Artificial intelligence's processing power creates more accurate reports for improved drug safety.

Harnessing Technology to Ensure Drug Safety

Lipids aren’t the only important ingredients influencing stability and in vivo performance.

Excipients Impact Stability in mRNA-LNP Formulations

PAT is crucial to process control and real-time release in continuous manufacturing of solid-dosage drugs.

Implementing Process Analytical Technology

The trends shaping the growth of the biologics outsourcing industry demand attention.

The Logistics of Outsourcing Biologics

Drug Solutions

Since the beginning of the COVID-19 pandemic, providers offering contract testing services have seen various changes and improvements to everyday processes. According to Lara Silverman, PhD, founder and principal consultant at LIS BioConsulting, it became increasingly crucial for contract testing labs to provide seamless services to clients and communicate any issues in a quick, efficient fashion. Dana Cipriano, senior vice-president of Testing & Analytical Services at the Center for Breakthrough Medicines, seems to second this observation, sharing that she has seen contract testing services demonstrate a major increase in the speed and efficiency of testing using new testing methods and technologies.

Some other new processes that have occurred in the bioprocessing/testing services space include new analytical technologies for fast in-process controls during virus-like particle production, according to Nik Barbet, PhD, head of Operations at Vector BioPharma. At Eurofins BioPharma Product Testing, Stanley Prince, Director of Biosafety & Cell/Gene Therapy Strategy, says they are focused on investing in automation and alternative methods and technologies, such as the RNA-based BioFire rapid mycoplasma test. Additionally, a proprietary degenerate polymerase chain reaction platform used to offer services for rapid detection of adventitious contaminants (Blazar), as well as rapid sterility testing with an emphasis on services are emerging from MilliporeSigma, where the company is focused on adopting rapid molecular and genomic methods, according to Benoit Gourdier, head of Contract Testing Services at MilliporeSigma.

With these analytical testing services, bio/pharma companies are still benefitting in terms of cost savings and efficient development times. Outsourcing analytical testing to contract testing companies helps to reduce the cost of drug development by providing access to state-of-the-art equipment and expertise and reduces the time required for drug development, according to Cipriano.

Shailesh Vengurlekar, senior vice president, Quality & Regulatory Affairs at LGM Pharma, adds that a lot of small- or medium-sized companies do not have enough qualified lab chemists, space, or equipment to meet their internal need of analytical method development and validation.These companies compete directly with larger organizations for on-time product approval and market share. However, the expense of testing facilities and qualified staff, along with regulatory costs, can be outrageous. By contracting analytical services, these companies can redirect their core competencies to meet company goals on time.

Barbet, meanwhile, explains how emerging analytical technologies require highly specific expertise, skills, and occasionally equipment that are not always easy to establish internally. As a result, corresponding services that are contracted with recognized service organizations are needed to solve technically demanding tasks. It can take time to onboard and prepare an outside testing provider.

In terms of upcoming changes to testing services from contract development and manufacturing company/contract manufacturing company (CDMOs/CMOs); although there are shifts happening, it can take time to onboard and prepare an outside testing provider, according to Silverman. “Instead, if internal capabilities exist, that process could be streamlined and therefore reduce cost to the customer and overall timelines. Also, for cell therapy products, specifically, where lot sizes can be very small, some of the major providers of testing services are unfamiliar with how to manage small lot sizes, which can cause delays as the team defines a sampling strategy to meet existing internal qualifications of tests,” she says.

Increasing the testing services offered for biologics, including characterization and stability, adds value for customers, Vengurlekar says.

Stability testing has been and will continue to be required for all drug products, including biologics, and according to Gourdier, they will assess both drug substance and drug product for attributes, such as potency and degradation at long term and accelerated storage conditions, sensitivity to heat, light, and humidity, and freeze-thaw viability.

As for the future of contract testing services and their impact on the industry, people such as Barbet hope that services for transducing particle quantification or for genomic purity and vector integrity will boost the demand for external testing services, especially for gene therapies. Prince explains that many organizations are attempting to still follow the traditional compendial approaches and guidance documents that were intended for biologics, where volumes and product concentrations are not an issue. As this industry continues to grow, Vengurlekar believes that—as new technologies are introduced—CDMOs can embrace the change and adopt these shifts into their service line offerings.

