Stakeholder input needed to achieve consensus on concomitant components.

Understanding Excipient Composition

Can shortened clinical trial timelines be sustained post-pandemic?

Putting the Pedal to the Metal

CDMOs tackle technology challenges technology to fill-finish COVID-19 vaccines.

Filling Vaccine Capacity and Process Demands

The technology awaits but challenges remain

Reshoring Pharmaceutical Manufacturing?

J&J rollouts out initial vaccine supply; Industry expedites vaccine production

Merck to Produce J&J Vaccine

on March 4, 2021 that its human medicines committee (CHMP) has begun a rolling review of the Sputnik V (Gam-COVID-Vac) COVID-19 vaccine. The review is based on results from laboratory and clinical trial studies that indicate the vaccine triggers the production of antibodies and immune cells. The rolling review will look at data as they become available and will continue until there is enough evidence to support a formal marketing authorization application. The usual standards for effectiveness, safety, and quality will be assessed by the agency for the vaccine, according to EMA.

Sputnik V (Gam-COVID-Vac) was developed by Russia’s Gamaleya National Centre of Epidemiology and Microbiology. EMA states that the vaccine is made up of Ad26 and Ad5 adenoviruses that “have been modified to contain the gene for making the SARS-CoV-2 spike protein; they cannot reproduce in the body and do not cause disease. The two adenoviruses are given separately: Ad26 is used in the first dose and Ad5 is used in the second to boost the vaccine’s effect.”

Articles

The European Medicines Agency has begun a rolling review based on laboratory and clinical studies of the Sputnik V (Gam-COVID-Vac).

Rolling Review of Sputnik V COVID-19 Vaccine Begins in Europe

on March 2, 2021 that, in collaboration with Health Canada, it has published the full clinical data set that was reviewed as part of the authorization of the Moderna COVID-19 vaccine. Publication of data is part of EMA’s efforts to be transparent in its authorization of COVID-19 vaccines.

“With the publication of the data package for Moderna’s COVID-19 vaccine, we are publishing the clinical reports that we assessed in support of the authorisation of this vaccine, and going forward, we will continue with this open data approach for all other COVID-19 vaccines,” said Emer Cooke, EMA’s executive director, in a press release. “EMA and Health Canada’s joint commitment to openness and transparency will support global research, allow for public scrutiny and reinforce society’s trust in COVID-19 vaccines as mass vaccination campaigns continue to be rolled out across the EU, Canada and the rest of the world.”

The published data are available on EMA’s clinical data website and Health Canada’s Public Release of Clinical Information portal. EMA stated that clinical data for the Pfizer-BioNTech vaccine will be published soon.

The European Medicines Agency and Health Canada have published clinical data used to support the authorization of Moderna’s COVID-19 vaccine.

Clinical Data on Moderna COVID-19 Vaccine Published

A united effort between federal agencies is underway to combat COVID-19 fraud that ranges from the sale of misbranded drugs claiming to treat COVID-19 to products claiming to prevent the virus. The situation is being monitored by FDA’s COVID-19 Fraudulent Products Task Force. Operation Quack Hack has resulted in hundreds of these products being removed from the marketplace, and FDA has sent more than 120 warning letters to various companies selling these fraudulent products. Fake vaccines have also been reported for sale.

“Consumers should know the COVID-19 vaccines that the FDA has authorized under Emergency Use Authorization cannot be sold online. Legitimate COVID-19 vaccines are being distributed for free. Unfortunately, the agency is aware of reports of unauthorized websites and listings on online marketplaces purportedly offering COVID-19 vaccines for sale. When such online listings are found by or reported to the FDA, the agency notifies the online marketplaces, who can then remove the listings. We are also aware of emails sent to consumers featuring the FDA logo, advising consumers to call a phone number to schedule a vaccination. If consumers are contacted directly by someone who says they are from the FDA about a COVID-19 vaccine appointment, it is a scam,” said Judy McMeekin, Pharm. D., associate commissioner for Regulatory Affairs, in an 

FDA is asking the public to help by being alert about COVID-19 fraud schemes. Resources to help consumers protect themselves from fraud can be found on the agency’s 

The agency is working to identify and obstruct scammers looking to profit from the pandemic.

FDA Protects Consumers Against COVID-19 Scams

Many COVID-19 treatments and vaccines use glass vials and stoppers as their container closure system (CCS), and supply of these components may become constrained, according to FDA. Because of this, manufacturers may need to update approved applications to make changes to CCS components. FDA, therefore, 

on March 4, 2021 providing recommendations for reporting and implementing changes to COVID-19 CCS components that consist of glass vials and stoppers for parenteral sterile drug products and biologics.

“In response to this public health emergency, FDA will consider risk-based approaches to facilitate implementation of chemistry, manufacturing, and controls (CMC) changes to a CCS in an effort to mitigate the disruptive effect of the COVID-19 pandemic. These measures may include, but may not be limited to, recommendations for adjustments to submission content and reduction in reporting categories for CMC changes,” the guidance states.

The guidance discusses regulatory approaches to CMC changes and common changes to glass vials and stoppers. The guidance also discusses risk-based tools for implementing CCS changes and comparability protocols.

The guidance document provides recommendations for reporting and implementing changes to container closure system components consisting of glass vials and stoppers for sterile drug products.

FDA Publishes Guidance on Changes to COVID-19 Container Closure Systems

Merck (known as MSD outside the United States and Canada) will receive up to $268 million from the Biomedical Advanced Research and Development Authority (BARDA), US Department of Health and Human Services, to adapt and make available some of the company’s manufacturing facilities for the production of COVID-19 vaccines and medicines.

On March 2, 2021, the company announced multiple agreements with BARDA and Janssen Pharmaceuticals, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson (J&J), to support the manufacturing and supply of J&J’s single-dose COVID-19 vaccine. Merck will produce drug substance, formulate, and fill vials of the vaccine at US facilities.

Biden Administration invoked the Defense Production Act

 to equip the Merck facilities for this “historic manufacturing partnership” of two pharmaceutical giants, a White House spokesperson said.

“We are steadfast in our commitment to contribute to the global response to the pandemic as part of the remarkable efforts of the entire medical and scientific community,” said Mike Nally, executive vice president, Human Health at Merck, in the press statement. “This funding from BARDA will allow us to accelerate our efforts to scale up our manufacturing capacity to enable timely delivery of much needed medicines and vaccines for the pandemic.”

“At Merck, we have a rich legacy in vaccine manufacturing and look forward to combining our expertise with Johnson & Johnson to help increase supply and expand access to authorized SARS-CoV-2/COVID-19 vaccines,” said Sanat Chattopadhyay, executive vice president and president, Merck Manufacturing Division, in the statement.

anssen COVID-19 vaccine received Emergency Use Authorization from FDA on Feb. 27, 2021 

and initial supplies of vaccines shipped on March 1, 2021.

Merck discontinued development of two COVID-19 vaccine candidates

, when studies showed the immune response was inferior to levels following natural infection. The company announced plans to focus research and production capabilities on two COVID-19 therapeutic candidates.

With funding from the federal government, Merck will expand capacity to produce J&J’s COVID-19 vaccine.

Merck to Manufacture J&J Vaccine

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

For a vaccine to be effective, the components of the disease of interest that provide protection from disease (an antigen) must be incorporated or present in the candidate and induce a strong and appropriate immune response in the vaccine. Viral vaccines specifically can be classified into ‘classic or traditional vaccines’ and include attenuated/killed virus. Recombinant vaccines include subunit, virus-like particle (VLP), conjugate, and viral-vectored vaccines. Genetic vaccines include messenger RNA (mRNA)/DNA. Alternatively, vaccines can be classified into live and non-live vaccines, which is important when considering safety profiles.

