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

Waters Corporation announced the launch of the XBridge Premier GTx BEH size exclusion chromatography (SEC) columns on August 1, 2023. The new SEC columns are designed to improve analysis while lowering the cost of gene therapies, specifically for adeno-associated viral (AAV) vectors.

According to a company press release, the columns aim to reduce the cost of gene therapies by using 3 to 10x less sample, generating faster results, and offering more drug substance information. Additionally, a new multi-attribute quantification method is intended to double analytical speed, quadruple sensitivity, and increase resolution of target analytes by up to 50%.

According to the release, SEC is a technique used for aggregate and fragment analysis in the research, development, and manufacturing of biotherapeutic proteins, such as insulin and monoclonal antibodies. The Xbridge columns are designed to take robust physicochemical characterization and quantitative measurements. Aiming to double the speed of measuring the potency and safety of AAVs, the SEC columns are intended for process development, formulation studies, regulatory filing support, ongoing process monitoring, and quality control.

"We are witnessing a revolution in medicine thanks to gene therapies like AAVs," said Erin Chambers, vice-president, Consumables and Lab Automation, Waters Corporation, in the release. "A small quantity of a gene therapy, such as one of the best-selling eye treatments, can retail for more than $400,000 per eye. This makes it imperative that process and formulation development tests measure multiple attributes of the drug at once while consuming as little of it as possible. It's why Waters' low adsorption … SEC columns are such a good choice for process development, formulation studies, regulatory filing support, along with ongoing process monitoring as well as quality control."

Articles

Waters XBridge Premier GTx BEH size exclusion chromatography (SEC) columns are designed to improve analysis while lowering the cost of gene therapies.

Waters Launches SEC Columns for Gene Therapy Applications

Kiefel, a German company specializing in thermoforming and joining technology, announced the launch of its Solutionperformer KFS modular form-fill seal machine on August 3, 2023. According to a company press release, the machine is built to form, fill, and seal up to 6,000 infusion, parenteral nutrition, or dialysis bags per hour. It is available in both standardized and individually configurable solutions.

According to the release, the line manufactures, fills, and seals the bag on a single machine. Bags can be customized from sizes of 50 to 6000 ml. Precision mass flow meters, optional residual oxygen content control, and automatic sealing of the bags are intended to ensure maximum output combined with constant quality monitoring.

"With the [Solutionperformer] we have developed a new generation of a modular and optimally coordinated machine concept," said Thorsten Emge, global director, Medical & Pharma, Kiefel, in the release. "With the best price-performance ratio, it meets the high requirements of our customers in terms of output, efficiency and bag quality."

Kiefel’s new machine is designed to form, fill, and seal up to 6,000 infusion, parenteral nutrition, or dialysis bags per hour.

Kiefel Launches Modular Form-Fill Seal Machine

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On July 28, 2023, FDA approved RiVive, 3 mg naloxone hydrochloride nasal spray for over-the-counter (OTC), nonprescription use as emergency treatment of confirmed or suspected opioid overdose. This product is the second nonprescription naloxone FDA has approved, increasing consumer non-prescriptive access to naloxone. The manufacturer will determine the timeline for availability and the price of this product. 

A study from the manufacturer showed comparable levels of RiVive reach the bloodstream as an approved prescription naloxone product. The drug showed it was safe and effective for use as outlined in its labeling. The manufacturer submitted data exhibiting consumers can comprehend how to safely and effectively use RiVive without a healthcare professional’s supervision.

“We know naloxone is a powerful tool to help quickly reverse the effects of opioids during an overdose. Ensuring naloxone is widely available, especially as an approved OTC product, makes a critical tool available to help protect public health,” said FDA Commissioner Robert M. Califf, M.D in an FDA press release. “The agency has long prioritized access to naloxone products, and we welcome manufacturers of other naloxone products to discuss potential nonprescription development programs with the FDA.”

Drug overdose continues to be a major public health concern in the United States. Over 105,000 fatal overdoses were reported in the 12-month period ending in February 2023, most of which were driven by synthetic opioids such as illicit fentanyl. Naloxone, which quickly reverses the effects of opioid overdose, is the standard treatment for opioid overdose.

Individuals who are dependent on opioids may experience severe opioid withdrawal while using RiVise, whose symptoms include the following: body aches, increased heart rate (tachycardia), diarrhea, runny nose, fever, sneezing, goose bumps, yawning, sweating, nervousness, restlessness or irritability, nausea or vomiting, shivering or trembling, abdominal cramps, weakness, and increased blood pressure.

This approval is part of a series of steps FDA has taken to enable better access to products that treat opioid overdose, while reducing opioid exposure and curbing new cases of addiction. Other products approved by the agency include 

the first generic nonprescription naloxone nasal spray product in March 2023

the first generic nonprescription naloxone nasal spray product in July 2023

. Over the last year, the FDA endeavored to decrease the non-medical use, accidental exposure, and overdose of opioids, with new programs such as the 

. FDA wrote that it “remains focused on responding to all facets of substance use, misuse, substance use disorders, overdose and death in the U.S.”

The nasal-spray drug can be used to reverse the effects of opioid overdose.

FDA Approves OTC Opioid Overdose Treatment

Analytical testing forms a vital part of the development lifecycle of bio/pharmaceutical drugs as it provides assurances of the safety and effectiveness of the products prior to patient use. As industry focuses on more complex molecules, growth within the analytical testing services sector is inevitable. In fact, according to recent market research, the sector is expected to experience compound annual growth of 11.4% between 2022 and 2027 (1), largely driven by the swell of biologics and biosimilars in development.

Another aspect altering the analytical testing landscape has been the COVID-19 pandemic, which significantly boosted demand for clinical services as numerous companies raced to develop safe and effective vaccines and medicines to treat the disease.

Since the start of the COVID-19 pandemic, there has been a greater level of investment into analytical testing and services, points out Kishore Hotha, vice president, Global Head of Analytical Research & Development at Veranova.

“The shift to remote work has also impacted the industry, prompting the development of remote analytical testing technologies to support remote operations,” Hotha adds. “Moreover, the pandemic has accelerated the utilization of artificial intelligence (AI) and machine learning (ML) in analytical testing. These technologies offer automation, improved accuracy, and efficiency in testing processes while enabling the identification of potential drug-related issues. Additionally, there has been a heightened emphasis on personalized medicine, which involves tailoring drugs and treatments to an individual’s genetic makeup and medical history.”

