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A “Plan, Prevent, Prove” Approach

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On Dec. 19, 2023, FDA announced a joint Q&A document with the European Medicines Agency (EMA) that addresses questions about FDA’s breakthrough therapy (BT) designation and EMA’s priority medicines (PRIME) scheme. Specifically, the 

discusses expediting quality development for these therapies that treat unmet medical needs. It describes FDA’s policy on quality assessments for expedited products in the Center for Drug Evaluation and Research’s 

The document was developed after a 2018 workshop held by FDA and EMA where quality challenges and scientific approaches were discussed by regulators and members of industry to be sure robust quality and manufacturing data packages are submitted in a timely manner. Real case studies were explored at the workshop that showcased challenges with chemical molecules, biologicals, and advanced therapy medicinal products (ATMPs). Process validation, control strategy, compliance with current good manufacturing practice (GMP) requirements, comparability, stability, and regulatory tools were chosen as topics for discussion.

“These conversations focused on enabling timely access to medicines for patients while keeping in mind the importance of drug safety, efficacy, and quality and maintaining current regulatory standards of approval. FDA and EMA have engaged in further discussions on these topics, sharing their experiences and regulatory expectations in the context of PRIME/BT applications, and this new document is the result of these discussions,” the agency stated in a press release.

The document is broken down into questions on the following four sections:

Annex 1. Q&A on Control strategy considerations for PRIME/BT applications

Annex 2. Q&A on Process validation approaches for PRIME/BT applications

Annex 3. Q&A on Alternatives for determination of re-test period or shelf-life for PRIME/BT applications

Annex 4. Q&A on GMP considerations for PRIME/BT applications.

“These documents are only intended to provide general information and do not constitute regulatory guidance. Applicants interested in pursuing the approaches described in these Q&A documents should discuss the strategy required for their specific product with the relevant regulatory authority ahead of their marketing submission,” the Q&A document states.

Articles

The agencies published a joint guidance document regarding quality development for breakthrough therapies and PRIME programs.

EMA and FDA Answer Questions About Breakthrough Therapies

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

Adapting to Solid Dosage Development and Manufacturing Needs

In this exclusive Drug Digest video interview, Felicity Thomas, Europe/senior editor, 

Group, interviews experts about trends shaping solid dosage drug development and manufacturing. During this episode, Felicity chats with Jan Vertommen from Lonza at CPHI Barcelona about key trends, such as advances to help overcome solubility issues and the increasing importance of sustainability, as well as the role of a CDMO in solid dosage development and manufacturing. Additionally, Dave DiProspero from CRB Group details the progression of oral solid dosage manufacturing and the transformation of continuous processes in the sector.

Jan Vertommen, Vice President, Head of Commercial Development, Small Molecules at Lonza.

Jan Vertommen currently serves as Vice President, Head of Commercial Development, Small Molecules at Lonza. Jan has more than 25 years of experience in operational and commercial roles in the pharmaceutical industry. He joined Lonza in 2003 and held operational positions in product development as Head of Product Development and as Site Leader of manufacturing sites, as well as business-oriented positions in business and commercial development. Jan received his degree of pharmacist and made his PhD thesis on pharmaceutical delivery technologies at the Catholic University of Leuven, Belgium. He has authored several publications in scientific journals and has given numerous presentations at scientific symposia on pharmaceutical dosage form development and manufacturing.

Dave DiProspero, Senior Fellow—Director of Pharmaceutical Process Technology, CRB Group.

Dave DiProspero has 25 years of pharmaceutical engineering experience with a specialty in oral solid dose (OSD) form manufacturing operations/facilities/equipment/technology. His primary expertise is in internationally regulated, CGMP operations with a strong engineering, process, containment, equipment, material handling and facility systems integration background. Dave is experienced in site master planning, conceptual/preliminary/detailed facility design, engineering, procurement, qualification, project management and facility assessments. He is a long-term member of the International Society for Pharmaceutical Engineering and has chaired numerous committees–many related to education. Dave is currently the chair of the Facility of the Year Committee and steering committee advisor of the OSD Community of Practice. He is the steering committee manager for the OSD Baseline Guide Volume 3 revision effort.

