Aligning mRNA Progress with Regulatory Streamlining

BioPharm Peer Exchange

Dosage Forms: Roundtable on Oral Solid Dosage Trends

Drug Solutions Podcast: 

Pharmaceutical packaging must advance to adapt to new, complex modalities

Out-of-the-Box Packaging Advancements

From Theory to Reality: Automating Process Development

Drug Digest: 

The Importance of Appropriate Supplier Oversight

Ask the Expert

Text sign showing Industry News. Business photo text delivering news to the general public or a target public | Image Credit: © Artur - © Artur - stock.adobe.com

 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.

Articles

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

Feliza Mirasol is the science editor for 

Lonza announced on Sept. 24, 2024 that it has entered into a long-term commercial supply agreement with Vertex Pharmaceuticals under which it will manufacture Casgevy (exagamglogene autotemcel), the first clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein 9 (Cas9)-gene-edited cell therapy for treating sickle cell disease (SCD) and β thalassemia.

Under the agreement, Vertex will have access to Lonza’s scientific, regulatory, and manufacturing expertise as well as its global manufacturing network and its experience in the commercial manufacture of cell therapy products. Lonza plans to manufacture Casgevy at its cell therapy manufacturing facilities in Geleen, the Netherlands, with plans to expand to its Portsmouth, NH manufacturing facility in the United States.

“It is a privilege to work with Vertex on bringing its innovative and cutting-edge medicines to patients suffering from life-threatening diseases. We are also pleased to reach a significant milestone towards supporting the commercial manufacture of Casgevy by receiving the regulatory approval at our state-of-the-art cell therapy manufacturing site in Geleen,” said Daniel Palmacci, president, Cell & Gene, Lonza, in a company press release.

The Geleen facility recently received a good manufacturing practice (GMP) license from FDA, the European Medicines Agency (EMA), and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Lonza expects the Portsmouth site to begin GMP operations in 2025.

“Manufacturing a first-of-its-kind therapy [such as] Casgevy is complex and requires advanced technology and capabilities. The Lonza team have been excellent partners as we have invested in our global manufacturing network to ensure Casgevy will be available for the patients who need it. We look forward to our continued collaboration,” said Morrey Atkinson, PhD, executive vice-president and chief technical operations officer, head of Biopharmaceutical Sciences and Manufacturing Operations, Vertex, in the press release.

Casgevy was approved by the MHRA in November 2023 (1), by FDA in December 2023 (2), and by EMA in February 2024 (3). Following the MHRA and FDA approvals in late 2023, Vertex 

, a UK-based cell and gene therapy contract development and manufacturing organization, in December 2023 (4) to manufacture Casgevy. RoslinCT runs manufacturing facilities in Edinburgh, Scotland, and Boston, Mass., which are purpose-built for cell therapy products. The CDMO had been working with Vertex on an adaptive basis while Vertex moved through clinical and regulatory development of Casgevy.

1. Vertex Pharmaceuticals. Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, Casgevy (exagamglogene autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. Press Release, Nov. 16, 2023.
2. FDA. 

FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease

. Press Release, Dec. 8, 2023.
3. Vertex Pharmaceuticals. European Commission Approves First CRISPR/Cas9 Gene-Edited Therapy, Casgevy (exagamglogene autotemcel), for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. Press Release. Feb. 13, 2024.
4. RoslinCT. RoslinCT to Manufacture First-Ever US FDA Approved CRISPR-Based Gene Therapy Casgevy (exagamglogene autotemcel). Press Release. Dec. 11, 2023.

Lonza signed a long-term supply agreement to manufacture CASGEVY (exagamglogene autotemcel) for Vertex at its facility in Geleen, the Netherlands, and plans to expand manufacturing to Portsmouth, NH, in the United States.

Lonza and Vertex Enter Commercial Supply Agreement for CASGEVY, the Sickle Cell Disease Gene-Edited Cell Therapy

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

Hand shaking which print screen on wooden cube block in front of human icon for business deal and agreement concept. | Image Credit: © Dilok - stock.adobe.com

Ori Biotech, a manufacturing technology company with hubs in London and Philadelphia, and Charles River Laboratories, headquartered in Wilmington, Mass., jointly announced on Sept. 18, 2024, some results of a collaboration between the two companies that began earlier in 2024, with Charles River using Ori’s LightSpeed Early Access Program to access Ori’s next-generation cell and gene therapy manufacturing platform, known as IRO (1).

