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

Felicity Thomas

In November 2020, the European Commission (EC) published its 

, which comprises four main objectives: affordable medicines access; support of the European Union’s pharma industry’s competitiveness, innovation, and sustainability; boosting crisis preparedness and response; and strengthening the EU’s global position in pharma. Additionally, as part of its broader strategy, the EC published its roadmap for revising pharmaceutical legislation in March 2021. Here, experts will discuss the strategy in greater detail and will also touch upon the potential for regulatory alignment between the European Union and United Kingdom post-Brexit.

Pharmaceutical Technology’s Regulatory Sourcebook eBook

Pharmaceutical Technology’s September 2021 Regulatory Sourcebook eBook

When referring to this article, please cite it as F. Thomas, “Mapping Out Pharma’s Future,” 

Pharmaceutical Technology’s Regulatory Sourcebook

Articles

There are expectations that changes to pharma regulations in the EU, forming part of the regions broader strategy for the industry, will be positive and should offer flexibility for industry to advance through innovation.

Mapping Out Pharma’s Regulatory Future in Europe

The SARS-CoV-2 outbreak, which started late in 2019, has demonstrated how devastating novel infections can be for the global population. In response to the infectious threat posed by the novel coronavirus, the pharmaceutical industry rallied and managed to develop effective parenteral vaccines in record breaking speeds. However, the COVID-19 pandemic has also brought to the fore the development and distribution challenges associated with mass vaccination programs as well as difficulties ensuring equitable access to vaccines—a particular challenge for low-income countries.

Mucosal pathogens, such as SARS-CoV-2, are a major cause of infectious diseases across the world, and the mucosal route of vaccination has been of interest for some time, primarily due to the induction of immune response that is achievable with this form of delivery (1).

Although there are numerous avenues available for mucosal vaccination, the most commonly employed routes are via the mouth and nose. However, the number of licensed mucosal vaccine formulations is limited, and the available formulations tend to use attenuated strains of pathogenic bacteria or viruses, which carry specific risks such as reactogenicity and post-vaccination reversion of the pathogen to a virulent form (1).

Nevertheless, mucosal vaccines provide a strong immune response in patients, both in mucosal sites and systemic circulation (2). Additionally, these types of vaccines also offer cost and administration benefits over the traditional injectable forms (2).

Nasally administered vaccines are widely accepted and easily accessible, and have reportedly achieved a better systemic bioavailability and protection from gastric enzymes when compared with orally or parenterally administered vaccines (3). Yet, there are multiple hurdles that can hamper development of nasal vaccines.

Challenges to the formulation of nasal vaccines include, but are not limited to, the size of the dose required, limited efficacy of the vaccine due to mucociliary clearance, the necessity for adjuvants to enhance immunogenicity, restricted delivery volume in the nasal cavity, and normal human defense mechanisms (3). According to expert opinion, the incorporation of effective adjuvants that can trigger both mucosal and systemic immune responses are necessary for noninvasive vaccine delivery, and a more extensive understanding of mucosal immunity is required (4).

Currently, the commercially available intranasal vaccines are FluMist/Fluenz Tetra (AstraZeneca) and Nasovac (Serum Institute of India), which are both liquid, live-attenuated vaccines for influenza administered via a nasal spray (5). Other formulations for nasal vaccines include solutions administered via drops, powders, gels, and solid inserts, although there are no other nasally administered vaccines approved for marketing authorization globally.

Spraying a solution into the nasal cavity is simple for administration purposes; however, some of the formulation may leak from the nasal cavity or into the oral cavity, which would reduce potential therapeutic effect and dose. To overcome these potential issues, it has been suggested by some experts that gelling agents, such as polymers, included in the formulation could increase the residence time of the vaccine in the nasal passage (5).

Solid formats for nasal vaccines can offer the advantage of being more stable than liquid formulations but may have disadvantages in terms of cost and ease of administration due to the potential requirement of specialist applicators. Additionally, there has been interest in the development of particulate carrier systems, such as liposomes, for vaccine products (5). To achieve success, however, vaccine formulations that are designed for intranasal administration must maintain the antigen stability, provide sufficient residence time in the nasal mucosa, and should be compatible with other components, such as adjuvants (6).

For COVID-19, it has been specified that the intranasal route of administration for a vaccine is promising due to the fact that the normal route of infection for the SARS-CoV-2 virus is also via the nose (6). Furthermore, it is widely reported that vaccines administered intramuscularly are less likely to provide immunity protection in the upper respiratory tract—the area of primary attack from SARS-CoV-2.

At the time of writing, the World Health Organization (WHO) has reported that there are 112 vaccines in clinical development and 184 in pre-clinical development for COVID-19 (7). Of those candidates in clinical phase, only eight vaccines are formulated for intranasal administration (7).

