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

cell culture at the laboratory of cell culture medical and medicine | Image Credit: ©murat - stock.adobe.com

The bio/pharmaceutical industry has seen the development of a variety of emerging therapies, such as messenger RNA (mRNA) vaccines and cell and gene therapies. These innovative modalities often require a need for new test methods, which has changed analytical testing requirements, says Jan Bekker, PhD, head of Global Commercial Operations at BioCina.

According to Milena Quaglia, PhD, senior associate principal scientist, RSSL, “the analytics required for these emerging therapies benefit from the knowledge and progress in the protein biopharmaceutical sector. Some of the chromatographic and biological methods have rapidly been adapted to the measurements of, for example, viral vectors. The increased opportunities, funding and industry needs have played a significant role in driving the enhanced robustness of analytical platforms, particularly those used in R&D (such as mass spectrometry) for routine analysis. The complexity of cell therapy and its production at a different scale render the analytical requirements and the location of the analytical physical sites challenging. Additionally, the development of potency cell bioassays for cell therapy has proven to be extremely complex due to the heterogenicity of the product.”

Cell and gene therapies, as well as mRNA, have developed alongside advancements in long-read technology to provide more holistic testing, says Andrea O’Hara, PhD, strategic technical specialist, Next-Generation Sequencing, GENEWIZ from Azenta Life Sciences. “A great example here is product characterization for AAV [adeno-associated virus] and mRNA therapeutics. While these two therapeutics are quite different, both require effective utilization of long-read technology to accurately characterize and confirm expected products,” says O’Hara. “For AAV, this option is necessary due to the intricacies of the product and its secondary structure around the inverted terminal repeats (ITRs), which are difficult to sequence with traditional approaches. For both AAV and mRNA therapeutics, the ability of long-read sequencing to effectively capture the full molecule is critical to ensure the purity and fidelity of these products.”

Currently, according to Bekker, technologies used in biopharma analysis include chromatography (e.g., high-performance liquid chromatography [HPLC] and ultra-high performance liquid chromatography [UHPLC]) with ultraviolet–visible spectroscopy (UV–Vis), fluorescence, MS, refractive index, evaporative light scattering, electrochemical, and charged aerosol detection. “BioCina uses different modes of chromatographic separation, such as [reversed phase]–HPLC, [ion chromatography]–HPLC and SE–HPLC [size-exclusion HPLC], coupled with UV–Vis, fluorescence, MS, or evaporative light scattering detection for purity analysis of in-process, release, and stability testing across the microbial, plasmid DNA, and mRNA product modalities,” says Bekker.

Other technologies include enzyme-linked immunosorbent assay (ELISA), capillary electrophoresis, gel electrophoresis, cell-based assays, microbiology test methods, coupled enzymatic assays, dynamic light scattering (DLS), among others, says Bekker. “[We use] DLS for the determination of particle sizes and analysis of particle size distribution for microbial products and lipid nanoparticles, including mRNA vaccines and other LNP-encapsulated products,” he states.

“Biopharmaceutical analytical workflows are currently well accepted in industry with an increasing confidence in mass spectrometry (particularly for host cell protein analysis and bi-specific antibodies) and bioassays including analytics supporting their development/validation,” says Quaglia.“While the development of bioassays for cell and gene therapy is still in its infancy, an increased appreciation of the data generated by mass spectrometry-based methods for AAV capsid characterisation, mRNA sequencing, purity determination is observed. The requirements for robust next generation sequencing are also increasing in the cell and gene therapy sector.”

Modern techniques are making analytical procedures more robust. According to Melissa El Khouri, head of Quality, BioCina, analytical development can be sped up and testing across multiple product modalities can be achieved by using modern analytical equipment and techniques compatible with high throughput testing. In addition, different types of analysis for multiple biologics modalities can be achieved by using sodium dodecyl sulfate capillary electrophoresis (CE–SDS), RNA, capillary isoelectric focusing (cIEF), and glycan analysis, according to El Khouri.

“While Sanger and short-read [next-generation] sequencing [NGS] have always been popular, long-read sequencing is on the rise,” says O’Hara. “Long-read sequencing has become more cost effective as the technology has advanced and offers insights that confirm or even surpass traditional Sanger and short-read NGS options.”

High-resolution analytical technologies, such as sensitive capillary electrophoresis sodium dodecyl sulfate (CE-SDS), are replacing older techniques, says El Khouri. “Modern capillary electrophoresis systems provide automated, quantitative, and highly repeatable sizing and purity analysis across multiple modalities. Operation is automated and sample preparation is kit-based, which minimizes processing time and reduces
processing errors,” she says.

 testing have been reduced by the increased use of cell-based bioassays; however, to ensure reliable data, analytical controls and standards are fundamental, says Quaglia. She stresses that regulatory requirements are not well-defined, which can cause confusion about which analytical procedure should be used for new modalities. “mRNA sequencing requires robust analytical and sample preparation platforms together with standards and standardized analytical workflows/guidelines. Availability of materials of good quality and at reasonable costs are often the main drawback for method development/improvement and implementation,” she says.

The development of assays for new modalities requires consideration of the potential product and possible pitfalls of that product, says O’Hara. “For example, with mRNA vaccines, we anticipate a full-length RNA with a specific length polyA tail. An assay to confirm this product needs to be extremely precise to confirm the exact sequence and length, down to the final nucleotide. However, we also need to consider what may go awry in the development process and test for that as well: partial or incomplete products, short or long polyA tail, missing tails, even alternative products. A robust assay will consider both the expected and the unexpected,” she states.