Head-to-head process runs compared IRO’s biological performance to a process optimized by Charles River specifically for chimeric antigen receptor (CAR)-T cell therapy, over two years, with an alternative manufacturing technology.

The Ori Biotech platform’s performance outdistanced the legacy technology, Prodigy, with an average of 51% CAR+ expression and 2.1 billion total CAR+ cells, in a seven- to eight-day process, versus 1.6 billion CAR+ cells in the legacy technology, according to the press release (1).

“We are excited to share [these] data from our ongoing partnership with Charles River, showcasing the IRO platform’s ability to simultaneously deliver both superior biological performance and the benefits of automation,” said Jason C. Foster, CEO of Ori Biotech, in a press release (1). “For too long, therapy developers have had to sacrifice biological performance for automation, but not anymore. IRO automates better biology to solve critical manufacturing bottlenecks and improve product viability by dramatically increasing throughput, decreasing COGS [cost of goods sold], and reducing batch failures, with the ultimate goal of enabling widespread patient access to life-saving cell and gene therapies.”

Ori Biotech’s website said IRO is compatible with all suspension cell therapies, has achieved higher transduction efficiency and cell yields than the contemporary “gold standard” cell expansion system, reduces manufacturing process times by an average of one to two days, and mitigates risk of process change and comparability between the clinical and commercial stage (2). The company said the platform is good manufacturing practice (GMP)-ready—enabling manufacturing in GMP Grade C or D cleanrooms—and 21 

) Part 11 compliant, able to increase throughput per square foot to the tune of approximately 1000 doses per year in 1000 sq. ft.

“Charles River’s work with Ori is part of a larger commitment to improve and scale advanced therapies through the adoption of cutting-edge closed and automated platforms to meet the growing patient demand for life-saving therapies,” Matthew Hewitt, PhD, vice president, CTO Manufacturing Business Division, Charles River, said in the press release. “The test of Ori’s new IRO platform using head-to-head process transfer runs shows promising results and provides therapeutic developers another option for manufacturing and helps to address the manufacturing bottleneck challenge.”

To put some numbers on the advantages the two companies’ executives touted, Ori Biotech said that IRO has the potential to reduce labor up to 70%, cut cost of goods by up to 50%, reduce processing times by approximately 25%, and reduce tech transfer times from months to weeks (1).

1. Ori Biotech. Ori Biotech and Charles River Laboratories Collaborate to Accelerate Life-Saving Cell and Gene Therapy Development and Manufacturing. Press Release. Sept. 18, 2024.

The next-generation IRO platform was found to significantly outperform the legacy Prodigy system, showing improvements in cell growth, CAR+ cell yield, and overall efficiency.

Ori Biotech, Charles River Cell Therapy Manufacturing Platform Collaboration Yields Promising Results

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

Cartridge and blue medicine inhaler in a room front view | Image Credit: ©Davizro Photography - stock.adobe.com

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.

Formulating Inhaled Medicines

Researcher analyzing green powder pigment in petri dish with magnifying glass | Image Credit: ©motortion – stock.adobe.com

Having the correct materials for the formulation and manufacture of drug products is crucial. But what happens if a supplier can no longer provide the needed product? Changing a supplier mid-development or mid-production can be tricky. Contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs) can assist sponsor companies with this difficult task.

“Changing suppliers mid-cycle can affect various aspects such as chemistry, equipment, scale, testing methods, and other analytical controls and specifications, potentially impacting the quality of material made by different suppliers,” says Joshua Hoerner, general manager and executive vice president, Purisys (part of the Noramco Group).

When a product is already in production, making changes such as a new supplier or a raw material requires attention to regulations and quality considerations. “Depending on where you are at in a process, changing anything can have a deep impact, so it is important to take proper steps,” says Iain McGhee, vice-president of Quality at Ascend Advanced Therapies. “And, of course, materials should only be changed when necessary and with full agreement of the sponsor.”

Sundar Narsimhan, chief procurement officer at Neuland Labs, stresses that a careful review of the following important factors should be done before switching material suppliers:

 “It is possible that in some markets, sponsors must test, validate, and ensure stability before incorporating the supplier’s material into their supplies. Other markets follow a ‘do and tell’ regime, where, if the synthesis route remains unchanged, the material can be utilized with minimal additional testing,” says Narsimhan.

Capability of new supplier to meet requirements. 

“Their relationship/control over the upstream supply chain, risk, and likelihood of non-supply must be verified,” says Narsimhan. “This is paramount since any supply disruption or quality incident can derail and sabotage the market performance of their product and can prove very costly.”