In terms of identifying genetic markers associated with diseases and targeted therapies, Hotha feels the changes should persist in the post-pandemic era, as the pharmaceutical industry develops novel drugs and treatments to address unmet patient needs. “Overall, the COVID-19 pandemic has therefore catalyzed advancements in analytical testing, promoting innovation and enhancing the industry’s ability to deliver safe and effective pharmaceutical solutions,” he says.

A prime example of innovation that is helping to expedite testing processes is the rising use of robotics and AI, according to Hotha. These kinds of technological advances benefit both the patient and the pharmaceutical company when utilized properly.

“Labs are implementing new processes in analytical drug testing to enhance safety, efficacy, and efficiency. These include using robotics for automated tasks, cloud-based data storage and analysis, AI, and machine learning (ML), and personalized medicine approaches,” Hotha says. “Robotic systems automate tasks like pipetting and centrifugation, improving accuracy, efficiency, and cost-effectiveness. Cloud-based systems enable seamless data sharing and collaboration, enhancing testing accuracy and efficiency while facilitating the development of novel methods. AI and ML aid in developing new testing techniques, identifying potential drug issues, and improving result interpretation.”

In the case of personalized medicine, testing needs to be individualized to the patient, taking into account genetic makeup and medical history, specifies Hotha. “[Automated] processes foster safer and more efficient drug development, making testing more affordable and accessible. Labs can accelerate testing, improve accuracy, and reduce costs by leveraging automation, data-driven analysis, and tailored approaches,” he emphasizes.

Efficiency: cost versus development time?

For Hotha, analytical drug testing services continue to be highly beneficial for pharma companies, particularly in the face of emerging trends in the industry. He explains that the increasing demand for personalized medicine, which focuses on tailoring drugs and treatments to individual patients based on their genetic makeup and medical history, has created a significant need for robust analytical testing.

“These services play a crucial role in identifying genetic markers associated with various diseases, enabling the development of targeted therapies,” Hotha comments. “Furthermore, there is a growing emphasis on safety and efficacy in drug development. Analytical drug testing services ensure that drugs are safe and effective before administering them to patients. They help assess pharmaceutical products’ quality, purity, and stability, ensuring that they meet regulatory standards and minimize potential risks.”

In addition, researchers are working on treatments for more intricate diseases, which is leading to an increasingly complex drug development landscape, Hotha continues. “Analytical drug testing services play a vital role in unraveling the complex mechanisms underlying these diseases and aiding in developing effective treatments. Through advanced analytical techniques and data-driven approaches, these services enable scientists to gain insights into the intricate aspects of drug behavior and optimize their therapeutic interventions,” he says. “Analytical drug testing services remain indispensable for pharma companies to develop high-quality, targeted therapies that meet the evolving needs of patients and regulatory requirements.”

Contract development manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs) are a major component to vaccine and therapy development, as well as fill/finish operations, toxicity testing, and cost control. In terms of analytical testing, CDMOs/CMOs are hoping to enhance their testing services and make the changes necessary to do so, according to Hotha.

Hotha points out that there are some fundamental approaches to improve efficiency, accuracy, and customer satisfaction, including investment in advanced technologies, expanded testing capabilities, focus on quality systems and compliance, and collaboration/partnerships. For example, expanded testing capabilities hope to cater to broader client needs, he reveals.

In terms of collaboration and partnerships, Hotha adds that specialized testing laboratories collaborate well with CDMOs/CMOs. “Collaborations enable CDMOs/CMOs to offer comprehensive solutions and access a broader range of testing services, contributing to their competitiveness,” he says.

“Success for CDMOs/CMOs in the testing services realm is achieved through a combination of factors,” Hotha continues. “A robust infrastructure, skilled personnel, adherence to strict quality standards, and customer-centricity are critical. CDMOs/CMOs consistently deliver high-quality testing services within defined timelines and budgets and tend to excel in the industry. Flexibility and adaptability in tailoring testing services to meet specific client requirements are highly valued. These strategic initiatives enable them to provide comprehensive, reliable, and customer-centric testing services, positioning them as preferred partners in the pharmaceutical industry to transform molecules into medicines.”

Testing can differ depending on the size of the molecule and the phase of development. The variances may also be based on the drug’s nature, therapeutic area, regulatory guidelines, and individual company strategies. Therefore, flexibility and adaptability in testing methodologies are critical to meet the specific needs of different molecules and development stages.

Large-molecule testing, involving biologics like proteins and antibodies, present more complex challenges than small-molecule testing, according to Hotha. “Large-molecule analysis requires specialized techniques such as mass spectrometry and nuclear magnetic resonance spectroscopy for structure and composition identification. Sample preparation for large molecules is more challenging due to their instability and susceptibility to degradation, necessitating specific preservation methods. Data analysis for large-molecule testing is also more intricate, as these molecules often have multiple subunits with varying biological activities,” he explains.

As for early phase versus late-phase development, Hotha emphasizes how different the testing requirements can be in each phase. “In early-phase development, the focus is on safety, toxicity, and dosage optimization. Analytical methods concentrate on identifying and characterizing drug candidates, stability assessments, and early safety evaluations using qualified analytical test methods with minimum requirements,” he adds. “Late-phase development involves comprehensive testing to meet regulatory safety, efficacy, and quality standards. This includes extensive validation, impurity profiling, stability studies, and method transfer/validation for commercial production.”

The future of analytical drug testing services

In Hotha’s opinion, the future of testing services holds significant promise for the pharmaceutical industry, with new analytical methods of technologies and more collaborations among analytical testing labs with other stakeholders and pharmaceutical companies to further improve the accuracy, efficiency, and reliability of drug testing. “Improvements in technology, automation, and data analytics will enhance the speed and precision of testing processes, leading to quicker turnaround times for results and faster decision-making in drug development,” he summarizes. “Integrating advanced analytical techniques such as mass spectrometry, high-throughput screening, genomic analysis, and imaging will provide a comprehensive understanding of drug properties and mechanisms of action. This knowledge can drive the discovery of new therapies and the optimization of drug formulations.”

Healthcare Analytical Testing Services Market by Type (Biomarker Testing, Stability Testing, Raw Material Testing, Batch-Release Testing, Cleaning Validation), End User (Pharmaceutical Companies, Medical Device Companies, CRO), and Region—Global Forecast to 2027

When referring to this article, please cite it as Murphy, J. 

Laboratories are focusing on more automated processes while also trying to maintain an efficient, safe, and personalized experience with each analytical test.