Silverman highlights how important contract testing services are to the industry in helping enable drug developers to bring novel products to patients. She hopes that contract testing labs are prepared to understand new modalities and provide meaningful technical insight and regulatory advice to cutting-edge companies. “Following approvals, testing laboratories must be ready to support the potential high volumes and fast turn-around times during commercial use, which means building a strong relationship with the drug developer and preparing capabilities to support product release in a timely manner. For some patients, these products are lifesaving and delays are simply unacceptable,” she asserts.

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

Combatting Testing Services Solidify Their Place in the Manufacturing Value Chain

Articles

Contract testing services demonstrate a major increase in the speed and efficiency of testing using new testing methods and technologies.

Contract Testing Services Solidify Their Place in the Manufacturing Value Chain

Regeneron Pharmaceuticals announced on March 22, 2023 that FDA has extended the approval of Evkeeza (evinacumab-dgnb) as an adjunct to other lipid-lowering therapies to treat children aged five to 11 with homozygous familial hypercholesterolemia (HoFH), an inherited condition characterized by extremely high low-density lipoprotein cholesterol (LDL-C). The treatment was initially approved in February 2021 as an adjunct to other lipid-lowering therapies in those aged 12 years and older with HoFH.

HoFH is an ultra-rare inherited condition that affects approximately 1300 people in the United States and is the most severe form of familial hypercholesterolemia, according to a company press release. Those living with HoFH are at risk for premature atherosclerotic disease and cardiac events even in their teenage years.

“At the Family Heart Foundation, we know that children with homozygous familial hypercholesterolemia, and those caring for them, often live in fear of what the future holds as they contend with the dangerously high levels of bad cholesterol, or LDL-C, caused by this genetic disorder,” said Mary McGowan, chief medical officer of the Family Heart Foundation, in the release. “Only 5% of rare diseases actually have an FDA-approved treatment. With this FDA approval, the HoFH community now has a much-needed treatment for young children, potentially making it possible for many to achieve recommended LDL-C levels much earlier in the course of this rare disease. This is a hopeful development for those living with HoFH.”
Source: 

FDA has approved Evkeeza for young children with homozygous familial hypercholesterolemia. 

FDA Approves Evkeeza for Young Children with Ultra-Rare Form of High Cholesterol

Feliza Mirasol is the science editor for 

On March 27, 2023, Takeda Pharmaceutical announced that the Japanese Ministry of Health, Labour and Welfare has approved Entyvio (vedolizumab) in 108-mg pens for subcutaneous (SC) injection and 108-mg syringes for SC injection as maintenance therapy for moderate to severe ulcerative colitis.

Entyvio SC provides an alternative dosing option that allows for patients to choose the method of administration that best meets individual needs. According to a company press release, SC delivery may reduce the number of personnel, equipment, facilities, and time necessary to prepare an intravenous formulation. This reduction may minimize errors encountered in the administration of the drug. The SC delivery method is also intended to provide ease of handling and convenience and can reduce the time required per administration.

“We are delighted that the subcutaneous formulation of Entyvio has been approved. We believe that this approval will provide a wider range of dosing options for ulcerative colitis patients and healthcare professionals and will help meet their diverse needs and improve quality of life,” said Naoyoshi Hirota, general manager of Takeda Development Center Japan in the press release.

Takeda received approval in Japan for a subcutaneous injection formulation of Entyvio (vedolizumab) for treating ulcerative colitis.

Takeda Gets Approval in Japan for Entyvio Subcutaneous Injection 

Exothera, a Belgium-based contract development and manufacturing organization (CDMO), and Remedium Bio, a US-based biotechnology company, have entered into an agreement under which the two companies will collaborate to scale-up manufacturing and demonstrate the industrialization potential of Remedium’s lead gene therapy drug candidate, AAV2-FGF18, the companies announced on March 22, 2023.

