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

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The European Medicines Agency (EMA) announced on Dec. 18, 2023 that it has, along with the Heads of Medicines Agencies (HMAs), published a strategy for coordinating the use of artificial intelligence (AI) in medicines regulation. The Multi-annual AI Workplan 2023–2028 was developed by the HMA-EMA Big Data Steering Group (BDSG) to coordinate a strategy to best use the benefits of AI and minimize any risks associated with its use and help the European medicines regulatory network (EMRN) to utilize AI for the automation of processes and evaluating data.

“The increasingly sophisticated nature and the pace of change of AI bring opportunities but also challenges. The application of AI requires a collaborative, coordinated strategy to maximize the benefits from AI while ensuring that uncertainty is adequately explored, and risks are mitigated,” the 

The workplan focuses on four key elements:

Guidance, policy, and product support. The plan will give support for products in development and for guidance in development regarding the use of AI in a drug’s lifecycle. Preparations for the implementation of the EU AI Act will begin in 2024.

AI tools and technology. Frameworks will be identified and provided for the use of AI tools for data analysis and decision-making.

Collaboration and training. Initiatives will be created to develop capacity and capability of the EMRN, partners, and stakeholders.

Experimentation. Actions will ensure a structured approach to accelerated learning of AI.

“As AI technology is fast evolving, including the ethical and policy aspects related to it, the BDSG will regularly update the workplan. Regulators, medicine developers, academics, patient organizations, and other interested parties will be informed and engaged throughout the implementation of the plan,” EMA stated in a press release.

Articles

The Multi-annual AI Workplan creates a strategy to maximize the benefits and manage the risks of artificial intelligence.

EMA Publishes Guide for Use of AI in Medicine Regulation

Pharmaceutical compounding comprises activities associated with preparations that are not commercially available from major pharma industry. Compounded dosage forms have traditionally been prepared in response to individual patient needs in community settings; they are also prepared for future patients in physician’s offices and clinics. The scope of compounding considerations is extensive—patient information and therapeutics, dosage forms, preparation processes, regulations, personnel competencies, professional workplace settings, and so on. Compounded preparations include both sterile and non-sterile dosage forms—injections, ophthalmics, capsules, liquids, topicals, and numerous variations of each. Formulations address dosages of patients from neonates to seniors. Compounding occurs in many settings—community pharmacies, hospitals, outsourcing facilities, pharma industry, nursing homes, outpatient care, and numerous others. Regulations governing compounding include federal, state, and local requirements. Personnel involved in compounding have varied expertise and skills—pharmacists, physicians, nurses, scientists, chemists, engineers, technicians, and so on. Compounding also includes the preparation of equivalent commercial products when drug shortages occur; notable examples include certain beta-lactam products and ibuprofen (1–4).

FDA has defined human drug compounding and acknowledged its role in modern healthcare. FDA further commented on patient risk in using compounded preparations and described efforts to safeguard public health against poor quality compounding.

“Compounding is generally a practice in which a licensed pharmacist, a licensed physician, or in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient. Although compounded drugs can serve an important medical need for certain patients, they also present a risk to patients” (5).

“FDA’s compounding program aims to protect patients from unsafe, ineffective, and poor-quality compounded drugs, while preserving access to lawfully marketed compounded drugs for patients who have a medical need for them” (5).

“Compounding is also a practice that is under scrutiny by the Food and Drug Administration (FDA) because of instances in which medications, primarily injectable medications that are intended to be sterile, have endangered public health” (6).

 Compounding involves changes to materials or products to prepare new medicinal formulations. Changes to commercial products following directions provided by the manufacturer, such as reconstitution of multidose containers or dissolving sterile lyophilized products, is not compounding (7). Transfer of product to a different containeris repackaging and is not compounding; preparing individual syringes from a larger container of drug product is repackaging. FDA has issued multiple guidance documents addressing repackaging (8,9). When a dose of medication is drawn for administration at the patient bedside, this action is neither compounding nor repackaging but is preparation for immediate use (7). The 

) definition of compounding differs from the FDA definition, is much broader, and encompasses almost any manipulation of a commercial product (7,10,11).

Compounded preparations have traditionally been designed to address the therapeutic needs of individual patients. Name identification of the patient for whom medication is being compounded is a key requirement in traditional compounding

specific patient, prescribing physician, and pharmacist/designee who prepares medication for immediate use (ASAP). Compounded preparations prepared on a larger scale for future use (“office stock”) have expanded the definition of compounding; preparing formulations for future use is non-traditional compounding

 Specific patients are not identified in non-traditional compounding

Facilities engaged in non-traditional compounding may or may not be licensed pharmacies and are termed outsourcing facilitie

Prospective name identification of patients is a key element in differentiating types of compounding organizations in FDA regulations.

FDA has expressed concern for medication safety with use of compounded pharmaceuticals.Errors with compounded drugs are well known to have caused adverse events (12,13). Compounded preparations are not approved by FDA via the new drug application/abbreviated new drug application (NDA/ANDA) drug approval process. Medication safety in compounded preparations is the responsibility of compounding practitioners. The New England Compounding Center (NECC) incident in 2012 (14) heightened public awareness of problems with compounding and prompted regulations that significantly changed compounding practices. These regulations limited the scope of traditional compounding while enhancing patient safety in non-traditional compounding; GMP compliance is now required for non-traditional compounding.