Traditional vaccines and viral subunit/proteins directly elicit an immune response without the need for cellular transcription and/or translation of genetic material. Genetic vaccines use part of the virus’ own genetic code (either mRNA or DNA) to instruct cells to make a viral antigen that will stimulate an immune response. Viral-vectored vaccines allow selection of a non-disease causing, and in some cases, a replication-deficient virus to be used to carry and deliver the antigen of interest to the vaccine and offer a mixture of advantages and disadvantages of live and non-live vaccines.

Traditional vaccines have a long track record of safety and efficacy. They have been shown, according to Charles Christy, head of commercial solutions for the Ibex Dedicate at Lonza, to effectively treat global diseases and eradicate disease burden, or even eliminate diseases (polio, smallpox).

The immune response is triggered immediately with this type of vaccination; however, the body also has to fight the full viral or antigen load, which may facilitate adverse effects (e.g., feeling under the weather following the flu vaccine), notes Thomas Becker, site quality director for Recipharm.

The potential exists for adverse effects because live viral vaccines are attenuated by genetic mutation of the wild-type, disease-causing virus, either by passaging the virus through cells, eggs, or animals or purposeful deletion of sections of the viral genome, explains Kelly Lyn Warfield, vice president of vaccines research and development within Emergent BioSolutions’ Vaccines Business Unit. “For selection and use of live, attenuated viral vaccines, caution must be applied due to potential safety issues in immunocompromised individuals (i.e., primary immunodeficiencies, patients on immunosuppressant treatment, HIV-infected people, and sometimes the very young or old), since this type of vaccine has the potential to replicate in an uncontrolled manner, spread to other individuals due to shedding of the vaccine, or revert to a virulent (disease-causing) form,” she says. “Care must be taken, therefore, to select a candidate that has an appropriately balanced replication profile to maintain an acceptable safety profile but that can also induce a potent immune response,” Warfield adds.

To modulate the immune response and to increase the duration of the immunization, Becker says that the entire vaccination program may have to be applied in several doses, which can be inconvenient for patients. Live viral vaccines may also be challenged with stability issues and require frozen temperatures to remain viable and potent.

Similarly, a viral vector-based vaccine can cause an immune response to the viral vector itself in addition to the antigen of interest for which it is delivering the nucleic acid, according to Gregory Bleck, vice president of research and development at Catalent Biologics. “This issue can make repeated dosing difficult, since with additional dosing, the patient’s immune system may clear the viral vector before it has an opportunity to insert the nucleic acid into a cell for antigen production,” he observes.

There are a multitude of approaches for non-live viral vaccines that can be based on whole, killed organisms; purified or recombinant proteins; VLPs; or genetic vaccines, notes Warfield. “In contrast to live vaccines,” she comments, “non-live vaccines pose no risk to immunocompromised individuals and cannot spread or potentially cause disease.” Development of purified or recombinant proteins, VLPs, and genetic vaccines, however, requires knowledge of the protective antigens, including their identities and possibly structures, to ensure proper and robust immune responses, she adds. In addition, some protein-, VLP-, and killed virus-based non-live vaccines require addition of an adjuvant to improve their immunogenicity due to their non-replicating nature.

Genetic vaccines are different because they contain only a small part of the virus’ genome and cause cells to produce the desired antigen(s). Typically, the RNA or DNA sequence that instructs the human cell to produce the viral antigen(s) intended to trigger an immune response is formulated in a lipid nanoparticle that can enter the human cell after vaccination, according to Becker. He adds that because the human cell produces the antigen itself in order to produce the immune response, a smaller dose of vaccinating agent is required for genetic vaccines when compared with traditional vaccines.

Some people consider viral-vector vaccines, in addition to those based on DNA and RNA, to also be genetic vaccines, because the genome fragment is embedded within a virus that usually cannot multiply itself in the human body, but once inside the cell directs the cell to produce the viral antigen.

In the case of DNA-based vaccines—either plasmid/naked DNA- or viral-vector-based—explains Bleck, the cell that takes up the DNA will transcribe the DNA into mRNA, and then the mRNA will be translated into the protein-of-interest, which will be an antigen from the virus. In the case of mRNA vaccines, the transcription step is already completed, so the cells that take up the mRNA only need to transcribe the mRNA sequence into the protein-of-interest. Viral vector-based vaccines utilize the engineered virus to insert the nucleic acid encoding the viral antigen into the cell, where that molecule is then subsequently transcribed to mRNA and translated into the protein-of-interest.

DNA- and RNA-based genetic vaccines have been impeded by the ability to appropriately deliver the nucleic acids intact and to the correct site within the body or a particular cell type, according to Warfield, but this issue has more recently been overcome with the development of novel, improved delivery formulations such as more effective lipid nanoparticles.

Importantly, although they are considered genetic vaccines, the DNA of the human cell is not impacted by the vaccine, and Becker notes that antigen production only continues for a short duration before the RNA or viral vector are eliminated from the body. As a consequence, though, the immune reaction (and potential adverse effects) occurs in a more modulated and delayed manner, Becker asserts. “As a result, to achieve complete immune protection and to increase its duration, a prime boost dosing regimen in two consecutive vaccinations with the same or a different vaccine may be applied, which is what we’re seeing in the mRNA COVID-19 vaccines,” he says.

Indeed, while genetic vaccines hold much promise, they have not yet been widely commercialized. This situation has started to change with FDA granting Emergency Use Authorizations to the mRNA vaccines from Pfizer-BioNTech and Moderna for COVID-19 in late 2020 and approval for the viral-vector vaccine for Ebola from Janssen (Ad26.ZEBOV) followed by a second dose of MVA-BN-Filo from Bavarian Nordic, also in 2020.

Development and manufacturing advantages for genetic vaccines

What makes genetic vaccines so attractive is the potential to establish platform solutions that allow the rapid development of a range of vaccines against emerging infectious diseases based on a scalable novel core technology platform. “The process to develop and produce genetic vaccines is highly similar from one to the next, so we have already a lot of information from other vaccine projects that have used the same platform. This saves valuable time and energy when starting the development of a vaccine against a new disease,” explains a company spokesperson from Janssen Infectious Diseases & Vaccines.

The design and development of traditional vaccines is fairly complex. Most importantly, the best way to propagate the virus or its antigen needs to be newly developed in each and every case, Becker stresses. For killed or attenuated viruses, a mechanism must be explored and established that kills or lowers the infectious potential of the virus, without destroying it, so that the ability to generate the immune response remains. If this is not achievable, the traditional vaccine route is blocked for these viruses. For conjugated or VLP vaccines, the appropriate carrier substance or partner molecules also need to be explored and then combined with the antigen in the formulation process.

“While historical knowledge can be applied in the attenuation or formulation process, each case requires developmental activities to some extent. The more similar the new virus is to existing organisms, the easier it will be to use existing processes, reducing the amount of development time required. This is particularly true when creating vaccines for new mutations of known and treatable viruses such as flu,” Becker remarks.

“Traditional vaccines can take years to develop because they rely on the actual virus or viral proteins grown within eggs or cells,” Bleck agrees. “Viral proteins are developed and manufactured in cell-based expression systems, and they require time to generate a clonal cell line expressing the protein-of-interest and then optimize the manufacturing process so that it can be reliably scaled-up to clinical and commercial scale.” Traditional vaccines based on cell culture are also manufactured using large stainless-steel equipment, which is slower to scale up and requires longer construction timelines, Christy adds.