Remedium’s lead candidate is a disease-modifying gene therapy that is based on the clinically proven regenerative mechanism of fibroblast growth factor 18 (FGF18), according to Remedium in a company press release. The company is developing the gene therapy to treat osteoarthritis, a sector of rheumatology that has the largest unmet clinical need and which currently has no approved disease-modifying treatments, according to the press release.

 manufacturing center of excellence in Jumet, Belgium, Exothera, is well-positioned to supply clinical- and commercial-scale supplies of AAV2-FGF18, the company stated in the release. The CDMO will execute a proof-of-concept demonstration for transient expression of AAV2-FGF18 with suspension culture using a human embryonic kidney cells 293 cell line. Exothera aims to identify a high yield production process and reduce cost-of-goods for the lead candidate’s manufacturing process.

CDMO Exothera and biotech company Remedium are joining forces to scale up the manufacturing process for Remedium’s lead gene therapy candidate for treating osteoarthritis.

Exothera Partners with Remedium to Scale-Up Manufacturing of Gene Therapy Drug Candidate

Takeda Pharmaceutical announced on March 23, 2023 that it plans to invest approximately ¥‎100 Billion (US$754 million) into building a new manufacturing facility in Osaka, Japan, for plasma-derived therapies (PDTs). According to a company press release, this move represents Takeda’s largest investment in expanding its manufacturing capacity in Japan.

The investment is part of Takeda’s strategy to establish end-to-end manufacturing capability for PDTs at Osaka. According to the company in its press release, the new state-of-the-art facility will be the largest of its kind in the country. The facility is expected to be operational by 2030 and expands Takeda’s capacity for plasma manufacturing by almost five-fold. The company also has an existing plasma facility in Narita, Japan.

The facility will be built with automation and advanced digital technologies and will be a fully integrated plant, comprising teardown, fractionation, purification, and fill/finish capabilities as well as a cold storage warehouse. Takeda will use an environmentally friendly design to support its goal of achieving net-zero greenhouse gas emissions related to operations, including scopes 1 and 2, before the year 2035. The company’s existing Narita plasma manufacturing site will continue day-to-day operations until at least the end of the decade, during which time the company will make continued necessary investments for maintenance.

“Takeda has delivered plasma therapies to meet the needs of patients in Japan for more than 70 years. This new investment will strengthen our ability to continuously and reliably bring high-quality PDTs to a growing number of patients in Japan and worldwide. We will engage in discussions with the Ministry of Health, Labor, and Welfare to ensure we are contributing to sustainable patient care in an area of high unmet need in Japan,” said Milano Furuta, president of the Japan Pharma Business Unit at Takeda, in the company press release.

“We are pleased to make this investment in Japan, demonstrating our commitment to our fast-growing PDT business and to our home country,” said Thomas Wozniewski, global manufacturing and supply officer at Takeda, in the release. “Japan will play an even more critical role in our global manufacturing network, contributing to supply chain resilience globally. The new facility will provide a plasma fractionation capacity of more than [two] million liters per year. The company will unleash the power of automation and digitalization to deliver high quality products to patients reliant on PDTs, including those with diseases for which there are no alternative treatments.”

Takeda plans to build a new facility in Osaka, Japan, for the manufacture of plasma-derived therapies.

Takeda to Invest ¥‎100 Billion (US$754 Million) into New Plasma Therapy Manufacturing Facility

Roche announced on March 22, 2023 that it has entered into a collaboration with Eli Lilly to support the development of Roche’s Elecsys Amyloid Plasma Panel (EAPP), a blood test that aims to facilitate the earlier diagnosis of Alzheimer’s disease.

The EAPP is currently undergoing additional investigation to ensure clinical validation. The collaboration aims to support patients by improving the journey to a timely and accurate diagnosis and treatment of Alzheimer’s. If approved, the EAPP test would be an additional tool to identify low likelihood of amyloid pathology in symptomatic patients and determining whether further evaluation and testing may confirm a diagnosis.

According to a company press release, up to 75% of people living with the symptoms of Alzheimer’s do not have a diagnosis. Those who have received a diagnosis waited, on average, 2.8 years after symptom onset (1). The EAPP would be used as a tool to enable access to appropriate new therapies as they become available.

