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

Felicity Thomas

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Excipients commonly make up the largest proportion of many drug dosage forms, performing specific functions, such as modifying API release, enhancing drug stability, or masking the taste of the active ingredients, among others. However, despite the wide use of excipients within finished drug products, the importance of their grade and quality is not always clearly or fully comprehended, which can lead to potentially serious patient safety issues.

“FDA defines an excipient as a drug as it is part of the drug product, and for that, you need two things,” asserted Nigel Langley, global technical director, Gaylord Chemical Company and immediate past-chair of IPEC-Americas, in a panel discussion with Pharmaceutical Technology® (1). “You need to manufacture under good manufacturing practice (GMP) and also the material needs to comply with the relevant pharmacopeia and regulatory requirements.”

Pharmacopeial compliance for excipients depends upon the country where the drug product is being manufactured and distributed, for example, the 

) is followed in the United States and the 

) in Europe. For global products, multi-compendia are often required, Langley added. Local regulatory requirements that apply to the excipient must also be complied with, and this can create additional complexity.

Additionally, while excipients are traditionally used for pharmaceutical applications, some of the same chemicals can also be used in different applications, such as in personal care, in industrial applications, or as food ingredients, Langley explained. As a result of the broad applications of these chemicals, grades are employed to allow for differentiation. These grades can indicate different levels of purity, physical forms, or particle size distributions for the same material, Langley specified.

“A lot of people have historically tended to treat excipients like they are commodities,” added David Schoneker, president/owner, Black Diamond Regulatory Consulting, and Executive Committee member and QbD/Composition Committee chair, IPEC-Americas, in the panel discussion (1). Generally-speaking, companies search for a supplier that they believe has the correct grade of materials they need and then start using the materials without even discussing, or having the right conversation with the supplier, about the grade, Schoneker stated.

“Too many times, excipient [suppliers] never even find out what their customers are doing with their product until there’s an actual problem,” Schoneker continued. The supplier may have been able to avert the problem from ever happening had they been consulted beforehand because of the supplier’s knowledge of the material and ability to provide a recommendation for the right grade, he explained.

So, communication is an important first step, Schoneker specified, but how does a company make sure that their excipient supply chain is appropriate? “Well, that really does come down to properly qualifying each and every excipient supplier for your particular intended use,” he said. “The user of the excipient is ultimately the one responsible to make sure they are using the right grade from both a regulatory and technical perspective in their application.”

“[There have been a lot of incidents], like the cough syrup deaths, [that] really emphasize the importance of understanding [the] supply chain (2),” added Priscilla Zawislak, Global Regulatory Affairs Advocacy manager, IFF, vice-president of IPEC Federation, and vice chair, Science and Regulatory Policy, IPEC-Americas, in the panel discussion (1). “The fact is that sometimes companies do source [materials] and don’t really understand the full supply chain, and some of the recent incidents have actually involved excipients.”

Collaborative work undertaken by IPEC and the World Health Organization that looked at these incidents found that it is not always a case of a bad quality excipient being used, but that sometimes it is the incorrect grade of material or even counterfeit material being used, Zawislak confirmed. “And these are the kinds of things that you have to look at very carefully in your supply chain to make sure that you know exactly where [the excipient] was from the time it left the manufacturer till it got to your door,” she said.

“That’s where traceability comes in,” remarked Joseph Zeleznik, director, Technical Service, North America IMCD, and current chair, IPEC-Americas, in the panel discussion (1). “You need to be able to trace the entire supply chain back to the origin, so that if there was any adulteration, or if there was any repackaging of a material, an ingredient didn’t end up in a wrong container, whether it was intentional or inadvertent. If you don’t have traceability of your supply chain, you can run into risk of having issues later on.”

Therefore, a qualification process needs to be formalized and performed for every single excipient supplier that will be used, Schoneker asserted. Guides are available to help companies through these processes, he pointed out. At IPEC, a whole suite of guides are available to help companies properly qualify and control their supply chain, suppliers, and excipients. A key umbrella guide for companies would be IPEC’s guide and checklist, Qualification of Excipients for Use in Pharmaceuticals, which references a lot of other guides and how those guides can be used (3), Schoneker pointed out.

