Susan Haigney

Communication between the manufacturing plant and retail stores. | Image Credit: © Cagkan - © Cagkan - stock.adobe.com

Cryoport, a supply-chain service company, and SK pharmteco, a contract development and manufacturing organization, announced on Sept. 25, 2024 that the two companies are entering into a partnership to provide integrated logistics and manufacturing services to bio/pharmaceutical companies. Cryoport will support SK pharmteco by providing end-to-end cell and gene therapy services that include biomaterial collection, shipping systems, data solutions, and bioservices.

“We are delighted to be selected by SK pharmteco in supporting its manufacture of APIs and intermediates, biopharmaceuticals, and cell and gene therapies,” said Jerrell Shelton, CEO of Cryoport, in a press release (1). “Our organizations share a mission to support the life sciences by helping bring lifesaving treatments to patients. This relationship not only extends our reach to more people in need but also aligns with Cryoport’s strategic goal to further diversify and enhance our revenue streams, particularly as we continue to drive higher revenue from the support of commercial cell and gene therapies.”

Dana Cipriano, vice president, Analytical Services for SK pharmteco, added, “The cell and gene therapy industry continues to see substantial growth, and ensuring the safety and integrity of the supply chain is essential for these products. We are dedicated to our clients, and partnering with Cryoport reflects our commitment to providing the highest-quality services that are specifically tailored to meet the needs of our customers and the patients they serve.”

In April 2024, SK pharmteco also entered into an agreement with Ferring Pharmaceuticals to provide scale-up manufacturing capacity for the company’s gene therapy,Adstiladrin (nadofaragene firadenovec-vncg) to ensure long-term supply of the treatment for bladder cancer.

“SK pharmteco is proud to partner with Ferring Pharmaceuticals as a manufacturer of the breakthrough gene therapy Adstiladrin,” said Joerg Ahlgrimm, chief executive officer, SK pharmteco, in a press release at the time of the announcement (2). “Our integrated approach, incorporating customizable clinical and commercial GMP [good manufacturing practice] manufacturing solutions with comprehensive in-process testing, quality control, and lot release programs, provides unparalleled support to our partners throughout their product lifecycle and is in perfect alignment with our mission of expediting the delivery of potentially life-saving therapies to patients across the globe.”

In other company news, SK pharmteco’s facility in Swords, Ireland celebrated its 60th anniversary in August 2024 (3). The Swords facility was acquired in 2018 by SK biotek, and therefore, became the first Korean company in Ireland.

“It is an honor to commemorate 60 years of our Swords facility,” said Joyce Fitzharris, President of SK pharmteco Small Molecule, Europe, and leader of the Swords facility, in the press release. “This milestone is a testament to the unwavering dedication of our employees, who have consistently driven innovation and quality. We are committed to transforming lives through the development of life-impacting therapies, and this anniversary reflects our journey thus far.”

SK pharmteco. SK pharmteco and Cryoport Partner for Cell and Gene Therapy Logistics and BioServices. Press Release. Sept. 25, 2024.

SK pharmteco. Ferring Pharmaceuticals and SK pharmteco Enter into Commercial Gene Therapy Manufacturing Deal. Press Release. April 18, 2024.

SK pharmteco. SK pharmteco’s Swords Facility Celebrates 60 Years of Pharmaceutical Excellence. Press Release. Aug. 26, 2024.

Articles

The two companies are partnering to provide logistics and manufacturing services to biotechnology and pharma companies.

Cryoport and SK pharmteco Partner on Cell and Gene Therapies

Cell and Gene Therapy Production Facilities

Once a therapy has been discovered and proven, it has to be manufactured in order to reach patients. However, depending on the therapeutic modality, companies can be left with a difficult decision of whether or not their existing facilities will meet their manufacturing needs or whether they need a new facility entirely. Cell and gene therapies come with unique challenges that must be considered when either building a new manufacturing facility or expanding an existing one. Peter Walters, Fellow of Advanced Therapies at CRB Group, gives his insight on some of the challenges and benefits of creating new production facilities and/or expanding on what is already available.

To ensure one follows current good manufacturing practices when building a new facility for the production of cell and gene therapies, Walters stresses that one should understand the requirements by reading the European Medicines Agency (EMA) or the Pharmaceutical Inspection Co-operation Scheme (PIC/S) guidelines. “[T]hose, I think, are the most prescriptive in terms of what is expected and what is possible to do with your facility and your equipment, and the kinds of classifications [and] handling requirements required,” says Walters. “I think it's important to brush up on those, because cell therap[ies] especially have requirements that are a bit nuanced and different than a lot of other biotech—a lot going to chain of custody, a lot going to the degree of segregation that has to happen, the degree of quality control that has to happen, especially with open operations. A lot of these therapies can't be sterilized just prior to filling, and so they have to be handled with extreme care throughout the entire lifespan of their production, and so, … understanding those requirements is going to be crucial [to make] sure you've got a facility and an equipment plan and a development plan that's going to get you the whole way through to commercial.”

