Susan Haigney

Vivek Gupta, PhD, St. John’s University, discusses the formulation of inhalation drugs.

Developing Inhalation Drugs

The respiratory system is a complex organ that has specific implications to consider when developing drugs that are delivered through inhalation, according to Vivek Gupta, PhD, associate dean for Graduate Education and Research, associate professor, Pharmaceutical Sciences, St. John’s University, Queens, New York. One of the formulation considerations is the choice of excipients.

“When we talk about what kind of excipients can be used, and what impacts the choice of excipients, I think the primary thing that comes into mind is safety of those excipients. Because it's one thing for an excipient to be given orally, where it goes into the intestinal tract, gets delicate while it is traveling to the intestinal tract, and eventually into the bloodstream. Instead of that, when anything is given administered into the lungs, they tend to accumulate. They may or may not get metabolized, depending on what kind of environment, [the] kind of enzymes [needed] for metabolism, and they safety challenges [these excipients] pose. [Most] of the excipients that are used for inhaled dosage forms are more or less the same that have been approved for other routes of administrations as well. However, the quality of those excipients could be different.”

Click on the above video for a discussion with Dr. Gupta about the challenges of formulating inhalation drug products. Dr. Gupta will be providing an on-demand prologue discussion, 

Advances and Challenges in Inhaled Drug Product Development,

 for AAPS PharmSci 360 in 2024. AAPS PharmSci 360 is being held from October 20–23, 2024 in Salt Lake City, UT.

Videos

For a preview of what's to come at the AAPS PharmSci 360 show in October, Pharmaceutical Technology® spoke with Vivek Gupta, PhD, associate dean for Graduate Education and Research, associate professor, Pharmaceutical Sciences, St. John’s University, Queens, New York, about the formulation of inhalation dosage forms.

AAPS PharmSci 360 2024: Developing Inhalation Drugs

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The first nasal spray for emergency treatment of type 1 allergic reactions, including anaphylaxis, in adults and in children who weigh at least 30 kilograms was approved by FDA on Aug. 9, 2024 (1,2). Neffy is a single-dose epinephrine nasal spray used to treat allergic reactions and was approved through FDA’s Fast Track designation. Epinephrine has only been previously delivered by injection.

According to FDA, the approval of Neffy was based on four studies that measured epinephrine concentrations in 175 adults following administration of Neffy or injected epinephrine. Results of blood concentrations between Neffy and epinephrine injection were comparable. Similar increases in blood pressure and heart rate were also seen. Epinephrine blood concentrations in children who weighed more than 66 pounds and were given Neffy were similar to adults.

“Today’s approval provides the first epinephrine product for the treatment of anaphylaxis that is not administered by injection. Anaphylaxis is life-threatening, and some people, particularly children, may delay or avoid treatment due to fear of injections,” said Kelly Stone, associate director of the Division of Pulmonology, Allergy and Critical Care in FDA’s Center for Drug Evaluation and Research, in an FDA press release (1). “The availability of epinephrine nasal spray may reduce barriers to rapid treatment of anaphylaxis. As a result, Neffy provides an important treatment option and addresses an unmet need.”

According to ARS Pharmaceuticals, the company that applied for FDA approval of the drug, type 1 allergic reactions result in approximately 500,000 emergency room visits each year (2). Anaphylaxis, which is life-threatening, is considered a medical emergency.

“Until today, patients with severe allergic reactions, including anaphylaxis, only had one treatment option—an often painful and anxiety-inducing needle injection of epinephrine. In some cases, patients would delay or not administer the life-saving treatment at the onset of symptoms, increasing the risk for a severe reaction or negative outcomes requiring additional emergency medical treatment,” said Thomas B. Casale, professor of Medicine and Pediatrics and Chief of Clinical and Translational Research in the USF Health Morsani College of Medicine's Division of Allergy and Immunology at the University of South Florida in Tampa, Fl., in a press release (2). “FDA approval of Neffy means that patients with severe allergies finally gain a long-awaited, needle-free, easy-to-carry epinephrine delivery method that has the potential to reduce time to administration, which can lead to better clinical outcomes and improvements in quality of life for patients and their caregivers.”