Bekker points to the following as considerations for developing assays for mRNA vaccines and other new modalities: sensitivity of equipment, investing in modern analytical equipment across multiple modalities, minimizing outsourcing of analytical testing to expedite batch release, regulatory expectations, and development of platform methods to streamline analytical development. “BioCina employs a platform approach to the manufacture of plasmid DNA and mRNA products, as well as the analytical testing of these products. A platform approach negates the need for extensive analytical development with each new plasmid DNA product, because methods only need to be verified. This approach speeds up development time and is more economical for our clients,” Bekker says.

‘Dry Lab Only’ using artificial intelligence (AI) and machine learning (ML) is a major trend developing in biopharma analysis, according to O’Hara, with companies moving from heavy onsite testing and analysis to computational analysis. “By utilizing these tools effectively, these companies can keep their labs lean and streamlined, outsourcing from third party wet lab workflow as needed to fill in the gaps,” she says.

“Big data [and] AI used to predict the 3D structure of proteins and molecular modeling for optimization of formulation, stability prediction, have the potential to revolutionize some of the current processes and analytical,” Quaglia agrees.

Primary testing of potential therapeutics has been revolutionized by AI and ML, according to O’Hara. “We can proactively predict aspects based on previous studies and models, including drug targeting, folding structures, and off-target interactions. Instead of testing a large variety of options, we can now utilize AI and ML to whittle down the list of candidates dramatically, and smartly, to a highly refined candidate list for downstream testing,” she says.

“Developing a strategy for analysis of biopharmaceuticals requires availability of skilled staff for sample handling, method development, and data analysis as well as appropriate equipment,” says Quaglia. “Instrumentation that is commonly used for small organic compounds needs to be biocompatible and able to deal with smaller amounts of sample. [The] [m]ain challenges for bioanalysis as analysis of small molecules/biopharmaceuticals in biological matrices (e.g., for bio-kinetic studies) are extraction, selection of appropriate standards/procedures, data analysis, and reporting. Bioanalysis laboratories are often GLP [good laboratory practice] accredited, contrary to analytical batch release laboratories that are GMP [good manufacturing
practice] accredited.”

Understanding the physiochemical characteristics of the bio/pharmaceutical product is important in order to analyze that product, says El Khouri. A bioanalytical strategy should incorporate quality-by-design, she stresses, including critical quality attributes, critical material attributes, critical process parameters, and control strategies to link these together with API and excipient specifications. “With the design of any bioanalytical strategy, it is important to build in product quality, safety, and efficacy,” says El Khouri.


Vol. 48, No. 2
February 2024
Pages 12-13, 17

When referring to this article, please cite it as Haigney, S. Emerging Therapies Drive Analytical Advancements

Articles

The emergence of mRNA vaccines and cell and gene therapies has pushed innovation in analytical methods. 

Emerging Therapies Drive Analytical Advancements

Pramote Cholayudth previously was the managing director of the Professional Conference Center, Ltd. He currently is a validation consultant to Biolab Co., Ltd., in Thailand. He is the founder and manager of PM consult, cpramote2000@yahoo.com.

glove hand Concept of FDA approved. Food and drugs administration. Quality medcine, assurance, organization.| Image Credit: ©everythingpossible - stock.adobe.com

The underlying concept for acceptance value (AV) in <905> Uniformity of Dosage Units (UDU) is based on that of tolerance interval (TI). Its maximum allowed acceptance value (L1) is declared not more than (NMT) 15; therefore, meeting the limit will just imply that the lower the value the higher the degree of quality conformance. Due to the formula for L1 or AV (i.e., , the condition foris not justified, and so, compromising that, the AV results will easily pass the limit of NMT 15 most of the time. If recognized by United States Pharmacopeia, such a compromization will continue for official use in a new proposal on “Batch Release Testing for Ensuring Compliance with Uniformity of Dosage Units”.

One of the solutions for such a compromization issue is to simply implement the TI technique to demonstrate that at least 95% or more of the dosage units in routine batches will fall within the range 85–115% of label claim. The technique will provide useful data for batch releasing rather than depending on AV parameter alone.

Pramote Cholayudth, cpramote2000@yahoo.com, is the founder and manager of PM Consult. He is an industrial pharmacist with more than 40 years of experience. He is a guest speaker on process validation to industrial pharmaceutical scientists organized by Thailand’s FDA.

®
Vol. 48, No. 2
February 2024
Pages: 24-29

When referring to this article, please cite it as Cholayudth, P. Using Tolerance Intervals for Evaluation of Uniformity of Dosage Units Data in Routine Batch Release

This article introduces that the basic technique for tolerance interval is implemented using the conventional range 85–115% LC where the proposed range in the PF is not taken into account.