Testing Innovative Analytical Waters

Kevin O’Donnell is R&D manager at DuPont Nutrition & Biosciences

Cliff Campbell is senior consultant at KPC.

risk management and risk assessment concept | Image Credit: © janews094 - stock.adobe.com

A published paper, titled “Quality Quartets in Risk-Based Qualification” (1), provided a review of the International Society for Pharmaceutical Engineering’s (ISPE’s) 

Baseline Guide of 2019 on Commissioning & Qualification

 (C&Q) (2). That paper introduced a concept called “Quality Quartets” as a practical means of making use of four key concepts in the Baseline Guide: critical aspects (CAs) and critical design elements (CDEs), which were newly introduced in the 2019 Baseline Guide, and the already well established critical quality attribute (CQA) and critical process parameters (CPP) concepts.

A Quality Quartet is essentially a documented expression of the knowledge that a company has about the relationship between CAs and CDEs and the associated CPPs and CQAs. It can be considered a knowledge management output, serving as a practical means of facilitating science and risk-based commissioning and qualification. In addition, the Quality Quartet concept represents a simple and concise means of capturing and communicating product and process knowledge and understanding.

This paper describes the benefits of making use of this Quality Quartet concept as a means of achieving more knowledge-driven risk-based approaches to commissioning and qualification. The International Council for Harmonisation’s (ICH) Q9(R1), which is a revised version of ICH’s 

 guideline (3), can be referred to in this regard. As outlined in the ICH Concept Paper for that revision work (4), there were four main topic areas that the revision sought to address. These were:

High levels of subjectivity in risk assessments and in quality risk management (QRM) outputs

A lack of understanding as to what constitutes formality in QRM work

A lack of clarity on risk-based decision-making

Failing to adequately manage supply and product availability risks.

Two of these four areas, subjectivity and formality in QRM, are particularly relevant to the subject matter of this paper—risk-based approaches to commissioning and qualification, and the 2019 ISPE Baseline Guide—and the guidance presented in ICH Q9(R1) in those two areas is useful to consider.

ICH Q9(R1) highlights the importance of managing and controlling subjectivity when performing QRM activities, and it discusses how subjectivity can impact every stage of a QRM process, including the identification of hazards and the estimation of probabilities of occurrence and severities of harm. It indicates that subjectivity can also impact the estimation of risk reduction and the effectiveness of the decisions made from QRM activities. The revised guideline places a heavy emphasis on the use of knowledge in supporting the application of QRM principles. For example, it states in the Introduction section that QRM “is part of building knowledge and understanding risk scenarios” and that “knowledge is used to make informed risk-based decisions, trigger re-evaluations and stimulate continual improvements.” It highlights how “all decision making relies on the use of knowledge,” and it points the reader to ICH Q10 (5) for guidance on knowledge management.

In relation to applying QRM principles when designing and executing commissioning and qualification activities, it is important to minimize any subjectivity that may be present in the risk assessments that support such activities. The authors propose that applying the Quality Quartet concept as outlined in reference 1 is a practical means toward achieving this. This is because the Quality Quartet conceptessentially links process and product understanding with the technical knowledge that a site has in relation to its facilities, systems, and equipment. When risk assessments are performed to support commissioning and qualification activities as per the 2019 Baseline Guide, that knowledge can be used to make those risk assessments more evidence-based and objective and, therefore, less subjective. To illustrate this, consider the following scenario in relation to Quality Quartets:

An active substance manufacturing site produces an active substance for which there is a CQA associated with a particular impurity (X).

This is a five-stage manufacturing process involving a number of different unit operations, which include various chemical reactions, a salt formation step, a phase separation, a precipitation step, and isolation and drying steps.

The pH of a particular hydrolysis reaction at Stage 3 of the process is known to affect the generation of impurity X.

There is pH control during this hydrolysis reaction—this is considered a CA of the process—the pH of the batch at this step is considered a CPP, and the in-line pH probe on the reactor is considered a CDE.

The impurity X level is further reduced during the isolation step near the end of the process, which occurs in a filter dryer, whereby two methanol (MeOH) additions to the filter dryer remove the impurity from the product prior to the drying step.

The first MeOH addition is made when the batch is still in slurry form and under agitation at 10 RPM. The MeOH charge volume is considered a CPP. (The filter dryer agitation rate is not considered a CPP—it is classified as a process parameter.)

The batch is then filtered under pressure, resulting in a wet cake.

The agitator is then stopped, and a second MeOH charge is made—this washes the cake to remove any residual Impurity X. This second MeOH charge is also considered a CPP. (The cake is inspected during the MeOH wash for any cracks and channels which could impact the efficacy of the wash.).

There are two in-process controls (IPCs) in the process which relate to this impurity:

A pH measurement during the hydrolysis reaction at Stage 3 of the process—as indicated previously, this is done using an in-line pH probe on the reactor.

An off-line high-performance liquid chromatography (HPLC) impurity test performed on a sample taken from the filter dryer following the second MeOH charge.

The company has applied its product and process knowledge, as well as its technical knowledge about its equipment, to construct the following Quality Quartets:

CQA=% impurity X in the finished active substance

CPP–pH of the batch during the hydrolysis reaction at Stage 3 of the process

CA–Controlling pH during this hydrolysis reaction

CPP–Volume of first MeOH charge to the batch in the filter dryer, while the batch is under agitation

CA–Controlling the quantity of the MeOH addition

CDE–Flow-meter which measures the volume of MeOH charged.

CPP–Volume of second MeOH charge to the wet cake in the filter dryer while the batch is not under agitation

The above is an example of how one CQA can be part of three different Quality Quartets. This is not unusual; many CQAs relate to more than one CPP.

The above examples of Quality Quartets are illustrative only. The authors are aware that the above types of CPPs are not always registered within marketing authorisation dossiers; however, they still remain valid, when they relate to the protection or achievement of CQAs. 

Documenting Quality Quartets such as those above is considered useful, as it can help reduce the level of subjectivity in risk assessments that may be performed on a manufacturing process, and in the risk ratings that arise from such risk assessments, specifically by making the severity, probability of occurrence and detection ratings, more objective. This is illustrated by the following:

If failure modes relating to the in-line pH probe are being risk assessed, or if failure modes relating to that step of the Stage 3 process are being risk assessed, the severity ratings that are assigned to those failure modes can be informed by utilizing the knowledge represented by Quality Quartet 1. This indicates that such failure modes may directly impact upon a CQA (% Impurity X). This helps reduce any subjectivity in those ratings, because the process knowledge that Quality Quartet 1 is based on, lends objectivity to such severity ratings.

This is also the case with regard to failure modes pertaining to the isolation unit operation involving the MeOH addition steps.