“This approval marks a watershed moment in addressing an unmet medical need for people with Type I allergies—a treatment alternative that avoids the need to inject epinephrine with a needle, which can be fraught with anxiety and fear for many,” said Richard Lowenthal, co-founder, president, and chief executive officer, ARS Pharmaceuticals, in the company press release (2). “Epinephrine treatment is only effective if available, readily usable, and administered appropriately. Our team has worked tirelessly to create an easy-to-carry, easy-to-use, needle-free device that offers peace of mind to patients and caregivers by enabling them to administer epinephrine quickly and confidently when needed. We thank the FDA staff for their partnership and support in the development of Neffy, and are deeply grateful to the severe allergy community, including advocates, patients, parents, and healthcare professionals, for their contributions to the development of Neffy as an important, life-saving treatment.”

Nasal polyps and other nasal conditions may impact the absorption of Neffy, warns FDA. Side effects of Neffy includethroat irritation, tingling nose, headache, nasal discomfort, feeling jittery, tingling sensation, fatigue, tremor, runny nose, itchiness inside the nose, sneezing, abdominal pain, gum pain, numbness in the mouth, nasal congestion, dizziness, nausea, and vomiting.

FDA. FDA Approves First Nasal Spray for Treatment of Anaphylaxis. Press Release. Aug. 9, 2024. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-nasal-spray-treatment-anaphylaxis

ARS Pharmaceuticals. ARS Pharmaceuticals Receives FDA Approval for Neffy (Epinephrine Nasal Spray), the First and Only Needle-Free Treatment for Type I Allergic Reactions, Including Anaphylaxis. Press Release. Aug. 9, 2024. 

https://ir.ars-pharma.com/news-releases/news-release-details/ars-pharmaceuticals-receives-fda-approval-neffyr-epinephrine

Articles

The epinephrine nasal spray was approved for the emergency treatment of type 1 allergic reactions in adults and children.

First Nasal Spray for Anaphylaxis Approved by FDA

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Contract organizations offer sponsor companies flexibility by providing capacity, expertise, knowledge, and cost savings. Contract manufacturing organizations (CMOs), contract development and manufacturing organizations (CDMOs), and other contract organizations can also offer smaller bio/pharma companies greater opportunities, by providing the resources smaller biopharma companies may not have. According to Robert O’Brien, director operations—Packaging & Logistics at Almac Pharma Services, sponsor companies should consider if contracting activities to a CMO is more cost effective than performing those activities in-house. O’Brien points to direct access to specialists and equipment, a level of control of quality standards, and requirements for scale up as factors to consider when deciding whether to outsource or not. “Outsourcing enables the sponsor company to concentrate on their core competencies, product innovation, and strategic initiatives,” O’Brien says.

When making the decision to outsource a particular process to a contract partner, there are several things sponsor companies should consider. Tech transfer is an important step when outsourcing to a CDMO and should be evaluated when choosing to outsource processes, specifies Peter Ercoli, chief operating officer, Biologics, at BIOVECTRA. Ineffective tech transfers can lead to persistent complications, adds Ercoli. “Conversely, sponsors should ensure their processes are completely defined before initiating a tech transfer, unless they want the CDMO to define it for them. In the case where sponsors are leaning on the CDMO to define their tech transfer process, both parties must be clear on this understanding from the outset,” he says.

Not following regulatory requirements can also complicate the situation when working with CDMOs, according to Ercoli. “The last thing a sponsor wants is to successfully complete the tech transfer and scale-up phases only to fail a pre-approval inspection. Such a failure can be catastrophic, potentially setting back the project by months or even years. While other challenges can be managed with guidance or collaboration, the readiness of facilities and personnel for regulatory inspections is non-negotiable and must be thoroughly vetted,” he says.

