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

Felicity Thomas

According to market research, the size of the outsourcing sector serving the pharmaceutical and biotechnology industries is expected to expand, reaching $99.4 billion by 2028 (1). Demand for outsourced services is being driven by several factors, such as high demand for biologics and small molecules, a lack of in-house expertise, and rising costs associated with in-house development capabilities.

To find out more about how demands have changed for outsourcing partners providing method development services and the trends affecting this sector, 

 spoke with Jerry “Jr.” Mizell, senior director, Analytical Services, Metrics Contract Services.

 Could you provide a brief overview of how the demands have changed over the years for outsourcing partners in terms of method development services?

 Nowadays, there is an increased demand for sound methods to be developed early in the product life cycle. More customers want rugged and robust methods in place as early in the development process as possible, and they want methods that require minimal changes as their programs advance to commercial phases.

Shifting demands from industry innovators is leading to an increased need for flexible and agile outsourcing partners offering broad and integrated models. In 

, Xiaoyong Fu, PhD, chief technology officer and head of API Business, WuXi STA, discusses how process development demands have changed.

Based on the experience of Metrics Contract Services, customers also want to develop quality control (QC)-friendly methods that help maximize laboratory efficiency in the commercial phase. Across various methods developed in recent years, dissolution, in particular, has been in the spotlight. A comprehensive approach to dissolution should produce a discriminating method that can demonstrate that an adequate drug product has been manufactured. Current customer expectations also demand a detailed dissolution method development report describing how the dissolution procedure was derived. This is especially important for new drug applications (NDAs).

 How has demand of outsourced services for method development been impacted by the COVID‑19 pandemic?

 While we haven’t experienced a direct uptick in development services requested because of the COVID-19 pandemic, we have experienced supply chain challenges as a result of it. The delays and disruptions to key supplies have made it imperative to execute method development in the most effective means possible to align with clinical timelines.

Choosing a method development partner with vast experience and a proven track record becomes invaluable to customers who need to deliver treatments to patients at speed, while also ensuring that key project deliverables are met.

Have there been changes in expectations as to what an outsourcing partner should be able to provide or accomplish with method development services?

 The outsourcing partner, or contract development and manufacturing organization (CDMO), should have a vast array of development experience in solid oral dosage formulations. This experience will allow for expedited development services, especially when challenging formulations are being developed. These challenging formulations may include API loaded on resin or beads and molecules that do not contain chromophores, requiring alternative modes of detections.

CDMOs with experience in charged aerosol detection, evaporative light scattering detection, and refractive index detection for challenging molecules can be the deciding factor in awarding a project. Outsourcing partners with mass spectrometry (MS) capabilities are also at an advantage when impurity issues arise and identification is needed. Cost can be a primary focus for some programs; however, quality assurance and the ability to meet deliverable timelines are also very important qualities, which can often outweigh price differences.

 What other trends have impacted outsourced method development in recent years?

 Over the past few years, there has been an increase in the development of poorly soluble small-molecule drug products, which can be extremely challenging when developing a dissolution method. This type of program is challenging because introducing two APIs into the same formulation and combining products, with significantly differing physical and chemical characteristics, means that method development can take on a new level of difficulty.

From a safety perspective, highly potent APIs (HPAPIs) introduce additional challenges, as developers want user-friendly methodologies in place without jeopardizing laboratory staff safety.

 In your expert opinion, what trends might we expect to see in the future and why? Also, how might outsourcing partners be best prepared for future demands/industry trends?

 There should be more and more Biopharmaceutical Classification System Class II and IV molecules being discovered for evaluation.

Customers should seek outsourcing partners with extensive experience in dissolution development and alternative mode of detection in the event that a molecule does not contain a chromophore. Instrumentation must remain compliant with current industry standards to ensure method expectations are met.

There is also an expectation that future demands will call for methodology development for nitrosamine assessments, and the ability to meet FDA (and other regulatory bodies’) requirements for NDA filings and current commercial products on the market. This methodology requires MS, which if not currently available at a CDMO, may become a worthwhile investment to offer to customers. As with elemental impurities, this requirement will not go away and will only face increased scrutiny as time passes.

Biotechnology and Pharmaceutical Services Outsourcing Market Size, Share, and Trends Analysis Report by Service, by End Use, and Segment Forecasts, 2021–2028

Felicity Thomas is the European editor for Pharmaceutical Technology Group.


Supplement: Biopharma Outsourcing Innovation 2022
February 2022
Pages: s12–s13

When referring to this article, please cite it as F. Thomas, “Method Development in Demand,” Biopharma Outsourcing Innovation 2022 (February 2022).

Articles

Experience is an invaluable asset for outsourcing partners, particularly as more challenging method development services are in demand.

Method Development in Demand

By the year 2026, the global outsourcing market for formulation development is expected to reach a value worth $12.65 billion, growing at a 7.2% compound annual rate (1). Factors driving this market growth include the rising demand for innovation of novel drugs due to the increasing number of patent expirations for major drugs and the fact that many pharmaceutical and biotechnological companies are trending toward outsourced services for formulation development (1).

To learn more about outsourced formulation development services, including various industry trends impacting the sector, challenges for outsourcing partners, and key benefits for outsourcing formulation development, 

 spoke with Lynn Allen, vice-president of Business Development at MedPharm.