Subjectivity can also be minimized when probability of occurrence and detection ratings are being assigned to failure modes pertaining to the pH probe or to the flow-meter used in the MeOH additions. This is because it is likely that there will be clearly documented good manufacturing practice (GMP) controls in place to ensure the correct functioning of those two items of equipment, given the fact that Quality Quartets have been documented which link those two items of equipment directly with a CQA (% Impurity X), and which indicate that those items of equipment are critical in nature. Thus, any probability of occurrence or detection ratings related to failure modes for the pH probe and flow-meter can be based directly on a consideration of those GMP controls and not on subjective failure rate estimates with questionable validity (6).

Overall, and as indicated above, Quality Quartets that link CQAs and CPPs with CAs and CDEs can be used to directly help minimise the level of subjectivity in risk assessment work.

ICH Q9(R1) highlights that formality in QRM is not a binary concept (i.e., formal/informal); it states that varying degrees of formality may be applied during QRM activities. It also indicates that an understanding of formality may lead to resources being used more efficiently, where lower risk issues are dealt with via less formal means, freeing up resources for managing higher risk issues and more complex problems that may require increased levels of rigour and effort.

The revised guideline refers to the following three factors that might be considered when determining how much formality to apply to a given QRM activity:

 This relates to a lack of knowledge about hazards, harms, and consequently, their associated risks, and it may be reduced via effective knowledge management in making risk-based decisions.

 The more important a risk-based decision is with regard to product quality, the higher the level of formality that may be applied, and the greater the need to reduce the level of uncertainty associated with it.

 The more complex a process or subject area is to a QRM activity, the higher the level of formality that may be applied to assure product quality. Complexity is an attribute that can be expressed in many different ways.With regard to manufacturing processes, for example, it may be characterized by the number of unit operations and steps that make up the process, the number of starting materials and isolated intermediates that may be involved, or the extent of outsourcing that is used (7). But complexity may also be characterised by the type of process that is under consideration; aseptic processes, for example, are often regarded as being more complex when compared to manufacturing processes that generate non-sterile products, and while this may be true in many cases, it may be something of an oversimplification in other cases.

These three factors are useful to consider during QRM work, because, as ICH Q9(R1) indicates, an understanding of formality can support risk-based decision-making, “where the level of formality that is applied may reflect the degree of importance of the decision, as well as the level of uncertainty and complexity which may be present.” The revised guideline states that “higher levels of uncertainty, importance or complexity may require more formal quality risk management approaches to manage potential risks and to support effective risk-based decision making” (3).

All of this is relevant when applying QRM principles to determining the extent of commissioning and qualification testing that may be required for facilities, systems, and equipment in line with the ISPE’s 2019 Baseline Guide. Furthermore, the Quality Quartet concept is also directly relevant, as illustrated by the following scenarios:

 Certain equipment components or instruments used in a manufacturing process have been classified as CDEs in line with the ISPE’s 2019 Baseline Guide. These components or instruments are considered important by virtue of their criticality designation, but their relationship to CPPs and their role in supporting the achievement of product CQAs is not well understood. There is relatively high uncertainty in this area, and there are no Quality Quartets documented that include these CDEs.

 Other equipment components or instruments have been classified as CDEs, and their relationship to CPPs and product CQAs is known and firmly established. Thus, there is lower uncertainty with regard to their relationship to CPPs and their role in supporting the achievement of product CQAs. These components or instruments are considered important.

 Certain process parameters have been classified as critical by virtue of the process knowledge that is in place in terms of their relationship to one or more CQAs. These process parameters have been designated as CPPs, and they are considered important to control. These CPPs have been listed in a number of Quality Quartets, as in the pH and MeOH charge examples discussed previously, and the equipment components or instruments that support those CPPs are known. Thus, there is low uncertainty here.

 For certain other process parameters, their relationship to any CQAs is not well understood; there is significant uncertainty in this area. The relative importance of such process parameters is also not understood, and these parameters have not been included in any Quality Quartets to date.

In Scenario A—important equipment components or instruments, but significant uncertainty in their relationship to CQAs, and no Quality Quartets documented—it may be useful to apply a higher degree of formality to any risk assessments that will be used to help determine the extent of commissioning and qualification testing that is required. Doing this can be beneficial because, given the level of uncertainty that is present, higher efforts can be made when assessing risks to ensure that appropriate risk controls are identified which mitigate those risks.

In Scenario D—process parameters of unknown importance, where their relationship to CQAs is uncertain and no Quality Quartets have been documented—more effort will likely be needed when applying QRM principles to determine the extent of commissioning and qualification testing that may be required. Thus, a higher level of formality may be needed in any risk assessments that are performed to help determine the extent of commissioning and qualification testing that is required. The extra effort may yield increased process understanding in relation to the role that those process parameters have in risk control, if any. This should serve to reduce the level of uncertainty that is present and, thus, it should lead to risk reduction as knowledge increases.

In Scenarios B and C, there are important equipment components/instruments and process parameters in place, there is a low level of uncertainty about their relationship to CQAs, and documented Quality Quartets are also in place. Any risk assessments that are performed to help determine the extent of commissioning and qualification testing that is required will likely be more straightforward and easier to perform, given the extent of equipment and process knowledge that is in place.

Overall, and as indicated above, the concept of Quality Quartets is useful to consider when determining how much formality to apply when performing risk assessments and when applying QRM principles to commissioning and qualification activities. The presence (or absence) of documented Quality Quartets for a manufacturing process and its associated facilities, systems, and equipment can help a site understand the degree of uncertainty that may be present as well as the relative importance of various process parameters and items of equipment (or their components). This understanding can inform risk assessment and QRM activities.

But uncertainty and importance are not the full picture; complexity considerations are also useful to think about, and as noted above, complexity is a key factor that ICH Q9(R1) refers to when one is determining how much formality to apply to a given QRM activity. ICH Q9(R1) indicates that the more complex a process or subject area is to a QRM activity, the higher the level of formality that may be applied to assure product quality. Thus, with scenarios A through D, it is useful to also consider the level of complexity that is associated with the facility, system, or equipment that may be subject to QRM activities.

This paper illustrates the benefits of applying the concept of Quality Quartets, as introduced in reference 1, to the risk-based commissioning and qualification of manufacturing facilities, systems and equipment, and it discusses how the guidance in ICH Q9(R1) in relation to subjectivity and formality in QRM can be applied in practical terms.