When it comes to using a current facility to expand a cell or gene therapy pipeline, Walters says, “I think we've seen a number of companies successfully, effectively, more or less bolt on a production facility onto their existing building, or build a small [campus], [such as] create a small building that has a spine that connects it, or something like that.

And so that way you're not really disrupting your ongoing production, but you gain the access to that office space. You gain access to the labs and the warehousing and all of that sort of shared, common support space that maybe can be leveraged across both [and] utility systems can sometimes be split between the two. [T]hat way, you can create a new production that doesn't have to come with the cost of a whole new mechanical infrastructure, and especially if we're talking about cell therapy, typically, those types of facilities have a larger air handling load sometimes, but they can be smaller clean rooms. And so, the overall load could be small, and then the rest of the utility load might be very, very low.”

Click the video above to watch Peter answer the following questions:

My company is planning new construction of a cell and gene therapy production facility. How can we ensure it meetings CGMP requirements?

How can we use our current facility to expand our cell and gene therapy pipeline?

Peter Walters is Fellow of Advanced Therapies at CRB Group.

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

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

Videos

In this episode of the Ask the Expert video series, Peter Walters, Fellow of Advanced Therapies at CRB Group, discusses factors to be considered in constructing a new facility for cell and gene therapy production as well as using an existing facility to expand cell and gene therapy pipelines.

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In late September 2024, FDA approved two drugs for the treatment of neurological symptoms associated with Niemann-Pick disease, type C (NPC) in both adults and children. According to FDA, patients with NPC experience progressive neurological symptoms and organ dysfunction caused by changes in the NPC1 or NPC2 gene that impact the transport of cholesterol and other lipids in a cell. This is a rare genetic condition, and patients with NPC may live only approximately 13 years (1).

Miplyffa (arimoclomol), approved on September 20, is the first treatment approved by FDA for NPC and is an oral medication used in combination with the enzyme inhibitor miglustat to treat NPC symptoms in adults and children two years of age and older. FDA’s 

Genetic Metabolic Diseases Advisory Committee

 discussed the application for Miplyffa at its first meeting in August 2024 (2, 3). The approval was based on results from a randomized double-blind, placebo-controlled 12-month trial that included patients aged two to 19 years of age. Of those patients, 50 were “randomized 2:1 to treatment with weight-adjusted Miplyffa (31 to 124 mg) or placebo orally three times per day. Among these 50 patients, 39 (78%) received miglustat as background treatment in the trial.” These studies showed that Miplyffa resulted in slower disease progression compared to placebo.

“NPC is a serious disease that leads to enormous adverse impacts on patients and families. Despite extensive research efforts, there have not been approved treatments to meet the significant needs of patients,” said Janet Maynard, MD, director of the Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine in the FDA’s Center for Drug Evaluation and Research, in a press release (1). “The first-ever approval of a safe and effective drug option for NPC will undoubtedly support the essential medical needs of those suffering.”

The second drug, Aqneursa (levacetylleucine), was approved on September 24 to treat NPC in adults and children who weight at least 15 kilograms. A randomized, double-blind, placebo-controlled, two-period, 24-week crossover study found that patients treated with Aqneursa for 12 weeks had better outcomes in the functional Scale for the Assessment and Rating of Ataxia (fSARA) compared with those that received a placebo. The fSARA evaluates “gait, sitting, stance, and speech disturbance domains of the original SARA with modifications to the scoring responses” (4).

“This is the second treatment the FDA has approved for NPC within the span of a week. Today’s action further underscores the agency’s commitment to support development of new treatments for rare diseases,” said Maynard, in a press release (4). “This approval again demonstrates the FDA’s commitment to work with the scientific community toovercome the unique challenges that may arise with rare disease drug development.”

FDA. FDA Approves First Treatment for Niemann-Pick Disease, Type C. Press Release. Sept. 20, 2024.

FDA. Updated Public Participation Information: August 2, 2024: Meeting of the Genetic Metabolic Diseases Advisory Committee Meeting Announcement. Aug. 2, 2024.

FDA. Genetic Metabolic Diseases Advisory Committee. 

FDA. FDA Approves New Drug to Treat Niemann-Pick Disease, Type C. Press Release. Sept. 24, 2024.