. “Any new changes or variations, for example, in the impurity profile or stability of the drug product can be disruptive and should be avoided at all costs,” says Narsimhan.

Jonathan Rush, head of Supply Chain at Andelyn, stresses that comparability should be considered first when switching from one supplier to another. He also points to the importance of organization alignment between a company’s analytical and quality groups. “Our analytical development group is continually evaluating the latest testing and technologies in our space,” Rush says.

Regulatory and compendial compliance requirements need to be followed, according to Rush. “For example, if material is tested according to USP [US Pharmacopeia] but the client requires [European Pharmacopoeia compliance], even though they are harmonized, certain differences still arise. So, it’s important to manage the specification to the most stringent guideline among the various guidelines to ensure the highest level of qualification,” says Rush.

To ensure compliance with regulations when changing suppliers mid-lifecycle, Mayank Nagar, vice-president and head–Tech Services & New Product Launches, North Americas, Dr. Reddy’s Laboratories, and Himanshu Joshi, director, New Product Launches, North Americas, Dr. Reddy’s Laboratories, suggest evaluating a new supplier’s quality management systems. They also say comprehensive risk assessments should be performed. “Maintain clear communication with regulatory authorities and stakeholders throughout the transition. Implement a robust change control process to manage the switch seamlessly and mitigate risks associated with the supplier change,” Nagar and Joshi say.

“These [supplier] changes may have regulatory implications, especially if the product is commercially filed, as products are expected to remain equivalent or at least comparable between the old and new suppliers, if in the middle of a product’s lifecycle,” says Hoerner.

When it comes to material specification issues to consider when switching suppliers, McGhee says specification limits need to be maintained so performance is consistent. He also suggests that manufacturers determine if a change in supplier will result in changes to the manufacturing and in-process controls and how the materials will be handled.

Quality control includes determining validation ranges for release tests. McGhee suggests asking if validated in-process controls and release tests are comparable to the original material. Shelf life and stability studies parameters may also need to be validated, according to McGhee, as well as impurity profiles.

“When changing material suppliers during production, it's crucial to consider the validation status of the process. Ensure the new supplier's quality program is robust, reliable, and has a strong performance record. Conduct a thorough re-qualification of the new material to confirm it meets the original material's quality parameters and all necessary documentation requirements,” says Kim Arsenault, quality compliance manager at BIOVECTRA. “This ensures continuity in product quality and compliance with regulatory standards, minimizing risks associated with supplier changes.”

“Validate the consistency and compatibility of the new materials with existing processes through rigorous testing. Assess potential impacts on product efficacy, safety, and stability, and update all relevant documentation,” say Nagar and Joshi.

Packaging and transportation of the product should also be considered. “Is the product packaging the same or do additional studies (e.g., leachable/extractible tests) need to be performed? Where is the new facility located, will this involve longer and more complex transportation routes? Are there security risks with the route?” McGhee asks.

“There are often upfront costs associated with setting up a new supplier, including process and analytical technology transfer expenses,” adds Hoerner. “Lastly, changing suppliers can impact the continuity of supply. It is essential to consider the new supplier’s project management capabilities and the experience of its project managers in implementing new products on time and within budget,” he concludes.

Contract organizations offer assistance when managing changes to material suppliers during a product’s lifecycle.

Navigating a Material Supplier Change

With FDA's approved of Eli Lilly and Company’s (Lilly’s) EBGLYSS (lebrikizumab-lbkz), a targeted interleukin 13 (IL-13) inhibitor, a new biologic treatment is made available for moderate-to-severe atopic dermatitis (eczema) in adults and children 12 years of age and older. The treatment is applicable to patients who weigh at least 88 pounds (40 kg) and whose moderate-to-severe atopic dermatitis is not well controlled with topical prescription therapies.

FDA’s approval was based on results from several studies (ADvocate 1, ADvocate 2, and ADhere). These studies included more than 1000 adults and children (aged 12 and older) with moderate-to-severe eczema whose symptoms were not controlled with topical prescription medicines. At 16 weeks, the primary endpoint for these studies was evaluated; measurements showed clear or almost clear skin, according to the company press release.

"Patients still struggle to control their moderate-to-severe atopic dermatitis with currently available therapies. Many experience poor long-term disease control, and severe itch can significantly impact their daily lives," said Jonathan Silverberg, MD, PhD, professor of dermatology at George Washington University School of Medicine and Health Sciences in Washington, DC, and first author of the 

 manuscript summarizing EBGLYSS clinical trials (1), in a company press release. "[FDA’s] approval of EBGLYSS is a big win for patients, as we now have a new first-line biologic treatment option for moderate-to-severe disease when topical prescriptions aren't enough."