All commissioning and qualification activities involve making important decisions. For example, decisions need to be made about which items of equipment require qualification and which don’t. Related decisions concern how much leveraging can be made of factory acceptance testing, and how much in-house qualification testing will be required. The 2019 ISPE Baseline Guide places a heavy emphasis on the use of QRM principles when commissioning and qualifying facilities, systems, and equipment.ICH Q9(R1) states that “effective risk-based decision making begins with determining the level of effort, formality, and documentation that should be applied during the QRM process” (2). The guideline also indicates that addressing “uncertainty through the use of knowledge” not only facilitates informed decisions, it also helps recognize “where uncertainty remains, so that appropriate risk controls may be identified.” The scenarios discussed in this paper illustrate how those concepts in ICH Q9(R1) can be directly applied when developing risk-based approaches to commissioning and qualification. This is through the use of a knowledge management construct called a Quality Quartet, which is a construct of a site’s knowledge about the relationship between certain CQAs, CPPs, CAs, and CDEs.

To maximize the usefulness of the 2019 C&Q Baseline Guide, and taking into account the new guidance that the 2023 ICH Q9(R1) guideline provides, the authors suggest that the Quality Quartet concept would be useful to consider when manufacturing sites are working towards achieving true risk-based commissioning and qualification of their facilities, systems, and equipment.

The views expressed in this paper are those of the authors and should not be taken to represent the views of the Health Products Regulatory Authority (HPRA).

Campbell, C. Quality Quartets in Risk-Based Qualification. 

Baseline Guide Vol 5: Commissioning & Qualification

ICH. Concept Paper on the revision of ICH Q9, November 2020, 

O’Donnell, K.; Zwitkovits, M.; Greene, A.; Calnan, N. Quality Risk Management–Putting GMP Controls First. 

., 2012 May/June, Vol. 66, No. 3. pp 243-261.

A Recommended Model for Risk-based Inspection Planning in the GMP Environment

Kevin O’Donnell is Market Compliance Manager at Ireland’s Health Products Regulatory Authority.

Cliff Campbell is senior consultant, KPC.

When referring to this article, please cite it as O’Donnell, K and Campbell, C. Quality Quartets in Risk-Based Qualification: ICH Q9(R1) Considerations. 

Quality Quartets may be used to achieve knowledge-driven, risk-based approaches to commissioning and qualification that are consistent with ICH Q9(R1) principles. 

Quality Quartets in  Risk-Based Qualification: ICH Q9(R1) Considerations

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

Woman give pill to little girl | Image Credit: © Boris Riaposov - stock.adobe.com

Creating pediatric formulations with appealing taste and appearance has been a challenge since drugs were developed specifically for children. With regulations in the United States and Europe now requiring that palatability be addressed by pharma companies during clinical development of pediatric formulations, this issue has grown in importance. Patient adherence must be top of mind when formulating pediatric dosage forms, which cannot be achieved simply by reducing the size of an adult dose. Variables such as the age and weight range of the patient population, speed of symptom onset, liver enzyme function, swallowing capabilities, and ease of administration must be considered.

The most desirable attributes of pediatric formulations, says Joao Marcos Assis, global technical marketing manager at BASF Pharma Solutions, include acceptable taste and dosage form (typically oral), dosing flexibility, convenient and reliable administration, minimal manipulation needed by healthcare givers, minimal dosing frequency, minimum use of nontoxic excipients, and simple manufacturing processes that generate affordable and stable products (1).

Ultimately, an understanding of how to formulate for appropriate dose flexibility and patient compliance, along with an awareness of global regulatory changes regarding excipients, is needed to ensure a successful pediatric product, states Adam Hopper, president of the drug product business unit at Cambrex.

Pediatric drug formulations pose several unique challenges compared to adult drug formulations. These challenges arise due to the physiological and developmental differences between children and adults, according to Assis. In addition, age-appropriate pediatric-specific formulations and dosage forms that fit children’s needs at different ages are of the uttermost importance, adds Philip Schäfer, head of process and formulation materials at the Life Science business of Merck KGaA, Darmstadt, Germany. Furthermore, acceptance and preferences highly vary between children and are strongly influenced by several individual factors such as their socialization (2).

Dosage form selection can be particularly difficult, as children often have trouble swallowing tablets and capsules, Assis observes. The task is made more difficult for liquid dosage forms or formulations that disintegrate within the mouth due to the bitter taste of many APIs. “Drug size, texture, mouthfeel, smell, taste, and for liquids, viscosity and color, play an essential role in the child’s acceptability and adherence to treatment,” he notes.

Furthermore, precise dosing must be achieved based on age, weight, and body surface to reduce the risk of medication errors, which can be challenging due to the significant variability in drug absorption, distribution, metabolism, and excretion children exhibit compared to adults. Small volumes may be needed, such as for parenteral formulations administered to neonates, and potential modification of dosage forms in the home setting (crushing tablets, mixing with food, etc.) must also be factored into formulation designs, Schäfer comments.

Excipient selection must also be carefully considered, as there are excipients tolerated and widely used in adult formulations that can cause adverse effects in the pediatric population, according to Schäfer. He adds that impurities in excipientsmust also be controlled, as some have been known to cause severe consequences for children. To ensure safety and efficacy, Assis points out that pediatric formulations may therefore require additional studies to establish safety profiles and optimal dosing regimens.

Regulatory agencies require pharma companies to develop age-appropriate formulations. For oral dosage forms—solutions, suspensions, orally disintegrating tablets, and multipartculates (powders, granules, minitablets)—palatability remains the primary challenge, states Jeff Worthington, president and founder of Senopsys.

Taste is particularly important to children. Assis points to a survey conducted by the American Association of Pediatrics in 2023 that found unpleasant taste to be the most significant barrier to completing treatment for pediatric patients (3). “Acceptability, palatability, and ease for the caregiver to administer the medicine contribute to whether or not a child will ultimately take a medicine,” he says. Palatability includes not only taste, but the size of a tablet, the pH, texture, and volume of a liquid formulation, Hopper adds.

Many drugs are known to be bitter, some extremely so, or have other aversive sensory attributes including malodor and irritation, Worthington remarks. Each have fundamentally different perception pathways and importantly, require different amelioration approaches or technologies. “There are more technology approaches for managing a low or moderate taste masking challenge than a difficult one. For an extremely bitter drug active, it may be necessary to ‘sequester’ the API from taste receptors via particle coating, complexation, encapsulation, or other means,” he explains.