Two drugs, Miplyffa (arimoclomol) and Aqneursa (levacetylleucine), have been approved by FDA to treat neurological symptoms associated with Niemann-Pick disease, type C in adults and children.

FDA Approves Treatments for Niemann-Pick Disease, Type C

 on Sept. 23, 2024 (1), Darby Kozak, PhD, deputy director for the Center for Drug Evaluation and Research (CDER), Office of Generic Drugs, in FDA, provided a look back at the Hatch-Waxman Amendments of the Federal Food, Drug, and Cosmetic Act, also known as the Drug Price Competition and Patent Term Restoration Act of 1984. The Hatch-Waxman Amendments established an approval pathway for generic-drug products and granted FDA authority to approve abbreviated new drug applications for generic versions of branded drugs (2).

According to Kozak, the amendments were created to increase market competition between generic-drug companies and pharmaceutical companies. “Before the Hatch-Waxman Amendments, there weren’t many generic-drug products available, given the legal and regulatory challenges generic[-drug] companies faced. Unlike today’s process, generic-drug applicants couldn’t rely on the agency's determination of safety and effectiveness of the brand-name drugs they hoped to replicate. To apply for FDA approval of a generic drug, companies had to submit a full application package, which often included conducting their own clinical trials to establish safety and effectiveness of the generic drug. Repeating those clinical trials was expensive and unnecessarily time-consuming, since the brand-name drugs were already determined to be safe and effective,” said Kozak.

The amendments resulted in a growth in the generic-drug market, according to Kozak, with generic drugs increasing from 19% of the market in 1984 to 90% in 2024. The amendments also led to the Orange Book being created, which provides information on the safety and effectiveness of approved generic drugs.

“Additionally, the Amendments provided generic-drug companies a ‘safe harbor’ from patent infringement lawsuits during their generic-drug development and testing,” said Kozak. “Under Hatch-Waxman, a company can seek FDA approval to market a generic drug before the expiration of patents related to the brand-name drug that the generic seeks to copy. Brand-name drug manufacturers gained certain benefits as well, such as the ability to market their drug exclusively for required periods of time before a generic drug can be approved by FDA for market entry.”

Since the passage of the Hatch-Waxman amendments, Kozak points to the enactment of the Generic Drug User Fee Amendments (GDUFA) as a significant advancement in the generic-drug approval process. GDUFA provides predictable and timely review of generic drug applications, which, according to Kozak, is important because the volume of generic-drug applications has significantly grown, and the products have become more complex.

“When the amendments established the framework for generic drug review, most drugs were simpler small molecules in non-complex formulations with uncomplicated delivery devices,” said Kozak. “These products also generally used well-understood manufacturing processes and were easier to characterize and evaluate through traditional bioequivalence methods, such as systemic pharmacokinetic studies. Forty years later, many drugs have more complicated active ingredients, formulations, dosage forms, routes of delivery, and delivery devices, and therefore are harder and more costly to develop and assess. As a result, there are fewer of these ‘complex drugs’ on the market for the patients who need them.”

Kozak stated that he sees the complexity of generic-drug products as a challenge that needs the Generic Drug Program to facilitate their development and approval. “We also continue to grow the Generic Drug Program by creating and maintaining opportunities to communicate with the public and drug developers, so that we can respond to patients’ and consumers’ needs. We provide collaborative research, training, and facilitate exchange of resources among groups interested in the development of complex generic products,” he stated.

FDA. 40th Anniversary of the Generic Drug Approval Pathway. CDER Conversations. 

, Sept. 23, 2024 (accessed Sept. 25, 2024).

Congress.gov. "H.R.3605–98th Congress (1983-1984): Drug Price Competition and Patent Term Restoration Act of 1984." Sept. 6, 1984. https://www.congress.gov/bill/98th-congress/house-bill/3605.

FDA’s Darby Kozak provided commentary on the anniversary of the Drug Price Competition and Patent Term Restoration Act of 1984.

Hatch-Waxman Amendments Turn 40

The European Medicines Agency (EMA) announced on Sept. 19, 2024 that it recommends that the indication for the use of the smallpox and mpox vaccine, Imvanex, be extended to adolescents from 12 to 17 years of age. Imvanex contains a live, weakened form of “modified vaccinia virus Ankara” (MVA-BN) and is currently authorized in the European Union for smallpox and mpox in adults.

The agency’s Committee for Medicinal Products for Human Use (CHMP) decided to extend the indication after interim results of a study that compared the vaccine’s immune response in 515 adolescents to 211 adults showed the response was similar in both groups.