The discussion provides a general overview of US human drug compounding. Selected topics describe technical considerations, FDA regulations, and personnel responsibilities in the workplace environment—pharmaceutical compounding in a professional setting. Discussion topics include the following:

. Scientific and technical aspects of compounding such as formulation design, preparation, and calculations are fundamental in compounding. Compounded preparations must be technically sound.

. Regulations governing compounding include federal, state, and local regulations. GMP is required for certain compounding.

. Compounding experts design dosage forms; staff prepares dosage forms; management monitors compounding performance, executes traditional management activities, and provides a workplace environment conducive to thoughtful compounding execution.

This discussion has been developed considering academic teaching experiences, experiences in multiple settings, and published reports of medication adverse events. Compounding education typically includes theory and techniques using placebo formulations in a classroom or laboratory setting—preparatory skills are the primary focus of compounding education. Compounding in the workplace is a different reality—potent drugs, compromised patients, emergency circumstances, imperfect facilities, time pressures, insufficient information, electronic systems, and problematic logistics with interruptions, interferences, and other distractions—all of which may contribute to substandard compounding and medication errors. Workplace conditions may be complex depending on the type, size, and circumstances of the compounding organization. Traditional compounding pharmacies that prepare dosage forms and dispense directly to patients have much different challenges than non-traditional outsourcing facilities that globally distribute their preparations. This discussion addresses key topics relevant to all compounding—technical aspects, federal regulations, and personnel considerations in the workplace environment.

Technical pharmaceutics principles are fundamental in dosage form design and preparation in all compounding; pharmaceutics provides the scientific basis for compounded dosage forms. Technical concepts especially relevant to compounding include solubility, dissolution, bioavailability, bioequivalence, chemical and physical stability, and many other considerations; specific principles associated with individual types of dosage forms must likewise be considered. Formulation materials, preparatory processes, associated calculations, and actual compounding techniques are of obvious importance in compounding. Multiple personnel are likely involved in compounding, including technical experts who integrate available information and calculate dosage, specialists who prepare the designed formulation, and pharmacists who counsel patients/clients on proper use of the compounded medication.

Formulation design is fundamental in compounding. Formulation ingredients, including the API, inactive excipients, and the primary container, comprise the compounded dosage form. All formulation components must be sourced from approved suppliers, meet quality standards, be inherently stable, and not be contaminated with chemical, microbial, or other foreign substances. Ingredients must be properly stored, be within expiration dating, and be acceptable for use. Assuming an appropriate active drug to treat the patient’s condition, inactive formulation ingredients are very relevant in compounded dosage form design. Inactive ingredients in compounded dosage forms may replace problem ingredients in commercial products (e.g., lactose is not used in compounded preparations for lactose-intolerant patients; dyes are not used in preparations for patients allergic or sensitive to colorants; peanut oil is not used in preparations for patients with peanut allergies). Liquid formulations of solid products may be prepared for children or seniors who cannot swallow tablets or capsules. The combined ingredients and primary package must be compatible and stable during the expected period of patient treatment. If an administration device such as an intravenous administration set, inline filter, or other device is needed to administer the compounded drug, these also must be compatible with formulation ingredients.

There are numerous types of calculations potentially used in compounding, depending on technical considerations, patient needs, and other factors. Formulation calculations such as percent calculations, API conversions, ratio strength, and others are necessary for preparation of dosage forms. Drugs are dosed based on the active drug; chemical forms of active drugs may be available in salt or other forms, and the appropriate amount to be compounded is calculated. Formulation dosage considerations including pharmacokinetic factors, drug half-life, bioavailability, renal clearance, liver function, and others must be calculated. Certain compounding requires final product testing such as potency, moisture, dissolution, microbial, and other testing—all of which require calculations. Shelf-life calculations with attribute stability data are used to justify expiry extensions.

Procedures for preparation of compounded pharmaceuticals are likewise critical. After the compounded formulation and compounding process are designed and material amounts are calculated, actual dosage form compounding with specified techniques is initiated. Policies and practices must be appropriate; skilled personnel must be trained as needed; aseptic techniques are especially important. Compounding skills are essential; a well-designed compounded preparation will fail if execution by the compounding technician is substandard or lacking; these may include order of mixing low-dose ingredients, particle size reduction, mixing, encapsulation, filtration, levigation, and other technical procedures. Basic aseptic techniques, clean-room equipment, and controlled air-particulate facilities are critical for sterile compounded preparations. Sterile compounded preparations are high-risk preparations due to their potential for microbial contamination. Allen (15,16), Institute for Safe Medication Practices (ISMP) (17,18), Gudeman 

 (20) have addressed errors associated with compounded preparations.

Related technical activities executed after completion of compounding must also consider pharmaceutics principles. Dosage-form testing (visual, USP, or other reference), labeling, medical information, packaging, supply chain shipping, and communication with patients/clients advising on proper use of the compounded dosage form must be consistent with technical principles. Light protection, temperature control, administration methods, and other post-compounding technical considerations are relevant.