This episode of Drug Digest is sponsored by:

Drug Digest is a tech talk video series with the 

 editors, who interview industry experts to discuss the emerging opportunities, obstacles, and advances in the pharmaceutical and biopharmaceutical industry for the research, development, formulation, analysis, upstream and downstream processing, manufacturing, supply chain, and packaging of drug products.

 APIs, Excipients, and Formulation Advances

Videos

In this episode of Drug Digest, Pharmaceutical Technology’s European/Senior Editor, Felicity Thomas, chats about the trends shaping solid dosage drug development and manufacturing with Jan Vertommen from Lonza and Dave DiProspero from CRB Group.

Drug Digest: Adapting to Solid Dosage Development and Manufacturing Needs

Feliza Mirasol is the science editor for 

France-based Depixus, a life science technology company specializing in magnetic force spectroscopy-based technology, has formed a collaboration with Daiichi Sankyo under which Depixus will use its MAGNA technology to accelerate an RNA-targeted drug discovery program.

According to a Dec. 12, 2023 company press release, MAGNA enables high-throughput analysis of dynamic biomolecular interactions in real time with single-molecule resolution. Used on RNA, this analysis can reveal how small molecules and proteins bind to three-dimensional RNA structures. The technology can furthermore provide valuable information about binding kinetics and mode of action.

Under the collaboration, Daiichi Sankyo’s team will use MAGNA to explore the interactions of lead molecules with a number of undisclosed RNA targets. The data from these studies will inform hit-to-lead selection and lead optimization. Daiichi Sankyo anticipates that the technology will accelerate and de-risk its RNA-targeted therapeutics pipeline as candidates in that pipeline move towards the clinic.

In comparison with other analytical techniques that provide static snapshots, averaged bulk data, or indirect measurements of molecular interactions, MAGNA generates direct readouts of dynamic binding and conformational changes from thousands of individual molecules, according to Depixus. The technology can be used to study a wide range of molecular interactions, such as interactions between DNA, RNA, proteins, and small-molecule therapeutics. It can also have applications in areas such as RNA-targeted drug discovery, protein–protein interactions, proteolysis targeting chimeras, and molecular glues, the company stated in its press release.

“The world of RNA-targeted therapeutics has huge potential, yet is largely unexplored. We are excited to partner with Daiichi Sankyo to put MAGNA to work in pursuit of our shared vision of creating novel medicines to treat diseases with high unmet need,” said Gordon Hamilton, CEO of Depixus, in the press release.

Under a collaboration, Daiichi Sankyo and Depixus will use Depixus’ MAGNA technology to accelerate drug discovery efforts of RNA-targeted therapeutics.

Daiichi Sankyo Partners with Depixus to Accelerate RNA-Targeted Drug Discovery

US-based NightHawk Biosciences (NightHawk) announced in December 2023 that it will pivot to focus solely on being a contract development and manufacturing organization (CDMO), specializing in large-molecule biomanufacturing and development. The changeover follows the divestiture of certain non-core assets, as well as the separating out of its Elusys subsidiary, which the newly named entity will retain.

NightHawk will instead focus on its growing business, Scorpius BioManufacturing, with the changeover. On its first full year of operation Scorpus is expected to generate over $20 million in revenue. With this shift into a pure-play CDMO, NightHawk has eliminated most of its R&D and associated expenses to focus resources on growing and expanding Scorpius.

The divested assets will be acquired by a private company established by NightHawk’s CEO, Jeff Wolf, which will assume Elusys’ contracted financial commitments, currently estimated at over $40 million. Under the transaction, the private company will provide an upfront payment of $500,000, a note for $2.25 million (convertible into shares of NightHawk’s common stock), and royalties of 3% on all of Elusys’ gross sales until June 30, 2031, according to a Dec. 12, 2023 company press release.