“We are excited to be collaborating with Lilly on such an important area of unmet medical need,” said Matt Sause, CEO of Roche Diagnostics, in the release. “Today, over 55 million people are living with dementia, and this is projected to increase to nearly 140 million by 20502. Collaboration is essential to ensure these people receive a timely and accurate diagnosis. The Elecsys Amyloid Plasma Panel has the potential to streamline a person's journey to diagnosis and, therefore, access to future treatment options.”

1. Johns Hopkins. Life Expectancy Following Diagnosis of Alzheimer’s Disease Depends on Age at Diagnosis. Johns Hopkins Bloomberg School of Public Health. Nov. 18, 2002. 

Roche and Lilly will collaborate on the development of Roche Diagnostics’ Elecsys Amyloid Plasma Panel.

Roche Collaborates with Lilly to Enhance Early Diagnosis of Alzheimer’s Disease 

As part of ongoing coverage of DCAT, the PharmTech editors touched base with Pierre Luzeau, CEO of Seqens. In in our discussion, Pierre discussed various aspects of sustainability, including:

The extensive measures his company has put in place to committ to sustainability

Underappreciated practices and techniques that contribute to sustainability

Why sustainability will be so pivotal for biopharma companies over the course of the next ten years.

For more of our coverage on DCAT in 2023, viewers can visit 

Pierre Luzeau, CEO of Seqens, discusses Seqen's commitment to sustainability and how one can work toward it within their own company.

Setting Sustainability Goals with Pierre Luzeau (DCAT 2023)

On March 27, 2023, the US Supreme Court heard oral arguments from Amgen and Sanofi in a case that could have broad ramifications on the state of patents in the United States. The crux of the case concerns the enablement requirement, and whether “genus claims” (i.e., patents that cover various structurally and functionally related chemicals) satisfy it.

Amgen and Sanofi are in dispute over Amgen’s Repatha (evolocumab) and Sanofi’s Praulent (alirocumab), both of which are monoclonal antibodies that lower the levels of low-density lipoprotein cholesterol. Amgen initiated the suit, claiming that Sanofi was infringing on its patent, while Sanofi has argued that the patents themselves are invalid.

All patents are required to fulfill an “enablement” requirement, which has traditionally been defined as allowing “those skilled in the art to ‘make and use’ the claimed invention; genus claims are predicated on this definition of enablement. However, Sanofi is arguing that this definition does not actually fulfill the enablement requirement, and that it instead must enable “those skilled in the art to reach the full scope of claimed embodiments without undue experimentation.” After back-and-forth resolutions in the lower courts, the Supreme Court is now tasked with answering this question surrounding functional language.

If Amgen wins the case, the victory would allow the company to claim all antibodies that use this mechanism of action shared by evolocumab and alirocumab; this would extend to other patents, which has left some companies worried about their intellectual properties. Due to these concerns, as well as the fact that broad patent protection would make it more difficult to bring competitive drugs to market, major pharma companies such as Pfizer, Johnson & Johnson, and Eli Lilly and Company have publicly backed Sanofi (1).

Conversely, if Sanofi wins the case, then that outcome would likely result in the death of broad genus claims. Some, including Kisuk Lee, a patent lawyer specializing in biopharma operations, feel that a Sanofi win could depress innovation. According to Lee, while it requires billions in R&D to bring a molecule to market, it is not incredibly difficult to extrapolate research concerning one molecule to similar ones.

“Nowadays, antibody production is quite automated,” says Kisuk Lee, principal, St. Louis Metro Office. “If you have the roadmap as described in Amgen’s specification, with computer modeling anybody can quickly produce antibodies.”

Depending on how this case is ruled, individuals such as Lee are concerned about how it will impact funding of discovery efforts. If broader patents are struck down, pharma companies will not only need to make more patent applications, an expensive process which Lee notes typically takes three-to-six years, but pharm companies may also not be granted crucial patents that competitors could use for their own molecules.