FDA categorized pharmaceutical compounding facilities as 503A pharmacies and 503B outsourcing facilities in the Drug Quality and Security Act (DQSA) of 2013 (21). This amendment strengthened compounding requirements in the existing Food, Drug, and Cosmetic (FD&C) Act regulating compounded drugs and is the current legal basis for pharmaceutical compounding.

Section 503A of the FD&C Act identifies traditional compounding—individual patient, prescribing physician, registered pharmacist in a licensed pharmacy

 Section 503A specifically exempts pharmacy compounding from federal regulations concerning GMP compliance, labeling requirements, and drug approvals via NDA/ANDA processes.

Pharmacy Compounding Under Section 503A of the FD&C Act

 (22) specifies applications, conditions, provisions, requirements, and enforcement of Section 503A. Preparations are compounded for an identified individual patient. 503A compounding must be compliant with applicable USP requirements. Drug and excipient quality requirements are specified. Compounding must not involve preparations that are copies of commercial products or be identified by FDA as difficult to compound. Compounded preparations must not exceed 5% of total dispensed products of the pharmacy. FDA enforcement conditions specifying adulterated, unapproved, and misbranded drugs will follow risk-based concepts addressing public health.

Hospital and Health System Compounding Under Section 503A of the FD&C Act 

(23) discusses actual human drug compounding practice in hospitals and clarifies requirements stated in the above 503A guidance. These practices are regulated primarily by state agencies and are not required to comply with GMP requirements. Some 503A pharmacies have distribution practices for compounded preparations that extend beyond their individual facility (i.e., 503B-like practices); compounded preparations may be transferred to other hospitals, clinics, infusion centers, or other facilities within a corporate healthcare system. This guidance addresses compounded preparations made in advance of specific patient orders that are essentially copies of commercial products; policy with rationale and limitations is proposed.

FD&C Section 503B addresses organizations that prepare dosage units for sale to various healthcare providers in advance of specific patient identification (i.e., 

 for “office stock”). Outsourcing facilities providing these preparations are not required to be a licensed pharmacy but must be supervised by a licensed pharmacist. Section 503B exempts these facilities from NDA/ANDA approval processes, certain product labeling regulations, and drug security requirements. However, Section 503B requires outsourcing facilities to be compliant with GMP regulations per 21 

§210 and 211 (24). Facilities that manufacture 503B sterile products must also register with FDA and pay an annual registration fee.

Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act

 (25) addresses GMP requirements for outsourcing facilities. Specific sections in the guidance discuss quality assurance and quality control, facility design, control systems and procedures for maintaining suitable facilities, environmental and personnel monitoring, equipment, containers and closures, components, production and process controls, release testing, laboratory controls, stability/expiration dating, packaging and labels, and complaint handling (26).

This guidance reflects FDA’s intent to recognize differences between outsourcing facilities and pharma industry manufacturers while maintaining minimum safety standards for public health. The guidance follows a risk-based approach (i.e., it distinguishes between risk levels associated with compounding various dosage forms). Sections in the guidance specify considerations for sterile drug products. GMP-violative conditions in which FDA generally does not intend to take regulatory action are also described; two appendices further address GMP release testing and stability testing requirements.

Primary differences characterizing 503A and 503B preparations and associated facilities are summarized in 

. Items 1–3 list basic characteristics and specific exemptions from FD&C requirements; items 4–16 are requirements for compounded preparations; item17 lists GMP requirements. GMP compliance includes documented systems and procedures. Exceptions to described characteristics are possible (e.g., a facility may have both 503A licensed pharmacy and 503B outsourcing operations and must follow certain specified facility requirements). Item 18 identifies primary audit responsibilities. 

A summary of 503A and 503B characteristics. FD&C is Federal Food, Drug, and Cosmetic Act; NDA is new drug application; ANDA is abbreviated new drug application; GMP is good manufacturing practice.

Compounding organizations are regulated by state and federal requirements and may thus be audited by both state agencies and by FDA. 503A pharmacies are inspected primarily by state auditors. If FDA inspectors provide observations to 503A pharmacies, follow-up may be delegated to state authorities. 503B compounding facilities must comply with GMP requirements and are audited primarily by FDA. The FDA website provides FDA-483 observations, Warning Letters, and associated correspondences involving compounding facilities (27). FDA has discussed activities for compounding pharmacies following receipt of an FDA-483 (28).

Personnel in compounding organizations have significant responsibility in support of pharmaceutical compounding in the workplace setting. Excluding automated systems, much of the work in compounding requires human performance. Staff designs and prepares the compounded dosage forms—the objective of the compounding function. Personnel involved in pharmaceutical compounding must have appropriate technical expertise and must continually maintain their competence. Technical expertise includes theory, practice, techniques, and awareness of common errors experienced in compounding practice.