“There is a significant shortage of clinical-scale biologic manufacturing capacity within the industry as a result of growing demand for large molecule CDMO services. In turn, this has led to significant M&A [merger and acquisition] activity within the sector. We believe we are extremely well positioned to capitalize on these trends … ” said Jeff Wolf, CEO of NightHawk and Elusys, in the press release.

“The divestiture of our non-core assets enables NightHawk to focus its resources on growing its Scorpius subsidiary and will result in the immediate elimination of approximately $40 million of contractual obligations and reduction of over $13 million in operating expenses per year,” said John Prendergast, NightHawk’s lead director, in the press release. “Moreover, NightHawk will receive an upfront cash payment, as well as a $2.25 million convertible loan and at least $5 million in royalties on future Elusys gross payment receipts for approximately 7.5 years.”

Following the divestiture of its Elusys subsidiary and other non-core assets, NightHawk Biosciences will transform into a pure-play large-molecule CDMO. 

NightHawk Biosciences Shifts into a Pure-Play Large-Molecule CDMO 

Bristol Myers Squibb and SystImmune, a clinical-stage biopharmaceutical company, have entered into an exclusive license and collaboration agreement potentially worth up to $8.4 billion to jointly develop and commercialize SystImmune’s BL-B01D1, an epidermal growth factor receptor and human epidermal growth factor receptor 3 (EGFRxHER3) bispecific antibody-drug conjugate (ADC), in the United States.

Under the agreement, SystImmune will receive an $800 million upfront payment from Bristol Myers Squibb. The company can also receive up to $500 million in contingent near-term payments. SystImmune is further eligible to receive additional payments of up to $7.1 billion upon achieving certain development, regulatory, and sales performance milestones.

Also under the agreement, SystImmune will retain exclusive development and commercialization rights to BL-B01D1, through its affiliates, in mainland China. Bristol Myers Squibb will receive a royalty on net sales in that market. Outside the US and mainland China, SystImmune will receive a tiered royalty on net sales.

SystImmune (through its affiliates) will have sole responsibility for the development, commercialization, and manufacturing in Mainland China and will be responsible for manufacturing certain drug supplies for use outside of Mainland China. Bristol Myers Squibb, meanwhile, will assume sole responsibility for development and commercialization in the rest of the world.

BL-B01D1 is currently in a global multi-center Phase I study in metastatic or unresectable non-small cell lung cancer (NSCLC). Data from earlier clinical studies demonstrated promising anti-tumor activity in patients with a range of solid tumors, including NSCLC and breast cancer, who had progressed after standard of care treatments, according to a Dec. 11, 2023 company press release.

“Recent BL-B01D1 trials have shown broad potential across different solid tumors as well as a manageable safety profile,” said Yi Zhu, CEO, SystImmune, in the press release. “We have long admired Bristol Myers Squibb’s global clinical development and commercialization capabilities in oncology, and this strategic collaboration is an exciting step forward in delivering potential antitumor medicines to patients worldwide. We look forward to a productive partnership.”

“Our collaboration with SystImmune allows us to strengthen our leadership in oncology and is consistent with our strategy to diversify beyond immuno-oncology to transform patient care,” said Samit Hirawat, executive vice-president, chief medical officer, Drug Development, Bristol Myers Squibb, in the press release. “SystImmune’s BL-B01D1 adds yet another ADC to our diverse pipeline and helps strengthen our approach of matching the most appropriate therapeutic modality to areas of unmet medical need across solid tumor oncology. We look forward to working with SystImmune to advance BL-B01D1 in hopes of offering a differentiated treatment option for patients in need.”

Bristol Myers Squibb and SystImmune plan to co-develop and co-commercialize lead ADC candidate for cancer treatment in US.

Bristol Myers Squibb and SystImmune Enter Global ADC Collaboration Worth Potentially up to $8.4 Billion 

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.

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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Leveraging expertise in material science and particle engineering. Serán addresses the industry’s most challenging problem statements in drug development.

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

Identifying the best strategy and formulation technology for each program’s unique considerations and needs.

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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.

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