It is also important to note, Schoneker stressed, that it is not simply a one-to-one situation. There can be many distributors involved in the supply chain, and an understanding of each link in the chain is vital. There may have been someone in the distribution chain, for example, that has taken an industrial-grade material and up-tested it to meet USP requirements and sold it as pharmaceutical grade, Schoneker added. “Unfortunately, you can’t just up-test something to pharmaceutical grade,” he warned. “It doesn’t matter whether [the material] meets the specifications in the pharmacopeia; if it hasn’t been made under appropriate GMPs with appropriate controls, then that’s where you have problems.”

First of all, the definition of excipient, as outlined earlier, should be remembered, stated Katherine Ulman, owner and primary for KLU Consulting, and member/consultant for IPEC-Americas, in the panel discussion (1). “So, what that means is that [the excipient] manufacturer has to follow appropriate GMPs when producing the excipient, and also, if there’s a compendial grade of the excipient, then it needs to meet the compendial requirements, which means that it needs to follow the test procedures and meet the specifications limits of the applicable monograph,” she confirmed.

“When you test-up a material, you’re testing it up from a different grade, such as industrial, food, or cosmetic grade, and you’re testing it to meet pharmacopeial specifications using their test methods,” Ulman continued. “But what’s missing is that you’re not following the excipient GMP practices required for the manufacture of that material. So, to test-up is to just perform the physical and chemical testing, not to ensure that the material is pure, safe, and has the quality that is required for the excipient grade of material.”

While it is absolutely not acceptable to test-up a material to move from one grade to another without fully understanding the GMPs used to manufacture the material, it is possible to test-up a pharmaceutical grade material to meet other pharmacopeial requirements, Schoneker added. For example, if a pharmaceutical-grade excipient has been bought that meets 

 requirements but the product will also be used in Europe and the 

 specifications are a little tighter, then it could be possible to do some additional testing or show compliance to the tighter limits to meet the other pharmacopeial requirements as the material has been manufactured under appropriate GMP conditions, he explained.

The pharmacopeial tests and monographs were designed with the assumption that the materials being tested had been manufactured under appropriate GMP conditions, asserted Schoneker. “So, you could have an industrial-grade [material] that has some other contaminant [in it] because of the manufacturing processes [used], which is something nobody ever dreamed to test for in a pharmaceutical-grade [excipient],” he said.

This is an important issue, Langley stressed, because if there are impurities in the material being used because it has not been manufactured under GMP conditions, then these may not be identified, which could lead to potential degradation of the active ingredients and ultimately toxicity to the patient. “So, why take that risk when you don’t need to? If you use the appropriate excipient grade, which is manufactured under GMP, then you know you have some guarantee that it’s going to work every time,” he specified.

“There actually isn’t a compendial monograph for every excipient. So, there actually are non-compendial excipients out there, [that have] been used very safely for many years,” said Zawislak. “In the absence of having a monograph, though, you still have to demonstrate the safety of [the excipient] being used in a pharmaceutical (its quality), as it also has to be suitable for its intended use.”

Additionally, a company may encounter a scenario where a compendial monograph does exist but there is no commercially available pharmaceutical grade of that material to purchase that is certified by the supplier to meet the requirements of the compendia, Zawislak continued. In these instances, companies would need to do a risk assessment for the intended use of the excipient, which goes beyond the testing-up and GMP assessment as mentioned earlier, she added.

“Functionality-related characteristics (FRCS) are not universal,” stressed Zeleznik. “There is no requirement in, say 

, for FRCS, but there are some general chapters that can help. Whereas, in Europe, there are actually non-mandatory tests for FRCS for some ingredients [listed in the 

Commonly, the physical and chemical form of the ingredient is what drives the functional performance; however, while the chemistries may be the same and the compendial standards may be met, one grade of an ingredient may be appropriate for a formulation and another may not, Zeleznik explained. “What may be appropriate for a liquid formulation or topical may not be appropriate for an oral, solid dosage form,” he added. “So, FRCS may be important in order to establish [whether] you have the right material for the right application, and that’s going to depend solely on the context of use.”