Management in compounding organizations must monitor actual compounding as well as execute traditional managerial responsibilities such as hiring, scheduling, training and development, facilities and equipment maintenance, facility cleanliness, and numerous other activities. Management is ultimately responsible for policies, procedures, and quality systems supporting the compounding effort; this responsibility is substantial for 503B outsourcing facilities that must comply with GMP. Management must integrate technical compounding performance and daily workplace operations to develop and maintain a quality culture in the compounding organization conducive to serious thought and deliberation. Medication errors have been caused by dosage form design omissions, deficient technical knowledge, insufficient training, distractions, superficial documentation, inexperience, and other issues—all of which are caused by staff and ultimately attributable to management. Regular management communication to heighten staff awareness of problematic situations and potential medication errors has been recommended to mitigate the potential for medication errors (34).

Numerous references supporting 503A and 503B pharmaceutical compounding relevant to technical considerations and regulatory compliance are available from a variety of sources. 

<797>, and <800> (35–37) are primary documents describing compounding standards; these documents have legal basis and are often cited in FDA-483 observations. USP offers on-demand courses on these chapters (38). 

 also contains more than 100 compounding-related chapters (39,40). Current revisions to 

 <795> and <797> have proposed a designated person to be responsible for compounding policies, practices, and procedures in organizations (41). The Joint Commission offers certification in pharmaceutical compounding focusing on the above-mentioned 

 chapters (42). FDA offers training on various compounding activities through their 

Compounding Quality Center of Excellence 

(43). Other documents available through the American Society for Health System Pharmacists (ASHP) (44) and the ISMP (45) are useful to identify potential medication safety risks.

Quality risk management and human factors engineering

Organization staff and management must collaborate to develop a quality culture in the compounding organization. Principles associated with ICH Q9(R1) 

 (QRM) and Human Factors Engineering (HFE) are directly applicable to compounding organizations. ICH Q9(R1) describes hazard evaluation in various aspects of pharmaceutical manufacturing (46). Compounding organizations should use a similar approach to evaluate potential for problematic compounding issues. Risk analysis should be an ongoing activity using formalized methods such as failure mode and effect analysis (FMEA) or other risk methodologies; root cause analysis to mitigate hazard situations logically follows.

HFE is another discipline relevant to compounding organizations. HFE (47,48) addresses human performance and interactions with technology, processes, device operation, user interface, and the use environment in many industries. Whenever human performance is involved, errors, omissions, misunderstandings, shortcuts, and other potential deficiencies may occur—and essentially everything in compounding is done by humans. Electronic systems are commonplace in compounding equipment; personnel who override electronic systems designed to prevent drug safety issues exemplify HFE problems. HFE activities and training on equipment use must be ongoing in compounding organizations.

Preventive actions and corrective actions

Staff and management in compounding organizations must endeavor to proactively prevent hazards that may result in substandard compounding and medication errors; note the deliberate transposition of traditional corrective and preventive actions (CAPA) to preventive actions and corrective actions (PACA) to emphasize proactive vs. reactive responses to hazards. Medication error data indicate that 7000–9000 annual deaths in the United States are due to medication errors; FDA receives more than 100,000 reports of medication errors every year—both are likely conservative estimates (49,50). ICH Q9(R1) has also encouraged proactive hazard prevention rather than hazard correction after an adverse event (46). Patients obviously suffer when medication errors are made; overdoses may be toxic and underdoses ineffective. Healthcare practitioners responsible for errors are likewise affected—often suffering personal remorse and emotional distress, sometimes with fatal consequences (51). Responsible supervision and the organization suffer embarrassment, negative publicity, regulatory issues, legal action, financial liability, and other undesirable outcomes. Safeguards to prevent substandard compounding and possible medication errors should be integrated within the pharmaceutical compounding process.

Documentation is intrinsic to pharmaceutical compounding and GMP compliance; documentation is a primary responsibility of organization staff and management. Most relevant to this discussion is documentation directly associated with the preparation of compounded dosage forms. This documentation provides descriptive information, ingredient listing, ingredient lot numbers, preparative procedure, expiration/BUD, other key information, and accountability of personnel involved in the compounding process; this documentation provides lasting traceability of the dosage form. Other associated compounding documentation supporting site quality systems and GMP compliance include personnel training records, performance certification, equipment qualification, facility maintenance, cleaning, sanitization, and related activities. Representative documentation examples are illustrated in 

 chapters and compounding texts (15,39). The pharma industry adage “If it isn’t written down, it didn’t happen” must also be practiced in pharmaceutical compounding operations (52).

This discussion provides an overview of key elements in pharmaceutical compounding. FDA has generally defined pharmaceutical compounding. Compounded pharmaceuticals are specially prepared and are not commercially available from big pharma. Compounding requires changes to materials and is distinguished from repackaging and drug-readiness for administration. FDA has also cautioned against risks associated with compounded preparations.

Formulation, calculations, and actual compounding performance are primary technical pharmaceutics areas relevant to compounded preparations. Compounded pharmaceuticals may include sterile and non-sterile preparations prepared for individual patients at local pharmacies or in hospitals. Compounded pharmaceuticals also include formulations prepared in larger quantities and sold to physicians, clinics, or other treatment entities (“office stock”) for future patient treatment. Actual compounding technical competency in aseptic techniques is critical in sterile compounding. Multiple individuals are likely involved in the technical design and actual preparation of compounded pharmaceuticals ultimately leading to correct use of the compounded dosage form by the patient/client.