The furthest along the clinical lifecycle, according to WHO, are a viral vector (replicating) vaccine being developed by the University of Hong Kong, Xiamen University, and Beijing Wantai Biological Pharmacy, and a protein subunit vaccine being developed by the Center for Genetic Engineering and Biotechnology (7). Another potential intranasal candidate from Altimmune is no longer in development as a result of inadequate immune response in healthy volunteers (8).

Of the vaccines that currently have authorization from regulatory bodies to treat COVID-19, only one is in clinical development as an intranasal formulation (7). The University of Oxford announced the launch of a study investigating the efficacy of nasal administration of the ChAdOx1 nCoV-19 vaccine, which was originally co-developed for intramuscular administration with AstraZeneca, earlier in 2021 (9). The trial will assess the efficacy and immune response of either one dose or two doses of the intranasal vaccine in healthy participants and is expected to take four months (10).

Regarding the other potential intranasal COVID-19 vaccines in clinical development: two are live attenuated virus vaccines—COVI-VAC from Codagenix and Serum Institute of India, and MV-014-212 from Meissa Vaccines; two are non-replicating viral vector vaccines—BBV154 from Bharat Biotech International and PIV5-vectored vaccine from CyanVac; and one is an inactivated virus for intramuscular or intranasal administration from Laboratorio Avi-Mex. There is an additional protein subunit vaccine listed in WHO’s COVID‑19 vaccine candidate tracker, which is administered intramuscularly for the first two doses and then intranasally for a third dose, from Razi Vaccine and Serum Research Institute (7).

Another potential intranasal candidate that is currently in the pre-clinical stage is a vaccine that uses a common poultry virus, the Newcastle Disease Virus, to produce spike proteins of SARS-CoV-2 (11). The collaborative effort from the University of Lancaster (United Kingdom) and the Texas Biomedical Research Institute has garnered positive results with reductions in both disease impact and transmission in animals (12).

Rokote Laboratories Finland—an academic spin-out company from the University of Eastern Finland and the University of Helsinki—has secured funding that will help it push forward with clinical development of its intranasal COVID-19 vaccine candidate, FINCoVac (13). The vaccine is based on gene transfer technology that has proven successful in other fields.

A further intranasal candidate is in development by Dutch company Intravacc (14). The SARS-CoV-2 Outer Membrane Vesicle based recombinant spike protein candidate has delivered positive pre-clinical results in mice and hamsters, and the company hopes to move forward to in-human trials quickly. And, researchers from TheraVectys—a spin-out from Institut Pasteur—have been developing a lentiviral vector vaccine candidate, which it reports would represent “a second generation vaccine that could generate a durable cellular response against the original SARS-CoV-2 strain, existing, and future variants” (15).

, 196 (2) 205–214 (2019).
2. R. Mudgal, S. Nehul, and S. Tomar, 

, 16 (12) 2921–2931 (2020).
3. M. Ramvikas, et al., “Nasal Vaccine Delivery” in 

Micro and Nanotechnology in Vaccine Development

, M. Skwarczynski and I. Toth, Eds., pp. 279–301 (Elsevier, Amsterdam, The Netherlands, 1st ed., 2016).
4. M. Skwarczynski and I. Toth, 

., 17 (4) 435–547 (2020).
5. H. Yusuf and V. Kett, 

., 13 (1) 24–45 (2017).
6. V.P. Chavda, et al., 

, In Press, Corrected Proof, doi.org/10.1016/j.drudis.2021.07.021 (July 29, 2021).
7. WHO, COVID-19—Landscape of Novel Coronavirus Candidate Vaccine Development Worldwide [Accessed Aug. 24, 2021].
8. Altimmune, “Altimmune Announces Update on AdCOVID Phase I Clinical Trial,” Press Release, June 29, 2021.
9. University of Oxford, “University of Oxford to Study Nasal Administration of COVID-19 Vaccine,” Press Release, March 25, 2021.
10. The Jenner Institute, “COVID-19 Vaccine Intranasal Study (COV008),” Trial Information, 

 [Accessed Aug. 24, 2021].
11. Lancaster University, “Lancaster University Intranasal Vaccine Offers Promise to Block COVID-19 Where it Starts,” Press Release, Aug. 10, 2021.
12. J.-G. Park, et al., 

, 24 (9) 102941 (2021).
13. University of Eastern Finland, “Finnish Coronavirus Vaccine Developer Rokote Laboratories Finland Secures Significant Funding,” Press Release, July 7, 2021.
14. Intravacc, “Intravacc Announces Positive Pre-Clinical Data for its SARS-CoV-2 Nose Spray Vaccine,” Press Release, April 7, 2021.
15. TheraVectys, “Lenti-Covid: Robust Answer Addressing Long-Term Immunity and Emerging Variants,” Press Release, May 30, 2021.