The characteristics of an excipient, as reported on a certificate of analysis, really are just the tip of the iceberg, Zeleznik remarked. “You need to do a deep dive sometimes to understand what are the functional characteristics and how are they going to impact my formulation and, more importantly, drug delivery,” he said. “If you don’t choose the right excipient grade for that application, it may fail.”

“Ultimately, the [drug developer] is totally responsible for the use of the appropriate grade for their intended use,” remarked Schoneker. “So, from a legal perspective, and this is how regulators tend to look at it, [the drug developer] made the decision to put [a specific] grade of material into a drug product that now patients are going to be exposed to […] that is the overriding responsibility.”

For excipient manufacturers, their responsibility is making sure they have correctly graded and promoted the material for the appropriate applications, Schoneker explained. “If the manufacturer says, ‘I made this as a food grade’, that’s all they need to demonstrate,” he confirmed.

There are, of course, many instances where scenarios are not that simple, Schoneker continued. For example, a company may be selling a compendial grade of an excipient, but the supplier’s intended market for the material is for oral drug applications; however, a customer purchases the excipient and, without the supplier’s knowledge, uses the material for a parenteral product that needs to be sterile. Now, Schoneker asserted, in such a case the liability would be attributed to the user of the material rather than the manufacturer.

Another potentially controversial topic is that of atypical actives, which is where a material has been designed and manufactured as an excipient but has been used as an active by pharmaceutical companies. “It’s always important to recognize that the maker’s intended use is really what the overall basis is [for the material]. If I don’t intend to make an API and somebody’s using it as one, then that’s their responsibility,” Zawislak confirmed.

“Collaboration is critical,” emphasized Langley. If a drug company sees the value in an excipient supplier being part of the drug development process, many issues with regards to inappropriate materials being used will go away. This need for greater collaboration is also true for academics, who tend to buy materials from catalogues and don’t necessarily think about the grade of the materials being used in development studies, he said.

“So, the communication not only rides between the excipient supplier and the pharmaceutical company, but there should be a stronger understanding between academia and where they’re sourcing excipients from in the first place, because the outcome of their research could be a lot better,” Langley summarized.

1. Thomas, F. Drug Digest: Making the Grade: The Importance of Using the Correct Excipient Grade in Drug Products. 

, Jan. 31, 2024.
2. IPEC Federation. Latest Fatal Incidents with Contaminated Medicinal Syrup during 2022/2023, an Updated IPEC Federations Position Paper. August 2023.
3. IPEC Federation. 

Qualification of Excipients for Use in Pharmaceuticals

. Guide and Checklist, Second Version, 2020.

Felicity Thomas is associate editorial director for 

®
Vol. 48, No. 9
September 2024
Pages: 12–14

When referring to this article, please cite it as Thomas, F. Understanding the Value of Excipient Grade. 

Articles

Greater collaboration and understanding are needed to ensure the correct grade of excipient is used in drug products.

Understanding the Value of Excipient Grade

Evaluating Aseptic Processing and Manufacturing

Delving into Biopharmaceutical Development and Manufacturing

In this exclusive Drug Digest video interview, Felicity Thomas, Associate Editorial Director, and Feliza Mirasol, Science Editor, Pharmaceutical Technology Group, interview experts about aseptic processing and manufacturing. During the discussion, industry experts will evaluate the importance of aseptic processing and manufacturing, highlighting the challenges impacting industry, the intricacies of the regulatory landscape, the importance of understanding nuances between products and processes, the necessity of addressing QC/QA early on, best practices to ensure aseptic sterility, and potential future trends.