Legislation enacted following the New England Compounding Center incident in 2012 explicitly categorized pharmaceutical compounding operations. Compounding facilities are either 503A pharmacies (traditional compounding for identified patients) or 503B outsourcing facilities (non-traditional compounding for future patients). GMP requirements in 503B facilities include requirements for release testing, stability and file samples, validation, environmental monitoring, and other requirements. State inspectors audit 503A pharmacies; FDA investigators audit 503B facilities and may issue FDA-483 observations if non-compliant conditions are observed.

Compounded preparation quality is dependent on human performance in the workplace environment (i.e., functions that are the responsibility of staff and management). Human performance in compounded dosage form design, preparation, documentation, and user communication is critical for successful compounding. Workplace interruptions and interferences in expected performance may negatively impact human performance and compounded medication safety. Compounding personnel must be conversant with key compounding guidances such as 

 <795>, <797>, and <800>. QRM and HFE concepts are directly applicable to pharmaceutical compounding.Documentation and compliance considerations are routine performance by compounding personnel. Staff and management must collaborate to develop a quality culture in their organization.

Comments from Varanya Chaiyaperm, RPh, PharmD, clinical assistant professor, University of Illinois College of Pharmacy; Jan M. Keresztes, RPh, PharmD, pharmaceutical educator; Alan M. Mancini, RPh, pharmaceutical scientist; Jeanne Moldenhauer, pharmaceutical consultant, Excellent Pharmaceutical Consultants; William R. Porter, PhD, principle scientist, Peak Process Performance Partners; Richard Poska, RPh, pharmaceutical scientist, Flexo; and Nishant B. Thakar, RPh, PharmD, assistant professor clinical sciences, Roosevelt University College of Pharmacy are greatly appreciated.

 (accessed April 11, 2023).
2. Drugs.com. Current Drug Shortages. 

Guidance for Industry, Compounding Certain Beta-Lactam Products in Shortage Under Section 503A of the Federal Food Drug, and Cosmetic Act

Guidance for Industry, Compounding Certain Ibuprofen Oral Suspension Products Under Section 503B of the Federal Food, Drug, and Cosmetic Act

 (accessed April 11, 2023).
7. ASHP. Compounding Frequently Asked Questions. 

Guidance for Industry, Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities

 (Rockville, Md., 2023). DOI: 10.31003/USPNF_M523_05_01
10. USP. FAQs: Revised General Chapter <795> Published in 

, Nov. 1, 2022.
11. USP. FAQs: Revised General Chapter <797> Published in 

, Nov. 1, 2022.
12. Lisi, D. M. Pros and Cons of Pharmacy Compounding. 

The Special Risks of Pharmacy Compounding

The New England Compounding Center and the Meningitis Outbreak of 2012: A Failure to Address Risk to the Public Health

The Art, Science, and Technology of Pharmaceutical Compounding

, 6th ed.; American Pharmacists Association, 2020.
16. Allen, L. V., Jr. Pharmaceutical Compounding Errors, Parts 1–11. 

, Jan. 14–April 1, 2022.
17. ECRI/ISMP. ISMP Survey on Sterile Compounding in Pharmacies Reveals Gaps, Challenges. Press Release, Oct. 26, 2020.
18. ISMP. Death Due to Pharmacy Compounding Error Reinforces Need for Safety Focus. 

, June 15, 2017.
19. Gudeman, J.; Jozwiakowski, M.; Chollet, J.; Randell, M. Potential Risks of Pharmaceutical Compounding. 

 (1), 1–8. DOI: 10.1007/s40268-013-0005-9
20. Watson, C. J.; Whitledge, J. D.; Siani, A. M.; Burns, M. M. Pharmaceutical Compounding: a History, Regulatory Overview, and Systematic Review of Compounding Errors. 

 (2),197–217. DOI: 10.1007/s13181-020-00814-3
21. FDA. 

Guidance for Industry, Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act

Draft Guidance for Industry, Hospital and Health System Compounding Under Section 503A of the Federal Food, Drug, and Cosmetic Act

Current Good Manufacturing Practice (CGMP) Regulations

. ww.fda.gov (accessed June 13, 2023).
25. FDA. 

Draft Guidance for Industry, Current Good Manufacturing Practice—Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act

, Revision 2 (CDER, January 2020).
26. Poska, R.; Pluta, P. L. Application of US GMP to Outsourcing Facilities. 

Compounding: Inspections, Recalls, and Other Actions

What to Expect After an Inspection: 483s, Responses, and Beyond

. FDA/CDER/Small Business and Industry Assistance Webinar, Dec. 14, 2022.
29. FDA. 

Guidance for Industry, Prescription Requirement Under Section 503A of the Federal Food Drug, and Cosmetic Act

Bulk Drug Substances Used in Compounding Under Section 503A of the FD&C Act

. www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding-under-section-503a-fdc-act (accessed 6-13-23)
31. FDA. 

