cite it as Lavery, P. Companies Reveal Their Next Moves in Manufacturing. 

Articles

In discussions at INTERPHEX 2025, company representatives seized upon several common themes, most notably safety, sustainability, and the increasing utility of automation.

Companies Reveal Their Next Moves in Manufacturing

Despite the tremendous therapeutic prom­ise of cell and gene therapies (CGTs) for pa­tients globally, the space is at a crossroads. Long-standing issues around patient acces­sibility have contributed to investor pullback, biotech companies shuttering, and even a few life-saving therapies being pulled from markets.

The industry needs to do better to support all pa­tients in need. The biggest obstacle to accessibility has been pharma’s need to effectively reinvent manufacturing for living drugs made from human cells. It has not been possible to develop large-batch man­ufacturing as is done for most other therapeutic mo­dalities, meaning commercial-scale manufacturing has until now been unrealistic. Finally, the industry is beginning to incorporate Industry 4.0 concepts that have worked well for other types of manufac­turing, including automation.

Industry 4.0 is more than just the types of tech­nology that are deployed. Rather, these approaches underscore integration across the end-to-end patient journey. Many biopharmaceutical companies are still thinking about a black box (or several) to swap in for specific manufacturing processes, but that won’t enable the kind of scale most therapies will need to meet total patient demand. Still others are relying on contract development and manufacturing organiza­tions (CDMOs) to enable scale through next-generation end-to-end platforms, which can still be capacity constrained by upstream and downstream processes.

A new model is the integrated development and manufacturing organization (IDMO). As the name implies, this includes fully integrated smart manu­facturing facilities for true end-to-end scale. It relies on flexible manufacturing capabilities without re­quiring changes to hardware, meaning process modifications are entirely managed through software. As a result, technology transfer between smart facilities in any geography is streamlined through the lever­age of platform standards. Combined, these aspects will make it easier to scale cell therapies globally and meet total patient demand.

The tenets of the IDMO concept can be viewed from the top down: manufacturing facilities must be stan­dardized and interconnected, technology within each smart factory must ensure end-to-end integra­tion, and the platform technologies themselves must be robust enough to serve multiple functions.

Execution starts from the bottom up. From its be­ginnings, the biggest choke point in the cell therapy space has been manufacturing, which makes that the first place to start.

Today, commercial cell therapies have progressed toward becoming front-line treatments for certain hematological malignancies, meaning tens of thou­sands of additional patients may soon be eligible for these therapies. However, that number of batches haven’t even been manufactured yet in aggregate. It likely will not be long before cell therapies are also ap­proved in other indications, including autoimmune diseases. Even with heavy investment from pharma companies and the CDMO sector in new facilities and streamlined processes, traditional manufacturing is years away from meeting total patient demand.

Manufacturing at scale requires reducing the footprint, eliminating manual processes, increas­ing throughput, and lowering cost of goods. The most robust approach to address these issues is the deployment of fully closed and automated end-to-end manufacturing platforms. These platforms do not require traditional cleanroom spaces because manual process steps are eliminated through robotic orches­tration of streamlined and fully integrated manufac­turing processes.

“End-to-end” can be misleading. If a therapeutic de­veloper or CDMO has just purchased multiple units with the intent to scale, they will need to develop all new up­stream and downstream systems to match the system’s throughput. Even the best manufacturing system, in isolation, might just mask a bottleneck, rather than fix it.

The IDMO smart factory approach incorporates multiple ancillary technologies to enable the fullvalue proposition of end-to-end automated manu­facturing. That includes designed-for-purpose in­frastructure and facilities, requiring a high degree of engineering expertise.

John Tomtishen is senior vice-president and general manager (IDMO Business), Cellares.

When referring to this article, please cite it as Tomtishen, J. Ushering in Industry 4.0 with the IDMO Model to Solve the CGT Manufacturing Bottleneck. 

Global scale-up requires developing replicable processes that work the same no matter where they are performed. This can be accomplished with smart factories that utilize fully automated manufacturing platforms.

Ushering in Industry 4.0 with the IDMO Model to Solve the CGT Manufacturing Bottleneck

Pharmaceutical manufacturers, such as Pfizer, Johnson & Johnson, and Novartis, are driving digital transformation to enhance production efficiency and maintain compliance—an essential factor in ensuring product quality, patient safety, and commercial success. However, navigating the evolving pharmaceutical regulatory landscape presents significant challenges, requiring substantial investments in both human and technological resources.

Striking a balance between compliance and innovation can introduce security concerns and operational complexities, particularly as manufacturers become increasingly data driven. As pharmaceutical manufacturers collect and analyze large volumes of sensitive data, such as production metrics and quality control records, ensuring the security and integrity of this information becomes critical. Part of this challenge is also the ability to track readily available, accurate data for presentation to regulatory boards. To address these hurdles, approved work procedures, visible audit trails, and environmental monitoring help prevent quality issues and product loss.

Robust computerized maintenance management systems (CMMS) software provides a centralized system for compliance, asset protection, and operational data. By leveraging such technology, pharmaceutical manufacturers can enhance efficiency, reduce costs, improve quality control, ensure accurate documentation, and strengthen cybersecurity and data integrity.

Navigating a complex regulatory landscape is one of the biggest challenges that pharmaceutical manufacturers face. Regulatory compliance not only safeguards patients and consumers, it also plays a pivotal role in maintaining trust within the industry. However, the constantly evolving nature of global regulations requires organizations to be both vigilant and adaptable, often necessitating substantial investments in human and technological resources.