In addition, traditional vaccines are usually ranked as requiring an elevated biosafety level, and manufacturing facilities therefore need to comply with a higher level of biosafety requirements. “Such capacities may be limited worldwide, especially in pandemic situations, and facilities that are usually used for the manufacturing of ‘normal’ drug products cannot be used. Moreover, the virus propagation or the production of the antigens are biochemical processes that need to be run under controlled conditions and that may take a long time (weeks to months),” Becker observes.

Genetic vaccines, on the other hand, can be designed more rapidly and deployed as soon as the genetic sequence has been identified. The DNA product can be quickly expressed and scaled-up to clinical or commercial scale, Bleck adds. In the case of mRNA vaccines, the DNA precursor can then be transcribed in an 

 process that does not require the same long development timelines; for viral vector-based vaccines, the base systems are already established and the gene that encodes the antigen of interest only needs to be substituted into the vector backbones to start the process. Subsequent engineered viral production is performed using well-established manufacturing techniques.

As an example, Christy notes that Moderna went from sequence selection to shipping the first manufactured batch of the clinical drug product in 42 days. In addition, Lonza was able to scale up, build, and commercialize the Moderna vaccine in its Visp, Switzerland facility in only eight months, compared to the two to three years (or more) usually required to build a new cell-culture facility. This speed was also made possible by Lonza’s pre-investment Ibex Dedicate in a manufacturing complex and supporting infrastructure that was pre-primed and ready for fit-out, according to Christy.

“Part of the reason for this speed is that no cell bank or viral seed bank needs to be developed; this time-consuming task is often required for traditional vaccines,” says Christy. “Secondly,” he continues, “the dose for genetic vaccines is very low compared to traditional vaccines; an mRNA dose of 30–100 µg is being utilized. Such low doses require smaller facilities, which can be equipped with single-use (SU) technology, resulting in a faster scale-up and facility implementation.” Similarly, viral vaccines can be produced in small SU bioreactors, with 1000-L vessels sufficient for producing millions of doses.

“Theoretically,” adds Richard W. Welch, vice president of development services for Emergent BioSolutions’ CDMO Business Unit, “once a process and testing have been developed for a genetic or platform-based vaccine, that same process and the majority of the release assays can be used for any vector or antigen. For more traditional vaccines, each process and set of release assays must be developed separately.”

More specifically, the level of development effort required for platform-based vaccines is often substantially less than for more traditional vaccines from a chemistry, manufacturing, and controls perspective, Welch explains. “This decreased level of process and method development results in a substantial reduction in cost, and more importantly during a pandemic, the time from determination of identity and sequence of the target antigen or antigens sequence to clinical production and release of clinical trial material.”

Moreover, the biosafety level category for genetic vaccines usually is lower than for traditional vaccines. “The majority of these vaccines may not even require biosafety measures during production at all, merely the same techniques as those used for other biopharmaceutical products,” notes Becker. As such, facilities that produce “normal” biopharmaceutical drug products can be used also for the manufacturing of these vaccines.

In addition, Welch observes that a genetic- or platform-based approach can also avoid other potential delays for clinical production. “If a site has already manufactured, tested, and released that type of genetic or platform vaccine, then the equipment is in place and qualified for any vaccine that platform can support. Materials and suppliers are already qualified, and materials specifications are already developed and set. Often, long lead-time items with long expiry dates can also be held in stock, decreasing the time necessary to order, release, and supply material to the manufacturing or QC [quality control] suites,” he says.

However, Becker points out, genetic vaccines are a much younger class of drug product compared with traditional vaccine techniques. “The knowledge level for some of the required production techniques, such as the formulation of lipid nanoparticles, is still limited within the pharmaceutical industry. We can expect to accrue even more valuable knowledge over time to further enhance the effectiveness and efficiency of these vaccines,” he states.

Easy to modify in response to virus mutations

Viruses naturally mutate, and the longer they are in circulation and the more transmission that occurs, the more opportunities they have to develop mutations that enable resistance to established antigens. Depending on the mutations, the impact can range from minimal to substantial for traditional vaccines, according to Welch. Traditional flu vaccines offer an existing case where the seasonal variation has minimal to no impact on the production process. However, substantial mutations or changes in strains with increased potential for infection can result in substantial changes.

“If the mutation or shift in strains cannot be produced using the existing process, such as an avian flu not being able to be produced in eggs, then inactivated and attenuated vaccines could potentially require completely new starting strains or production platforms, which would essentially require anything from substantial to complete redevelopment and validation of the manufacturing process for the new strains,” he says. The same could hold true for protein-based or recombinant protein-based.

Because genetic vaccines trigger their immune response via a fragment of the virus genome, they will continue to provide an effective immunization route as long as the gene sequences in those particular fragments remain unchanged or display minimal mutations, according to Becker.

If the mutation is more significant, genetic vaccines also have the advantage of being extremely easy to modify. “That is the beauty of genetic vaccines; they represent a platform approach with a central technology (adenovirus, liposome particle mRNA, or other) that can be readily modified by inserting a new genetic sequence for rapidly response to virus mutations or even novel viruses (e.g., other coronaviruses),” Christy asserts.

The DNA template just needs to be modified to encode the new variants, and manufacturing of the updated vaccine can typically continue with very few, or no modifications to the process, Bleck notes. The existing body of knowledge about related virus strains facilitates the location and isolation of the relevant gene sequence, Becker says. Bleck adds, however, that the new vaccines still need to be evaluated in detailed clinical studies to confirm that the new mutated epitopes do not elicit unwanted immune responses in patients.

Like with traditional vaccines, developers of genetic vaccines must ensure sufficient process and product understanding to meet FDA, European Medicines Agency (EMA), and other regulatory guidelines, and they face scalability issues moving from early clinical phase to late clinical phase and commercial. “One key difference for genetic vaccines,” asserts Welch, “is that if the technology is a true platform approach, these issues only have to be worked out once for multiple indications.”

Companies, however, still need to define how much volume should be manufactured in order to meet demand and ensure that they—or their manufacturing partners—have the capacity to scale-up operations to meet the necessary peak volume. Genetic vaccines, while faster to develop than proteins, are still biologic products that require cell culture and sophisticated technology for development and manufacturing at both clinical and commercial scale, according to Bleck.

In a pandemic, adds Christy, the key challenge is manufacturing at risk during ongoing clinical trials. Further, the production scale-up to deliver hundreds of millions (if not billions) of doses places an enormous strain on the supply chain. Becker points out that currently there is only limited global capacity for biopharma production, some of which is required for existing drug and vaccine products. In addition, both traditional and genetic vaccines require filling under aseptic conditions, further reducing global capacity.

Genetic vaccine approaches have been contemplated for nearly 30 years, but until recently, Warfield says, they had been challenged by the need for large doses to induce mild to moderate immune responses, the instability of the nucleic acids (particularly with RNA candidates), and the inability to efficiently deliver the nucleic acids to targeted tissues or cells.

The recent success of the Pfizer-BioNTech and Moderna mRNA vaccines demonstrates that these issues have been overcome at least to some degree, but Warfield believes further improvements will need to be made for continued and future success of this class of vaccines. She highlights a need for the reduction of costs for raw materials and manufacturing processes and improvements in stability to reduce the need for storage at low or extremely low temperatures, which can create supply-chain challenges.