“If [the Supreme Court] decision only focuses on functional language, there will still be a good outcome for industry,” says Lee. “But if they say broad patent claims hinder competition and follow-on inventions, and you need to provide enabling disclosure for all variants falling within the scope, then it will be really damaging for our industry.”

Wingrove, P. Amgen-Sanofi Patent Case Divides Makers of Antibody Drugs. 

The Supreme Court heard oral arguments concerning the legitimacy of “genus clauses” in bio/pharma patents.

US Supreme Court Weighs Biologics Patents in Amgen vs. Sanofi Case

On March 29, 2023, FDA announced its approval of Narcan (four milligram naloxone hydrochloride nasal spray) for over-the-counter (OTC), nonprescription use. Naloxone, a standard treatment for reversing the effects of opioid overdoses, has been available via prescription (Rx) since 2015. The approval was granted to Emergent BioSolutions, a biotechnology company specializing in opioid treatment products, as well as vaccines and antibody therapeutics for infectious diseases.

According to an agency press release, more than 100,000 individuals suffered fatal overdoses from October 2021 to October 2022. Primarily driven by synthetic opioids, such as illicit fentanyl, the expanded approval from FDA is designed to fulfill a “dire public health need.”

“[FDA] remains committed to addressing the evolving complexities of the overdose crisis. As part of this work, the agency has used its regulatory authority to facilitate greater access to naloxone by encouraging the development of and approving an over-the-counter naloxone product to address the dire public health need,” said Robert M. Califf, commissioner, FDA, in the release. “Today’s approval of OTC naloxone nasal spray will help improve access to naloxone, increase the number of locations where it’s available and help reduce opioid overdose deaths throughout the country. We encourage the manufacturer to make accessibility to the product a priority by making it available as soon as possible and at an affordable price.”

“Naloxone is a critical tool in addressing opioid overdoses and today’s approval underscores the extensive efforts the agency has undertaken to combat the overdose crisis,” said Patrizia Cavazzoni, director, Center for Drug Evaluation and Research, FDA, in the release. “[FDA] is working with our federal partners to help ensure continued access to all forms of naloxone during the transition of this product from prescription status to nonprescription/OTC status. Further, we will work with any sponsor seeking to market a nonprescription naloxone product, including through an Rx to OTC switch, and encourage manufacturers to contact the agency as early as possible to initiate discussions.”

According to an Emergent BioSolutions company press release, the product is scheduled to be available OTC in the United States late summer 2023. This timeline was chosen to account for manufacturing changes needed for the transition from Rx packaging to OTC.

“Today’s landmark FDA OTC approval for N[arcan] Nasal Spray marks a historic milestone as we have delivered on our commitment to make this important emergency treatment widely accessible, given the alarming rates of opioid overdoses occurring across the country,” said Robert G. Kramer, president and CEO, Emergent BioSolutions, in the company press release. “We are dedicated to improving public health and assisting those working hard to end the opioid crisis—so now with leaders across government, retail, and advocacy groups, we must work together to continue increasing access and availability, as well as educate the public on the risks of opioid overdoses and the value of being prepared with N[arcan] Nasal Spray to help save a life.”

Narcan, from Emergent Solutions, will be the first naloxone product permitted for use without prescription by FDA.

FDA Approves First Over-the-Counter Naloxone Nasal Spray

As part of ongoing coverage of DCAT, the PharmTech editors touched base with Anil Kane, executive director, Global Head of Technical & Scientific Affairs at Thermo Fisher Scientific. In in our discussion, Anil discussed various topics within the outsourcing market, including:

The increased interest in technologies like cell and gene therapies and oral biologics

The continued rise of the "end-to-end" CDMO model and why biopharma partners are seeking it out

Recent investments made in new spaces by Thermo Fisher Scientific

Anil Kane, executive director, Global Head of Technical & Scientific Affairs at Thermo Fisher Scientific, discusses the growing role of CDMOs in the biopharma industry

Featured Content

Harnessing Technology to Ensure Drug Safety

Excipients Impact Stability in mRNA-LNP Formulations

Implementing Process Analytical Technology

The Logistics of Outsourcing Biologics

Drug Solutions