Using Tolerance Intervals for Evaluation of Uniformity of Dosage Units Data in Routine Batch Release

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

Scientist working in laboratory with test tubes , laboratory| Image Credit: ©BillionPhotos.com - stock.adobe.com

FDA, as well as other regulatory agencies around the world, have for many years been encouraging drug makers to switch from batch to continuous processing due to the many benefits this manufacturing technology offers. FDA has approved several small-molecule drugs, including novel products that were initially developed leveraging continuous processing and existing products for which some part of their production was switched from batch to continuous operation. The COVID-19 pandemic highlighted the need for such manufacturing solutions that can afford higher quality products more reliably and efficiently. Continuous manufacturing is attractive because it provides both cost and quality benefits, and is in fact in alignment with FDA’s initiatives focused on designing quality into processes from the outset, rather than relying predominantly on confirmational testing at the end of a production run.

Many advantages of continuous manufacturing

Continuous processing offers many advantages over batch production, including improved quality, lower costs, greater sustainability, more flexibility, and the ability to produce novel chemicals not accessible in batch mode (1–3). Higher drug-substance and/or drug-product quality results because continuous processes operate at an optimal steady state with minimal byproduct formation or processing failures, respectively. That results in fewer lost “batches,” greater confidence in product performance, improved manufacturing efficiency, and assurance of supply for patients.

For drug substances, flow chemistry performed in microreactors enables the implementation of highly exothermic reactions and the use of hazardous materials that might not be possible in batch mode. Higher purities and yields mean reduced purification needs for greater efficiency and lower cost.

For both drug substances and drug products, shorter processes with fewer steps are often possible, leading to shorter processing times. Smaller footprints and elimination of the need for intermediate hold and storage tanks also contribute to reduced costs. Continuous processing also affords the flexibility to increase or decrease production to meet changing market demands, increasing supply-chain security. Scale-up (or scale-down) can be achieved by running the process for a longer (shorter) time on the same equipment, eliminating any need
for additional process optimization in larger bioreactors.

Continuous manufacturing also supports a quality-by-design (QbD) approach to process development and leverages process analytical technology (PAT) for real-time quality monitoring.

As of late 2021, FDA had approved 10 continuous manufacturing applications, most for small-molecule drug products. The first approval was made in 2015. In 2020, however, the agency approved the first application for continuous production of an API and the first continuous process for a biologic (2).

Process development understanding and control at the heart of QbD and continuous manufacturing

Successful development and implementation of a continuous manufacturing process requires deep understanding of the process, most notably how changing process conditions impact product quality. Establishing the optimal steady state at which a continuous process should be run cannot be achieved without in-depth process knowledge. Real-time monitoring is then essential to ensure the optimal process conditions are maintained.

The QbD approach similarly requires deep process and product understanding (4,5). This knowledge is used to first establish a quality target product profile (QTPP) that will ensure safety and efficacy for the final drug product. Critical quality attributes (CQAs), or specific characteristics of the drug product and drug substance that impact product quality, are then identified during process development. Design-of-experiment (DoE) studies and process modeling can then be leveraged to determine which specific critical process parameters (CPPs) impact the CQAs. A control strategy is then established to ensure
those CPPs remain within acceptable limits, leading to the development of a highly robust process.

The reliance on process understanding links the QbD approach closely with continuous manufacturing (6). One is a quality strategy, the other a manufacturing method. When pursued simultaneously, continuous manufacturing, in fact, can lead to greater process understanding and ultimately process control, and thus more robust processes. It has been suggested that continuous manufacturing “can be seen as a practical application of the QbD principles, providing a mechanism to achieve the QbD goal of consistently producing high-quality products” (6).

Control strategies for continuous drug substance and drug product manufacturing

One of the challenges with continuous processing approaches in which multiple operations are linked together, such as flow chemistry for API synthesis with purification via filtration and crystallization and then continuous tableting, is the fact that any changes in process conditions in upstream unit operations may impact the performance of linked downstream unit operations.

That is one reason a QbD approach to process development can be highly beneficial. It enables the development of robust processes with well-defined design spaces that account for potential feed characteristics from upstream and potential impacts downstream combined with carefully established control strategies that ensure appropriate CPPs are maintained (4). The greatest benefits of such a process development strategy can be gained by using feedforward and feedback controls based on real-time data collected using PAT tools. Furthermore, because the same equipment can be used from early development to commercial production, typically once a control strategy based on CPPs is implemented and shown to be effective, it can be leveraged across all development stages.

During process development, the specific control strategy to be implemented should be determined by conducting a risk assessment (4). Strategies can be based on manual collection of process data all the way through automatic adjustment of feeds based on real-time data gathered using PAT tools. It is also possible for continuous processes to include the ability to divert material for a given time in the event it is found using real-time analysis to be nonconforming.

Verification of control is realized by testing the developed process with varied feeds and confirming process behavior (4). Proper performance of in-process analytics and control methods must also be demonstrated. Control ranges should be justified. Once a process has reached commercial stage, it is then necessary to perform periodic assessments to confirm continued effectiveness of the control strategy despite any variations in process equipment, raw materials, or environmental factors (7).

Regulatory support for emerging technologies

FDA has been a leader in championing the modernization of pharmaceutical manufacturing to enhance efficiency, quality, and safety. Its efforts began back in 2002 with launch of its Pharmaceutical cGMPs for the 21st Century: A Risk Based Approach initiative (8). The European Medicines Agency (EMA) and Japan Agency for Medical Research and
Development (AMED) have joined in more recently, also encouraging the use of emerging technologies.