Compounding and the FDA: Questions and Answers

Paul L. Pluta, PhD, RPh, is a pharmaceutical scientist with pharma industry, academia, journal editorship, community pharmacy, and hospital pharmacy experience.

Technical, regulatory, and personnel considerations characterize pharmaceutical compounding.

Compounding Overview: Primary Considerations in the Workplace

At the 2023 American Association of Pharmaceutical Scientists (AAPS) conference,

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How a partnership philosophy that emphasizes creativity and collaboration enables rapid development of advanceable formulations and processes with minimal material.

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Video interview with Wesley Tatum, PhD (Principal Engineer at Serán)

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FDA published draft guidance on Dec. 13, 2023 that provides recommendations for the development of peptide drug products submitted in a new drug application. The document describes the impact of clinical pharmacology considerations on a peptide drug’s pharmacokinetics (PK), safety, and efficacy.

The guidance defines a peptide as any polymer composed of 40 or fewer amino acids that can be isolated from animal tissue, produced synthetically, or produced through recombinant expression. According to FDA, there has been an effort to improve absorption, distribution, metabolism, and excretion (ADME) properties of native peptides. These efforts include increasing oral bioavailability, half-life, and conformational flexibility, as well as decreasing general hydrophobicity. Alterations (e.g., cyclization, pseudo-peptide bonds, unnatural 45 amino acids, and peptide conjugations) to the peptide structure have been included to gain more favorable ADME characteristics. Therefore, peptide drugs may exhibit distinct combinations of characteristics regarding their chemistry, pharmacology, PK disposition, and pharmacodynamics (PD), FDA said in the draft guidance document.

Topics discussed in the article include bioanalytical approaches, radiolabeled mass balance studies, and impaired renal function. Considerations for assessing immunogenicity include performing immunogenicity risk assessments, clinical immunogenicity assessments, and immunogenicity clinical impact analysis.

The guidance also addresses characterization of the impact of hepatic impairment, assessing drug interactions, and characterizing QT interval prolongation. Labeling considerations are also covered.

The guidance document discusses the impact of clinical pharmacology considerations on peptide drug development.

FDA Issues Guidance on Clinical Pharmacology for Peptide Drugs

FDA announced on Dec. 14, 2023 that the US District Court for the District of Massachusetts has entered a consent decree of permanent injunction against Pharmasol Corporation and its president, Marc L. Badia, for distributing adulterated drugs. The injunction orders the company to stop distributing products until it complies with requirements under the Federal Food, Drug, and Cosmetic (FD&C) Act. The complaint states the company violated the FD&C Act by distributing drugs through interstate commerce, which do not comply with current good manufacturing practices.

A 2022 inspection of the company’s facilities found repeated violations from a previous 2019 warning letter that include failures to investigate errors, follow written procedures, and adequately clean and maintain equipment. The 2019 warning letter stated customers complained of product leakage, which was not investigated properly by the company.

“When drug manufacturers violate the law and disregard safety standards, they put consumers at significant risk. In this case, the defendant’s company distributed adulterated, poor-quality drugs without regard for patients and consumers,” said Jill Furman, director of the Office of Compliance in FDA’s Center for Drug Evaluation and Research, in an agency press release. “[FDA] plays an important role in protecting consumers, and we will continue to work with our law enforcement partners to pursue and bring into compliance those who do not prioritize the health and safety of the American public.”

Pharmasol, which is under contract with several pharmaceutical companies, manufactures and distributes human and animal prescription drugs and over-the-counter drugs. Products include topical corticosteroids and inhaled anesthetics. Under the consent decree, the company is prohibited from directly or indirectly “manufacturing, preparing, processing, packing, repacking, receiving, labeling, holding and/or distributing any drug, at or from their facilities, unless and until defendants meet certain requirements.”

The US District Court for the District of Massachusetts entered a consent decree of permanent injunction against Pharmasol Corporation for distributing adulterated drugs.

Consent Decree Entered Against Pharmasol

Feliza Mirasol is the science editor for 

On Dec. 11, 2023, RoslinCT, a UK-based cell and gene therapy contract development and manufacturing organization (CDMO), announced that it will manufacture Vertex Pharmaceuticals’ Casgevy (exagamglogene autotemcel [exa-cel]), a recently approved clustered regularly interspaced short palindromic repeats (CRISPR)-based gene therapy for treating sickle cell disease (SCD) and β thalassemia.

FDA approved Casgevy on Dec. 8, 2023 for treating SCD in patients 12 years and older in the United States, and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) approved it for treating SCD and transfusion-dependent β thalassemia (TDT) in the UK on Nov. 16, 2023 (1). The gene therapy is also under review by FDA for treating TDT in the US, with a decision expected by March 20, 2024. In its press release, FDA stated that Casgevy is “the first FDA-approved treatment to utilize a type of novel genome editing technology, signaling an innovative advancement in the field of gene therapy.” CRISPR technology, being so new, 

led to quite a stir when the MHRA approved Casgevy in November

RoslinCT has been working with Vertex on an adaptive basis while Vertex moved through clinical and regulatory development of Casgevy. The collaboration has positioned RoslinRT in a place to support the manufacturing of a broad range of highly complex autologous and allogeneic cell therapies beyond Casgevy. The company runs manufacturing facilities in Edinburgh, Scotland and Boston, Mass., which are purpose-built for cell therapy products.

