Susan Haigney

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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 

Articles

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

Formulating Inhaled Medicines

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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

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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

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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

Korro Bio, a Massachusetts-based biopharmaceutical company that develops genetic medicines based on RNA editing, announced on Sept. 16, 2024 that it is collaborating with Novo Nordisk to develop targets to treat cardiometabolic diseases, such as obesity, diabetes, and cardiovascular diseases. Novo Nordisk will use Korro’s Oligonucleotide Promoted Editing of RNA (OPERA) platform as part of the collaboration.

According to Korro, “RNA editing can specifically and efficiently modulate protein function, potentially enabling access to previously undruggable targets for cardiometabolic diseases” (1). The company’s OPERA program uses “an oligonucleotide to co-opt a natural process in the human body to make changes in mRNA [messenger RNA] encoding the protein, leaving the DNA genome unaltered, thus aiming to bring a pharmacologically titratable approach using genetic medicine” (1).

“Novo Nordisk is a global leader in the discovery, development and commercialization of therapies for cardiometabolic diseases,” said Dr. Ram Aiyar, CEO and president of Korro, in a company press release (1). “This collaboration enables us to use our proprietary technologies and capabilities in RNA editing to develop potential new treatments for people living with chronic diseases without impacting our internal pipeline focus. This partnership will expand the opportunity to potentially bring targeted RNA editing to diseases with high prevalence.”

“We are excited to partner with Korro on its differentiated RNA editing platform as we explore novel technologies to address the unmet need for people living with cardiometabolic diseases,” said Uli Stilz, head of Novo Nordisk’s Bio Innovation Hub, in the Korro press release. “Korro’s platform aims to enable a titratable, transient, and highly specific editing approach at the RNA level which has the potential to transform care. With our deep knowledge of cardiometabolic diseases and Korro’s unique approach, we have the opportunity to establish a new paradigm of treatment modalities for cardiometabolic diseases by addressing otherwise undruggable targets.”

Korro is eligible to receive up to $530 million in upfront, development, and commercial milestone payments as part of the deal. The company will also receive tiered royalties and R&D funding. Preclinical development will be handled by Korro with Novo Nordisk advancing the treatment through clinical studies.

This collaboration adds onto Novo Nordisk’s recent plans to increase treatments for these types of diseases. In June 2024, the company announced it was expanding its facility in Clayton, NC, investing $4.1 billion (approximately DKK27 billion) in a fill/finish manufacturing facility to increase its production of current and future injectable therapeutics for treating obesity and other serious chronic diseases. The investment is one of the largest the company has made and will include 1.4 million square feet of production space for aseptic manufacturing and finished production processes, doubling the combined square footage at the company’s existing facilities in North Carolina. The new facility is expected to be completed in 2029 (2).

“It took us a century to reach 40 million patients, but through this expansion and continued investment in our global production, we’re building Novo Nordisk’s ability to serve millions more people living with serious chronic diseases in the future,” said Lars Fruergaard Jørgensen, president and CEO of Novo Nordisk, in the press release (2). “This is yet another real signal of our efforts to scale up our production to meet the growing global need for our life-changing medicines and the patients of tomorrow.”

Korro Bio. Korro Bio Announces Collaboration with Novo Nordisk to Develop Two Therapeutic Candidates. Press Release. Sept. 16, 2024.

Novo Nordisk. Novo Nordisk Announces 4.1 Billion USD Investment to Expand US Manufacturing Capacity. Press Release. June 24, 2024.

Novo Nordisk will use Korro Bio’s OPERA platform to develop RNA editing candidates for two targets to treat cardiometabolic diseases.

Korro Bio and Novo Nordisk Collaborate on Cardiometabolic Treatments

On Tuesday, Sept. 10, 2024, Nicholas Violand, director of Enterprise Regulatory Compliance at Johnson & Johnson, and Paul Palmer, managing director and pharmaceutical consultant at Paul R. Palmer Limited, gave presentations on challenges that may arise with aging pharmaceutical manufacturing facilities at the PDA/FDA Joint Regulatory Conference in Washington, DC.

Violand’s presentation focused on industry challenges for aging facilities, equipment risks, identifying such risks, and improving controls (1). He pointed out that drug shortages caused by outdated equipment and facilities are still a relevant problem, according to FDA, and that facility inspection issues are a “fast growing factor” in complete response letters for biologics license applications. Higher operating costs, risk of product rejections, and recalls for non-compliance may be associated with large, outdated facilities, according to Violand.

Some key risks involved in aging facilities that Violand pointed to are conditions such as temperature, mold, damage, and a lack of cleaning and maintenance. Damaged or deteriorating equipment may lead to quality defects, visibly unclean equipment can be difficult to validate, and poor facility design may lead to contamination, he said.

To mitigate some of these issues, Violand recommended business partnering and open lines of communication and oversight as crucial elements. He pointed to strategic planning to ensure baseline resource allocation. He also suggested internal and external site monitoring programs to identify risks involved in an aging facility.

Palmer’s presentation included two case studies involving aseptic facilities (2). He detailed environmental monitoring failures found at one of the facilities, which had recently experienced a change of ownership, that included squishy floors, mold, broken seals in windows, and a variety of other problems, including cheap fixes, during a consultation audit of the facility.

After their presentations, Violand and Palmer were joined by Sandra Boyd, drug national expert, OMPTO, ORA, FDA, for a Q&A session. The topic of limited capital was raised and what best practices can be used. Boyd said quality culture is “huge,” and it permeates throughout a company. If quality culture is good, then quality is a priority.

Violand said one should identify the problem and the risk associated with it. Most facility- and equipment-related action plans are not immediate, and one should contain the problem and then earmark it for the future to identify what can be done to fix it in the future, using metrics, etc., he said. Looking at the consequences can help decide to make an investment.

The question of FDA expectations for contract manufacturing organizations to transition to newer aseptic technologies in the future arose. Boyd commented that FDA inspectors will focus on old technologies, such as open restricted access barrier systems, instead of newer technology like isolators, which are difficult to maintain. Companies should not wait for FDA inspectors to come in and point out old technology, suggested Boyd, and she also said it’s a good idea to get an outside perspective on processes to see where things may be not ideal.

Violand cautioned that when FDA sees an open process, the inspector will spend time watching that process and will see things are outdated that may have gaps and, therefore, risk.

Violand, N. Risk Communication: Addressing Aging Facility Concerns to Ensure Sustainable Product Quality. Presentation at the PDA/FDA Joint Regulatory Conference 2024. Sept. 10, 2024.

Palmer, P. Aseptic Facility Communication and Assessment. Presentation at the PDA/FDA Joint Regulatory Conference 2024. Sept. 10, 2024.

During a presentation at the PDA/FDA Joint Regulatory Conference, Nicholas Violand of Johnson & Johnson and Paul Palmer of Paul R. Palmer Limited discussed how aging facilities can impact the quality of pharmaceutical products.