Averaging two of the studies (ADvocate 1 and 2), it was shown that 38% of people who underwent the treatment achieved clear or almost-clear skin at 16 weeks, compared to 12% with placebo. Ten percent saw the same results in as early as four weeks. Many responders also experienced itch relief in both studies with the treatment. On average, 43% felt itch relief at 16 weeks, compared to 12% on the placebo. Five percent of people felt relief as early as two weeks.

"Eczema can affect people of all skin tones, ethnicities, genders, and ages. Nearly 16.5 million adults in the [United States] have eczema, with 6.6 million experiencing moderate-to-severe symptoms [such as] itchiness, dry and scaly skin, discoloration, and rashes, which can lead to more scratching that may cause skin to crack and bleed, (2)” said Kristin Belleson, president and CEO of the National Eczema Association, in the release. "The approval of EBGLYSS provides hope and promise for the eczema community and those still seeking lasting relief from disruptive symptoms."

"People living with eczema have symptoms that can appear at the most inopportune times, creating unpredictability and impacting their everyday lives," said Daniel Skovronsky, MD, PhD, chief scientific officer and president of Lilly Research Laboratories, and president, Lilly Immunology, in the release. "Today's approval allows people the opportunity to reimagine life with eczema as EBGLYSS offers a targeted approach to reduce a main cause of eczema inflammation. EBGLYSS provides long-lasting symptom relief with a convenient once-monthly maintenance dose."

EBGLYSS was also approved in Europe by the European Commission in 2023 and in Japan in January 2024. Additional market approvals are expected later this year.

Lilly has exclusive rights for the development and commercialization of EBGLYSS in the US and the rest of the world outside Europe. Almirall, Lilly's partner, has licensed the rights to develop and commercialize the biologic for treating dermatology indications, including eczema, in Europe.

1. Silverberg, J. I.; Guttman-Yassky, E.; Thaçi, D.; et al. Two Phase 3 Trials of Lebrikizumab for Moderate-to-Severe Atopic Dermatitis. 

 (12),1080–1091. DOI: 10.1056/NEJMoa2206714
2. Chiesa Fuxench, Z. C.; Block, J. K.; Boguniewicz, M.; et al. Atopic Dermatitis in America Study: A Cross-Sectional Study Examining the Prevalence and Disease Burden of Atopic Dermatitis in the US Adult Population. 

 (3), 583–590. DOI: 10.1016/j.jid.2018.08.028

The approval of EBGLYSS (lebrikizumab-lbkz) by FDA puts a new biologic treatment for moderate-to-severe atopic dermatitis on the market for patients whose symptoms are not well controlled with topical treatments.

Lilly’s EBGLYSS Offers New First-Line Biologic Treatment for Atopic Dermatitis Following FDA Approval

On Sept. 20, 2024, the European Medicines Agency (EMA) announced that its Committee for Human Medicinal Products (CHMP) has recommended approval for eight new medicines and extended indications for an additional 12 drugs. The approvals include drugs for the treatment of cancers, hemophilia, meningococcus, and two biosimilars for treating age-related macular degeneration.

The recommended cancer treatments include Elahere (mirvetuximab soravtansine) for the treatment of ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Hetronifly (serplulimab) was approved for treating extensive-stage small-cell lung cancer. The generic medicine, Pomalidominde Teva (pomalidomide), was approved to treat the rare bone marrow cancer, multiple myeloma, that impacts plasma cells that produce antibodies.

Other medicines that received recommendations include the following:

Hympavzi (marstacimab), to treat bleeding episodes in patients 12 years old and above with severe hemophilia A or B

Penbraya, a vaccine for immunization against 

Theralugand (lutetium (177lu) chloride), for radiolabeling of carrier medicines developed for radiolabeling with lutetium chloride

Biosimilars, Afqlir (aflibercept) and Opuviz (aflibercept), for the treatment of age-related macular degeneration.

Updates to COVID-19 messenger RNA vaccines Spikevax (to target the SARS-CoV-2 JN.1 variant) and Comirnaty (for the KP.2 subvariant) were also given positive opinions by CHMP.

“The revision of these vaccines is in line with the 

 issued by EMA’s Emergency Task Force to update COVID-19 vaccines to target the SARS-CoV-2 variants for the 2024/2025 vaccination campaign,” the agency stated in the press release (1,2).