Felicity Thomas is the European editor for Pharmaceutical Technology Group.


Vol. 45, No. 9
September 2021
Pages: 26–28

When referring to this article, please cite it as F. Thomas, “Getting a Nose for Vaccines,” 

The intranasal route of administration is showing clinical promise, particularly for COVID-19, but there are multiple hurdles to overcome to ensure successful formulation.

Getting a Nose for Vaccines

Research investment in the global biopharmaceutical market helps to drive innovation and development of novel therapeutic products to treat many diseases and illnesses. According to recent figures highlighted by the International Federation of Pharmaceutical Manufacturers and Associations, there are currently more than 8000 compounds in development around the world (1).

“A recent market report has shown that there was an influx of new products in the pipeline at all stages of clinical development during the 2020/2021 period (2), especially of early-stage clinical products,” notes William Chin, manager, global scientific affairs, Catalent, citing recent research studies. “Moreover, cancer, infectious diseases, and diseases of the central nervous system came up as the top areas of clinical trial activity last year. The number of people suffering from these chronic conditions is expected to rise as population growth is anticipated in many developing countries (3). The development of complex dosage forms is also expected to grow in parallel to increased diversity in the drug pipeline.”

Over the past five to 10 years, the low water solubility of new molecular entities (NMEs) has been a major drug product development challenge, emphasizes Julien Lamps, product manager, Lonza Capsules and Health Ingredients. “Knowing the solubility performance attributes for the compound is important as it will aid selecting the right dosage technology,” he says.

“There have been numerous developments and innovations in drug delivery over the last few years to overcome challenges with products and formulations, such as biologics and complex entities like larger molecules,” adds Jnanadeva Bhat, head—formulation R&D (Pharma and Nutra), ACG Group. “Other trends that have evolved are prefilled syringes, wearable injectors, and needleless syringes, each of which have a niche market.”

Considering the route of delivery, Chin states that injectable dosage forms are dominant in the development pipeline. “The intravenous route [is] seen to offer more advantages in early-stage studies as a means to quickly deliver the desired concentration of drug to the target via systemic circulation, and to achieve the required pharmacological response,” he confirms. “However, simply having injectables may no longer be sufficient anymore because of the growing demand for more patient-friendly formats, such as oral solid dosage (OSD) forms.”

Bhat concurs that even though the sector for specialty products has witnessed growth, OSD forms have remained steady throughout the past decade. “There is demand for continuous innovation to improve efficacy, efficiency, and competence in [oral solid] dosage forms,” he says. “Developing novel and more efficient oral delivery routes also helps brands reach a larger audience. Thus, development scientists prioritize OSD forms because not only are they key to patient compliance, but they also have broad application.”

The growing demand for OSD forms has driven innovators to focus on patient-centricity early on in development, Chin continues. “This [trend] is especially true in the past year, where there has been an expectation to increase both the convenience of use and the therapeutic efficacy of the drug product, as well as ease of deployment without the need for cold-chain considerations, especially given the current focus on oral COVID-19 vaccine development,” he states.

“In biologics and small molecules, the trend shifted towards patient centricity,” adds Tatiana Nanda, director and program leader, The Center for Breakthrough Medicines. “Historically, the sole focus for drug product development was effective treatment of the disease while now additional emphasis is put on patients experience and quality of life during treatment.”

“As innovators are focusing more on solutions that allow them to develop patient-centric drug products, the priorities of drug development are expected to not only demonstrate clinical efficacy and safety in patients, but also to address key challenges such as improving usability, bioavailability, stability, and palatability, while eliminating any variability due to food effects,” confirms Chin. As a result of this shift in priorities, advanced dosage forms, such as modified-release products, multiparticulates, ODTs, or new fixed-dose combinations, are increasingly in demand, he adds.

Dosage form priorities have certainly been adjusted, Lamps specifies, with the deployment of common strategies and platforms that help to enhance drug oral bioavailability, such as cosolvents, salts, surfactants, particle size reductions, polymorphs, lipid-based systems, amorphous solid dispersions, and so on. “Additionally, it is becoming a best practice to evaluate the end dosage form earlier in the development cycle,” he adds.

“Drug product design is more focused on meeting patient-centric target profiles and has become the goal for drug companies,” agrees Nanda. “Previously drug product profiles were a derivative of what upstream/downstream capabilities allowed. Now the selected profile and dosage form drive the required API process, needed concentration, and purity.”

The priorities of pharmaceutical companies have shifted as a result of the drive toward patient centricity, Bhat concurs, with manufacturers seeking the most patient-friendly form that supports maximum therapeutic efficacy and safety of the formulation. “Regulatory bodies also encourage patient-centric dosage forms, which fuels this new focus,” he says.