Maik W. Jornitz, Founder and Principal Consultant, BioProcess Resources

Maik W. Jornitz, founder and principal consultant of BioProcess Resources, is a 35-year veteran of the industry. He is highly experienced in single-use bioprocesses, aseptic processing, and a subject matter expert in sterilizing-grade filtration and filter integrity testing. He has published multiple books, book chapters and over 100 scientific papers on various bioprocessing and facility design topics. He is the former chair of the Parenteral Drug Association (PDA) board of directors and science advisory board, and member of multiple PDA Task Forces, including the European Union Annex I response team. He is board member and senior business and strategy advisor of DIANT Pharma. As a faculty member of various training activities, including PDA Training and Research Institute, he trains members of the industry and regulatory authorities frequently. In his previous roles, he was the CEO of G-CON for 10 years, he worked 26 years for Sartorius, with his last role being the senior vice-president for Global Product and Marketing Management Bioprocess. He received his Master of Engineering in Bioengineering at the University of Applied Sciences in Hamburg, Germany, and accomplished the Program for Executive Development at IMD Business School in Lausanne, Switzerland.

Dan Strange, PhD, Chief Technology Officer, Cellular Origins

Dan Strange has been working at the intersection of engineering and biology for almost 15 years, and he is an inventor on 20 patents. After completing a PhD in regenerative medicine at the University of Cambridge, he moved to TTP where he developed complex drug delivery devices. He was instrumental in the creation of multiple technology platforms successfully licensed to large pharma in deals worth over $100 million. For the past four years, Strange has focused on cell therapy manufacturing equipment. Strange is an active member of various automation working groups and was a reviewer on the Alliance for Regenerative Medicines A-Cell report on cell therapy manufacturing.

Drug Digest is a tech talk video series with the 

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

Small Molecule APIs, Excipients, and Formulation

Solid Dosage Drug Development and Manufacturing

Videos

In this episode of Drug Digest, discussion with industry experts will highlight the challenges impacting aseptic processing and manufacturing, the intricacies of the regulatory landscape, and the necessity of addressing QC/QA early on, among other critical aspects. 

Drug Digest: Evaluating Aseptic Processing and Manufacturing

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In 2024, the warmest day in recent history was experienced on Earth, with the daily global average temperature reaching 17.16 °C (1). In fact, over the past 13 months there has been a vast difference in temperature when compared with previous records, which is demonstrating the impact of climate change at an alarming scale.

Trying to stem the impact of global warming is something that is continually being assessed across many global industries, including the bio/pharma industry. Various initiatives and strategies have been put in place, such as 

 (2), aimed at helping economies and society in general become more sustainable. However, according to research, the healthcare sector contributes to 4.4% of global carbon emissions (3).

A report from NIRAS, a global manufacturing consultancy company, has set out a strategic framework for decarbonization and emphasized the importance of ‘future state planning’ for life sciences companies (4). Future state planning is a methodical approach whereby companies start by analyzing current practices in detail to see where change is needed and then develop a framework through which they can measure progress being made while also ensuring accountability.

However, future state planning, as with decarbonization in general, should not just be considered as a singular event, as specified in the report: “Future state planning is not a one-time effort; it is an ongoing process that requires regular review and adjustment […] Embarking on the decarbonization journey is a commitment to transformative change. It is a voyage that requires meticulous planning, steadfast determination, and the agility to adapt to new discoveries and innovations along the way.”

“As the world moves towards a more sustainable future, the process industries must take bold steps to decarbonize their operations,” said Lis Thodberg, sustainability director, NIRAS, in the report (4). “This transition is not just an environmental imperative but also a strategic business move, as stakeholders increasingly value sustainability.”

1. Copernicus. New Record Daily Global Average Temperature Reached in July 2024. News Release, 25 July 2024.
2. EC. COM(2019) 640 Final. Communication from the Commission: 

. Brussels, Belgium (December 2019).
3. Dehipawala, S.; Goldman, E.; Hwang, E.; et al. The Pharmaceutical Industry’s Carbon Footprint and Current Mitigation Strategies: A Literature Review. Poster Presentation at the 2023 ISPOR Annual Conference, Boston, MA, 7–10 May 2023.
4. NIRAS. 

Decarbonisation in the Process Industries: What Can Manufacturers Do Now?

When referring to this article, please cite it as Thomas, F. Strategic Decarbonization. 