Pharmaceutical manufacturers must adhere to strict guidelines set by regulatory bodies and codes, such as FDA, the European Medicines Agency (EMA), the US Code of Federal Regulations (CFR), and other international authorities. These regulations are designed to ensure drug safety, efficacy, and quality while maintaining transparency in production and distribution.

Key regulatory frameworks govern electronic records and signatures, requiring pharmaceutical companies to implement strict access controls, audit trails, and validation processes to ensure data integrity. They also provide guidance on computerized systems used in pharmaceutical manufacturing, emphasizing risk management, system validation, and data security. Enforced globally, good manufacturing practices (GMPs) ensure that pharmaceuticals are consistently produced and controlled according to quality standards. Compliance requires meticulous documentation, validated production processes, and stringent hygiene protocols. As regulations continue to evolve, manufacturers must proactively adopt digital tools to streamline compliance efforts. Failure to meet these regulatory requirements can result in costly penalties, production halts, and reputational damage.

In an era of digital transformation, data integrity has become a critical component of regulatory compliance. Regulatory bodies mandate that pharmaceutical manufacturers maintain complete, accurate, and tamper-proof records throughout the product lifecycle. This diligence ensures transparency and accountability in the production process, helping to prevent the loss of millions in products, as well as errors, contamination, or fraudulent activity.

Ultimately, while compliance challenges can be demanding, they also present opportunities for pharmaceutical manufacturers to modernize operations, enhance efficiency, and build greater trust with regulatory authorities. Compliance also presents opportunities—adhering to regulatory standards can drive operational efficiency, reduce costs, enhance quality control, and strengthen cybersecurity measures.

Israel Ortíz is vice president and general manager at Accruent.

When referring to this article, please cite it as Ortiz, I. Digital Transformation in Pharmaceutical Manufacturing.

 Pharmaceutical Technology®/Pharmaceutical Technology® Europe/BioPharm International

Leveraging computerized maintenance management systems software can enhance efficiency, improve quality control, ensure accurate documentation, and strengthen data integrity.


Digital Transformation in Pharmaceutical Manufacturing

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.

 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.

 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.

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.

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Abdus-Samad, Jibril. FDA Drug Product Nomenclature. FDA.gov. Dec. 4, 2019.

https://www.fda.gov/media/134015/download

USP Nomenclature Guidelines. USP.org March 20, 2020. 

https://www.usp.org/sites/default/files/usp/document/usp-nomenclature-guidelines.pdf

https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/1121Nomenclature.pdf

USP. Guidance for Implementation and Exceptions: The Monograph Naming Policy for Salt Drugs I Drug Products and Compounded Preparations I General Chapter <1121> Nomenclature. 

https://www.usp.org/sites/default/files/usp/document/our-work/healthcare-quality-safety/usp-guidance-for-implementation-of-salt-naming-policy.pdf

FDA. Naming of Drug Products Containing Salt Drugs 

.https://www.fda.gov/regulatory-information/search-fda-guidance-documents/naming-drug-products-containing-salt-drug-substances (accessed Nov. 1, 2024).

FDA. Monograph Naming Policy for Salt Drug Substances in Drug Products and Compounded Preparations. December 2014. 

https://www.youtube.com/watch?v=DadC-tXartU

FDA. FDA’s Concerns with Unapproved GLP-1 Drugs Used for Weight Loss. 

Collins, S. Semaglutide Shortage Gives Rise to Unauthorized Products. 

FDA. FDA Reminds Compounders to Use Ingredients Suitable for Sterile Compounding. 

https://www.fda.gov/drugs/human-drug-compounding/fda-reminds-compounders-use-ingredients-suitable-sterile-compounding?utm_medium=email&utm_source=govdelivery

https://www.drugs.com/dosage/phenytoin.html

Tylenol with Codeine Prescribing Information. 

https://www.drugs.com/pro/tylenol-with-codeine.html

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https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022402s006lbl.pdf

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https://www.ismp.org/sites/default/files/attachments/2018-03/20180322_0.pdf

ISMP. Heparin Errors Continue Despite Prior, High-Profile, Fatal Events. ISMP.org. June 17, 2008. 

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Metoprolol succinate USP product label. Dr. Reddy’s Laboratories, India.

Metoprolol succinate USP product label. Mylan Pharmaceuticals, Morgantown WV, USA.

Metoprolol succinate USP product label. Ohm Laboratories, New Brunswick, NJ, USA.

FDA. Potassium phosphates USP product label. Highlights of Prescribing Information, Potassium Phosphates Injection. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212121s000lbl.pdf

Potassium phosphates USP product label, Hospira, Inc. 

https://labeling.pfizer.com/ShowLabeling.aspx?id=4586

Anectine succinylcholine chloride injection, USP. Sandoz, Inc. Princeton, NJ. FDA.gov. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/008453s027lbl.pdf

Succinylcholine chloride injection, USP, product label. Hospira, Inc., Lake Forest, IL 60045.

Succinylcholine chloride injection, USP, product label. Amring Pharmaceuticals Inc., Berwyn, PA 19312.

Comments from Alan M. Mancini, RPh, pharmaceutical educator; Richard Poska, RPh, Flexo CMC Consulting; Jan M. Keresztes, RPh, PharmD, pharmaceutical educator; and William R. Porter, PhD, pharmaceutical educator and principal scientist, Peak Process Performance Partners, are greatly appreciated.

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

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Pharmaceutical Compounding Calculations, Part One–Non-Salts, Salts, and Policy-Exception Salts