Additionally, the change of priorities for development have led to the integration of patient-centric design early on in the development cycle, Bhat continues. “The physicochemical properties of an API usually point the formulator to the most suitable route of administration, as well as dosage form. The solubility of APIs specifies approaches for dose selection, excipient selection, and stability of the final product,” he says. “Bigger challenges are observed for larger molecule oral absorption, which need to be addressed adequately by formulation scientist.”

Discussions between innovators and contract development and manufacturing organizations (CDMOs) on dosage form design are taking place relatively early on now, Chin states. Furthermore, manufacturability of the dosage form is being addressed earlier on by innovators, which is an aspect that has received less attention historically speaking, he notes. “Innovators have recognized that a druggable molecule alone does not automatically imply successful commercialization of a pharmaceutical drug product, but that there is also a need at an early stage to establish all other key considerations that will meet the target product profile covering patient and manufacturing requirements,” Chin says.

Taking patient opinions and assessments of dosage forms into consideration during design and development can also help to create user-friendly products, Bhat highlights. As patient-centricity is becoming more prominent, so too are tailored dosage forms, which directs the industry away from a one-size-fits-all approach in terms of dosage forms, he explains. “With this trend, dosage forms will perform more effectively for individuals, and this is shifting pharma R&D towards new pathways,” Bhat says.

For Bhat, some of the most important innovations in drug dosage forms have been seen in the area of inhalation. “Local inhalation administration delivers sufficient levels of drug to the target organ, the lungs, while minimizing systemic exposure and side effects (primarily due to the reduced drug dose needed as compared to oral administration),” he says.

“Additionally, there is mounting interest in inhalation segment, where conventional molecules are converted into inhalation formulations,” Bhat continues. “In this area, dry powder inhalation formulations via hard capsules is a trend formulators and manufacturers are showing great interest in. Capsules are not only robust and easy to use, but also help with effective delivery through the inhalation devices.”

Capsule-based dry powder inhalation (cDPI) formulations offer an affordable option that incorporate characteristics—such as reduced dosing frequency and side effects—and easy administration, which are preferable for patients, Bhat asserts. “The most impressive developments taking place in this field go beyond conventional respiratory therapeutic segments,” he says. “Many leaders are exploring cDPI for other therapeutic segments like Parkinson’s disease, migraine, tuberculosis, cystic fibrosis, and lung infection.”

Techniques, such as particle size reduction, spray-dried dispersions, and lipid-based formulation platforms, have helped overcome solubility-related issues, Lamps states. Additionally, as the techniques are complementary, they are applicable to a broad compound space, he says.

For large molecules, being able to reach high protein concentration and co-formulating with dispersion enhancers, such as hyaluronidase, has been a significant advancement, reveals Nanda. “[This innovation] allowed delivery of a high volume—up to 20 mL—of drug product as a single injection into subcutaneous space,” she stresses.

However, it is also important to consider innovation from the perspective of manufacturing, rather than just on new technologies that are centered on the discovery and development path, Chin emphasizes. “For example, one of our core expertises is in manufacturing softgel dosage forms for both immediate- and modified-release applications. The typical development option for a modified-release softgel is through the formulation of the fill content followed by the coating of the capsules,” he says. By using a proprietary modified-release softgel capsule, which combines pectin and gelatin, a separate capsule coating step can be avoided, Chin adds.

“The capsule technology allows innovators to design the delayed-release profile to be incorporated directly into the softgel capsule shell, thereby making a separate capsule coating step unnecessary,” Chin continues. “This [innovation] reduces manufacturing time and yield loss and eliminates potential quality issues associated with coated softgels.”

“An important driver that could steer the dosage form market is the increasing demand for solutions that could overcome cold supply chain bottleneck constraints, especially given the current focus on vaccine development for COVID-19, as most vaccines are available as solution for injection that require ultra-cold chain storage,” Chin asserts. “A lot of effort and investment will be made to develop an alternative dosage form that could effectively deliver such biomolecules via the oral route. If this alternate dosage form could not only overcome enzymatic and permeability barriers, but also ensure stability and biological activity without the need for ultra-cold storage solutions, this could be expected to positively impact the global pipeline in the coming years.”

A rising demand for tailored or customized formulations and precision medicine will greatly impact drug dosage form development in the near future, according to Bhat. “The increased focus on patient centricity will certainly lead the development pipelines away from a generalized approach to more individualized treatments,” he stresses. “[This shift] will also allow for the creation of more innovations in combination delivery to achieve better dose compliance by minimizing the number of medicines that need to be taken separately.”

For example, combining dosage forms in one hard capsule is a possible option, Bhat adds. “Pellet technology, or minitablets, are a great example of converting conventional technology into personalized solid oral dosage form,” he says. “Minitablets can be filled in capsules as it is relatively easy to blend them together to attain combinations of multiple drugs in accurate doses and with different release profiles, if required. This solution is customized and user-friendly as it will reduce the dose regime.”