“The lower stability of genetic vaccines is definitely the major challenge when it comes to widespread adoption of this new technique,” Becker agrees. Formulation of the lipid nanoparticles required to protection of mRNA vaccines from degradation can be challenging, however; the correct ratio of lipids, proteins and nucleic acids is needed to form the nanoparticle, in addition to any additional excipients, adjuvants, etc., according to Bleck.

In addition, genetic vaccines may only undergo a limited number of freeze-thaw cycles, and thus the bulk vaccine should be filled into vials immediately after the formulation process is completed. In addition, he notes that the filling process should be followed immediately by visual inspection and label and pack operations. “With this in mind, the size of a batch, which is processed in one run, may be limited in order to shorten the exposure of the vaccine to room temperature,” he comments.

Because genetic vaccines are so new, there is also a need for careful short- and long-term monitoring and understanding of side effects to assist in the development of next-generation candidates that are potentially safer with less untoward effects, Warfield adds. “Achieving understanding and approval of the safety and efficacy profile of genetic vaccines by the general public, and especially amongst those with existing vaccine hesitancy, will be required for efficient and broad acceptance of genetic vaccines in the future for a larger set of pathogens outside the current COVID-19 pandemic,” she continues.

Overall, Christy observes that as with any new technology, genetic vaccines will progress through a maturation curve. Equipment and production processes must be optimized and standardized so processes can be made robust and scalable and global supply can be achieved at acceptable costs. He also stresses that the human capital factor must not be neglected. “The availability of trained, regulatory-compliant GMP manufacturing staff and quality control and quality assurance personnel is a critical success factor,” he says. Much investment in facilities will be needed as well, which during the COVID-19 pandemic been supported by numerous government and private partnerships.

A similar challenge common to all vaccines is the delivery of a safe and efficacious dose to patients. “Full focus on SISPQ (safety, identity, strength, purity, and potency) is common to all medicines. However, for genetic vaccines, this means developing a whole new battery of analytical methods, especially around purity and potency,” Christy states. “Methods exist, but these generally are research-based techniques (such as sequencing, infectivity, transfection assays), and they need to be fully developed to be robust, validatable, GMP-compliant, and able to be routinely implemented across multiple sites (globally for both drug substance and drug product),” he says.

Methods for genetic sequencing and product release, adds Bleck, require specialized expertise and equipment not required for traditional vaccines. In addition, he notes that for mRNA-based vaccines, their instability relative to most proteins will typically expand the scope of stability studies required.

The shortened timelines for manufacturing of genetic vaccines, Becker comments, also means that with currently accepted analytical methods, analysis results for intermediate production materials, such as formulated bulk product or product in filled but unlabeled vials, are not available at the time of processing. “This situation results in an increased risk that non-conforming product may undergo further value-adding manufacturing steps before being identified and discarded,” he says.

Because genetic vaccines are still a relatively new class of treatments, there is significant potential for further development. Primary opportunities revolve around the selection of more appropriate excipients, observes Welch. Work is ongoing to improve the target product profiles of genetic vaccines to improve their stability, Christy adds. “Formulation development with a range of stabilizers offers the potential to improve both the temperature stability and the shelf life of such vaccines,” he states.

In some cases, Welch believes that the use of existing or novel drying technologies will improve the stability of genetic vaccines. Becker agrees that transferring liquid formulations into lyophilized products can potentially improve thermal stability and reduce the need for cold-chain handling. Recipharm’s site in Wasserburg, Germany, for instance, successfully developed and implemented a lyophilization cycle that can freeze-dry a COVID-19 mRNA vaccine. “Initial results indicate that the lyophilized product has a significantly improved thermal stability profile in comparison to the liquid formulation,” Becker says.

The need for formulation improvement, however, creates its own challenges for vaccines being used to treat emerging infectious diseases, especially in the case of pandemics, where speed is of the essence, according to Welch. “Opportunities to increase stability that involve substantial revision of the final formulation may require additional and extensive clinical trials to establish efficacy and safety along with revalidation of the drug product production process.”

While there are many advantages to genetic vaccines, there are also many reasons why traditional vaccine approaches will continue to be used. “Traditional vaccines have been on the market much longer than genetic vaccines and, in most cases, can currently be made at a significantly lower cost,” Bleck. “Over time,” he adds, “these technologies have evolved to adapt to changes in the viruses that they protect against. In addition, if necessary, multiple antigenic proteins in certain ratios and configurations can be expressed to get the correct epitopes produced for a neutralizing immune response, which is currently difficult to achieve in genetic vaccine formats. Furthermore, getting adjuvants to work effectively with genetic vaccines can also be difficult.”

Traditional approaches might be preferential when preclinical animal studies indicate that an effective vaccine requires the presentation of an antigen or antigens in a complex structure that cannot be engineered or can only be effectively and reproducibly done using the entire infectious agent, a company spokesperson from Janssen Infectious Diseases & Vaccines says. In addition, when the protective antigens are not known for an emerging pathogen, traditional approaches incorporating the entire pathogen (live or killed viral vaccines) may be required until a firm understanding of protective immune responses are established, Warfield notes.

Furthermore, Becker points out that traditional approaches allow the combination of vaccination agents for different diseases, which may not be possible for genetic vaccines for the foreseeable future, as they are less robust. “With this in mind,” he says, “traditional vaccines may be more appropriate not only to address a wider variety of mutations of one virus type in one vaccination, but for routine vaccination programs against different diseases.”

Finally, Warfield notes that killed virus, protein, and VLP vaccines potentially have the advantage of more temperate storage requirements compared to some live virus- and genetic-based vaccines, which can be particularly important in remote areas and developing countries that lack the necessary cold-chain infrastructure.

But genetic vaccines are creating real excitement

The arrival of the new class of genetic vaccines heralds an exciting time in vaccine development, asserts Becker. “This new technology offers a number of promising routes to help us not only enhance infectious disease prevention, but to progress the fight against other serious diseases, such as cancer,” he says. The fact these vaccines can be manufactured in standard multi-product facilities, rather than on specialist sites, will also enhance efficiency for pharmaceutical companies and offers greater scope for maximizing vaccine production capacity in the event of future pandemics.

Process and product regulations for genetic vaccines and viral-vectored vaccines still have to mature, however, as the technologies thus far have only recently produced commercially viable products that have been approved by stringent regulatory agencies like FDA and EMA. “Our expectation is that both technology regulations and platform regulations will evolve over the next several years,” says a company spokesperson from Janssen Infectious Diseases & Vaccines.

As more genetic vaccines become available, Welch envisions a shift to their use not only for pandemics, but also for existing and emerging infectious diseases. “Such as shift could enable companies to decrease time and cost, at least for manufacturing development, from inception to market,” he notes.

New advances in mRNA vaccines and other novel vaccines may indeed mean that we are entering into a new “golden age” for vaccines, according to Christy, but with the caveat that important work remains to be done to ensure global access, adequate capacity, and ease of administration, as well as education to ensure widespread uptake. He also notes that effective vaccines have yet to be developed for many well-known viruses, and more than 80 emerging viruses have been identified since 1980, with two novel viruses appearing every year. “Despite recent successes, much remains to be achieved to protect humanity,” he insists.

In addition to novel genetic vaccine technologies, Christy is excited about mucosal vaccines that aim to boost local immune memory and effector responses at the point of entry of pathogens and mRNA vaccines in development as cancer vaccines, intra-tumoral immune-oncology therapies, and localized regenerative therapies. Other cancer and T-cell vaccine are in development to treat antibody evasive viruses, and existing vaccines are being re-developed to provide better protection and coverage.

“Ongoing global pre-investment by governments, private foundations, and other groups will be needed to drive further advances in technology, manufacturing capacity, and infrastructure that will enable effective response to epidemics/pandemics going forward,” Christy concludes.