CHMP also extended indications for the mpox vaccine, Imvanex, as well as Aflunov, Buccolam, Darzalex, Dupixent, Esperoct, Fasenra, Keytruda, Otezla, Pravafenix, Synjardy, and Zavicefta.

CHMP also confirmed its refusal to grant authorization to Syfovre (pegcetacoplan). The committee is also planning to re-examine its opinion of Leqembi (lecanemab) at the request of the applicant.

These approvals bring the 2024 yearly total of positive opinions for new medicines to 79. There have been four negative opinions in 2024 so far, and 63 extensions of indications.

In addition, EMA announced that Bruno Sepodes, a specialist in pharmacology, has been elected as the new chair of CHMP. He has a been a member and vice-chair of CHMP in the past, as well as a member of the agency’s Committee for Advanced Therapies, Committee for Orphan Medicinal Products, and the Emergency Task Force.

“As chair of the CHMP, my number one priority is ensuring the highest standards of medicine quality, safety and efficacy for patients in the European Union (EU),” said Sepodes in a press release (3). “Together, we will address the challenges and opportunities presented by novel technologies, including complex advanced therapies, the integration of digital health technologies and the use of artificial intelligence. We strive to facilitate rapid development and deployment of medicines, in particular when faced with health threats. Advancing regulatory science to support more efficient and evidence-based decision making remains crucial to deliver for patients across the EU."

Sepodes will begin a three-year term on Sept. 21, 2024.

1. EMA. Meeting Highlights from the Committee for Medicinal Products for Human Use (CHMP) 16-19 September 2024. Press Release. Sept. 20, 2024.

2. EMA. EMA Confirms its Recommendation to Update the Antigenic Composition of Authorized COVID-19 Vaccines for 2024-2025. Statement. July 19, 2024. 

https://www.ema.europa.eu/en/documents/other/ema-confirms-its-recommendation-update-antigenic-composition-authorised-covid-19-vaccines-2024-2025_en.pdf

3. EMA. EMA’s Human Medicines Committee Elects New Chair. Press Release. Sept. 18, 2024.

Approvals were recommended for treatments of ovarian cancer, lung cancer, bleeding disorders, respiratory disease, and more.

EMA Gives Approval to Several Cancer Treatments

Leadership and innovation, featuring a single red paper boat forging a unique path ahead of a fleet of white paper boats on a striking blue background. | Image Credit: ©John - stock.adobe.com

There are a variety of factors pushing innovation in formulation of drug products forward. The desire to create new delivery methods for biologics, the need to increase patient adherence, and technologies such as artificial intelligence (AI) are some of the trends drug developers in the industry are cultivating.

According to Sibaji Biswas, executive director and chief financial officer at Syngene International, patient-centric approaches have led to formulation strategies being reshaped, especially for biologics, with compounds for low solubility and oral bioavailability in small-molecule drugs continuing to see growth. “This has increased demand for solubility and bioavailability enhancement technologies, with CDMOs [contract development and manufacturing organizations] now needing more comprehensive capabilities so they can take a ‘fit-for-purpose’ approach to any challenge,” says Biswas. “Solid dispersion technology and other solubility enhancement methods are gaining prominence, while AI and machine learning [ML] are helping transform pharmaceutical formulation by predicting properties and behaviors.”

The use of ML and AI has been increasing in the bio/pharmaceutical industry. For formulation, they are being used to enhance modeling and predictive approaches, according to Shahrzad Missaghi, senior manager of Product Development, at Colorcon.

ML and AI allow for rapid innovation, according to Asma Patel, VP, Integrated Development Services, Quotient Sciences, as long as members of the industry are open to using these technologies. “From a discovery perspective, this can continue to fuel complexity in small new chemical and new molecular entities (NCEs/NMEs). Regardless of AI/ML, NCEs/NMEs continue to see an increase in average molecular weights and generation of new classes such as PROTACs [Proteolysis targeting chimeras], both creating solubility challenges for pharmaceutical formulation,” says Patel.

Vincent Levet, PhD, director, Formulation Development and Production, Ardena, agrees. “[AI] is showing great potential to revolutionize formulation development, from supporting excipient selection to predicting outcomes and optimizing processes.”

Additional formulation trends include delivery through lipid nanoparticles, ultra-high protein concentration formulations, continuous manufacturing, automation, and the creation of orphan drugs.