To further encourage adoption of new manufacturing technologies, FDA in 2004 published PAT–A framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, guidance encouraging the use of a QbD approach and PAT (9). In its 2011 Strategic Plan for Regulatory Science, FDA called for research to identify better technologies that enable continuous manufacturing (10).

In 2017, the agency reiterated its support for continuous processing in Advancement of Emerging Technology Applications to Modernize Pharmaceutical Manufacturing Base, guidance issued by FDA’s Emerging Technology Team (ETT) (11). FDA then addressed quality issues for continuous manufacturing in the 2019 draft guidance, Quality Considerations for Continuous Manufacturing (12).

Overall, FDA consistently stresses the alignment of QbD with continuous manufacturing and emphasizes the fact that continuous processes can be developed and implemented with the existing regulatory framework (7) and using a data-driven approach (12). In addition, success can be best assured by leveraging well-established data models constructed using multivariate data analysis and real-time process monitoring technologies during process development and when implementing continuous processes to aid with process control, reduce variability, and improve product quality and consistency (13).

The concept of quality by control (QbC) has been proposed in recent years as a means for taking QbD even further (3). In this approach, active feedback control is used for process design and development, which can for certain processes accelerate identification of optimal CPPs using much less expensive materials.

2023 Final ICH Q13 guidance on small- and large-molecule continuous processing

The most recent regulatory guidance for continuous drug manufacturing was finalized in March 2023. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q13 Continuous Manufacturing of Drug Substances and Drug Products (14) “describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing” for both small- and large-molecule drugs and builds on existing ICH quality guidances (15).

The document was developed through collaboration of FDA, EMA, and other international regulatory bodies with pharmaceutical companies and industry trade groups. In the section of pharmaceutical development, the ICH Q13 guidance specifically refers to the need for application of QbD principles and the importance of establishing deep process understanding and effective process control strategies and the appropriate use of mathematical modeling (6). The importance of effective control strategies is reiterated in sections on manufacturing and control strategy implementation, which also emphasize the need to use a science- and risk-based approach for the development and implementation of continuous processes.

The ICH Q13 guidance can, according to some, be viewed as a “comprehensive framework for the implementation of continuous manufacturing processes” that not only provides regulatory clarity on the subject, but also emphasizes the adoption of a lifecycle approach to process validation; integrates QbD and risk-management approaches for improved quality and consistency; highlights the potential for increased sustainability; encourages innovation and modernization; and creates opportunities for increased manufacturing flexibility and efficiency (6).

To date, approved products that are manufactured using continuous processes leverage hybrid approaches in which one or two unit operations have been implemented in a continuous fashion. The ultimate goal will be to achieve fully integrated continuous manufacturing solutions in which, for small molecules, raw materials undergo conversion via flow chemistry into APIs that are then directly purified (e.g., continuous crystallization) in a continuous fashion, with the purified material then directly fed into a continuous drug-product production process, possibly involving blending with excipients, traditional extrusion, tableting, and coating, as well as hot-melt extrusion, spray-drying, and electrospinning for the formation of amorphous solid dispersions (3).

Such an end-to-end (E2E) or fully integrated continuous manufacturing process would provide even more benefits that have been observed with the continuous processes approved to date (3,7). The Novartis-MIT Center for Continuous Manufacturing (CCM) demonstrated the first end-to-end continuous process for production of aliskiren hemifumarate starting from advanced synthetic intermediates through tableting in 2012 (16). Compared to the traditional process, this solution took approximately one-sixth the time. A much smaller version of the reconfigurable flow chemistry unit was then developed and used to produce diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride, which were purified in batch mode to generate liquid dosage forms (17,18).

The success of this academic-commercial relationship recently spurred follow-on activity by this involving exploration of continuous manufacturing for mRNA products (19), which is heavily encourged by Peter Marks at FDA.

Based on this initial work, the company Continuus Pharmaceuticals was spun out of the CCM in 2012 to commercialize ICM solutions. The company has collaborated with Italian pharmaceutical equipment maker IMA to develop practical solutions. The first true end-to-end integrated continuous manufacturing system for production of small-molecule oral solid dosage forms was introduced by the company in 2019 (20). Today it offers a pilot-scale E2E system (21) for late-stage process development and early clinical manufacturing. In 2021, Continuus Pharmaceuticals won a $69-million grant from the US government to produce in the United States using a good manufacturing practice-certified, E2E continuous manufacturing facility three small-molecule drugs considered to be essential medicines (22).

Vezina, A. Quality by Design Procedure for Continuous Pharmaceutical Manufacturing: An Integrated Flowsheet Model Approach (2017). Electronic Theses and Dissertations. 5690. 

Zeta, L.; Johnson, J.; Roberts, D.; and Slater, S. FDA Leads Global Work on Continuous Manufacturing Approaches to Up Quality, Supply Chain Resilience. Hogan Lovell Engage, Press Release. August 23, 2021.

Domokos, A.; Nagy, B.; Szilágyi, B.; Marosi, G.; and Nagy, Z.K. Integrated Continuous Pharmaceutical Technologies—A Review. Org. Process Res. Dev. 2021, 25, 4, 721–739. 

Ishimoto, H., et al. Approach to Establishment of Control Strategy for Oral Solid Dosage Forms Using Continuous Manufacturing. Chemical and Pharmaceutical Bulletin, 2021 69 (2). 