 Could you provide insights into industry trends that have affected the formulation development outsourcing market?

 The pharmaceutical industry continues to adapt to new business conditions. Life cycle management continues to drive the need for outsourced formulations, often in developing products for alternate routes of delivery.

Companies that are looking to improve patient compliance or reduce systemic side effects can look at new formulations for local delivery through topical dosing. Based on MedPharm’s experiences, there have been increases in the demand for formulation services of ophthalmic preparations and respiratory delivery, primarily intranasally. An increase in the number of biologics with targeted topical delivery routes has also been a trend. As a contract development and manufacturing organization (CDMO) that specializes in dermatological, nail, eye, airway, mucosal membrane, and otic product development, MedPharm continues to support topical formulation development services for local delivery market needs.

Additionally, proprietary nonclinical models that test formulations for effectiveness at early stages continue to be an asset to the company’s client base. For example, MedPharm’s reconstructed human nasal epithelia model is a living representation of the nasal membrane, and allows formulations that are targeted for the different regions of the nose (local, systemic, or brain) be tested to evaluate formulation parameters such as delivery, irritancy, mucoadhesion, and effectiveness.

 What type of formulation work is more commonly outsourced currently?

 There is continued growth in product development by specialty and virtual pharmaceutical companies. As large pharma looks for investments in late-stage assets, start-up companies that effectively deliver well-developed products with effective clinical data are highly sought out for licensing and acquisition deals.

Consequently, start-up companies require formulation expertise at the earliest stages of development and often do not have extensive research labs to perform critical assessments such as screening multiple APIs. Outsourcing of these early research activities continues to grow, and MedPharm continues to invest in these services to support both early start-up and specialty pharma companies.

 What are the biggest challenges for outsourcing partners when working on a formulation project?

 In the fast-paced environment of drug development, it can be challenging to ensure that all stakeholder needs are being articulated at the start of formulation activities and continue through the development process. When sponsors have not conveyed all needs or if they are not prepared to make decisions on formulation priorities when challenges arise during development, it can often mean repeating activities or delaying timelines.

 How do outsourcing partners overcome these challenges?

 One key aspect that must be stressed at the start of any program is the necessity of a well-defined target product profile. The key attributes of what the formulation should achieve and, particularly in the topical space, how it should feel when applied or how it should be packaged and used by the patient are critical considerations of development. Internal expertise is also critical which includes program management, development, or regulatory resources.

 What are the key benefits of outsourcing formulation development?

 When formulation development is not an internal strength or if the delivery route is outside of in-house formulation expertise, the broad experience of a service provider dedicated to these services can save time, money, and avoid the pitfalls of an ineffective, poorly developed formulation. CROs [contract research organizations] and contract development and manufacturing organizations, particularly those focused on niche markets like MedPharm, have broad experience and can pull from decades of experience and current real-time learnings to guide development activities in the constantly changing regulatory environment. Service providers can also offer more dedicated resources when companies need to prioritize critical programs.

Formulation Development Outsourcing Market—Growth, Trends, COVID-19 Impact, and Forecasts (2021–2026)


Supplement: Biopharma Outsourcing Innovation 2022
February 2022
Pages: s14–s15

When referring to this article, please cite it as F. Thomas, “Gaining Formulation Expertise through Partnerships,” Biopharma Outsourcing Innovation 2022 (February 2022).

A key benefit for companies when outsourcing formulation development is the broad experience they can gain from a dedicated service provider, particularly for niche markets.

Gaining Formulation Expertise through Partnerships

Over the years and in light of various industry trends, the demands for outsourced services have increased and evolved. In this interview, 

 discusses how process development demands have changed for service providers with Xiaoyong Fu, PhD, chief technology officer and head of API Business, WuXi STA.

Trends impacting process development services

 How have process development demands evolved over the years for outsourcing partners?

 Molecules are getting more complex, pipelines more diverse, and at the same time, increasing numbers of targets are on accelerated pathways. Put these factors together and there is a need for contract development and manufacturing organizations (CDMOs) that can handle integrated and accelerated pathways with a full suite of technologies from biocatalysis and flow chemistry through to crystallization and spray drying. Integrated models provide much greater flexibility and enable API and formulation teams to work side by side.

Phase-appropriate development is also often asked of many CDMOs, and this usually means running pathways sequentially. Another way timelines can be accelerated is by developing an ‘end-in-mind’ process strategy to seamlessly connect discovery, development, and commercial API needs from milligram to metric ton scale. But the CDMOs will need a large R&D team with the right expertise and a broad technology platform to ensure the most appropriate chemistry at every scale.

The final trend that is being seen and, in some ways is linked to the challenges of the pandemic, is the requirement of a partner who can ensure supply chain stability with a robust continuity business plan including multiple facilities available, technologies to avoid or minimize the use of scarce material, or even the ability to manufacture them in the event of shortages. This means forward-looking innovators are seeking backing by a contract partner that has a solid network of vetted vendors and a large chemistry organization and a diverse manufacturing and technology platform that can react and adapt quickly.

 What other trends have impacted outsourced process development in recent years?