The benefits of an outsourcing partner extend to most, if not all, aspects of development and manufacturing, and analytical testing is no different. “CDMOs amass a great breadth and depth of knowledge through their exposure to a wide range of product types including small molecules, peptides, biologics, conjugates, highly potent, and controlled substances,” says Susan Hackett, associate director—Technical Operations, Almac Sciences. “Additionally, not all companies have the appropriate infrastructure to accommodate analytical testing; therefore, outsourcing these operations to an established CDMO helps to save time and cost.”

Outsourcing finished product testing is beneficial for sponsors, because it can provide unbiased results, according to Shailesh Vengurlekar, senior VP Quality & Regulatory Affairs, at LGM Pharma. Sponsor companies should consider the quality of the work and the data provided by a contractor when selected a testing partner. Turnaround time, infrastructure, cost, and communication are also key, according to Vengurlekar.

“Sponsors typically benefit most when outsourcing complex testing services that they may not have the capability (equipment, personnel expertise, time, etc.) to perform in-house,” says Vengurlekar. “[Whereas], it is also beneficial to sometimes outsource simple and routine testing involving a lot of the sponsor’s time and labor. The time can be better utilized by the Sponsors to develop their product database as well as on timely submissions to meet company goals.”

A robust methodology can be achieved by outsourcing method development and validation, remarks Hackett. “As the drug develops, working with a provider who has a dedicated team utilizing orthogonal techniques such as mass spec[trometry], ID testing, can be hugely beneficial and help to resolve any issues much quicker,” says Hackett. “For finished product testing, outsourcing to a partner who has the capability, capacity, and resources to manage all testing aspects together can alleviate many of the issues which inherently arise during drug development.”

Hackett stresses that both the sponsor and the contractor are responsible for analytical testing and should maintain good communication. “Ensuring that there is equivalent equipment between the labs is an obvious solution, and that the methods are fully understood by both teams,” she says. “Robust processes, particularly with method transfer and familiarization, should also ensure the chances of success. However, as stated, having access to a team who are well experienced in orthogonal techniques can be hugely beneficial if [testing failures] occur to conduct deeper analysis to troubleshoot and find a resolution,” says Hackett.

“[Testing results] may vary [from sponsor to contractor] if the method transfer has been incorrectly performed or same methodology/equipment are not used by testing laboratories. Significant variations or laboratory errors are observed due to lack of proper training, poor quality of protocols, or detailed procedures,” says Vengurlekar. “Typically, collaboration between both parties is required to investigate the results from both ends to determine the true value. The sponsor should always take the lead to investigate the root cause and guide contractor labs to put appropriate corrective and preventive actions (CAPAs) in place.”

Packaging is one of the final steps when manufacturing a bio/pharmaceutical product and sending it out to the market. The quality of a product can be compromised by a variety of factors, including temperature; therefore, O’Brien notes that packaging materials should be carefully selected. Other challenges include labeling and serialization requirements.

Packaging providers can provide cost savings by sparing a sponsor from having to invest in equipment, facilities, personnel, and a broad network of suppliers, according to O’Brien. Contractors may offer state-of-the-art technology and staff training, he states. “[O]utsourcing allows sponsors to achieve scalability and flexibility, enabling them to scale their packaging operations up or down based on demand. This flexibility is crucial for adapting to market fluctuations and growth opportunities,” O’Brien states.

Contracting out packaging services can also offer a layer of quality control. Contract packagers offer experience with regulations in various territories and can help ensure safety and quality standards are correctly met, specifies O’Brien. “External partners often have robust quality control systems in place. This ensures that packaging adheres to industry and highest quality standards ensuring products maintain stability throughout the supply chain,” he says.