While product appearance is generally of minor concern for drug products unless required for placebo color matching or masking an aversive API color, it can be important in pediatric applications, according to Schäfer. “It is important that the appearance of medications is clearly distinguishable from candy in order to avoid mix-ups which could expose children to a high safety risk,” he explains. In the case of bitter-tasting APIs, Schäfer contends that formulators should ensure that the taste does not attract children too much; the final taste of pediatric formulations should thus be more neutral than sweet.

Bitterness is not only a challenge with respect to overcoming this undesirable taste experience. There are also significant challenges to predicting if new compounds are bitter, according to Assis. He does note, however, that the process for identifying bitter APIs has rapidly progressed in the past few years.

Assis points to BitterDB, a free database with more than 1000 naturally bitter and synthetic compounds available to formulators, as one example (4). Machine learning algorithms trained with these known bitter API molecules are leveraged to predict the bitterness of new compounds. Based on such predictions and additional physiochemical API properties, pharmaceutical formulators can proactively select taste-masking technologies. In addition to advanced digital technologies, trained human panels are still employed to test and optimize taste-masked formulations.

Another important issue in formulation of pediatric medicines is the need to maintain bioavailability while formulating to mitigate bitter taste or undesirable appearance, notes Hopper. “Successfully achieving this goal requires balancing solubility, molecular size, lipophilicity, and overall acidic strength—all of which impact the overall bioavailability,” he comments. Another consideration is how different patients may respond to medications, as liquid and tablet formulations can be held in the mouth for varied times.

In fact, palatability is comprised of four elements—basic tastes (sweet, sour, salty, bitter, and umami); aroma (fishy, oxidized oil, orange, grape, mint), trigeminal irritation (chemesthesis or mouthfeel); and texture (hardness, fracturability, grittiness), according to Worthington. “Each have different biological perception pathways that require tailored approaches to overcome,” he explains.

Bitterness is, as a result, not the only challenge in creating palatable, patient-accepted drug products. Senopsys compiled data from 150 API taste-assessment studies the company completed (excluding over-the-counter drugs). The primary taste masking challenge was bitterness for nearly 70% of the APIs (mostly new chemical entities) (5). Of the other basic tastes, sour and salty were problematic for 3% and 4% of APIs, respectively.

Aversive odors (“aromatics”) were the primary sensory challenge for approximately 7% of APIs, according to Worthington. Some descriptors of these malodors included “phenolic” (like Band-Aids), “sulfidy” (overcooked cruciferous vegetables), “oxidized oil” (like old paint), and “solventy” (e.g., acetone, or ether-like).

The primary challenge for another 4% of the APIs was a strong intensity trigeminal irritancy such as oral or throat burning, numbing, and tongue sting. Finally, 16% of APIs were fundamentally tasteless, but their challenge was driven by the negative sensory attributes of the excipient system (e.g., surfactants, co-solvents, and solubilizers).

Worthington also notes there is a general misconception that most APIs have a single aversive attribute, but that is not the case. Secondary taste masking challenges for those same 150 APIs are heavily represented by aromatics (malodor), followed by trigeminal irritancy, sour and salty basic tastes, “other” (e.g., aversive mouthfeels and textures), and bitter basic taste (5).

High-dosage drugs, meanwhile, are more challenging than low-dose formulations and typically require a combination of more advanced and efficient taste-masking strategies, such as particle film coating, Assis contends.

It is also worth noting, according to Assis, that previous approaches relying on the use of sweeteners or viscosity-modifying agents to suppress API bitterness generally have not been preferred by patients, as they generally require high concentrations of sweeteners, leading to a metallic taste. “Patients are even more opposed to both sweet-bitter sensations on the tongue, and many viscosity-modifying agents are not entirely tasteless or can provide an unpleasant texture,” he adds.

Addressing the palatability challenge for pediatric formulations, says Worthington, depends on the physical and chemical properties of the API, the dosage form, and the specific taste masking needs. He outlines five broad taste-masking approaches that are employed to improve palatability, including signal interruption, using flavor systems, altering the form of the drug substance, complexing the API, and physically encapsulating the API.

Still in the research stage, signal interruption uses an antagonist to inhibit taste via ligand binding, according to Worthington. Taste masking via the use of flavor systems is a common approach, but can be insufficient for particularly challenging actives. Modifying the active molecules as a prodrug, freebase or salt can be effective, but extends development timelines, may cause pharmacokinetic changes, and may still require the use of masking technologies. Complexation traps the API in a chemical matrix to hide it from the taste buds, but generally results in decreased drug loadings, may also cause pharmacokinetic changes and is generally limited to solid forms. Application of a physical barriervia encapsulation has similar limitations.

Assis reiterates that the taste of an API is pronounced if the drug is solubilized in saliva and able to interact with the taste buds, and thus less soluble APIs have a lower aversive taste than highly soluble ones. In addition, he notes that micronized drugs have more chance to interact with the taste receptors within the mouth. For such APIs, “using a more palatable prodrug or salt and a less soluble polymorph or unionized form to reduce drug-taste bud interactions can be alternative,” he says. He also points out that pharmacokinetic and bioavailability properties might be negatively impacted, and thus changes must be made with careful consideration to the effects they may have on other drug-substance attributes.

While formulation challenges with respect to taste, palatability, and appearance differ depending on the API and dosage form, all approaches have the same aim, according to Schäfer, and many rely on same or similar excipients.

High-intensity sweeteners such as neotame and sucralose, for example, offer benefits for any formulation type as they are safe, sugar-free, non-cariogenic, and effective in cost and use due to their high sweetness potency in both liquid and solid formulations, Schäfer comments. Mannitol, meanwhile, is also popular in pediatric formulations because it provides superior mouthfeel, which is particularly important for orally disintegrating tablets (ODTs).

There are some disadvantages to using excipients. Often a trial-and-error approach might be needed to identify the best mix of flavors and other additives to hide the bitterness of a particular API in a particular dosage form. In addition, all excipients, Assis says, should be evaluated for potential allergic and other side effects, particularly those that do not provide efficient masking effects and need to be used in large quantities. As a result, formulation development timelines can be extended.

Functional film coatings are used to prevent direct contact of the drug substance with the tongue, thereby avoiding an unpleasant taste sensation, according to Assis. Reverse-enteric polymers, such as methyl-methacrylate and diethylaminoethyl methacrylate copolymer (from BASF) are used for this purpose. “These film coatings are not soluble in saliva pH (pH 6.2 - 7.0), so they maintain the drug covered by the polymer. After swallowing, the film is immediately solubilized in the stomach for fast API release, allowing drug dissolution out of the coated core and its absorption in the stomach and intestine,” he explains.