Automation has had a significant impact on the development of medicines delivered in capsule and tablet forms, according to Vinay Patil, Product Development Manager at Sharp Services. “Modern machines offer high-speed, precision filling and can handle various fill materials such as powders, granules, pellets, and even liquids,” says Patil. “Even more currently, micro-dosing technology allows us to accurately dose small quantities of API, which is critical when working with potent drugs. These advancements have increased the speed and precision of drug production and expanded the range of materials that can be used.” Patil also points to advances in granulation, compression, and coating that have impacted formulation.

“The introduction of high-shear granulators, fluid-bed processors, and roller compaction has enhanced the production of tablets with better mechanical properties and dissolution profiles. Coating technologies have also advanced, with enteric coatings and controlled-release formulations becoming more common,” says Patil. “Recently, continuous manufacturing processes have improved tablet production efficiency, allowing for real-time monitoring and increased production speed. One very recent advancement is the use of 3D printing technology, which has allowed for the production of tablets with controlled release profiles personalized to individual patients.”

®
eBook: Trends in Formulation 2024
September 2024
Pages: 34–37

When referring to this article, please cite it as Haigney, S. Forging Ahead in Formulation. 

Pharmaceutical Technology®/Pharmaceutical Technology EuropeTM

New and existing technologies, as well as a patient-centric focus, are pushing drug formulation into exciting directions.

Forging Ahead in Formulation

A joint press release on Sept. 18, 2024 announced an imminent partnership between Adare Pharma Solutions, a Philadelphia-based contract development and manufacturing organization (CDMO) focused on oral dosage forms and associated technology, and Laxxon Medical, headquartered in New York City with R&D operations centralized in Jena, Germany (1). The alliance will work to provide current good manufacturing practice (cGMP) 3D printing capabilities to the pharmaceutical market, originating out of an Adare facility in Milan, Italy.

Utilizing Exentis Group’s Screen-Printed Innovative Drug (SPID) technology, 3D-printed oral dosage forms containing advanced geometric internal structures, plus a heterogeneous distribution of APIs, will be created, according to the press release (1). The end results desired by the two companies are formulation of complex pharmaceuticals whose properties are optimized—including but not limited to customizable release profiles of one or more APIs—improved bioavailability, and tailored pharmacokinetics.

“Our Pessano facility provides comprehensive CDMO solutions to customers in Europe, the United States, and Asia,” Tom Sellig, Adare CEO, said in the press release. “Adare’s collaboration with Laxxon expands our ability to provide incredible dose flexibility options such as taste masking, solubility enhancement, shape modifications for ease of swallowing, and multiple APIs.”

In May 2024, Adare announced that it would expand its high-potency handling capabilities in the US and Europe, including upgrades to the 220,000-sq-ft Pessano facility in Milan (2). Other improvements were to be made to Adare locations in Philadelphia and Ohio, with construction slated to be completed by the fourth quarter of 2024.

Similarly, the 3D printing system and new bulk preparation mixer installed at the Pessano site with the Adare-Laxxon partnership in mind should be fully operational by Q4 2024, the press release said (1).

“Laxxon’s partnership with Adare represents a significant step forward in actualizing our mission to drive disruptive global drug delivery and manufacturing solutions,” Helmut Kerschbaumer, CEO of Laxxon Medical, said in the press release. “This is an essential collaboration for Laxxon; Adare, with their CDMO expertise and state-of-the-art cGMP facilities, will enable us to produce clinical samples for our partners as well as our own internal pipeline.”

At INTERPHEX in New York City in April 2024, 

 spoke to Bill Whitford, strategic solutions leader at Arcadis, about the role and impact of 3D bioprinting for biologics (3).

“Machine vision now is really simple,” Whitford said at the time. “Ordering 3D printing and the ability to both direct and inspect a nascent print job using artificial intelligence (AI) … they feed on each other. The availability of bioprinters and what we call bio ‘inks’ is, in a commercial sense, what's really driving the final applications.”

1. Adare Pharma Solutions. Adare And Laxxon Announce 3D-Printing Collaboration. Press Release. Sept. 18, 2024.
2. Adare Pharma Solutions. Adare Expands Global High Potency Handling and Packaging Capabilities. Press Release. May 1, 2024.
3. Spivey, C. 

Bill Whitford of Arcadis Discusses 3D Printing for Biologics (INTERPHEX 2024).

The announcement of the pairing comes several months after Adare Pharma Solutions said it would upgrade several of its facilities, including in Milan, Italy, where the 3D printing operations will be located.

Featured Content

Drug Solutions Podcast:

Out-of-the-Box Packaging Advancements

Drug Digest:

Ask the Expert