 Undoubtedly, bioavailability and solubility are increasingly common challenges and process characteristics are, therefore, a must for any outsourcing partner—they need to have the full suite of particle size engineering tools and expertise from crystallization, micronization, nano-suspension to amorphous solid dispersion. There has also been an increase in the need of highly potent APIs, which necessitates highly specialized facilities and expertise. And, more recently, there has been a high demand for the CDMOs that can handle oligos, peptides, and various complex conjugates. Novel conjugates involving combinations of oligos, peptides, high potency payloads, linkers, and specific carriers are increasing, but the resources required are lagging worldwide.

One of the other major trends is that innovators are seeing the benefits of integrated networks with R&D and manufacturing teams in one location and, taking this a step further, having drug product formulation and manufacturing within the same or nearby facility, especially, in the case of oligos, peptides, and conjugates, having an injectable formulation development and manufacturing capability to be paired with the API project. These obviously bring tremendous benefits in reducing transfers—of materials or knowledge—and enable formulators and chemists to work closer and reduce time to market or milestone.

Shifting demands from industry innovators is leading to an increased need for flexible and agile outsourcing partners offering broad and integrated models.

Evolving Demands of Process Development Services

Whether characterizing particle size or structure, or investigating any possible contamination, particle analysis plays a critical part in bio/pharmaceutical development and manufacture. “Particle analysis is a critical tool to define, help manage, and deliver product quality,” confirms Michael Lindsay, SGS Global scientific director.

“Desired product performance greatly influences how the API needs to perform with regards to solubility, rate of solubility, and permeability to access the target site or be available for systemic circulation,” Lindsay continues. “Typically, the API is blended with other non-active ingredients, each with their own contributing property attributes, to help deliver the API in the desired media to a patient as a solid, semi solid, liquid or gas/powder.”

Essentially, achieving a sufficiently homogenous mixture and product is a key manufacturing goal, but there are multiple characteristics that can impact this, such as physical aspects (size, shape, density), particle charge, smoothness, and the ability to blend and flow, Lindsay notes. “These features can be critical quality attributes in process steps from: initial synthesis through crystallization, if needed; processing and blending in production into the final package to contribute final product performance,” he says. “Collectively, these factors influence which particle analysis methods are used to evaluate material behavior to determine criticality; and, with defined specifications become necessary to ensure consistent product quality and performance.”

During manufacture, drug products come into contact with other surfaces and can be exposed to the air, which could lead to potential contamination from particulates, Lindsay asserts. “Therefore, particle analysis also serves as an investigative tool to ensure there are no unacceptable contaminants,” he says. “Where contaminants are present, particle analysis helps identify root causes for such contaminants, so that actions are taken to eliminate them to further ensure product safety.”

There are numerous techniques that are currently available for particle analysis, which can be categorized around both chemical and physical properties, Lindsay explains. Additionally, it is possible to use single or multiple methods to reveal the expected materials performance so that an acceptable product can be yielded, he adds.

 “Material solubility is a significant contributor to product performance where particle size reduction corelates with increased surface area to influence rate of dissolution. Thus, multiple methods are used to measure particle size,” Lindsay says. “A desirable decrease in particle size can facilitate higher dissolution with increased surface area and can also increase the rate of degradation and impact product stability too. Therefore, particle size analysis is one of the most important techniques.”

A relatively easy method that requires minimal expertise and no sample preparation is sieving, which includes air jet sieving, specifies Lindsay. However, with this method between 10 g and 100 g of material is consumed, there is a lower particle size limit (>20–50 µm), the range of sieves reduces data points, and it is only possible to be used with dry materials, he states.

Through the use of light microscopy with high resolution-image analysis, it is possible to fully visualize and inspect particles, Lindsay confirms. This method provides such advantages as a 1–1000 µm dynamic range, visualization of solubility (if it occurs), capability of confirming aggregation and particle fragmentation, and the ability of confirming crystallinity, degree of crystallization, crystal quality, and shape. Considerations to take into account when using this approach are solvent evaporation; multiple fields of view; and non-random particle orientation if particle size or shape is also being measured.

Laser diffraction only requires a small amount of sample (>10 mg to a few grams), can be used with wet or dry particles, and offers a dynamic size range of 0.01–2500 µm (dependent on instrument, technique, and configuration of instrument), Lindsay continues. For wet analysis, however, the solubility of the material should be considered, he adds. Additionally, expertise for method development is required, and the particle shape needs to be contemplated when the technique assumes a sphere.

A small quantity of sample (±1 mg or less as a minimum) is also required when using dynamic light scattering (DLS) as a technique for particle size analysis. The dynamic range offered is between 0.3 nm–10 µm and the estimated average molecular weight range catered for is 1 x 103 to 1 x 107 Daltons (both dependent on instrument, technique, and configuration of instrument), Lindsay states. Similar considerations are required for DLS as with laser diffraction: solubility, expertise, and particle shape.

Dynamic image analysis or Micro-Flow Imaging (ProteinSimple, Calif., USA) is another particle size technique that only requires a small quantity of sample (<1 mL). This approach offers a dynamic range of 1–300 µm (dependent on instrument, technique, and configuration of instrument), provides the ability to see particles, allows visualization and measurement of particle shape and morphology, tests most of the sample, can be used with high viscosity samples (up to 20 centipoise), and can enable visualization of contaminant particles, Lindsay asserts. Solubility and expertise are considerations to take into account with this method, along with the need to view sufficient images for confirmation of particle distribution because particles are visualized in a random orientation.