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


Vol. 45, No. 3
March 2021
Pages: 18–23, 64

When citing this article, please refer to it as C. Challener, "Genetic Vaccine Platforms Demonstrate Their Potential, "

In a pandemic, genetic vaccines offer several advantages over traditional approaches.

Genetic Vaccine Platforms Demonstrate Their Potential

Matthew D. Tandy, PhD,* mtandy@xenon-pharma.com, is associate director of chemistry, manufacturing, and control; Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC, Canada.
*to whom all correspondence should be addressed.

Jay A. Cadieux, PhD, is vice-president of product development & operations; Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC, Canada.

Rostam Namdari, PhD, is senior director of translational drug development, Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC, Canada.

The authors have developed a granular formulation of ezogabine, XEN496 (1–6), suitable for administration to children, including newborns. They used a modified quality-by-design (QbD) approach, as well as a risk-based matrix, to guide development of various prototypes of this Biopharmaceutical Classification System (BCS) Class 2 drug. 

First, they established excipient compatibility for ezogabine through an accelerated-condition stability study of binary mixtures of ezogabine and excipients at40 °C and 75% relative humidity. Lead blends within the compatibility space were then designed and their in-vitro dissolution profiles determined. Blends with the most promising dissolution profiles were then dry granulated and re-tested for dissolution prior to stability assessment.

The authors also assessed the impact of drug loading on dissolution performance, along with the potential for non-specific binding to occur with common plastics, such as those used in feeding bottles and nasogastric (NG) feeding tubes. Rat pharmacokinetic (PK) studies were then performed in order to confirm the candidate formulation’s biopharmaceutical performance in vivo, after which it was evaluated for taste/mouth feel and placed on long-term stability studies.

This article describes the overall process taken to design and test prototype pediatric formulations of ezogabine, which led to the identification of XEN496. Data so far suggest that granules containing ezogabine show rapid dissolution, good polymer compatibility and stability, suitable particle size distribution, and ease of dosing on a body weight basis, without requiring extemporaneous compounding. In addition, the final product shows a neutral taste profile, which could potentially enhance both patient and caregiver convenience and patient compliance.

Ezogabine was synthesized by a qualified good manufacturing practice (GMP) facility and re-crystallized to a chemical purity of 99.88% a/a. The crystalline form was determined to be Form A (i.e., the same form that had previously been used in the manufacture of Potiga) (7). A number of excipients were then selected for evaluation: Hydroxypropyl methylcellulose (Dow, Midland, MI);Starch 1500 (Colorcon, Stoughton, WI), Butylated hydroxytoluene (BHT) (Spectrum Labs, New Brunswick, NJ); Microcrystalline cellulose (FMC, Philadelphia, PA); and Copovidione (Ashland, Mill Creek, WA).To determine the bioequivalence (BE) of the new formulation, male Sprague-Dawley rats were used for pharmacokinetic (PK) evaluation of XEN496 and Potiga.

High-pressure liquid chromatography (HPLC) chemical purity.

 Analysis was performed using an HPLC device (Shimadzu LC-20ADXR)equipped with an auto-sampler and a 150 x 4.6-mm, 2.7-µm column (Advanced Materials Technology Halo C18). The sample was analyzed using a gradient method with 0.1% H3PO4 in water v/v as mobile phase A and acetonitrile as mobile phase B. The run time was 28 minutes, and the column temperature was 30 °C with an injection volume of 10 µL per sample and a 1 mL/min flow rate.

Analyte detection was carried out by UV analysis at 254 nm with a bandwidth of 4 nm. This method was developed and fully validated for use with ezogabine and its formulated products. Using this method, the parent peak for ezogabine was well resolved. However, the dimers, although observed, were not fully resolved and were (along with certain other impurities) deemed to be related substances for this product.

The excipient compatibility screen was performed with samples consisting of ezogabine mechanically admixed with excipients in proportions typically employed in solid oral dosage products. Samples were stored at 40 °C and 75% relative humidity for four weeks before being analyzed by HPLC for changes in total related substances (TRS).

 The excipient compatibility data were used to design a series of prototype formulations prepared via dry granulation to create immediate release (IR) dosage forms. Each of these prototypes consisted of a combination of ezogabine, binders, fillers, antioxidants, and disintegrants in ratios that aimed to promote an optimal release profile of ezogabine along with a minimum degree of degradation caused by interactions with the excipients.

Dissolution testing was performed using a dissolution testing system (Agilent 708-DS) with 0.1 M HCl as the dissolution medium as n=6 samples at 37 °C ± 0.5 °C. The dissolution equipment was set up as per 

 <711> as Apparatus 2 (paddles) with a paddle speed of 50 rpm and sampling points at 5, 10, 15, 30, 45, and 60 minutes, after which time the paddle speed was increased to 200 rpm.

The last sampling time point was taken at 75 min. At each time point, 1 mL of the media was sampled, filtered using a 0.45-µm polypropylene filter and analyzed by HPLC using a HPLC (Shimadzu LC-20ADXR) equipped with an auto-sampler and a 150 x 4.6 mm, 2.7-µm column (Advanced Materials Technology Halo C18). The sample analysis was performed using a gradient method with 0.1% formic acid in water v/v as mobile phase A and 0.1% formic acid in acetonitrile v/v as mobile phase B. The run time was 28 minutes and the column temperature was 37 °C with an injection volume of 10 µL per sample and a 1 mL/min flow rate. Ezogabine detection was carried out by UV analysis at 254 nm with a 4 nm bandwidth.

 A PSD analyzer (Malvern Mastersizer 3000) equipped with a micro tray accessory (Malvern Aero S) was used for dry powder dispersion analysis. The sample was analyzed using 0.5 bar pressure with a feed rate of 60%, which gave a laser obscuration of 0.14% over a 30 second measurement time. Data analysis was performed using Mie theory (i.e., based on the scattering of electromagnetic waves). No particle size data were gathered for the majority of the formulations prepared, because dissolution was the key parameter for this product. Additional work is planned in the future, to formally explore the relationship between particle size and biopharmaceutical performance for XEN496 as this product progresses through development.

 Male Sprague-Dawley rats (7–8 weeks old, N = 6/group) were used for BE evaluation. Rats were dosed at 10 mg/kg via oral gavage; blood samples were collected via jugular vein at specific time points: 0.25, 0.5, 1, 2, 4, 8, and 24 hours, and processed to plasma by centrifugation at ~4 °C and 3200 g for 10 min within 30 min of collection, and kept frozen at -70 °C – 10°C. The samples were then analyzed for ezogabine levels using a validated method combining liquid chromatography with tandem mass spectrometry. Plasma concentration-time data were analyzed via a non-compartmental model using Phoenix WinNonlin 6.3 software (Pharsight Corporation).

 A taste test was performed on the lead prototype formulation (Blend B or XEN496) of the granulated material. Two healthy adult human subjects each took a sub-therapeutic dose of XEN496 in a taste test designed to ensure that the formulation had a neutral character and to determine its mouth feel.

 Ezogabine non-specific binding to glass, along with three of the most common materials used in feeding bottles and NG tubes (polyether sulfone, polyphenyl sulfone and polypropylene), was tested by preparing a stock solution of the API in purified water at a concentration of 0.025 mg/mL and transferring aliquots to feeding bottles made of the different materials. The bottles were hand shaken for one minute before 1-mL aliquots were tested by HPLC and the amount of material recovered calculated.