Bio/pharma companies should be approaching their decarbonization journey as a strategic business move for the future as industry stakeholders are placing greater value on sustainability.

Strategic Decarbonization

Submitting Regulatory Applications Connects to Quality

Ask the Expert: Submitting Regulatory Applications Connects to Quality

In this episode of the Ask the Expert video series, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, vice president, Technical at Parexel, discuss submitting biologics license applications and working with suppliers. These two topics have a few things in common, most importantly common steps to ensure product quality.

“[The] best way to make sure that you're giving [FDA] what they need is to really talk with them. I think calling up the center, getting your advocate, [and telling them] here's what I'm intending to file early on in your process is where you need to be to understand. Because I would think that this is geared towards not a more common biological but more of a novelty,” says Schniepp in the episode.

Schmitt agrees with getting clarification and addressing gaps in knowledge. “Now, of course, you can ask the agency. [Hopefully you have] some in-house expertise, but again, it is sensible to understand. Where are the gaps? Where would you perhaps need external expert support? [And] as we said with all the other questions before, you need to have a quality system that makes sure that whatever external support [you choose], you select those who are most suitable for your needs and can provide you with some quality expertise.”

Click the video above to watch Sue and Siegfried answer the following questions:

“My company is preparing a BLA to provide to FDA for approval. How can we be sure we’ve given the agency everything it needs?”

“How do I assess the quality culture of a current or new contract provider?”

ICH—International Council for Harmonisation

Susan J. Schniepp is distinguished fellow at Regulatory Compliance Associates and a member of 

Siegfried Schmitt is vice president, Technical at Parexel and a member of 

Welcome to the Ask the Expert video series. This series is an extension of the PharmTech Group’s long-running print column in which industry experts answer common quality and regulatory questions from the industry. This new video series will expand on topic areas to include development and manufacturing concerns to help those working in the industry better understand bio/pharmaceutical requirements. Have a question you would like answered? Send it to 

, and it may appear in a future episode or print column.

In this episode of the Ask the Expert video series, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, vice president, Technical at Parexel, discuss submitting biologics license applications and working with suppliers. 

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A swelling population that is aging and increasingly suffering from chronic conditions is leading to a greater demand for bio/pharmaceutical products. However, developing a bio/pharmaceutical therapy is a long and expensive journey that does not always end in commercial success or even, for many drugs in the pipeline, commercial viability at all. In fact, according to research, attrition rates for drug candidates remains stubbornly high, sitting at around 90% for those drugs that have reached the Phase I trial stage (1).

Some key trends impacting many industries worldwide, including the bio/pharmaceutical industry, are digitalization and robotics. These trends are also expected to positively impact drug formulation by improving efficiencies and, hence, lowering the potential risk of failure.

“Digital enablement, in general, is gaining momentum, with around 75% of business-to-business customers preferring engagement with digital platforms over in-person interactions,” remarks Shahrzad Missaghi, senior manager, Product Development at Colorcon. “Intuitive digital platforms empower companies to make the right decisions at the start of the process and reduce formulation iterations.”

According to Sibaji Biswas, executive director and chief financial officer at Syngene International, machine learning (ML) and artificial intelligence (AI) have the potential to provide the bio/pharmaceutical industry with significant opportunities to enhance the formulation process and avoid potential failures. “For example, AI and ML technologies are already being increasingly used to predict drug–excipient interactions, which allows for the rapid selection of optimal formulation compositions,” he says. “These predictive models are also employed in the pharmaceutical space to forecast the properties of drug products, such as tablets, based on data sets generated during development.”

In concurrence, Himanshu Gadgil, CEO, Enzene, notes that ML and AI are proving to be transformative for many industries and offer significant formulation advantages by way of improved efficiency and effectiveness. “ML leverages vast amounts of historical data to predict outcomes and identify trends,” he says. “By analyzing [these] data, AI can anticipate the properties of new formulations and validate them before they undergo costly laboratory testing. This capability not only streamlines the development process but also reduces costs by identifying potential issues early on, thus minimizing the risk of failures.”