“A consideration for all methods discussed is that the sample tested must be representative of the bulk; particle size is measured through a variety of techniques, where in development orthogonal approaches may be taken to evaluate which provides the more meaningful data to control quality,” Lindsay stresses.

 “Other techniques can be employed to visualize particles, isolated or not, to better describe the particle and aid in identification of potential contaminants,” states Lindsay.

When evaluating surface area of particles, it is possible to use the Nitrogen Brunauer-Emmett-Teller (BET) method. “Surface area most influences solubility of a material in solution and can be additionally measured as an orthogonal technique to particle size,” Lindsay says. “As particle size decreases surface area increases per unit mass and reported as m2/g to positively increase potential dissolution rate. Thus, particle size/surface area is used to help control dissolution rate in some products.”

Measuring the surface area of particles becomes particularly important for chemically unstable compounds, Lindsay explains. For these compounds, if there is an increased surface area there will be an increased degradation rate, which influences the formulation protection or coating that has been implemented to prevent degradation.

Surface charge method can be used to evaluate the Zeta potential—the charge on a particle at the shear plane. This property is important for the understanding and prediction of how particles will interact in and successfully stay in suspensions with other particles, Lindsay confirms.

Flowability of particles, which is critical for powder blends, can be measured with a variety of methods, such as funnel, angle of repose, powder viscometry/rheology, and so on. “The ability to flow evenly is a requisite for gravity assisted processes, where flow is uneven or there are vibrations differences in flow, density, particle size can lead to size or material separation to de-mix a once uniform blend,” Lindsay says.

Pycnometry/a densitometer can be used to measure the material density at a material level and to measure that property at a bulk scale, it is possible to use tap and bulk density testing. The latter method can also provide details that will allow for an understanding of how particles will settle together, Lindsay notes.

 All products to be administered via injection need to undergo a visual inspection to check for particulates as per regulatory guidance, such as the United States Pharmacopeia Chapter <790> and European Pharmacopoeia Chapter 2.9.20 (1,2). The visual checks involve an inspection of the sample against a black and against a white background, with the naked eye and without magnification, under standardized light conditions, Lindsay states.

Light microscopy can be used to visualize the particles and their surface properties to a size of 1 µm. Additionally, this technique allows for particle geometry to be evaluated and measured, and can provide confirmation of crystal properties, Lindsay reveals. A simple count of particles in liquid samples, at set sizes between 10 µm and 25 µm, can be done using light obscuration, he adds.

Microscopy coupled with Fourier-transform infrared or Raman spectroscopy may be used to identify particles greater than 10–20 µm, although particles must be cleaned of other materials to improve spectral quality, Lindsay stresses. Scanning electron microscopy and energy dispersive X-ray analysis are useful for the visualization of the material and for elemental identification, particularly for metal/alloy contaminants.

“Particle analysis techniques have advanced greatly from the simple sieve to the use of laser and high-speed image and spectroscopic systems to gather more meaningful sample data on the particle to better describe the particle shape, size, density, and identity faster,” says Lindsay. “Also, providing the sample is representative, results are obtained with much less material thus enabling accurate measurements on very expensive materials at lower cost.”

Thanks to advancements in optical and spectroscopic techniques, it is now possible to capture images of the particle flow in real-time, allowing for particle identification, Lindsay reveals. Additionally, smaller particles (>0.3 nm) can be optically detected and measured using light scattering techniques, he adds.

“Data processors, detectors, and processing speed have contributed significantly to the advancement of new instrumentation that are both smaller and faster than previous instruments,” Lindsay says. “Bench instrument components are now being built into flowing or blending processes to also enable real-time in-situ non-destructive analysis and include final in vial measurements so that no additional material is consumed. Spectroscopic techniques, with complex libraries and processing for spectral analysis, enable real-time monitoring of blends to confirm material concentration and uniformity.”

In the future, continued advancement in analytical measurement abilities for all aspects of particle analysis to the limits of what physics will allow is expected, Lindsay emphasizes. Further miniaturization of instruments to enable measurements of lower volumes and greater speed in flowing systems and an increased use of process analytical technology (PAT) solutions that separate offline analysis will transpire, he states.

“In time industry should expect to see more analytical instrument techniques be part of the PAT solution to reduce some laboratory testing outside of the particle analysis areas too,” Lindsay adds. “The regulations already support alternate techniques to better manage risk and assure quality. Data analytics with smarter artificial intelligence will help identify and correct processes, within defined and approved design and quality-by-design spaces, seamlessly to enable more effective production.”

 <790>, “Visible Particulates in Injections,” 

 Chapter 2.9.20, “Particulate Contamination: Visible Particles” (Strasbourg, France, 2008).

Particle analysis provides assurances of the quality and performance of the final dosage form in pharmaceutical development.

Without a Particle of Doubt

The year 2021 has been transitional for the most part, with many stakeholders of the bio/pharma industry getting used to the ‘new normal’ or post-pandemic working life. Industry continues to drive innovation across the board, with continued efforts to tackle COVID-19 and a large number of approvals for a range of products.

Potential big changes in pharmaceutical legislation, however, are on the cards for Europe (1), as the European Commission (EC) continues working on its pharmaceutical strategy for the region, which was adopted in 2020 (2). The reformation of the pharmaceutical legislation is foreseen to be implemented by the end of 2022 and will be the first time the European Union’s rules on how drugs are made, approved, and sold have been comprehensively reviewed in 20 years (1).