. Samples were blended using a blender (NanTong Beite Pharmaceutical Machinery Co., Ltd. HTD-200), then processed in a roller compactor (Alexanderwerk WP 120), after which granulate was sieved using a vibratory sieve shaker (Fritsch Spartan).

Pediatric formulation development of ezogabine began by testing the stability of the API in the presence of a range of excipients. The goal was a formulation with minimal degradation (i.e., no inherent instability due to unfavorable interactions with inactive ingredients). Excipient compatibility screen results are presented in 

 This screen was performed with samples consisting of the API mechanically admixed with excipients in proportions typically employed in solid oral dosage products. Many of the samples showed limited or no change in total related substances (TRS) readings after storage at 40 °C and 75% relative humidity for four weeks compared to Day 1. A number of excipients were determined to be potentially suitable for use in the formulation development with ezogabine.

 The main prototype formulations prepared for ezogabine at different drug loads are presented in 

. Based on the projected clinical dosing regimen for various pediatric age ranges, a relatively wide range of drug loads (ranging from 5% to 20% w/w ezogabine) was evaluated by dry granulation to create immediate-release (IR) dosage form prototypes. Each of these prototypes consisted of a combination of the API, binders, fillers, antioxidants, and disintegrants in ratios that aimed to afford an optimal release profile of ezogabine along with a minimum degree of degradation caused by interactions with the excipients (

 To compare formulations based on ezogabine release under simulated gastric conditions, dissolution tests were performed as described. The resulting dissolution profiles are presented in 

 with target criteria being a repeatable dissolution profile with Not Less Than Q+5 (Q=75%) at T=15 minutes for the blend. The optimum blends were designated as the lead (Blend B, XEN496) and back-up (Blend I) formulations for subsequent development. The lead formulation showed in-vitro dissolution profiles (both pre- and post-granulation) consistent with an IR product (e.g., 91.2 ± 1.2% released after 10 minutes, 99.1 ± 1.0% released after 45 minutes).

Analysis of the formulations between 10–60 minutes in the dissolution profile gave no clear impression of function/property relationships for the excipient types used. For example, Starch 1500 is used in these formulations as a binder between 19.99–79.05%. While the formulation with the optimum dissolution rate gave the lowest binder level, other formulations with the same percentage of binder had only moderate dissolution rates, approximating those of formulations with the highest level of binder.

What did seem to have a significant effect was the level of API in the formulation. Typically,formulations with the poorest dissolution have low levels of the API (5%) and the optimum formulations for dissolution have the highest percentage of API (20%). It can therefore be postulated that ezogabine in these granules acts as a disintegrant or dissolution enhancer. At this point, no research has been performed to explain how this mechanism might work. Future studies are planned to elucidate the mechanism underlying this observation.

 The formulations selected for advancement on the basis of their dissolution profiles (Blends B and I) were re-prepared and placed on stability under nitrogen in a potential clinical presentation (i.e., 2 g of XEN496 in 80 x 80-mm sachets made from a polyethylene terephthalate/aluminum/polyethylene [PET/Al/PE] compound film designed for pharmaceutical packaging). The samples were placed under International Council for Harmonization (ICH) accelerated conditions (40 °C / 75% relative humidity) for 36 weeks, with appearance and HPLC purity/related substances evaluated at the time points described in 

 Ongoing stability assessments have shown that ezogabine is stable in both the lead and back up formulations under ICH accelerated conditions.

 Because the molecule had been previously marketed, it is desirable to show there was no significant change in oral bioavailability and PK profile between the IR Potiga tablet and the current XEN496 granule formulation. To mimic the reported off-label use for pediatric patients, Potiga tablets were crushed before administration, and these crushed tablets were compared head-to-head with the XEN496 granules in a rat PK study.

The crushed Potiga tablets and the XEN496 granules were dosed (10 mg/kg) orally in a rat cross-over PK study. Both formulations were dosed as a suspension at a concentration of 1 mg/mL in 0.02% w/v aqueous carboxymethyl cellulose (CMC); the CMC concentration was selected to match the viscosity of infant formula.

The plasma-concentration curves of the crushed Potiga tablets and XEN496 (

) are virtually superimposed, indicating that the granule formulation was equivalent to Potiga in terms of biopharmaceutical performance. 

This was confirmed through PK analysis, which showed that the geometric mean ratio and its 95% confidence intervals of the PK parameters were within the BE range of 80–125% (

Taste is a key parameter in the development of medicines for pediatric populations, particularly infants, who have functioning taste buds on their tongue, tonsils, and at the back of their throats. This makes them more sensitive to bitter and sweet tastes than adults, and they have a strong preference for slightly sweeter flavors (8). Because infants cannot understand or comment on flavors they find unpleasant, they will reject any food which tastes bitter, which, in the case of medicines, may cause an under-dose due to incomplete intake of the administered dose. Pediatric formulations, therefore, must be specifically designed to be neutral or slightly sweet so that they would be accepted by the infants taking the medication.

An informal taste test performed on XEN496 (Blend B), showed it to be slightly sweet with a slightly grainy texture; however, this test used the granulated material, which would be either completely or partially dissolved in the dosing matrices, hence eliminating or mitigating any potential disagreeable mouth feel. It is therefore expected that this product will be accepted by infants when mixed with food.

 The dissolution profiles indicate that XEN496 will dissolve in 0.1 M HCl; however, the dissolution profile in baby formula could not be determined, because this medium caused interferences in the UV spectra. Because this could, in principle, affect the ability to dose patients effectively and accurately, the particle size distribution of the granules was carefully controlled so that they could pass through the nipple of an infant feeding bottle.

Laser light scattering was used to determine the particle size distribution of the XEN496 granules. It indicated that they would be small enough to pass through the nipple of a standard baby bottle or pediatric NG tube (i.e., with a d10 of 13.4 ± 0.4 µm, a d50 of 41.6 ± 1.6 µm, and a d90 of 153 ± 31 µm). By comparison, typical baby bottle nipple apertures are
>500 µm, and size 4 Fr pediatric NG tubes have a 1330-µm inner diameter. XEN496 is therefore considered compatible with pediatric dosing, including common feeding devices without risking blockages, which may impair administration.

The effect of polymer binding on drugs is well-known (9) and can be extremely beneficial when designing a drug delivery system; however, it can also cause undesired effects when polymers trap or adsorb to the API so that it cannot be effectively and/or efficiently absorbed. Because XEN496 is designed to be added to foods, including baby formula, it is important that there be limited polymer binding such that the full API dose can be readily available for absorption in the body.

Glass and three of the most common materials used in feeding bottles and NG tubes (polyether sulfone, polyphenyl sulfone, and polypropylene) were tested for non-specific binding with ezogabine. Analysis of the samples showed 100% recovery from the glass vessel and minimal binding to each of the polymers, with recoveries of 96.9% for polyether sulfone; 96.7% for polyphenyl sulfone; and 96.5% for polypropylene: 96.5%. However, these levels are not expected to affect patient dosing.

The challenges inherent in this project were threefold: to develop a stable pediatric formulation of ezogabine; to ensure that the formulation has adequate PK characteristics and preferably is bioequivalent to Potiga; and to make sure that the formulation would meet the stringent requirements of pediatric dosing, yet still facilitate preparation and accurate dosing of the patients without having an unpleasant taste or mouth feel.

The approach used for this work was initially to develop a formulation that would allow the API to be dosed in a manner suitable for the patient population, in a formulation that was stable under accelerated conditions.Once a suitable formulation was prepared, its properties were controlled through particle engineering activities such as micronization and encapsulation of specific strengths, which can be combined to allow for effective and accurate dosing based on each patient’s weight. The approach used in the development of the formulation has proven to meet all design characteristics established in the initial project plan.