Some customized generative pre-trained transformer or open-access platforms, such as FormulationAI, are being developed specifically around formulation development, asserts Vincent Levet, director, Formulation Development and Production, Ardena. “[These platforms are] offering solutions that can enhance the creativity of scientists, for instance by helping to review literature very quickly, evaluate compounds through predictive models, or support the actual formulation process by generating design of experiments (DoEs) studies and help to analyze the data,” he says. “However, as it is still in its early stages, it’s important to mention that the adoption of AI also brings concerns regarding IP [intellectual property] protection and potential data breaches, which is particularly crucial as companies must protect their pipeline to survive.”

“AI is [only] as good as the data used to train it,” warns Hanns-Christian Mahler, CEO and board member of ten23 health. While AI is a tool that has the potential to provide value in formulation development, it is important to start off with expert knowledge and an understanding of specific liabilities and challenges of molecules or therapeutic modalities—the critical quality attributes (CQAs), he adds.

“Adequately large data sets of molecules that are characterized in depth and where differences and similarities are well understood, in combination with expert knowledge, can effectively guide and train AI,” Mahler says. “Sadly, most companies do not have such large data sets by themselves, so some cross-company initiative may be needed to support such developments.”

The large datasets, such as those seen in other AI applications used in other industries, are simply not available yet within the bio/pharmaceutical field, agrees Bernard Sagaert, CEO, etherna. “However, making sure that your data [are] structured in a way that makes [them] accessible to perform the first steps in AI and ML has helped [the industry] already in limiting screening efforts and predicting certain pathways to follow,” he says.

For Vinay Patil, product development manager at Sharp Services, the focus for AI and ML tools will be placed upon gaining efficiency in target identification. “[Because] formulation development can only begin once a target compound has been identified and characterized, I expect that more AI/ML efforts will be made in the drug formulation process as the technology matures, and once the industry gains additional experience and, more importantly, success in the use of AI for drug discovery,” he affirms.

At Abzena, an integrated biologics contract development and manufacturing organization (CDMO) and contract research organization (CRO), AI and ML are being leveraged to create a model that is capable of predicting formulation stability over long-term storage using early-stage data, adds Gary Watts, senior manager in Analytics, Abzena. “This model has been validated with multiple formulations of various therapeutic molecules and is particularly beneficial in projects with tight timelines driven by client needs,” he says.

“With the use and evolution of ML and AI, companies have a greater ability to prototype quickly and in a more cost-effective way,” continues David Ferrizzi, director of New Product Development, Colorcon. This ability affords companies opportunities to tackle challenges that may have been insurmountable previously. “For example, certain diseases that were not a focus before are now coming into focus,” he says. “Personalized medicine and a focus on speed and lower total cost are also enhanced as a result of ML and AI.”

“Patient-centricity plays a crucial role in formulation design and the final product’s market success,” says Biswas. “An integrated strategy is often more effective to create an optimized product for the patient, keeping in mind the clinical conditions and individual therapy requirements.”

While patient-centric approaches were traditionally centered on transitioning from immediate-release to modified-release products and creating therapies suitable for patients with a given clinical condition, the landscape is now changing to more personalized approaches, Biswas explains. “One emerging trend is patient-customized medications, where formulations are tailored to meet individual needs, reflecting a shift towards individualized therapies,” he specifies. “New chemical entities are also being formulated with advanced technologies including devices to minimize side effects and reduce dosing frequency, further enhancing patient convenience and compliance.”

Sagaert points out that there are numerous factors to consider to obtain a patient-centric formulation. “Companies need to constantly have all aspects of the platform and the product in mind,” he states. “For RNA-LNP [RNA-lipid nanoparticle]-based products, this is clearly making sure the RNA is non-immunogenic and highly expressed in the target cells, and not expressed in other cells to reduce dose and side effects. The LNPs need to target the right cells and organs to avoid off-target expression as much as possible, and the route of administration needs to be as convenient as possible for the patient in his disease setting.”