For Jürgen Hönig, pharmacist, senior director, Regulatory Business Intelligence at PharmaLex, the expectations for the year have been surpassed. “Although the pandemic has tremendously influenced the social and economic environment, the pharma industry has demonstrated that by having established robust process it has been possible to maintain the supply chain,” he says. “Furthermore, it has been shown that how medicinal products for the treatment of COVID-19 and related diseases were developed in a short time using creative and holistic approaches and in compliance with regulatory requirements.”

“The obvious theme [for 2021] has been the turnaround of COVID-19 vaccines, magnifying trends already seen before and showing that promising new technologies can actually hold their promise, and that it is possible to optimize drug development to speed up delivery,” states Christian K. Schneider, MD, head of Biopharma Excellence and chief medical officer (Biopharma) at PharmaLex.

A surprising trend from 2021 has been the rapid adoption of digital technologies in clinical trials, Schneider notes. The use of such technologies has enabled the decentralization of readouts in clinical trials through mobile phone applications, he adds. “Finally, we’ve seen more companies diversifying their portfolios and investing in therapies for rare diseases so that advanced therapies, and in particular, gene therapies—which were deemed experimental and risky when I was involved with the European Medicines Agency’s Committee for Advanced Therapies some 10–12 years ago—take centre stage,” Schneider continues. “Cell therapies, by comparison, may have slipped behind a bit—but will catch up.”

The year’s expectations were unsurprisingly centred around COVID-19 for Martin Lush, global vice president, Health Sciences, NSF International, who revealed that despite there being some successes for the industry over the year there were also some disappointments. In terms of achievements, the pharma industry has surpassed all expectations in turning around safe and effective vaccines at ‘high’ speed and has coped with COVID-19 disruptions remarkably well, he emphasizes.

However, the fragility of the supply chains, as demonstrated by the pandemic, has persisted with continuing drug shortages occurring, and governments have failed at unifying efforts to make the whole population safe as is being proven by the Omicron variant. “We are not safe until we are all safe,” Lush adds. “This can only be achieved by a global collaborative focus on getting as many needles in as many arms as possible, starting with Africa. Africa will remain a petri dish for COVID-19 for decades to come. More variants are mutating away as we speak. Two things are certain for 2022: more disruption and more uncertainty. If I were a CEO, I would be obsessing about how I look after my people and how I become really agile.”

Gabriela Marton, director of Regulatory Affairs, Quality and Compliance at Arriello, also agrees that 2021 progressed as anticipated, due to the pandemic and resulting focus around vaccines development. “[2021] was a year in which all the important players in the biological pharmaceutical industry strived and, in some cases, succeeded in developing their own vaccines against the SARS-CoV-2 virus,” she says. “Those that had already achieved this in the previous year, meanwhile, continued with the task of gathering safety data to support the vaccination scheme.”

Furthermore, 2021 bore witness to restructuring of Big Pharma, in the guise of acquisitions and partnerships to support biotech business growth, thanks to the high demand for medicines to treat diseases in specialist therapeutic areas, such as oncology, autoimmune, metabolic, hormonal, cardiovascular, neurological, and inflammation and infectious, Marton states. “I would say that this is a continuation of trends seen during the past five years, but with a faster pace due to the pandemic,” she notes.

During the course of 2021, face-to-face events started taking place again after an unprecedented hiatus due to the pandemic. In attending a pharma conference, Lush revealed that despite feeling better informed on his departure, he was also highly concerned as delegates were seemingly discussing quite different topics and trends to those that were presented by the industry experts during the event.

“In short, the experts were focused on the science whilst those at the coal face were focused on their people,” Lush says. “[The workers] are worried about the possibility of massive attrition and the war for talent. They want to know more about organizational agility (via simplification), so they can pivot at the drop of a hat. They are having sleepless nights about managing, leading, and motivating their teams in a world gone crazy. They want to become expert ‘risk-based’ decision-makers. They want guidance on fast and effective change management. They want to make their organizations more risk smart and less risk-averse—but they do not know how to achieve this. The disconnect between the experts and the workers is now causing me sleepless nights!”

However, there will also be promising potential in digital technologies, according to Hönig, who believes that technologies, such as artificial intelligence (AI), digital transformation, and cloud technology, will facilitate the translation of languages and provide industry with an open platform for discussion. This aspect will, in turn, accelerate drug discovery and development, as well as allow the decentralization of clinical trials, he states.

Additionally, personalized medicine will be a prominent trend in 2022 for Hönig, who states that these medicines will help tailor options for patients and optimize the effectiveness of treatment and hence improve patient outcomes. There will also be implementation of the “lessons learnt during the pandemic,” Hönig continues, which will afford the industry smoother approval and decision processes.

A continued focus on biotech, automation, and AI development will happen over the course of 2022 as a result of the high demand in certain therapeutic areas and the need for faster ways to collect and manage data, adds Marton. “Many big pharma companies will continue down the path of externalising services for small molecules and/or known molecules maintenance, to keep their focus on novel molecules,” she explains.

There is the additional prospect of the European market gaining more interest from start-ups from the United States and small companies that have a modest portfolio of innovative products thanks to the evolving legislation in the region allowing accelerated approvals, Marton continues. “The pandemic highlighted how quickly changes can be triggered, and I expect this rhythm to be maintained,” she says.