“We are delighted that patients in both the US and UK are now able to access this transformational medicine. This approval by [FDA] further demonstrates our … capabilities in development, support, and manufactur[ing] … cell and gene therapies such as Casgevy. We are proud to have supported Vertex in achieving this significant milestone and look forward to supporting their team as they bring the first approved CRISPR treatment to patients in the US, UK, and beyond.”

In addition to Casgevy, FDA also approved bluebird bio’s Lyfgenia (lovotibeglogene autotemcel) for treating SCD in patients 12 years and older on Dec. 8, 2023. Lyfgenia uses a lentiviral vector for genetic modification.

“Sickle cell disease is a rare, debilitating, and life-threatening blood disorder with significant unmet need, and we are excited to advance the field especially for individuals whose lives have been severely disrupted by the disease by approving two cell-based gene therapies today,” said Nicole Verdun, director of the Office of Therapeutic Products within FDA’s Center for Biologics Evaluation and Research (CBER), in the agency’s press release. “Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited.”

“These approvals represent an important medical advance with the use of innovative cell-based gene therapies to target potentially devastating diseases and improve public health,” said Peter Marks, director of CBER, in the release. “Today’s actions follow rigorous evaluations of the scientific and clinical data needed to support approval, reflecting [FDA’s] commitment to facilitating development of safe and effective treatments for conditions with severe impacts on human health.”

FDA granted both Casgevy and Lyfgenia priority review, orphan drug, fast track, and regenerative medicine advanced therapy designations.

1. Vertex Pharmaceuticals. Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, CASGEVY (exagamglogene autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. Press Release, Nov. 16, 2023.

RoslinCT will manufacture Vertex Pharmaceuticals’ CRISPR-based gene therapy, Casgevy, recently approved for treating sickle cell disease and β thalassemia.

RoslinCT to Manufacture CRISPR-Based Gene Therapy Casgevy

FDA announced on Dec. 12, 2023 that the agency is creating the 

Genetic Metabolic Diseases Advisory Committee

, which will provide independent advice and recommendations on technical, scientific, and policy issues regarding treatments for genetic metabolic diseases. The committee will advise FDA on products used to diagnose, prevent, or treat metabolic diseases under the purview of the Division of Rare Diseases and Medical Genetics.

Committee members will include experts in metabolic genetics, management of inborn errors of metabolism, small population trial design, translational science, pediatrics, epidemiology or statistics, and related specialties. There will be nine voting members, and there will be a consumer representative and an industry representative. Members will serve overlapping terms of up to four years.

“Advisory committees allow [FDA] to receive invaluable input from clinicians, industry experts, academia, patients, caregivers, and other external stakeholders when evaluating the potential benefits and risks of a new therapy. They are an essential part of [FDA’s] work,” said Patrizia Cavazzoni, director of FDA’s Center for Drug Evaluation and Research (CDER). “These expert panels support the agency by helping ensure [FDA’s] decisions on the safety and efficacy of drug products are informed and in line with our priorities and goals.”

Genetic metabolic diseases impact a person’s metabolism and develop when a genetic flaw causes a protein or enzyme to be faulty or non-existent. Most of these diseases are rare and can be life limiting, according to FDA.

“Genetic metabolic diseases include very rare diseases that individually affect a limited number of patients. Drug development for these conditions has unique and complex challenges, therefore few treatments are available to patients,” said Janet Maynard, director of the Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine. “This new advisory committee will provide a forum for discussion of complicated issues with specialized and diverse technical and scientific experts in the field of metabolic genetics.”

The new advisory committee will provide the agency with technical and scientific advice and recommendations on potential treatments for genetic metabolic diseases.

FDA Announces Advisory Committee for Genetic Metabolic Disease Treatments

On Dec. 11, 2023, Sanofi announced that it will be terminating its licensing agreement with Maze Therapeutics for the development of a rare disease drug candidate. Sanofi released a statement expressing its disappointment with the Federal Trade Commission’s (FTC’s) same-day announcement that the agency is seeking a preliminary injunction against the proposed licensing agreement between Sanofi and Maze. Sanofi had announced the licensing agreement on May 1, 2023 for MZE001, Maze’s glycogen synthase 1 (GYS1) inhibitor program, which completed Phase I and is in development for Pompe Disease, a rare, inherited disorder that disables the heart and skeletal muscles and is often fatal.

In its statement, Sanofi said, “We respectfully disagree with the action by the FTC which also delays potential advancements that could impact the lives of patients. The Maze partnership was designed to apply Sanofi’s resources, knowledge, and expertise to accelerate the development of MZE001, with the hope of addressing unmet medical needs for this devastating condition. The delay associated with a long litigation has led Sanofi to conclude that it would not be in the best interests of patients to contest this litigation, and Sanofi will therefore be terminating the agreement with Maze in accordance with its terms. Sanofi remains committed to address the Pompe patient community’s unmet needs.”