Manser. B and Glenz, M. Quality by Design in Continuous Bioprocesses. Pall Corporation Technical Regulatory Topic, July 15, 2021.

Chandramouli, R. Embracing the Future: ICH Q13 Guideline on Continuous Manufacturing of Drug Substances and Drug Products. LinkedIn Pulse, June 8, 2023. 

https://www.linkedin.com/pulse/embracing-future-ich-q13-guideline-continuous-manufacturing-r

Wahlich, J. Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms. Pharmaceutics. 2021 Aug; 13(8): 1311. doi: 

FDA. Guidance for Industry: Pharmaceutical Current Good Manufacturing Practices for the 21st Century: A Risk-Based Approach (Rockville, MD, February 2003).

FDA. Guidance for Industry: PAT–A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (Rockville, MD, October 2004).

FDA. Strategic Plan for Regulatory Science (Rockville, MD, August 2011).

FDA. Guidance for Industry: Advancement of Emerging Technology Applications to Modernize Pharmaceutical Manufacturing Base (Rockville, MD, September 2017).

FDA. Draft Guidance for Industry: Quality Considerations for Continuous Manufacturing (Rockville, MD, February 2019).

Sartorius. Why the FDA Encourages Continuous Manufacturing Supported by Data Models. Sartorius Science Snippets Blog, May 11, 2021. 

ICH. Q13 Continuous Manufacturing of Drug Substances and Drug
Products Guidance for Industry, Level 1 Guidance (2023).

FDA. Guidance for Industry: Q13 Continuous Manufacturing of Drug Substances and Drug Products (Rockville, MD,
Mar. 2023).

Trafton, A. Continuous Drug Manufacturing Offers Speed, Lower Costs. MIT News, March 12, 2012. 

https://news.mit.edu/2012/manufacturing-pharmaceuticals-0312

Adamo, A.; Beingessner, R. L.; Behnam, M.; Chen, J.; Jamison, T. F.; Jensen, K. F.; Monbaliu, J.-C. M.; Myerson, A. S.; Revalor, E. M.; Snead, D. R.; Stelzer, T.; Weeranoppanant, N.; Wong, S. Y.; Zhang, P. On-Demand Continuous-Flow Production of Pharmaceuticals in a Compact Reconfigurable System. Science
2016, 352 (6281), 61– 67, DOI: 10.1126/science.aaf1337

Zhang, P.; Weeranoppanant, N.; Thomas, D. A.; Tahara, K.; Stelzer, T.; Russell, M. G.; O’Mahony, M.; Myerson, A. S.; Lin, H.; Kelly, L. P.; Jensen, K. F.; Jamison, T. F.; Dai, C.; Cui, Y.; Briggs, N.; Beingessner, R. L.; Adamo, A. Advanced Continuous Flow Platform for On-Demand Pharmaceutical Manufacturing. Chem.–Eur. J. 2018, 24 (11), 2776–2784, DOI: 10.1002/chem.201706004

Zach Winn, “MIT Researchers to Lead a New Center for Continuous mRNA Manufacturing,” MIT Press Release, July 13, 2023.

Hu, C.; Testa, C. J.; Wu, W.; Shvedova, K.; Shen, D. E.; Sayin, R.; Halkude, B. S.; Casati, F.; Hermant, P.; Ramnath, A.; Born, S. C.; Takizawa, B.; O’Connor, T. F.; Yang, X.; Ramanujam, S.; Mascia, S. An Automated Modular Assembly Line for Drugs in a Miniaturized Plant. Chem. Commun. 2020, 56 (7), 1026–1029, DOI: 10.1039/C9CC06945C

Testa, C. J.; Hu, C.; Shvedova, K.; Wu, W.; Sayin, R.; Casati, F.; Halkude, B. S.; Hermant, P.; Shen, D. E.; Ramnath, A.; Su, Q.; Born, S. C.; Takizawa, B.; Chattopadhyay, S.; O’Connor, T. F.; Yang, X.; Ramanujam, S.; Mascia, S. Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study. Org. Process Res. Dev. 2020, 24, 2874 DOI: 10.1021/acs.oprd.0c00383.

Kansteiner, F. MIT Spinout Continuus Pharmaceuticals Nets $69M to Onshore Production of Critical Meds. Fierce Pharma, Jan. 28, 2021.

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

Pharmaceutical Technology
Vol. 48, No. 2
February 2024
Pages: 14-17

When referring to this article, please cite it as Challener, C.A. QbD for Small-Molecule Continuous Process Development. 

Continuous manufacturing and a quality-by-design development approach are a natural fit.

QbD for Small-Molecule Continuous Process Development

Pharmaceutical compounding comprises activities associated with preparation of dosage forms 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 in larger quantities for future patients in the physician’s office. The scope of compounding considerations is extensive—patient therapeutics, dosage forms, preparation processes, regulations, personnel, and so on. Compounded preparations include both sterile and non-sterile dosage forms—injections, ophthalmics, capsules, liquids, topicals, and many others. Compounded drug dosage amounts range from neonates to seniors. Compounding occurs in many settings—community pharmacies, hospitals, outsourcing facilities, pharma industry, nursing homes, outpatient care, and 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 (reconstitution of multidose containers; dissolving lyophilized products) are not compounding (7). Product transfer to a different container is repackaging; preparing individual syringes from a larger container of drug product is repackaging (8,9). When a dose of medication is drawn for administration at the patient bedside, this is preparation for immediate use (7). The 

) definition of compounding differs from the FDA definition 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; traditional compounding identifies a specific patient; traditional compounding occurs in a compounding pharmacy. Compounded preparations prepared on a larger scale for future use (“office stock”) have expanded the definition of compounding; this 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 facilities.