“The emergence of pre-competitive industry consortia is promising. During the pandemic, we have seen smaller [consortia] forming around co-development, and now with new technologies, we’re seeing a growing desire by companies to join forces so that they don’t duplicate effort via individual development programmes,” Schneider highlights. “We’re starting to see evidence of regulatory agencies working together more, which I hope will lead to greater convergence of regulatory frameworks. We certainly need that to improve speed to market with new treatments. The UK Medicines and Healthcare products Regulatory Agency has now joined the Australia-Canada-Singapore-Switzerland Consortium. This has fuelled the building of a strengthening regulatory player, which may prompt a fresh look at other regulators’ frameworks towards increased harmonization and reduced complexity.”

As mentioned earlier, the EC is seeking to overhaul the pharmaceutical legislation for Europe by the end of 2022. As a part of the changes, Schneider specifies that it would be good “to see the cost/benefit of a drug or therapy (the payer’s role) addressed in the same uniform way as risk/benefit (the regulator’s role) in Europe.” Under the current rules, reimbursement is a complex issue due to the fact that each member state of the EU makes its own decision on this matter, Schneider adds. As a result of this complexity, there can be much negotiation and, hence, delay in access to medicines, he explains.

“I’d also like to see novel methodologies finding a more permissive and open climate, so that there is faster regulatory action not just for advanced therapies and small and medium-sized enterprises, but also for academia, companies of larger sizes, and those working with other therapies,” Schneider says. “A review of incentives is needed: these are currently exclusive to only a few stakeholders.”

“I would expect that the regulatory processes across the EU need to be modernized to keep pace with the new development of medicines,” asserts Peter Gough, vice president, Pharmaceutical Services, EMEA, NSF International. Certain regulatory challenges need to be addressed, Gough continues, such as point-of-care manufacturing of medicines, monitoring of supply chains to identify potential areas of shortages prior to affecting patients, improving measures to fast-track new vaccines and therapies in the event of future pandemics, and reducing bureaucracy to make the EU more attractive for investment and speed up the ability to bring innovative medicines to market.

Certain changes, such as those that have already been announced and included in the ‘Pharmaceutical Strategy for Europe’ will more than likely be implemented, Marton confirms. These changes include revisions to the centralized procedures with respect to complexity, timelines, and identification of routes for different types of products, and an even more centralized approach across EU authorities for evaluations, inspections, decisions, and so on, she adds.

“The pandemic showed that there is a need for fast evaluations, authorization, and decision-making, which the previous, 20-year-old legislation couldn’t provide for,” Marton emphasizes. “What I would like to see changed is the way that national authorities across the EU implement EU legislation. I would like to see that done faster and more clearly, so that we avoid a long and ambiguous transition period. I would like to see more guidance from national authorities on how to fulfil local requirements.”

“The rules of maintenance of marketing authorization, especially the variation system, are complex and not currently easy to navigate,” adds Hönig. “And so, a facilitation of such rules would be welcomed.”

However, Hönig cautions that any revisions should build upon the existing legal acts that have already been implemented over the past two decades and proven to be a good basis for pharmaceutical legislation. “The revision should ensure a reliable EU regulatory system which is attractive in a competitive global environment with fast decisions and transparent approval times allowing for flexibility and lean maintenance procedures,” he says. “A revision of the variation system would lead to a more efficient and less administrative regulatory procedure. Furthermore, the revision should take into account the technical development of the last decade and should foresee future developments.”

Schneider is encouraged by the fact that Europe is aware of the need for international regulatory convergence, which will help the EU become a more attractive market as it will be easier to navigate for companies with treatments already approved in other territories. “Patient centricity and empowerment are other big themes, and we’re seeing regulators becoming more directly involved here,” he notes. “For rare diseases, [patient centricity] is particularly important as a patient’s appetite for risk might differ from their doctor’s or a regulator’s, for example.”

Further issues that will be better addressed with closer collaboration of regulatory bodies and patient groups include the use of placebos and the issue of clinical trial readouts being subjective and possibly not standing up to regulatory rigour, Schneider confirms.

“Medicinal product research, development, and manufacture is a global industry, and the EU needs to help ensure that it remains attractive to both new start-up companies and Big Pharma. Most generic medicinal product manufacturing has already moved outside the EU with the resulting supply chain vulnerabilities,” Gough stresses. “If the EU gets the revised legislation right, the impact [on industry] should be positive, but if it just adds more complexity and restrictions, it will be very negative as the industry will continue to migrate to more agile regions.”

European bio/pharma is a source for innovation and development for novel medicinal products, Hönig asserts, with many EU countries home to well-equipped manufacturing sites for bio/pharmaceuticals that are proven to manufacture high-quality, safe, and efficient products. However, more recently the vulnerabilities of the supply chain have become apparent, mainly as a result of discontinuation of supply of important active ingredients or the needed finished products manufacturers in certain Asian regions, he specifies.

“The reasons for [these issues] range from a lack of raw materials, insufficient quality, price increases, problems in logistics, and political decisions,” Hönig says. “In order to become less dependent on these numerous imponderables, and to be able to guarantee EU consumers a fair and necessary supply, pharmaceutical companies will relocate production or parts of it to existing manufacturing sites in the EU or will set up new manufacturing sites.”