The primary consideration, however, is the patient population, adds Mahler. “Studying patient preferences and patient needs for a given indication and use case is key,” he says. “For the various modern therapeutics, such as biologics, ADCs [antibody-drug conjugates], CGTs [cell and gene therapies], oligos, all of these require sterile injection of infusions. For some indications and modalities the answer is probably to aim for subcutaneous (SC) administration using syringe or cartridge solutions with adequate (possibly high concentration) formulations, in combination with a device such as [an] autoinjector, pen, or on-body injector (OBI). Even in the case of cancer therapies, developing products for SC use offers significant benefits for patients.”

“‘Personalized’ medications are a hot topic in current times, and there have been greater efforts to understand the differences in sub-groups of patients such as different ethnicities and those prone to certain conditions,” continues Watts. “Until the science is clearer, formulation strategies must continue to focus upon the target patient population for each drug individually and ensure that this aligns with the design of the final drug format.”

Focusing on pediatric patients, Asma Patel, vice president, Integrated Development Services, Quotient Sciences, remarks that patient centricity is a growing need as these patients require age-appropriate and palatable dosage forms. “In pediatrics, liquid and solid dose formulations that are easier for infants and children to swallow are preferred, including solutions, suspensions, powder for reconstitution, and minitablets, and the taste and palatability challenges of these forms need to be overcome and confirmed by taste assessment studies,” she says. “There are also applications for these dosage forms for other patient populations, such as the elderly and those with disabilities, where easier-to-administer or easier-to-swallow dosage forms can ensure ease of administration, patient compliance, and efficacy.”

“Patient compliance and convenience are key elements in the design and development of formulations,” says Missaghi. “Gaining a deep understanding of patient preferences is the first step in informing the design of the dosage form.” For solid oral dosage products, formulators must consider factors, such as taste, size, shape, color, dosing frequency, and swallowability, which can all help with patient satisfaction and lead to compliance, she confirms.

“Companies can ensure that they’re developing formulations with the patient in mind by soliciting patient input throughout the development process,” adds Patil. “When possible, the proposed drug should be developed as a flexible dosage form. And on the clinical side, drug sponsors should ensure that the protocols are written in such a way that minimizes the burden on participants to the most reasonable degree possible, such as reducing the number of visits, offering home-based assessments, and using virtual consults when possible.”

According to Levet, by employing quality-by-design principles, formulators can define target product profiles matching the needs of the patients, and they can also identify CQAs that focus on patient safety and clinical efficacy from the outset of development. “Choosing excipients that are safe and can enhance drug stability and patient tolerance also plays a big part in being ‘patient-centric’,” he says. “Finally, fast-tracked and phase-appropriate development approaches, designed to get the right level of information to be able to reach the next clinical trial phase and evaluate (but also reject) new therapies as fast as possible allow, in the end, a better focus of the resources available, and ultimately quicker patient access to the most efficient treatments.”

“Selecting the right development partner with a proven track record can be a deciding factor in clinical and eventually commercial success,” asserts Patel. “When selecting a CRO/CDMO partner, the availability of integrated CMC [chemistry, manufacturing, and controls] and clinical research services from one company can be invaluable to streamline drug development processes, along with having a strong foundation of formulation development expertise.”

Partners play a crucial role in drug formulation, particularly during early development, confirms Missaghi. “Some key areas a partner can enhance the process include: offering technical capabilities and competence, including development and troubleshooting experience; knowledge of regulatory and quality standards, aiding in compliance; and a full understanding of the formulation landscape including patient adherence, common pain points, and industry challenges,” she says.

Levet points out that the broad skillset and experience offered by outsourcing partners is invaluable for drug formulation. “[Outsourcing partners] guide customers towards efficient and cost-effective formulations without overextending resources on a compound’s development before its potential is fully realized over the clinical phases,” he says. “With a ‘phase-appropriate’ development, they can help expedite the development process, which is essential, particularly for small and virtual companies to secure funding for subsequent phases.”