This discussion provides a general overview of US human drug compounding—primary considerations that characterize pharmaceutical compounding. Selected themes describe technical topics, FDA regulations, and personnel responsibilities in a workplace environment. Topics include the following:

 Scientific and technical aspects of compounding such as formulation design, preparation, and calculations.

Regulations governing compounding include federal, state, and local regulations. Good manufacturing practice (GMP) is required for certain compounding.

 Compounding staff designs and prepares dosage forms; management monitors performance and provides a suitable workplace environment.

This discussion has been developed considering academic teaching, experiences in multiple settings, and published reports of adverse events. Compounding education typically includes theory and techniques using placebo formulations. Compounding in the workplace is different reality—potent drugs, sick patients, emergency circumstances, imperfect facilities, time pressures, insufficient information, electronic systems, and problematic logistics with interruptions, interferences, and other distractions. Additional discussion on these topics may be found on 

Technical pharmaceutics principles are fundamental in dosage form design and preparation. Technical concepts especially relevant to compounding include solubility, dissolution, compatibility, and chemical and physical stability. Formulation materials, preparatory processes, associated calculations, and actual compounding techniques are of obvious importance. Multiple personnel may be involved in compounding, including technical experts who integrate available technical information, specialists who prepare the designed formulation, and pharmacists who advise patients/clients on drug administration.

 Formulation design is fundamental in compounding. Formulation ingredients (API and inactive excipients) and the primary container comprise the compounded dosage form. All formulation components must be sourced from approved suppliers, meet quality standards, be stable, and not contaminated (chemical, microbial). Ingredients must be properly stored and be within expiration dating. Inactive formulation ingredients are very relevant in compounded dosage form design. Inactive ingredients may replace problem ingredients in commercial products (e.g., no lactose in lactose-intolerant patients; no dyes and or peanut oil in allergic patients). Liquid formulations are prepared for children or seniors who cannot swallow solids.

 There are numerous types of calculations potentially used in compounding. Formulation calculations such as percent calculations, API conversions, ratio strength, and many 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. Formulation dosage considerations including pharmacokinetic factors, drug half-life, renal clearance, and liver function must be calculated. Final product testing (potency, moisture) may require calculations. Stability data calculations justify expiry dating.

 Procedures for preparation of compounded dosage forms are likewise critical. Skilled personnel must be trained; aseptic techniques are especially important. A well-designed compounded preparation will fail if execution by the compounding technician is substandard (mixing order, particle size reduction, levigation). Basic aseptic techniques, cleanroom equipment, and controlled air-particulate facilities are critical for sterile preparations. Allen (13,14), Institute for Safe Medication Practices (ISMP) (15,16), Gudeman 

. (18) have addressed errors associated with sterile and non-sterile compounded preparations.

 Related technical activities executed after completion of compounding must also consider pharmaceutics principles. Dosage form testing (e.g., visual, 

, or other reference), labeling, medical information, packaging, supply chain shipping, and communication with patients/clients (light protection, temperature control, administration methods) have technical considerations.

FDA expressed concern for medication safety with use of compounded pharmaceuticals. Compounded preparations are not approved by FDA via the new drug application/abbreviated new drug application (NDA/ANDA) drug approval process. The New England Compounding Center (NECC) incident in 2012 (19) heightened public awareness of problems with compounding and prompted regulations that significantly changed compounding practices. FDA categorized pharmaceutical compounding facilities as 503A compounding pharmacies and 503B outsourcing facilities in the Drug Quality and Security Act (DQSA) of 2013 (20). 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.

 503A pharmacies exemplify traditional compounding—individual patient, prescribing physician, and registered pharmacist in a licensed pharmacy. 503A pharmacies are exempt from federal regulations concerning GMP compliance, labeling requirements, and drug approval via NDA/ANDA processes.

 Section 503A of the FD&C Act (21) addresses applications, conditions, provisions, requirements, and enforcement of 503A regulations. 503A compounding must be compliant with applicable 

 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 addressing adulterated, unapproved, and misbranded drugs will follow risk-based concepts. 503A hospital and health system compounding practices are also addressed (22); some 503A pharmacies have distribution practices that extend beyond their individual facility, i.e., compounded preparations may be transferred to other hospitals, clinics, or infusion centers within their corporate system. 503A pharmacies are regulated primarily by state agencies.

 FD&C Section 503B addresses organizations that prepare dosage units for sale to various healthcare providers in advance of specific patient identification (i.e., non-traditional compounding 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 (23). Facilities that manufacture 503B sterile products must also register with FDA and pay an annual registration fee.

Section 503B (24) addresses requirements including GMP compliance. Specific sections 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 (25).

These documents reflect FDA’s intent to recognize differences between outsourcing facilities and pharma industry manufacturers while maintaining minimum safety standards for public health. Risk levels associated with compounding various dosage forms is acknowledged. 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; appendices further address GMP release testing and stability testing. 503B facilities are audited by FDA.