Existing non-harmonized reimbursement procedures are of particular concern for Hönig, who believes that in many EU member states, procedures are not fit for purpose and forming part of the underlying reasons as to why production is forced out of the region. “Certain regulatory flexibility will contribute to more security of supply,” he confirms. “Creating unnecessary regulatory and financial burdens for the industry will not contribute to a solution.”

The pandemic has clearly shone a light on some supply chain issues, concurs Schneider, not least of all the issues of shipping ‘fragile’ products, such as messenger RNA vaccines, across distance. “For gene or cell therapies—individually manufactured and with a very short shelf life—we see patients needing to come to the medicine, rather than the other way round. Either this requires a very rapid and solid supply chain, or the creation of special centres near hospitals where patients can readily access the treatments they need,” Schneider emphasizes. “An appropriate regulatory framework could help enable this.”

For Marton, a number of changes that have already been evident in the bio/pharma industry over the past five years will force companies to approach their business differently. “As mentioned, the pandemic highlighted the potential for and impact of accelerated development and approval; then there’s the growing emphasis on specialist therapeutic areas,” she says. “In addition, newly-implemented clinical trial legislation will come in to support companies’ growing interest in new and innovative products.”

In Marton’s opinion, 2022 will more than likely be the year when companies will need to define their direction and targets for the future. “Legislation will bring the need for greater transparency across the supply chain and product stocks, so we can expect to see companies preparing to implement the new rules, with execution over the following years,” she adds.

When predicting what awaits the industry for 2022 and beyond, Lush reveals that COVID-19 disruption is here to stay. How disruptive the virus may be, however, will depend upon the work of the governments around the world, he asserts. “One thing is for sure—the virus is not wasting time,” Lush adds. “Pasteur famously said, ‘the Microbe will always have the final word’. We have the science and the pharma industry to prove Pasteur wrong, but we just need the political will. The ability to pivot at short notice will be key, which requires simple systems, fast (bottom-up) decision-making, and a world-class change management system to keep track of everything.”

More drug shortages will be on the cards as China and India continue to prioritize meeting domestic demands, Lush continues. “Reshoring manufacturing to improve resiliency sounds great in theory—but will take years to accomplish. Supply shortages will be with us for some time,” he says.

Post-pandemic clearance of the backlog of regulatory audits will require a more nuanced (hybrid) risk-based approach, according to Lush, which could potentially affect compliance levels. “Within the next 15 years, medicines based on mRNA platforms and technology will account for 30–35% of approved meds and turn the traditional vaccine business model on its head,” Lush adds.

Pricing pressures will ramp up as governments attempt to pay for increasing healthcare costs with very little money, Lush remarks. As a result, companies will need to simplify and reduce costs or watch margins evaporate, he specifies. Governments will also increase pressure on sustainability issues. “Sustainability ‘words’ must turn into actions,” Lush stresses. “One of the major contributing factors to this pandemic is climate change. Shockingly, the pharma industry generates 11–12% more carbon emissions than the automobile sector.”

In addition to these trends, Lush expects there to be massive growth in in-vitro diagnostics and combination products as industry “moves from a treatment-based ‘disease care’ system to a ‘prediction and prevent’ healthcare system,” he notes.

Finally, Lush iterates the importance of ‘the people’ in 2022. “When asked ‘what it takes to manufacture high-quality medicines consistently,’ my great friend and mentor, David Begg, responded, ‘It is all about the people—stupid!’ Before we make medicines, we must make (and look after) our people,” Lush summarizes. “We have to rethink our recruitment and retention strategies to make our workforce more diverse in every regard. We need more rebel thinkers and fewer clones. We cannot solve many of the challenges we face with old thinking. Of course, you do not have to do any of this—survival is not compulsory.”

European Health Union: Towards a Reform of EU’s Pharmaceutical Legislation

Affordable, Accessible, and Safe Medicines for All: The Commission Presents a Pharmaceutical Strategy for Europe


Vol. 34, No. 1
January 2022
Pages: 10–13

When referring to this article, please cite it as F. Thomas, “Changes Afoot: 2022 Outlook for Pharma and its People,” 

An obvious theme for 2021 has been COVID-19, but the next 12 months will see industry and its people experiencing further change.

Changes Afoot: 2022 Outlook for Pharma and its People

Increasingly, poorly soluble compounds are forming part of the development pipeline, driving greater innovation in ways to overcome the associated challenges these compounds give rise to. To learn more about solubility and bioavailability considerations in drug development and innovations in the field, 

 spoke with Kyle Smith, president and COO of Aprecia, and Jim Huang, PhD, founder and CEO of Ascendia Pharmaceuticals.

 Could you provide some insight into the issue of poor solubility/bioavailability and how it impacts bio/pharmaceutical formulation, both currently and into the near future?

 Up to 40% of commercial products require solubility/bioavailability enhancement for sufficient exposure to achieve therapeutic action (1). For compounds in development, it is estimated that up to 90% require solubility/bioavailability enhancement (1). Development of products to achieve required solubility and absorption presents a critical challenge to clinical dosage formulation and process development, which can add significant time to early formulation development work. Furthermore, scientific rationale, quality-by-design, and quality risk assessments become more critical when trying to formulate poorly soluble compounds, as they are necessary to define the functionality, reproducibility, and assurance of consistent performance related to efficacy and safety to patient.