FTC sought to block the proposed deal, issuing an administrative complaint and authorizing a lawsuit in federal court that alleged the deal, valued at up to $755 million, would eliminate a competitor that could challenge Sanofi’s monopoly in the Pompe disease therapy market. FTC stated in its press release that “Sanofi is a monopoly supplier of Food and Drug Administration (FDA) approved drugs to treat the disease.”

According to FTC’s complaint, MZE001 “threatens to undermine this monopoly as the first oral medication available for Pompe disease patients.” The complaint also names Genzyme, Sanofi’s subsidiary, which was seeking to license the drug from Maze. In its complaint, FTC alleges that the transaction would protect Sanofi’s monopoly and eliminate competition between Sanofi and Maze to develop new Pompe drugs. FTC cautioned in its complaint that this deal would deny patients and doctors the benefits of competition, including lower prices and greater innovation.

“Sanofi’s acquisition of Maze’s Pompe disease drug threatens to deprive patients of a new, innovative treatment and maintain a status quo of exorbitant pricing for essential life-saving medicines,” said Nate Soderstrom, acting deputy director of FTC’s Bureau of Competition, in the agency press release. “The FTC is challenging Sanofi’s deal with Maze because it’s critical that patients and doctors have access to innovative, affordable treatment options.”

In its complaint, FTC also pointed out that “Sanofi singled out MZE001 as a significant threat to its lucrative Pompe monopoly shortly after Maze publicly revealed its development plans in 2021. MZE001 threatens to not only capture substantial market share from Sanofi, but also potentially replace Sanofi’s treatments as the standard of care for Pompe disease altogether.”

In addition to the administrative complaint, FTC has authorized its staff to seek a temporary restraining order and preliminary injunction in federal district court with the aim of preventing Sanofi from acquiring MZE001, pending the agency’s administrative proceeding. FTC’s federal court complaint will be filed in the US District Court for the District of Massachusetts, and a public version of the complaint will be made available at a later time, according to the agency.

Sanofi has issued a statement expressing its disappointment with FTC’s decision to block an exclusive licensing agreement with Maze Therapeutics for a rare disease drug candidate.

Sanofi to Terminate Rare Disease Drug Licensing Agreement with Maze Therapeutics in Wake of FTC’s Challenge

On Dec. 12, 2023, the European Medicines Agency (EMA) announced that the first version of the Union list of critical medicines was published by EMA, the European Commission (EC), and the Heads of Medicines Agencies (HMA) with the intention of preventing potential drug shortages in the European Union/European Economic Area (EEA). The list contains more than 200 APIs considered critical in the EU and, therefore, supply should be made a priority.

EMA stressed in a press release that medicines on the list are not necessarily in shortage, but the potential may be there in the future, and such a shortage could be harmful to the public. The agency considers medicines used to treat serious diseases and that may be hard to replace by other drugs as critical. Medicines must meet certain criteria and be critical in more than one third of the EU/EEA.

A review of 600 APIs from six national lists was conducted to create the list, which includes substances from a variety of therapeutic areas, vaccines, and treatments for rare diseases. EU Member States used an agreed upon methodology for the review that was designed in consultation with key stakeholder groups, such as patient organizations and industry associations. The list will be expanded in the coming year and updated every year after.

The Union list does not impact existing national lists of critical medicines or lists in development, but it may be used to support efforts to create national lists. The list will also support the EC’s supply chain analysis to determine possible vulnerabilities.

“Medicines on the list can continue to be prescribed and used as usual by patients and healthcare professionals. Additional reporting requirements for marketing authorization holders and national competent authorities will be established and become effective once the proposed pharmaceutical legislation becomes applicable,” EMA stated in the press release.

Regulators in the European Union have published the first version a list of critical medicines in the EU to avoid potential shortages.

List of Critical Medicines Published in EU

FDA announced on Dec. 11, 2023 that InvaGen Pharmaceuticals, a wholly-owned subsidiary of Cipla Limited, was voluntarily recalling one lot of Vigabatrin for Oral Solution, USP 500 mg. The recall comes after it was found that the product had seal integrity problems resulting in powder leakage from the pouch. Vigabatrin for Oral Solution, USP 500 mg is an adjunctive therapy for the treatment of refractory complex partial seizures in patients two years of age and olderwho have responded adequately to alternative treatments; it is not a first-line agent.

According to FDA, improper sealing of the pouch may cause powder blend to leak outside the pouch, resulting in lower product content than what is listed on the label and, possibly, underdosing. “For a small minority of patients, who might have severe or repeated breakthrough seizures, a drop in their phenytoin blood levels could result in life-threatening seizures requiring immediate emergency room treatment,” according to a press release.

The recalled product is packaged in foil pouches with 50 foil-sealed pouches in a shelf pack. The affected lot is NB301030, with an expiration date of 03/2025, and was distributed nationwide to partnered distributors and consignees.

Cipla has stated that it has not received any reports of adverse events related to the recall. Adverse events may be reported to FDA via its MedWatch Event Reporting Program.

The product is being voluntarily recalled because of powder leakage due to seal integrity issues.

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