 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; item 17 lists GMP requirements. Exceptions to described characteristics are possible (e.g., a facility may have both 503A licensed pharmacy and 503B outsourcing operations). Item 18 addresses usual inspections. The FDA website provides FDA-483 observations, Warning Letters, and associated correspondences involving compounding facilities (26,27). 

 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.

Personnel in compounding organizations have significant responsibilities; essentially, all work in compounding requires human judgment and performance. In brief, staff designs and prepares the compounded dosage forms. Management must monitor actual compounding as well as execute support responsibilities (hiring, scheduling, training, facilities, equipment, maintenance, budgets). Management is responsible for policies, procedures, and quality systems supporting compounding—a substantial responsibility for 503B outsourcing facilities requiring GMP. Management must integrate technical compounding performance and daily workplace operations to develop a quality culture. Compounding errors caused by dosage form design omissions, insufficient training, distractions, inexperience, and other issues are caused by staff and attributable to management. Regular management communication to heighten staff awareness of problematic situations is recommended to minimize potential for medication errors (33).

 Numerous references supporting 503A and 503B pharmaceutical compounding relevant to technical considerations and regulatory compliance provide the fundamental bases for personnel performance in compounding organizations. 

 <795>, <797>, and <800> (34–36) are primary documents that have legal basis cited in FDA-483 observations. 

 also contains more than 100 compounding-related chapters (37,38). FDA offers training on various compounding activities through their Compounding Quality Center of Excellence (39). Principles associated with ICH Q9(R1) 

 (QRM) and Human Factors Engineering (HFE) are directly applicable to compounding organizations. ICH Q9(R1) describing hazard identification and evaluation (“what might go wrong?”) in pharmaceutical manufacturing (40) is likewise applicable to compounding. HFE (41,42) addresses human performance with technology, processes, device operation, and user interface; electronic systems overridden in compounding activities exemplify HFE issues. Staff and management must collaborate to proactively prevent—as opposed to correct—hazards causing substandard compounding and medication errors (40). Documentation is intrinsic to pharmaceutical compounding and GMP compliance. Most relevant is documentation associated with the preparation of compounded dosage forms (descriptive information, ingredients, lot numbers, preparative procedures) and personnel accountability. 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. The pharma industry adage, “If it isn’t written down, it didn’t happen” must also be practiced in pharmaceutical compounding operations (43).

This discussion provides a brief overview of pharmaceutical compounding—key topics that characterize compounding. FDA has defined compounding; 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.

 Assuming correct patient considerations, formulation, calculations, and actual dosage form preparation are primary technical areas relevant to compounded dosage forms. Compounded pharmaceuticals may include sterile and non-sterile preparations.

 Legislation enacted following the NECC 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—staff and management—in the workplace environment. Human performance in dosage form design, preparation, documentation, and user communication is critical for success. Workplace interferences may impact 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 is a key requirement in compounding. Staff and management must collaborate to continually improve the quality culture in the compounding 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; Richard Poska, RPh, pharmaceutical scientist, Flexo; William R. Porter, PhD, principle scientist, Peak Process Performance Partners; 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

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

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

apter <1178>, Good Repackaging Practices. 

 (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 

Compounding Overview: Primary Considerations in the Workplace

The Art, Science, and Technology of Pharmaceutical Compounding

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

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

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

 (1), 1–8. DOI: 10.1007/s40268-013-0005-9
18. 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
19. US Senate. 

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

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

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).
25. 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.
28. 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

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

Compounding and the FDA: Questions and Answers

Guidance for Industry, Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application

 (CDER, January 2018).
33. ISMP. Targeted Medication Safety Best Practices for Community Pharmacy. 

 <795>, Pharmaceutical Compounding—Non-Sterile Preparations. 

 (Rockville, Md., November 2022).
35. USP, 

 <797>, Pharmaceutical Compounding—Sterile Preparations. 

 (Rockville, Md., November 2022).
36. USP, 

<800>, Hazardous Drugs—Handling in Healthcare Settings. 

 (Rockville, Md., November 2023).
37. USP. Courses. 

 (accessed April 11, 2023).
38. Shrewsbury, R. P. 

Applied Pharmaceutics in Contemporary Compounding

, 3rd ed; Morton Publishing, 2015.
39. FDA. 

 (accessed April 11, 2023).
40. ICH, Q9(R1) 

Guidance for Industry and FDA Staff, Applying Human Factors and Usability Engineering to Medical Devices

 (CDRH, Feburary 2016).
43. FDAnews. Good Documentation: More than Entering Data. 

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


Volume 48, No. 2
February 2024
Pages 18–22

When referring to this article, please cite it as Pluta, P. L.Compounding Overview: Primary Considerations for the Workplace.

Technical, regulatory, and personnel considerations characterize pharmaceutical compounding.

Compounding Overview: Primary Considerations for the Workplace

Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

Not long-ago, automation in pharmaceutical manufacture meant robots picking items from a conveyer belt, placing them for different robotic arms to neatly position them for further processing, and, ultimately, folding them into their packaging. Shortly after robotic pipetting became the norm, the X-Y robot platform began to find a home in research to help build combinatorial libraries in drug discovery, or to deposit samples for experiments, and perhaps off-the-shelf commercial microarray platform products. Revolutionary in their day, these now seem antiquated compared with several generations, spurred in part by FDA’s encouragement of process analytical technology (PAT), of sophisticated spectroscopy and software integration systems.