“Therefore, it is inferred that the vaccine will provide similar protection in adolescents to that expected in adults,” the agency said in the press release (1). “According to the submitted data, the safety profile of Imvanex in adolescents was comparable to that seen in adults and no additional risk has been identified.”

The marketing authorization holder has been asked by EMA to provide the agency with the final results of the study by May 30, 2025.

The World Health Organization (WHO) declared mpox a public health emergency of international concern in August 2024 (2).

"The emergence of a new clade of mpox, its rapid spread in eastern DRC [Democratic Republic of the Congo], and the reporting of cases in several neighboring countries are very worrying,” said WHO Director-General Tedros Adhanom Ghebreyesus, in a press release (2). “On top of outbreaks of other mpox clades in DRC and other countries in Africa, it’s clear that a coordinated international response is needed to stop these outbreaks and save lives.”

WHO announced the MVA-BN vaccine as the first vaccine on its prequalification list in September 2024.

“This first prequalification of a vaccine against mpox is an important step in our fight against the disease, both in the context of the current outbreaks in Africa, and in future,” said Ghebreyesus in the press release regarding that announcement (3). “We now need urgent scale-up in procurement, donations, and rollout to ensure equitable access to vaccines where they are needed most, alongside other public health tools, to prevent infections, stop transmission, and save lives.”

According to EMA, this assessment to extend the indication may impact the global response to the mpox outbreak in the DRC and other countries; EMA is the regulatory agency responsible for prequalification of this mpox vaccine (3).

“This means that CHMP’s assessment constitutes the basis for WHO prequalification approval to facilitate timely and increased access to this vaccine in communities with urgent need. Previously, EMA’s assessment was also taken into account by the national regulatory authority of the DRC in the fast-track approval of the vaccine. In addition, WHO has cooperated in EMA’s assessment of the extension of indication in adolescents, a population that is particularly vulnerable to mpox,” the agency said in the press release (1).

EMA. EMA Recommends Extending Indication of Mpox Vaccine to Adolescents. Press Release. Sept. 19, 2024.

WHO. WHO Director-General Declares Mpox Outbreak a Public Health Emergency of International Concern. Press Release. Aug. 14, 2024.

WHO. WHO Prequalifies the First Vaccine against Mpox. Press Release. Sept. 13, 2024.

The agency is recommending the extension of the smallpox and mpox vaccine, Imvanex, to adolescents aged 12 to 17.

EMA Recommends Mpox Vaccine for Adolescents

The lungs are one of the most complicated organs in the body. Therefore, there are several considerations that come into play when formulating a new inhaled drug. “I don’t think I would be exaggerating if I [said] that [the] lungs are probably one of the most complex organs in the body,” said Vivek Gupta, PhD, associate professor, Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John’s University, in 

1). “We are talking about multiple branching going from trachea to brochi, and … millions of air sacs, where most of the blood gas exchange happens, [and] where the lungs will give oxygen into the blood for circulation all over the body.”

Because the trachea branches off, the delivery pathway decreases. Therefore, according to Evonne Brennan, consultant at Evonne Brennan Consulting, “To reach its region of impact, a precise micronized dose of drug substance will need to be delivered in an aerosolized state, through the aid of a device and a formulation designed for delivery from that device, through simple actuation or a synchronized undertaking by the patient, the aerosolized particles travel with the patient’s airflow through a series of pathways where it is deposited.”

Obstacles caused by disease could restrict delivery further and cause increased mucus, remarks Brennan. “Deposition of the drug substance is required to deliver its pharmacological response,” Brennan stresses. Other complications for delivery of drug substance via inhalation can be caused by age, post-reflux cough, and patient compliance.

“For a given indication and drug substance, there are many physiological factors that need to be considered during product development for inhalation, such as patient pulmonary function, clearance mechanisms, etc., and these are addressed in an integrated way at the formulation and device development levels,” says Eunice Costa, R&D director–Inhalation and Advanced Drug Delivery, Hovione.

Attributes such as formulation particle size and density and inhaler dispersion performance need to be controlled to ensure successful deposit of the product into the lungs, according to Costa. “Once deposited, bioavailability of the drug becomes a function of additional factors such as intrinsic chemical properties as well as solid state and formulation composition, being that dissolution and/or permeation needs to occur at a faster rate than the clearance mechanisms in place in the local diseased microenvironment,” Costa says.

When referring to this article, please cite it as Haigney, S. Formulating Inhaled Medicines. 

Pharmaceutical Technology Trends in Formulation 

Excipient and delivery device selection play crucial roles in the formulation of inhaled drugs.