“Phase appropriateness is [essential] because it is a very important lever in expediting the screening and evaluation of drug candidates,” concurs Biswas. “This approach helps expedite drug candidate evaluation, allowing rapid assessment in Phase I but without compromising necessary quality. Smaller biotech’s operating on milestone-driven development, require CDMOs’ expertise for quick, risk-based decisions. Outsourcing partners with their extensive and diverse experience can provide a solid and effective platform for quicker delivery of these milestones through deployment of phase appropriate systems and processes.”

Sponsor’s look for a range of integrated development services when selecting an outsourcing partner, therefore, a capable partner should offer comprehensive solutions that include the breadth of the drug development process, asserts Gadgil. “Moreover, in today’s digital era, it is increasingly important for outsourcing partners to embrace innovations like AI and real-time data integration,” he concludes. “An effective outsourcing partner will not only showcase expertise across these domains but also leverage modern technologies to offer integrated, forward-thinking solutions for drug development.”

1. Sun, D.; Gao, W.; Hu, H.; Zhou, S. Why 90% of Clinical Drug Development Fails and How to Improve It? 

®
Vol. 48, No. 8
August 2024
Pages: 10–13

When referring to this article, please cite it as Thomas, F. Integrating Strategies for Formulation Success. 

Employing novel technologies and more patient-centric approaches can help to reduce the potential of formulation failure.

Integrating Strategies for Formulation Success

It is rare indeed for the European Commission (EC) to go against the decision of the European Medicines Agency (EMA); however, for Spanish pharmaceutical company, PharmaMar, such a rare occasion has become a reality.

Six years ago, in July 2018, the EC implemented its decision to reject the marketing authorization application of PharmaMar’s multiple myeloma treatment, plitidepsin (Aplidin), in concurrence with the opinions of EMA’s Committee for Medicinal Products for Human Use (1). PharmaMar contested the decision and filed a lawsuit against the EC, aimed at getting the rejection decision annulled (2).

After being assessed in the General Court of the European Union (EU) in 2020, PharmaMar’s claim that there was a conflict of interest in the experts appointed to assess plitidepsin by EMA was upheld. However, the decision was appealed before the EU Court of Justice, and three years on, in July 2023, the 2020 judgement was set aside, and the case was referred back to the General Court of the EU to rule again (3).

In July 2024, PharmaMar received notification that the EC had revoked its refusal to grant marketing authorization for its multiple myeloma treatment as a result of a member of the EMA’s scientific advisory group’s conflict of interest (2). This is unusual, not least because of the rarity of such an occurrence happening, but also because the EC did not wait for the final judgment of the General Court (4).

And this is not the only case in progress pertaining to conflicts of interest within EMA advisory committees. French independent pharma company, D&A Pharma, has also had the refusal decisions of EMA and the EC for its alcohol dependency treatment sodium oxybate (Hopveus) overturned in court (5).

For now, EMA will need to re-evaluate plitidepsin with absolute impartiality; whether such actions will become more commonplace in the future remains to be seen, but if they do, the integrity of the regulatory authority for Europe could be called into question.

Commission Implementing Decision of 28.6.2024 Revoking Decition C(2018) 4831 (final) Refusing Marketing Authorization Under Regulation (EC) No. 726/2004 of the European Parliament and of the Council for “Aplidin–Plitidepsin”, a Medicinal Product for Human Use

. Brussels, Belgium, 28 June 2024.
2. PharmaMar. Aplidin Will Be Re-evaluated by the EMA. The European Commission Revokes the Decision that Initially Denied PharmaMar’s Marketing Authorization for Multiple Myeloma due to a Conflict of Interest. Press Release, 8 July 2024.
3. EMA. Aplidin. 

 (accessed 4 Aug. 2024).
4. Miñano, L. Deadly Prices: European Commission Rejects Cancer Drug Removal over ‘Impartiality’ Concerns. 

, 22 July 2024.
5. D&A Pharma. The Court of Justice of the European Union Overturns the Decision to Reject the Marketing Authorization for Hopveus: A New Hope for Patients. Press Release, 27 March 2024.

When referring to this article, please cite it as Thomas, F. Demanding Impartiality. 

Potential conflicts of interest with advisory group members have led to EMA’s impartiality coming into questioned for some marketing authorization decisions. 