The pharmaceutical automation market is projected to reach $18.2 billion by 2029 at a compound annual growth rate of 12% from 2022 to 2029 (1). This growth is still partly driven by early FDA encouragement alongside White House and other national programs to modernize industry and each nation’s manufacturing competitiveness. The Advanced Research Projects Agency for Health (ARPA-H) and BioMADE come quickly to mind. BioMADE is a manufacturing Innovation Institute (MII) sponsored by the US Department of defense. In the United Kingdom, the High Value Manufacturing (HVM) Catapult or the Medicines Manufacturing Innovation (MMI) Centre stand out. By pooling funds, adoption of novel, complex, or costly equipment can be quickly trialed, assessed, and encouraged to be broadly adopted. All this is done with a mind’s eye, ultimately, on current good manufacturing practice (CGMP) and regulatory compliance. But if the technology is especially novel or effective in a new way, these adoptions can even help drive evolution in the regulations themselves.

In manufacturing tightly regulated healthcare products, human performance has long been second best. Society has oriented itself more toward the magic of silicon chip processors and digitalization, so manufacturing has embraced what has become admiringly termed “Industry 4.0”, with a view to attain end-to-end task automation. As these manufacturing tasks in pharmaceuticals become not only more complex and diverse but also more expensive, analytical tools and sensors have been raised on high as inseparable from “success” itself. While the complicated and costly new analytics provide a healthy positive return on investment in many applications, they are not always the optimal answer. These analytics necessitate a more highly skilled workforce with cross-team integration that includes built-in flexibility and a willingness to continually learn new skill sets, repeatedly.

Mauricio Futran, owner of Pharmaceutical Engineering Solutions, who spent 40 years in Big Pharma, working for Merck, Bristol Myers Squibb, and Janssen, a Johnson & Johnson company, stated in 2023 that “segregation and lack of uniformity have been a traditional issue in the industry. The beauty of continuous manufacturing is that the issue of segregation goes away … we now have process analytical tool (PAT) sensors that can assure you are on the right quality in real time, the systems are super steady without drift, and also, when talking about tableting, you can actually assay every single table with near Infra-red, and have [individual tablet-level] quality assurance and control of the process” (2).Taking this into consideration, and taking a step back to look at the wider-picture implications of this digitalization, Futran went on to conjecture that “this is going to drive an evolution in regulations ... and in concepts of validation ... on top of which you add multivariate analytics, this gives an assurance that what you are doing is right on track of where it should be, compared with all your preceding batches” (2).

Digital twins and artificial intelligence as employable skills

In the 1960s, NASA pioneered the use of digital twin technology. This in-silico method of comparison and extrapolation kept humans safe while drastically reducing operation and equipment costs for hard to repeat experiments. To better predict risks and reduce trial and error delays, pharmaceutical equipment designers have begun to embrace and deploy digital twin technologies. A recent high-profile example was GSK using digital twin technology “to fine-tune their manufacturing process when scaling up production of their vaccine adjuvant in response to the C[OVID]-19 pandemic” (3). In her study of its use, Alison Doughty goes on to say, “The Empa research center in Switzerland [The Swiss Federal Laboratories for Materials Science and Technology] is working on digital twins to optimize drug dosage for people afflicted by chronic pain, taking into account factors such as age and lifestyle to help customize the digital twin” (3).

In the hopes of early and less costly optimization, the efforts are typically coupled to machine vision and machine learning (ML) models, along with cloud-based historical batch process performance. In this way much can be learned and tried in a quick and cost-effective manner, especially when first approaching a new molecular therapy or chemical modality. When married to artificial intelligence (AI) and ML, this can be perhaps the most effective way to experimentally churn through the largest number of potential solutions in any given pharmaceutical challenge. But turned to more mundane efforts, such as keeping an eye on a bioreactor process or flow chemistry system for, say, critical quality attributes (CQAs), it has revolutionary potential.

In a presentation at the 2022 PDA–FDA Joint Regulatory conference, Martin Van Trieste spoke about drug quality, Industry 4:0, Six Sigma, and the data deluge, saying, “We’re now using machine learning and AI, and that will really help eliminate failures, eliminate deviations, eliminate non conformances, and get past what I call blind compliance” (4).He went on to say that because of AI, “the future looks really bright for patients with improved safety, reliability, and quality, and all at a lower cost, some of which will be passed on to the consumer. Now if the future is bright for this group of people, it must be bleak for somebody else. And it’s going to be bleak for the dinosaurs of the industry, for the large quality organization that have been built around testing and inspecting the product, because if you are doing AI, you don’t need large testing organizations. The computer will not allow a mistake to happen, and it will safety check everything at the end … It’s really good for the patients. It’s not good for the quality unit, so I suggest that you really learn data analytics, you really learn AI‚ become that resource in the company, because that’s how you’re going to keep your job in the future” (4).

Pharmaceutical Automation Market by Component (Plant-level Controls, Enterprise-level Controls, Plant Instrumentation), Mode of Automation (Semi-automatic, Fully-automatic), End User, and Geography—Global Forecast to 2029

. Market Research Report, May 2022.
2. Mirasol, F.; Spivey, C. Drug Digest: Advancements in the Implementation of Continuous Manufacturing. 

Effective analytics will eliminate failures, deviations, and non-conformances.

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