In Lamps’ opinion, lipid-based formulations will continue to impact dosage form developments in the future by addressing the solubilization challenge. “As [the technology] maintains solubilization during the dispersion/digestion step in the gastrointestinal lumen, it’s favoring efficient diffusion through the mucus layer to reach the intestinal epithelium,” he explains.

Additionally, amorphous solid dispersions (ASDs), which dissolve rapidly to higher concentration than crystalline forms and maintain supersaturation in the intestine, promoting drug absorption, will impact dosage forms in the future, Lamps continues. “[ASDs] broad applicability, flexibility, and quenching rates makes them amenable for high-dose compounds,” he says.

A high priority effort for many drug developers is the creation of an appropriate dosage form for cell and gene therapies (CGT), Nanda specifies. “Formulation and manufacture of CGT drug products represents specific challenges not encountered by small molecules and biologics,” she says. “Early-phase clinical trials for advanced therapies are rather complex and include wide dose ranges. It becomes extremely important to introduce a proper, robust formulation for CGT therapies early on, to be able to accommodate an intended route of administration, indication, and dose level.”

Although CGTs are still only administered in a clinical setting, the requirement for an optimal dosage form is just as critical as it is for therapies (large and small molecule) that are administered at home, Nanda emphasizes. “Both healthcare professionals and patients greatly appreciate using a therapy that allows a streamlined and simple administration, reduces the number of doses, or does not require specialized surgical instrumentation for delivery,” she says. “CGTs will require significant development in the container closures most suitable for efficient storage and shipment and convenient withdrawal for administration. Continued innovation of novel devices and adaption of existing platforms will also help enable advanced (tissue specific) therapy delivery.”

1. IFPMA, “The Pharmaceutical Industry and Global Health: Facts and Figures 2021,” 

 (April 2021).
2. K. Sedo, “2020 Global Drug Delivery & Formulation Report: Part 4, The Drug Delivery and Formulation Pipe-line,” 

 (June 2021).
3. PricewaterhouseCoopers, “Chronic Diseases and Conditions Are On the Rise,” 


Vol. 45, No. 8
August 2021
Pages: 16–20

When referring to this article, please cite it as F. Thomas, “Putting the Patient at the Heart of Dosage Design,” 

Dosage form priorities are shifting to focus on user-friendliness, leading to greater engagement with outsourcing partners earlier in development timelines.

Putting the Patient at the Heart of Dosage Form Design

The formulation development outsourcing market is expected to grow at a compound annual rate of 7.2% between 2021 and 2026 (1). Major factors driving growth in this sector are expected to be increasing innovation of novel drugs due to patent expirations, a focus on developing poorly water-soluble compounds that require bioavailability enhancement, and overcoming the risks associated with development (1).

To learn more about the industry trends, common requests, biggest challenges, and benefits of outsourced formulation services, 

 spoke with a panel of experts. The panel includes Sabine Hauck, senior vice-president of Corporate Development, Leukocare; Alexander Faude, director Process Science, Downstream Processing, and Marvin Kadisch, director Process Science, Upstream Processing, both at Rentschler Biopharma; and Stefan Heindl, business development manager, Coriolis Pharma.

 Could you provide some insight into industry trends that have been impacting the formulation development outsourcing market in recent years?

 Formulation development has gained momentum in recent years. Beyond the stabilization of the drug substance by molecular design, formulation development is a key opportunity in the process of drug product development that offers potential to generate further commercial value. To accommodate this trend, continuous expansion of formulation expertise is recommended so that client requirements for viral vector stabilization, vaccines and advanced therapy medicinal products (ATMPs), higher drug substance concentration, longer storage time at higher temperature, or creation of new intellectual property can be met. For example, Leukocare has successfully managed the development of targeted formulations by applying its database and algorithm-based formulation development approach.

Formulation development itself has developed rapidly, making use of highly sophisticated analytical methods and bioinformatics. This trend supports outsourcing formulation development to a specialized provider, such as Leukocare, that excels with high-end scientific expertise, an analytical toolbox, and bioinformatics excellence. Especially for smaller companies, using an outsourcing partner allows access to best-in-class formulation development.

 The value and benefits of early formulation development have increasingly gained recognition and acceptance across the industry. Hence, companies are looking closely at all aspects of biopharmaceutical production, from start to finish, to identify opportunities for timeline optimization. As a result, it has been the experience of Rentschler Biopharma that the trend of collaborating with external experts in formulation development is picking up.