A novel pediatric formulation of ezogabine (XEN496) was successfully developed for use in the pediatric population (through dispersal in breast milk, infant formula, or soft foods) as granules packaged in a way that would allow for highly accurate body weight-based dosing. XEN496 has shown suitable physiochemical properties such as dissolution rate and stability. The rat cross-over PK study with XEN496 and Potiga showed that these formulations of ezogabine were bioequivalent, which makes XEN496 suitable for further clinical development and, potentially, for use in pediatric clinical trials in patients with KNCQ2-DEE. XEN496 has since been manufactured under GMP conditions for Phase I/III clinical studies.

1. Medline Plus Website, medlineplus.gov, medlineplus.gov/druginfo/meds/a612028.html.
2. M. Douša et al., 

 94, 71-76 (2014).
3. M.R. Groseclose and S. Castellino, 

., Publication Date (Web): Jan 14, 2019.
4. S.V. Mathias and B.W. Abou-Khalil, 

 (7), 61–63 (2017).
5. DrugBank Website: drugbank.ca, www.drugbank.ca/drugs/DB04953.
6. J.J. Millichap et al., 

 2:1-5 (October 2016).
7. P. Meisel et al., US Patent 6,538,151; Mar. 25, 2003.
8. G.K. Beauchamp and J.A. Mennella, 

, Mar; 83(Suppl 1), 1–6 (2011).
9. W.B. Liechty et al., 

Submitted: July 2, 2020.
Accepted: September 2, 2020.

When citing this article, please refer to it as: M. Tandy, J. Cadieux, R. Namdari, “Using Modified QbD to Develop a Novel Pediatric Formulation of Ezogabine,” 

An adult tablet formulation of ezogabine (retigabine) (i.e., Potiga [also known as Trobalt]) was developed and marketed by GlaxoSmithKline (GSK), as an adjunctive treatment for focal-onset epilepsy in adults. Ezogabine is a potassium channel opener and primarily works by activating the voltage-gated potassium channels in the brain. Ezogabine was shown to be an effective treatment for many patients, however; under certain conditions, it could generate cyclized dimers, some of which have been implicated in pigmentation abnormalities in a subset of patients. Even though these abnormalities were reversible and had no toxic effects, they may have played a part in the decision to withdraw the drug from the global market in 2017. 
Potiga had never been studied in a formal clinical trial in young children, but crushed and/or compounded Potiga tablets have been used, off-label, to treat children affected by developmental and epileptic encephalopathy, often with favorable outcomes. The efficacy of this off-label treatment has highlighted a need for clinical testing of ezogabine in the pediatric population. The first step is developing a suitable pediatric formulation of ezogabine (XEN496). A formulation has been developed that is compatible with a range of food matrices, chemically stable, bioequivalent to Potiga in a rat model, compatible with feeding bottle plastics, and has a pleasant taste and mouth feel.


Using Modified QbD to Develop a Novel Pediatric Formulation of Ezogabine

Excipients are essential to the formulation of drug products because they enable the effective delivery of drug substances and can account for as much as 80–90% of the drug product formulation. Despite the exposure that excipients pose to patients, currently there is no independent pathway for approval or assessment of novel excipients.

Other materials, which have higher levels of exposure, have established approval procedures. For example, food additives—including flavorants and colorants—can be approved via a petition to FDA or through the Flavor and Extract Manufacturers Association generally accepted as safe (GRAS) process. Cosmetic ingredients undergo the Personal Care Products Council’s well-accepted Cosmetic Ingredient Review process.

Many excipients used in approved drugs are listed in FDA’s Inactive Ingredient Database (IID); however, most have been used for decades and few were initially developed specifically for use as pharmaceutical ingredients. Novel excipients are those compounds not listed in the IID or compounds listed in the IID, but intended to be used for a new route of administration, at a higher dosage level or modified in some way, such as co-processed excipients that have been combined and enhanced in a physical manner through particle engineering.

The lack of an independent approval pathway for all of these types of novel excipients is creating significant challenges for drug formulators. “In recent years, there have been astonishing advances in the fundamental understanding of disease biology leading to remarkable treatments for once deadly diseases. Many drug candidates for these transformative and breakthrough treatments suffer from very poor physical and/or chemical properties,” observes Eric A. Schmitt, senior director of pharmaceutics at AbbVie and co-leader of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) Working Group on novel excipients.

For oral drug candidates, excipients that can mitigate challenges associated with poor aqueous solubility and/or permeability can enable drug development for these otherwise potentially undevelopable candidates, Schmitt notes. For parenteral delivery, driven by the growth of macromolecules, there are significant needs for excipients that can improve solubility and chemical and physical stability, and reduce viscosity, he says.

“Similarly, tolerability (e.g., pain on injection for parenteral medicines), acceptability (e.g., taste for pediatric patients), and manufacturability challenges can all hinder the development of innovative medicines,” Schmitt says. “These challenges occur across therapeutic modalities, routes of administration, and dosage form types. Novel excipients, or expanded use scenarios of existing excipients, can provide formulation scientists much needed tools to address these challenges,” he concludes.

Novel dosage forms in use and under development today also have unique needs. “The industry as a whole is evolving to different methods for dosage and delivery—transdermal, mucoadhesive, and targeted immunotherapies for instance—that require unique solutions that in many cases cannot be provided by IID-listed options and will only be possible through the introduction and acceptance of novel excipients,” says Meera Raghuram, director of regulatory and sustainability with Lubrizol Life Science.

The bottom line, according to David R. Schoneker, president/owner/consultant with Black Diamond Regulatory Consulting, is that drugs today present different formulation challenges, and the numerous excipients used for 100 years no longer resolve these issues, nor do they enable optimization of new manufacturing methods such as continuous processing and 3D printing.

“It is important,” stresses Nigel Langley, global technology director for pharma solutions at BASF, “to think about novel excipients as offering a means for designing functionality to address specific problems given the challenges that drug developers currently face. Without fit-for-purpose excipients, many unmet needs will simply remain unmet,” he states.

Strong perceived risk prevents use of novel excipients

Novel excipient approvals, however, are tied to new drug approvals, which adds risk to an already high-risk endeavor. It is natural that adding additional risk with an unapproved excipient will be avoided and only pursued as a very last resort, according to Schmitt. “Tying a new drug product approval to a novel excipient approval essentially doubles the risk of regulatory approval and significantly increases the cost of development. Even worse, if either one fails, the investment in both is lost,” he says.

There have also been examples in the past, notes Priscilla Zawislak, global regulatory affairs advocacy manager at IFF and immediate past-chair of the International Pharmaceutical Excipients Council (IPEC)-Americas, of drug developers being told by FDA that they really should use only excipients listed in the IID. “Hearing such comments can be very discouraging for pharmaceutical companies that have invested time and effort with novel excipients,” she says.

It is also frustrating for companies producing novel excipients, adds Langley. “Drug developers may want to use novel excipients in formulations that can be developed without them to provide improved quality or performance. Without an independent approval process, however, they rarely do so unless the potential reward outweighs the higher risk. Excipient manufacturers therefore don’t have any incentive to develop new products that may not bring a return for 15–20 years,” he asserts.

Some of the risk is perceived, because most novel excipients have more supporting toxicity data than the older approved excipients ever had, according to Schoneker. “It is the uncertainty that results from the lack of an established pathway that is the problem,” he states.