These types of polymers can be applied to cover API particles, granules, pellets, tablets, and minitablets. The coating process can be performed using organic solutions or polymeric dispersions or suspensions in standard equipment like fluid beds and drum-coater machines, according to Assis. It is also possible to obtain coated particles through microencapsulation, high-shear granulation, melt coating, and spray drying.

Because the polymers have a high molecular weight, absorption is not expected, ensuring safety. Film-coating technology can be used for very strong APIs at low or high doses. One potential disadvantage is that solid drug formulations with large surface areas may involve lengthy coating processes. Optimization is possible, however, using a well-designed formulation and process parameters, according to Assis.

Lipophilic polymers such as ethyl cellulose and hydrophobic components such as carnauba wax are other alternatives, but they can impact drug absorption due to excipient insolubility and possible delayed release, Assis comments. “In addition to the need to confirm effective drug masking, formulators should guarantee complete drug solubilization and absorption to ensure bioavailability using suitable excipients,” he adds.

There are some potential disadvantages of API sequestration that Worthington notes. “Particle coating results in an increase in particle size that can result in a gritty texture. The presence of particulates can also encourage chewing as part of normal oral processing, which can lead to coating rupture and release of the API into the oral cavity. Multiparticulate formulations, if added to foods with physicochemical properties (e.g., pH, water, sugar, fat, and flavor content) that can interact with pH-sensitive polymers, may also have a negative effect on palatability,” he explains.

New dosage forms are improving the viability of oral solid dosage forms for pediatric use. Hopper points to advances in mini-tablets, multi-layer beads, and ODTs, all of which allow for dose flexibility and improved compliance due to improved palatability and ease of administration. “These new innovation areas make flexible dosing based on age and weight possible, leading to increased dosage form acceptability and safety,” he observes.

Schäfer highlights oral thin films, which he says have become more popular due to their ability to overcome swallowing difficulties associated with traditional oral solid dosage forms while also enabling taste masking. Mini-tablets, he adds, have been shown in some studies to be superior to liquid formulations (6).

Titanium dioxide is widely used in tablet formulation as a white colorant and opacifier to ensure a uniform appearance. Toxicological concerns about nanoparticulate titanium dioxide and its ban from use in foods and nutritional supplements in the European Union have led to increased interest in suitable alternatives to titanium dioxide for use in drug products, Schäfer observes. MilliporeSigma has for this purpose developed a particle-engineered calcium carbonate with a unique morphology and designed particle size distribution that provides uniform tablet finishing and good opacity.

Using novel excipients can be challenging given the lack of a separate approval pathway. Currently, new excipients can only be approved within a drug formulation, and drug developers are generally hesitant to risk approval by using a novel excipient.

FDA’s Center for Drug Evaluation and Research (CDER) has launched a new pilot program for the review of novel excipients. BASF and Senopsys support CDER’s pilot program. “Many pharmaceutical technologies and excipients trace their roots to the food industry. Co-processes, sustained-release flavor and sweetener systems like those used in confectionary and chewing gum products could potentially be used with great effect in drug products, particularly with APIs with long aftertastes, such as clarithromycin and many others. Such excipient developments have been to date hindered by the current lengthy approval pathway,” says Worthington.

Signal interruption, one of the five main approaches to improving palatability noted by Worthington remains, he says, a “Holy Grail” of taste masking. Bitterness is detected by a family of several dozen receptors (TAS2Rs), and APIs generally activate multiple TAS2Rs simultaneously, making development of signal interruption solutions challenging.Bitter blockers work by biochemically interfering with the taste transduction from the mouth to the brain via an antagonist that inhibits a specific bitter receptor site, blocking the taste cascade (interrupting the G-protein coupled receptor, or GPCR, signal cascade) (3), notes Assis.

This approach is challenged by the large number of different bitter taste receptors and their high genetic diversity. Trial and error is often required to identify compounds that follow the same receptor pathway as the API, leading to longer development times, Assis notes. There are novel compounds under development that act as antagonists to these receptors, Worthington notes, but the technology is still in its infancy, and the regulatory risk is high and commercialization timelines are unknown.

Schäfer is interested in the potential of three-dimensional (3D) printing for the production of pediatric medications, as it offers the opportunity for tailored dosage forms and can be implemented for the manufacture of age-appropriate solutions. Assis adds that 3D-printing technologies enable the manufacture of pharmaceutical dosage forms according to patient requirements, such as dose, release profile, color, texture, and size, which are all highly relevant to pediatric drugs. “With production via direct powder or filament-based extrusion combined with a functional taste-masking polymer or a lipidic, this approach can provide the right taste-masking,” he states.

For parenteral pediatric products administered in a clinical setting, there is a need for technologies that enable the administration of higher doses in smaller volumes to children, according to Schäfer. One new development in this field is MilliporeSigma’s Viscosity Reduction Platform, which allows for highly concentrated, small-volume protein formulations to be administered to patients.

The most challenging topic when formulating a pediatric drug is developing suitable options to overcome swallowing issues with an appropriate taste for better convenience and compliance. Worthington agrees that palatability and swallowability will continue to be a challenge for not only pediatric populations, but increasingly for geriatric and special needs populations as well.

Easier-to-swallow dosage forms, however, increase the opportunity for contact with oral cavity receptors—gustatory (taste buds), smell (olfactory receptors), and irritation (chemoreceptors). “Accordingly,” observes Worthington, “many of these alternative, age-appropriate dosage forms have increased palatability challenge compared to traditional tablets and capsules.”

“Defining the most efficient taste-masking approach to hide or minimize the unpleasant taste of a drug, aiming to improve patient adherence to treatment when taste is the main reason for non-compliance, still needs further understanding and research,” Assis contends. Improvements in taste masking and bioavailability enhancement, Hopper believes, will continue to be critical. “As our understanding of how the pharmacokinetics can change within different age populations, it will make flexible dosing and potentially different release profiles even more important,” he states.

Litalien, C.; Bérubé, S.; Tuleu, C.; Gilpin, A.; Landry, ÉK; Valentin, M.; Strickley, R,; Turner, MA. From Paediatric Formulations Development to Access: Advances Made and Remaining Challenges. 

Mennella, J. A. and N. K. Bobowski. The Sweetness and Bitterness of Childhood: Insights from Basic Research on Taste Preferences. 

Walsh, J.; Cram, A.; Woertz, K.; Breitkreutz, J.; Winzenburg, G.; Turner, R.; Tuleu, C.. European Formulation Initiative. Playing Hide and Seek with Poorly Tasting Paediatric Medicines: Do Not Forget the Excipients. 