 Coriolis began specializing in formulation development in 2008 when formulation was often not the highest priority during drug product development. This has changed and the formulation development outsourcing market has been in a sustainable growth phase for several years now. Daily work at Coriolis has demonstrated a clear trend towards more complex products, for example, highly concentrated liquid formulations (HCLFs) with protein concentrations of up to 300 mg/mL or higher, or novel protein formats that require dedicated scientifically driven formulation strategies, rather than standard platform approaches. Also, requests regarding vaccine development, particularly in the context of the ongoing coronavirus pandemic have increased in the past two years; nucleic acid-based therapeutics gain more and more importance. However, the most important trend in my view is the increase in ATMPs, such as viral-vectors, oncolytic viruses, and other genetically modified organisms, that are entering the scene. Many of these products require new and innovative formulation approaches, analytical strategies, as well as special facilities.

 What type of formulation work is more commonly outsourced and has the type of project changed over the years?

 Formulation development services are requested across all stages of development, from early-stage pre-formulation work to late-stage reformulation projects, in-use studies, or trouble-shooting activities. Two different trends have been seen at Coriolis. One trend is an increasing demand for the outsourcing of complete packages, including pre-clinical tox manufacturing and good manufacturing practice (GMP) manufacturing (e.g., for first clinical phases of the developed formulation). To meet this demand, it is important to expand the service portfolio, for example, by expanding tox-batch manufacturing capabilities for liquid and lyophilized formulations. Moreover, it is necessary to seek out and maintain partnerships with other established players in the field to cover GMP manufacturing. These close partnership networks allow for comprehensive outsourcing packages to be offered while keeping the number of interfaces for the client low. The second one is outsourcing of highly challenging and individual formulation tasks that require a scientific background and a very specialized formulation approach. For this trend, it is important that the service provider has the required track record, experience, and scientific background for the task.

 All kinds of formulation development are outsourced, depending on the needs of the sponsors. Early pre-formulation development supports stability already in tox studies and allows de-risking success of a clinical candidate due to stability issues. Fully fledged formulation development is outsourced in all stages of clinical development, depending on the clinical development strategy. Even if the asset is planned for out-licensing after clinical stage, a well-designed formulation will increase the value of the drug product package. In general, time has become more critical over the years, while quality requirements are still increasing. That´s why it is key to outsource formulation development to an expert contract development and manufacturing organization (CDMO) developing high-quality formulations in an accelerated period.

 What are the biggest challenges for outsourcing partners when approaching/working on a formulation project with a sponsor company?

Faude (Rentschler Biopharma): When collaborating with a sponsor company, the success of early formulation development depends heavily on material that has been generated via ‘preliminary’ processes. These processes are themselves undergoing development and optimization. Hence, they are bound to change right until first current GMP production for clinical development. Moreover, the process may undergo further improvement or adaptations for market approval. Therein lies a challenge for the outsourcing partner but also great benefit for the sponsor company’s product. This is because these adaptations can be sequentially incorporated into formulation development to further maximize product potential.

 The role of the outsourcing partner as an expert consultant for the sponsor company is also very crucial. It is essential that the outsourcing partner sees the project as an extension of their own operations and advises the client from this point of view. Aspects such as which formulation best suits the molecule in question, subsequent implementation and regular project status updates are central to a successful collaboration.

 Well, every client is different, and each molecule of interest and target product profile require a dedicated strategy. A common aspect is that the timeline is always key. While in early stages, drug substance availability is often a challenge, though mostly manageable, real challenges arise when formulation development is squeezed in between other development activities such as drug substance development and drug product manufacturing. Depending on the drug substance and client, knowledge about the stability profile of the API can be very scarce. Due to all these reasons, an understanding of the specific requirements of each client, a smart, scientifically-sound study design with built-in flexibility and a clear expectation management is important.

 Formulation development is always linked to other aspects of product development, such as process development for upstream processing and downstream processing, pharmaceutical development or fill/finish, logistics, and product administration. It is important to consider interactions and interdependencies.

 How do outsourcing partners overcome these challenges?

 At Coriolis, for example, a lot of investment is made into the upfront discussions with the client to understand the particular needs for the project. In combination with our experience as a formulation specialist, these discussions provide the basis for a tailored and scientifically-sound proposal considering all specific requirements of the client. During an ongoing project, open and transparent discussions on a regular basis (e.g., in weekly or biweekly meetings) help to align development efforts and allow for quick reactions to scope changes or unforeseen issues. Especially during early-stage projects, a high degree of flexibility is often needed, requiring a specific skill set of the team working on the projects to quickly provide a stable formulation backed-up by a suitable analytical toolbox and stability data.

 A very helpful solution to tackle these challenges are access to a large database, as well as experience with different classes of molecules. This includes tools like in-silico modeling and more targeted wet-lab trials. This can significantly accelerate the development of suitable formulations for the sponsor company’s product.