 Poor solubility/bioavailability is still a big issue for drug discovery and development in a high percentage of small molecules and a portion of peptide and large molecules. Low solubility causes poor oral bioavailability and insufficient drug loading for parenteral dosage forms, which cause issues in generating enough drug plasma concentration that is required for drug toxicity and efficacy evaluation in preclinical and clinical studies.

 What formulation approaches are employed to overcome solubility/bioavailability challenges?

 Using our practice and experience at Ascendia Pharma as an example, typical approaches for solubility and bioavailability enhancement includes salt formation, micronation, solution, micelle, lipidic solution, complex formation; advanced technologies to address the challenge include nanoemulsion formulation, amorphous solid dispersion, and nanosuspension; new technologies, such as amorphous nanoparticles and lipid nanoparticles, have been proved useful for certain challenging compounds.

 A number of approaches can be explored based on the API’s inherent physicochemical nature. Some current approaches include micronization of API, nanoparticles of API (obtained via ball mill, cyromills, jet mill, and Nanoform’s Controlled Expansion of Supercritical Solutions [CESS] technology), cocrystals, complexes, prodrugs, solubilization (lipids, oils, surfactants, absorption enhancers, etc.), and amorphous solid dispersions (e.g., hot melt extrusion, high pressure dispersions [DisperSol], spray-dried dispersions, drug layering on substrate). However, many of these approaches require a larger design space and/or minimal exposure to process stress to ensure optimal solubility/absorption is achieved.

 Could you highlight some novel techniques and how such techniques or disruptive technologies, such as three-dimensional printing (3DP), can provide formulation advantages when approaching poorly soluble compounds?

 3DP can offer many advantages, such as rapid formulation prototypes, fast-to-clinic and to-market via expedited timelines for clinical supplies and commercialization, a reduced development time, improved stability due to less aggressive processing conditions (e.g., less heat, water activity, pressure, particle deformation), and dose flexibility. Additionally, the technology is inherently suitable for process condition monitoring and advanced process control; there is the option for flexible controlled drug delivery if it is required, and it is a mature technology that has been proven for commercial product good manufacturing practice (GMP) manufacturing. Further to these benefits, the technology can provide unique branding and commercial imagery possibilities and a unique and pleasant patient experience that aids with compliance. It can be used to create easy-to-administer and swallow products that allow patients to overcome dysphagia, and is suitable for use when formulating drugs for most patient age groups.

Essentially, 3DP can expediate formulation development, potentially allowing clinical supplies with minimal excipients or solid oral dosage forms with substantially higher API content, which can be a limitation of conventional tablets or capsules related to swallowable size limitations. To take advantage of these benefits, Aprecia is partnering with technology companies, including Glatt and Nanoform, to develop novel dosage forms that help to overcome many of the challenges associated with conventional manufacturing.

 Novel technologies such as 3DP may prove to be useful for orally disintegrating dosage forms for certain patient populations, who have difficulties with swallowing traditional oral solid dosage forms, as well as for drugs that need fast absorption and to bypass first pass [metabolism]. When evaluating a new technology, a tailored approach would be practical because every compound has unique properties, its own specific patient population, intellectual property strategy, dose amount, and manufacturing cost requirements, which may impact the selection of technology for use in dosage form development.

 Are there any limitations with the current availability of excipients that might hinder formulation of poorly soluble compounds? Might the new pilot program for novel excipients drive innovation?

 New excipients that improve solubility and bioavailability are certainly very welcome for use in dosage form development. However, expensive long-term pharmacology and toxic effects of novel excipients have to be evaluated using animal models before FDA can approve them for use in humans, which could be a barrier to exploration of novel excipients for use in drug development.

 A broad range of excipients used in approved products are available that provide broad functionality to support novel approaches for solubility and bioavailability enhancement. This approach can potentially provide intellectual property advantages. In general, and in the interest of time to market, complexity, and cost, the preference is to use materials already approved for pharmaceutical use within the maximum amounts established by the FDA. Novel pharmaceutical-grade excipients can be utilized when necessary but require additional testing to meet FDA regulatory requirements.

 What does the future hold for formulators in terms of poor solubility and bioavailability?

 The future is here! Up to 90% of new compounds for formulation and process development require solubility/bioavailability enhancement. In addition, over half of new compounds are eligible for accelerated registration pathways. New technology platforms provide opportunities for efficient and effective formulation and process development to move compounds quickly through Phase Ia and Ib so ‘go/no-go’ decisions can be made quickly. With earlier decisions, resources for failing candidates can be quickly redeployed to other programs.

Enabling Phase Ia and Ib product development programs to be robust enough to move quickly into Phase II, Phase III, and commercial without reformulation or redesign of the manufacturing process is a key driver for technology innovation. In addition, continuous processing provides a further opportunity for eliminating the risks and costs associated with scale-up and technology transfer of conventional batch processes.

 For most of the compounds in development, traditional technologies in combination with nano-based technology should be able to address solubility and bioavailability issues. New technologies and processes, such as amorphous nanoparticles, are worth exploring for certain types of compounds.


Vol. 46, No. 1
January 2022
Pages: 26–27

When referring to this article, please cite it as F. Thomas, “Tackling the Big Issue of Solubility,” 

Poor solubility remains a big issue for drug development and, as such, is driving innovation in approaches and use of novel technologies to help overcome the associated challenges.