There is real risk, though, asserts Raghuram, due to FDA’s silence on the issue, the lack of any specific policy, and the chance that an application containing a novel excipient might land in the hands of an new drug application reviewer that doesn’t really understand how to do this type of assessment. “The awareness of issues related to safety of novel excipients is limited, and this is not surprising as there is no guidance available. It also cannot be expected that considerations related to innovation or an assessment of the positive impact of a novel excipient on the drug landscape will be part of a drug regulatory review process. An independent safety review process is, therefore, very important for novel excipients.”

A 2020 US Pharmacopeia (USP) survey of 264 respondents who formulated or supervised the formulation of generics, branded medicines, biologics, or biosimilars during the past five years revealed the extent to which drug developers find the lack of access to novel excipients a problem (1). Eighty-four percent said that currently used excipients have imposed limitations on drug development. Seventy-seven percent experienced challenges using novel excipients in advancing formulations through drug development for the US market, with regulatory acceptance, approvals, and other requirements the most common challenges. Forty percent felt compelled to reformulate a drug product for the US market because of an excipient’s limitations, while 28% experienced a discontinuation of drug development as a result of excipient limitations.

The internal structure of pharmaceutical companies that says risk must be managed has led to limited use of novel excipients, even if it means lower performing formulations are pursued, according to Langley. Today, Schmitt agrees, there is a high barrier to using novel excipients in drug development, which can stifle drug product design and potentially lead to suboptimal products with respect to pill burden, injection volume, stability, etc., as well as less efficient and/or robust manufacturing processes.

“What we have today is product development by IID and acceptance of ‘good enough’, rather than quality by design,” Schoneker asserts. In some cases, development projects have actually been halted because to move forward would require the use of novel excipients, meaning patients have therefore not had access to medications that could help them, he adds. In many cases, novel excipients have been available and shown to solve the specific issues, but the drug developers could not justify the perceived risk of using them.

While there is no lack of ideas or energy around the concept of novel excipients, given the hesitancy on the part of drug developers to use them and the lack of a path to market, the business model for excipient suppliers has become impractical, according to Raghuram. “Very few excipient companies are willing to invest resources in innovation and development,” she observes.

“At a time when we have never needed novel excipients more, there is too much uncertainty about using them and thus little reason for anyone to actually develop them. Due to the lack of an appropriate pathway for bringing products forward, very few companies are making decisions to get involved in real novel excipients any more. The only advances we are seeing are minor modifications to existing excipients, and in a few cases, co-processed excipients,” comments Schoneker.

Independent approval pathway could address uncertainty

If an independent approval or qualification pathway for novel excipients was established, then the requirements would be defined and everyone would know what must be done, says Zawislak. “FDA expectations would be clearer and more interest would be created in using novel excipients,” she says. For excipients that have FDA opinions generated and made public, drug developers would also know that there is safety data to support their use, at least for certain intended levels, Schoneker adds.

“Not only would an independent approval pathway encourage pharmaceutical companies to evaluate novel excipients, it would also give excipient suppliers a path to market that does not involve waiting 15–20 years,” observes Langley. Indeed, once an excipient receives a favorable review, suppliers can present that product to pharmaceutical companies and show that it has already been reviewed and therefore represents a higher likelihood of success, according to Zawislak.

Langley also believes such a pathway would act as a catalyst to stimulate innovation and collaboration between pharmaceutical companies and excipient suppliers. “An independent approval or qualification pathway for novel excipients could facilitate development, not only potentially reducing the attrition rate, but would also allow for a more cost-effective development process,” he states.

Access to more patient-friendly delivery solutions could also improve patient compliance, adds Katherine Ulman, principal consultant at KLU Consulting. Meanwhile, a new pathway may also lead to an update of the FDA guidance related to excipient safety, which was issued more than 15 years ago. In fact, IPEC is currently working on the revision of the 1996 Safety Guide for Pharmaceutical Excipients to incorporate current thinking related to safety evaluation techniques. IPEC hopes to publish this revised guide later in 2021.

For branded drugs, novel excipients could be used to optimize drug product performance and presentation, and possibly develop candidates that were deemed undevelopable, leading to transformative medicines with optimized patient presentations, according to Schmitt.

For generic drugs, novel excipients based on new chemical entities may not be appropriate for use; they would be best suited for use with innovator drugs that must go through clinical studies rather than bioequivalence studies. But other types of excipients including co-processed excipients and existing excipients used at higher levels or via different routes of administration, as well as food ingredients used for the first time as excipients, should be suitable for generic drugs. Because these materials have much less safety risk associated with them, the level of safety data required for assessment is typically lower.

“Novel excipients based on new chemical entities should go through a more drug-like approval process, while those based on existing excipients should have a less rigorous approval process that would enable their use by the generic-drug industry,” Schoneker asserts. If this approach was taken, generic-drug developers could make better quality products more efficiently and leverage advances in manufacturing techniques. Co-processed excipients or excipients used at higher levels, for example, might allow more cost-effective manufacture or improve patient compliance while still ensuring bioequivalence of generic formulations.

FDA proposed pilot program promising start

 Notice requesting comments on a proposed pilot program for reviewing the toxicology studies of a limited number of novel excipients via and process independent of the investigational new drug, new drug application, and biologics license application processes (2). Any novel excipient found to be safe under the proposed Novel Excipient Qualification Pilot Program would be listed in the IID with acceptable use levels. In the Federal Register Notice, the agency sought input on seven topics, including what criteria should be evaluated for novel excipients and whether such a program would help overcome the hesitancy of pharmaceutical companies to use them.

By the time the docket closed in early February 2020, 26 respondents had provided overwhelming support for the program (3). There has since, however, been no official public announcements from the agency regarding next steps. “We know FDA is working on the program, but we don’t know what they are going to do or when,” observes Schoneker.

The pharmaceutical industry’s perspective, according to Schmitt, is that in the past 20 years, tremendous advances have been made with respect to both small- and large-molecule drug substances, but formulators are still limited to the same excipients that were available two decades earlier with very few new excipients approved.

“We believe this situation is a direct consequence of the historical approval process for novel excipients and are excited to partner with FDA in this pilot program. We are very encouraged and hope to capitalize on this momentum by seeing the program implemented and novel excipients enter the assessment process in 2021. We also urge readers to encourage their organizations to consider novel excipients when they can make a difference and take advantage of the pilot program if/once it is implemented,” Schmitt states.

The proposed FDA pilot program is the first solid development following many years of effort on the part of excipient suppliers, pharmaceutical companies, IPEC-Americas, the IQ Consortium, and USP to reach out to and educate the agency on this important issue. “For the first time, we are seeing the possibility of a path forward that will encourage excipient innovation and in turn drug product innovation in ways that haven’t been possible before,” Schoneker asserts.

“That is tremendously exciting, and we are eager to work together with FDA to bring the program to fruition,” adds Langley. IPEC-Americas is also willing to provide suggestions for possible candidates for the pilot program that could serve as a means for seeing how the process might work. “We would love to have that kind of discussion with the agency once the decision is made to take the next steps,” Schoneker says. In addition, IPEC also has a team of toxicologists from around the world developing a new safety guide with information FDA might find useful for the proposed assessment process, according to Ulman.

Longer term, there is hope that ultimately some level of global consistency can be achieved regarding the approval of novel excipients. Doing so will be critical to realize the benefits of the US pilot program for patients, according to Schmitt. “The biopharmaceutical industry develops treatments for patients across the globe and a harmonized approach will be required,” he explains. One possible solution would be to have the topic addressed by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use.

Without an independent approval pathway for novel excipients, true pharmaceutical innovation could be stymied.

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