 Requests for faster formulation development should be met with innovative strategies; extending the analytical toolbox can help to save time and material. Moreover, automation in formulation and analytical technology supports parallelization and thus supports higher turn-over. Making use of bioinformatic expertise leads to timesaving as well as quality improvement for projects.

 To overcome these challenges a review of the ‘fit of the formulation to the product’ can be continuously addressed during preclinical and clinical product development. This allows one to quickly identify ‘constellations of fitness’ that can then be focused on to further optimize both formulation and the end product.

 What are the key benefits for outsourcing formulation development?

 Based on the experiences of projects undertaken by Rentschler Biopharma, it is believed that the seamless integration of formulation development into the entire product life cycle and timelines harbors two key benefits: it allows for exceptionally efficient product optimization and ensures that project delays are avoided. Furthermore, the consultation provided by the outsourcing partner is key in defining the best-fit for both client and product.

 Outsourcing partners, such as Rentschler Biopharma, have holistic offerings where the entire process and formulation development is offered in an optimally integrated form. In this manner, clients can greatly benefit from the experience and expertise of the outsourcing partner for an ‘improved’ product within optimal timeframes.

 Essentially, it enables companies to gain access to best-in-class formulation development. For smaller companies with few products, an external formulation development team can be used just for the short period of time needed and avoids the efforts required of recruitment and training. Typically, it is much easier for an outsourcing partner to answer short notice demand on higher required effort. Formulation development can be performed whenever it suits best.

 In the context of the increasing complexity mentioned before, the outsourcing of such projects to specialized and experienced service providers can significantly improve development times and the probability of success. Outsourcing to service providers offering all required analytical capabilities in-house also expedites development as shipment between third-party labs and time-consuming data consolidation can be avoided. Finally, following a first-time right approach with a specialized formulation partner in the long run also saves money, and includes the possibility to generate and protect intellectual property in a collaborative and transparent approach.

The outsourcing of formulation development activities should be seen less like a one-way service and more like a collaboration between two partners. If both parties work together collaboratively and maintain an open and transparent communication, a positive project outcome is almost guaranteed.

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


Vol. 45, No. 8
August 2021
Pages: 52–56

When referring to this article, please cite it as F. Thomas, “Developing the Best Formulation Partnership,” 

Collaborative partnerships can foster success in formulation development projects.

Developing the Best Formulation Partnership 

In 2015, a global framework was set up to ensure dangerous climate change was avoided through efforts to limit global warming. The Paris Agreement is aimed at achieving climate-neutrality before the end of the century and is a universal, legally binding global agreement (1).

International governments and parties, such as the European Union and its member states, involved in the Paris Agreement have agreed to work on emissions reductions to meet the ultimate goal of the agreement. Additionally, countries have submitted national climate action plans in contribution to the objectives of the agreement. The EU’s most up-to-date and enhanced national determined contribution was published in December 2020 and specified a target to reduce emissions by at least 55% by 2030 compared to the levels in 1990 (2).

The environmental performance of the chemical industry, which includes pharmaceuticals, of the EU and its member states, that is to say, the reduction in greenhouse gas (GHG) emissions, has improved since 1990, according to the European Chemical Industry Council (Cefic) (3). However, there is still much work to do in order to meet the goal of the Paris Agreement.

A new association, Alliance to Zero, was formed earlier this year (2021) by eight companies representing the pharmaceutical supply chain, with the specific purpose of aiding the pharma sector with compliance to net zero GHG emissions (4). To learn more about this non-profit organization, 

 spoke with Sebastian Gerner, president, Alliance to Zero.

 Could you please provide a brief introduction to the Alliance to Zero association?

 Alliance to Zero is a non-profit membership association for pharma and biotech supply chain companies that aims to facilitate the transition of the pharma sector to compliance with net-zero GHG emissions. As a working group with commonly shared goals, we will engage in collaboration with academia and non-profit organizations as well as sponsors projects. We will involve, connect, and coordinate suppliers, pharmaceutical companies, manufacturers, and service providers along the supply chain of pharma products. While the alliance is registered in Switzerland, the reach and intention of this membership association is global, and each of our founding companies have operations and facilities across the globe.

 Why is it important for members of the pharmaceutical industry to participate in associations, such as Alliance to Zero?

 Climate change is a global challenge that affects all of us. The Alliance to Zero is committed to developing a common standard for GHG emission reduction methodology within the pharmaceutical supply chain. The overarching goal is to collaboratively shape a net-zero emissions product offering, which is certified by a third party. This can only be reached with a powerful working group of individual suppliers co-developing net-zero standards and implementing them within the value chain.

 What sort of work is already underway by the founding members of the association?

 The alliance was founded on 1 June 2021 and is currently establishing working groups to progress on a net zero emission concept for pharmaceutical manufacturing and supply chain products. This foundational work also includes agreements on harmonized language and principles for the assessment and control of the total emissions footprint for the final pharmaceutical products, as well as the company-specific responsibilities.