Wiener, A.; Shudler, M.; Levit, A.; Niv, MY. BitterDB: A Database of Bitter Compounds. Nucleic Acids Research. January 2012.

Klingmann, V., H. Linderskamp, et al. Acceptability of Multiple Uncoated Minitablets in Infants and Toddlers: A Randomized Controlled Trial. 

Cynthia Challener, PhD is a contributing editor for Pharmaceutical Technology Group.


Vol. 47, No. 8
August 2023
Pages: 20–25

When referring to this article, please cite it as Challener, C. Overcoming Challenges to Formulation Development for Pediatric Medicines. 

The biggest hurdle is developing palatable formulations that are efficacious and patient friendly. 


Overcoming Challenges to Formulation Development for Pediatric Medicines

Kevin M. Kane, PhD, is CMC strategy director, Strategic Development Consulting, at PPD, part of Thermo Fisher Scientific.

Eugene J. McNally, PhD, is vice-president, early engagement and regulatory strategy, Strategic Development Consulting, at PPD, part of Thermo Fisher Scientific.

Jeff L. Garwin, PhD, MD, is associate clinical science director, Strategic Development Consulting, at PPD, part of Thermo Fisher Scientific.

Debra A. Schaumberg is vice-president and global head, Strategic Development Consulting, at PPD, part of Thermo Fisher Scientific.

Drug development is a risky business. For a drug entering Phase I clinical trials, there is an estimated 10% probability of eventual US Food and Drug Administration approval (1). At each milestone, the financial stakes increase for the next development phase: average costs are US$30 million (€30 million) in Phase I, US$70 million (€64 million) in Phase II, and US$310 million (€283 million) in Phase III (2). These increasing stakes demand robust, strategic scientific and regulatory support for each transition. 

This article was published in the Aug. 2, 2023 issue of 

Even big pharmaceutical companies (collectively, Big Pharma) have challenges in managing the end-to-end development process of new molecular entities (NMEs). For example, in 2016, Pfizer’s cumulative probability of success from start of Phase I (first-in-human [FIH] study) through approval was 4%, versus 8% for the entire industry (2). By 2020, Pfizer had revived their R&D pipeline (2) to achieve greater end-to-end success in the clinic, achieving a cumulative success of 21%, versus 11% for the industry (2). Pfizer has attributed their improvement in success rate to their increased early investments in understanding the biology of the target disease and the pharmacology of an NME, including exposure at the site of action, binding to the pharmacological target, and expression of pharmacological activity. Having a portfolio of NMEs enabled Pfizer to use this enhanced understanding to weed out failures early and take calculated risks to accelerate “winners” (2,3). Eli Lilly and Company (Lilly) (4,5) and AstraZeneca (6) have employed similar “truth-seeking” early development strategies that prune portfolios early of NMEs that are likely to fail during Phase II due to lack of efficacy. Lilly claims similar success for its autonomous Chorus early-stage drug development unit (4,5). AstraZeneca has published their framework of determinants for project success and for effective decision-making: right target, right patient, right tissue, right commercial potential, and right culture (6).

In contrast, the business model for most small pharma—include emerging, virtual, and small biotechnology companies—is different than those of Big Pharma and frequently anticipate investment tranches upon achievement of certain developmental milestones, such as opening an investigational new drug (IND) application, initiation of the FIH study, or the completion of a Phase II proof-of-concept (POC) study. Frequently, the achievement of the next value inflection point for development milestones results in activity for executing a strategic plan to attempt to sell and/or license the asset, make a public offering, or take on a partnership arrangement that can enable product commercialization. Reaching these milestones for the one (or few) small pharma-owned assets is sometimes at odds with the type of “truth-seeking” early development strategies that have allowed Big Pharma’s improved odds of success at the portfolio level.

This paper describes an intelligent drug development paradigm that enables small pharma to implement a truth-seeking early development approach such as those used by progressive Big Pharma companies, aimed at efficiently maximizing the value of information needed to inform key milestone decision points and optimize the probability of success.

All pharma developers face challenges in early clinical development (Phase I and Phase II) associated with drug substance manufacture, drug product formulation and manufacture, and anticipating the doses needed for clinical trials. These challenges arise from a lack of communication of and adherence to a common overall drug development strategy, generally as defined in the clinical development plan (CDP) to address the target product profile (TPP) across the siloed disciplines.

Historically, Big Pharma companies established standard operating procedures and ways of working within and across siloed disciplines, approaching drug development largely sequentially, handing an NME off from one siloed discipline to the next, with collaboration occurring at the end of each task. Big Pharma companies run programmes in-house, and/or contract with contract development and manufacturing organizations (CDMOs) and clinical research organizations (CROs) for development services, and they have in-house teams with diverse expertise who build a robust early development strategy to accelerate entry into the clinic and keep the development programme on track (4).

In contrast, today’s small pharma companies often have deep expertise in narrow areas, but they may lack internal expertise, infrastructure, and operating procedures to conduct many core drug development activities in-house, necessitating engagement of external vendors such as CDMOs, CROs, and consultants (7). This multi-vendor outsourcing approach often leads to fragmented operational challenges, loss of continuity, and failure to maximize information at each stage of development. In most cases in small pharma, the CDMO vendor is not responsible for creating the overall development strategy. Small pharma sponsors are often ill-equipped to define this strategy and yet are responsible for choosing the strengths/doses to manufacture, bearing the risk if development fails due to improper dose or formulation selection.

Further complicating this stage of development, the manufacturing of drug substance and drug product often occur in separate locations and on highly variable timelines. Drug substance and drug product manufacturing vendors have no incentive to align their schedules, leading to schedule adjustment at the Phase I clinic if drug product delivery is delayed.

With far fewer resources than Big Pharma, small pharma sponsors often feel pressure to minimize expenditures by limiting the scope of chemistry, manufacturing, and controls (CMC), nonclinical, and activities preparatory to start of an FIH or other Phase I study until the next investment tranche. Speed-to-clinic feels critical because a small pharma sponsor’s next round of funding may be tied to an upcoming development milestone, such as enrollment of the first subject in an FIH trial. The primary objectives of FIH clinical studies are to assess the safety, tolerability, and pharmacokinetic (PK) behaviour of a compound, but due to financial and time pressures, sponsors may delay some critical tests until later POC studies. This rush through Phase I is often at the expense of gathering critical data that would lead to stronger Phase II trials with better chance of achieving POC and a higher probability of eventual marketing approval.

An intelligent drug development paradigm can enable small pharma to implement an effective early drug development approach.

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