 How will the work progress? Could you provide a roadmap of what progress is expected to be achieved and the timeframe in which it will be done?

 The alliance targets the commercial launch of net-zero pharmaceutical products in regulated markets by no later than 2030. To reach this date, the alliance founding members commit to developing a collaborative net-zero offering by 2026 to leave time for the pharmaceutical companies to finalize the overall product based on this offering.

Each alliance member has begun programmes to realize substantial GHG emission reduction that relates to their business responsibility and area of influence. The alliance is supporting those programmes via best-practice exchange and providing guidance and inputs on emission reduction or circular economy principles.

 Will the work of the association be transferrable to other contributors/providers within the pharmaceutical sector?

 The alliance started off as a working group of motivated companies, which came together to initiate a change in the industry. The alliance targets are being established to develop standards for the pharmaceutical industry and share a common language. Based on this approach, other companies could profit from and contribute to it.

 Are there plans to expand the alliance in the future?

 Currently the alliance represents the majority of the value chain along pharmaceutical injectable products. Initially, the work is intended for a small group of highly committed companies to set up the basic directions and get things started. Nevertheless, the alliance will accept applications from a few companies with high motivation for active input which would enrich the value chain and fill potential gaps in the near future.

, accessed 26 July 2021.
2. EC and Germany, “Update of the NDC of the European Union and its Member States,” 

, 17 Dec. 2020.
3. Cefic, “2021 Facts and Figures of the European Chemical Industry: Environmental Performance,” 

, February 2021.
4. Alliance to Zero, “Alliance to Zero Founded to Achieve Net Zero Emissions Across the Pharmaceutical Supply Chain,” Press Release, 2 June 2021.


Vol. 33, No. 8
August 2021
Pages: 40–41

When referring to this article, please cite it as F. Thomas, “Working Towards Zero Emissions” 

Pharma and biotech supply chain companies are working together to help facilitate the transition of the pharma industry to net zero emissions compliance.

Working Towards Zero Emissions

Within Europe, drug pricing regulations are in place to ensure affordable access to drugs; however, these regulations do not mean that more expensive drugs are ‘off the table’ for patients or that pharma companies won’t ever increase prices of currently available medicines (1). External reference pricing is one way in which a European country can have an idea of the ‘reasonable’ cost of a drug. This policy allows governments to compare the price of a drug to that charged in other countries to gain a benchmark price.

In 2016, Pfizer and its distributor Flynn Pharma had a record fine imposed upon them for excessive price hikes to the United Kingdom’s National Health Service (NHS) for phenytoin capsules, which were priced much higher than in any other European country at the time, as determined by the UK’s Competition and Markets Authority (CMA). However, this decision was appealed, and in 2020, the Court of Appeal dismissed the attempts by the CMA to reinstate the fines (2).

In July 2021, however, several cases were raised against pharma companies regarding price hikes. Most recently, the CMA issued a fine of more than £100 million (€117 million/$139 million) to Advanz and its former private equity owners after an investigation demonstrated ‘excessive and unfair prices’ were being charged for liothyronine tablets (3). A little earlier in the month, the CMA had also imposed fines worth £260 million (€306 million/$361 million) on a number of drug companies for price increases on a steroid treatment by more than 10,000% (4). Additionally, the Dutch authority—Netherlands Authority for Consumers and Markets (ACM)—has issued a fine worth €19.5 million ($23 million) on the Italian pharmaceutical company Leadiant Biosciences for excessive pricing of a drug to treat cerebrotendinous xanthomatosis, which the company had raised by 1800% (5).

Whether or not these fines are appealed against or are upheld, it is apparent that authorities are closely examining pricing strategies and are sending a clear message to the industry that infringements of the Competition Act 1998 will not be tolerated.

WHO Guideline on Pharmaceutical Pricing Policies, Guideline

, 1 Jan. 2015.
2. Simmons and Simmons, “Appeal Court Dismisses CMA Attempt to Reimpose Fines on Pfizer/Flynn,” Insight Article, 10 March 2020.
3. BBC, “Drug Firm Fined for Huge Price Rise that Hit NHS,” Press Release, 29 July 2021.
4. K. Beioley, “Pharma Companies Fined After 10,000% Price Rise for Life‑Saving Drug,” 

, 15 July 2021.
5. B. Nijhof, “Dutch Competition Authority ACM Fines Pharmaceutical Manufacturer €19.5 Million Over Price Increases of More than 1800%,” 

When referring to this article, please cite it as F. Thomas, “Pricing Scrutiny Increases” 

Excessive drug pricing is being scrutinized across Europe, as hefty fines are set to send out a clear message of intolerance to anti-competition conduct.