When partnering with a contract packager, O’Brien stresses that specifications, timelines, and quality standards must be aligned with both parties. “Risk management is a key concern—it’s vital to mitigate potential disruptions to the supply chain that may arise due to unforeseen events. Quality control is similarly critical—consistency and compliance across the packaging process must be maintained. Cost management—balancing cost-effectiveness with quality—is a perpetual consideration,” says O’Brien. “Lastly, intellectual property protection must be addressed to safeguard proprietary information during collaboration. Overall, these challenges can be overcome through close collaboration, transparency, and clear agreements between both parties to ensure successful outcomes.”

Partnerships don’t always work out. But what if that partnership is the development and/or manufacture of an important drug product? If a sponsor company must change from one contract manufacturer to another when a project is already underway, what challenges may they face? Transferring mid-project from one contract to another requires close coordination, according to O’Brien, to minimize delays and costs.

“Proactive planning and open communication including full, and early, transparency regarding any concerns, is key to overcoming these challenges,” says O’Brien. “In addition, rigorous quality control measures are essential to ensure consistent quality between the existing and new provider. Finally, internal and partner teams should be cautious and thorough when migrating data, documentation, and intellectual property to avoid delays and errors during the transition. Both parties need to adjust to new processes, communication channels, and expectations therefore continual briefing, communication and escalation, where required, is essential throughout.”

“When switching from one CDMO to another during a project, the new partner or CDMO should be given access to communicate with the innovator directly,” says Ercoli. “This approach allows for a clear understanding of the development context and enables questions to be answered accurately. Direct access to the innovator ensures that the original intent of the project is preserved. Otherwise, transitioning from one CDMO to another often results in miscommunication. The process can resemble a game of ‘telephone’, where information is passed along through multiple intermediaries, leading to potential distortions. By the time the message reaches the new CDMO, the original intent may be lost, complicating the project further. To mitigate these risks, all parties involved should strive to keep open lines of communication as much as possible during the transition.”

Outsourcing can provide a variety of benefits for a sponsor, whether the outsourced service is testing, packaging, manufacturing, or another process in the lifecycle of the product. If a sponsor chooses to outsource work, they should keep quality in mind. Contractors will most likely have several customers; therefore, sponsors should look for customized quality control (1).

“When CDMOs develop quality agreements with a greater focus on client needs, it can increase trust, compliance, and even make audits easier to manage. Complex procedures can be simplified by engaging all parties and clearly documenting in the quality agreement from the start. While this may add initial time and cost, over the long run this will pay out with less process issues, including errors or oversights,” said Iain McGhee (1).

Taking these factors into consideration can help a sponsor company create the best outsourcing strategy for the company, the product, and the patient.

1. McGhee, I. Ensuring Quality in Contracted Support. 

BioPharm International Partnerships for Outsourcing eBook.

®
Vol. 48, No. 8
August 2024
Pages: 31–33

When referring to this article, please cite it as Haigney, S. Contracting Out Frees Sponsors Up. 

Contract organizations offer sponsors specialized equipment, capacity, and expertise for testing, manufacturing, and packaging bio/pharmaceutical products.

Contracting Out Frees Sponsors Up

The US Pharmacopeia (USP) announced on July 26, 2024 that its Microbiology Expert Committee has approved the inclusion of Chapter <86> Bacterial Endotoxins Test Using Recombinant Reagents into the

 United States Pharmacopeia–National Formulary (USP–NF). 

The chapter permits the use of non-animal-derived reagents for endotoxin testing; the finalized chapter will be published for early adoption in November 2024 before becoming official in May 2025. The new chapter is part of USP’s commitment to expanding the use of animal-free methods and materials.

Endotoxins may cause irreversible side effects and even death in severe cases at sufficient concentrations in the bloodstream (1). Bacterial endotoxins are found in the outer cell membrane of Gram-negative organisms and are known to be one of the most potent toxins. “These toxins are harmless outside of the body and in the alimentary canal. They are extremely potent, however, once introduced in the bloodstream or intrathecally,” Allen L. Burgenson, Testing Solutions, Lonza Pharma & Biotech, said (1).

“Bacterial endotoxins (also referred to as pyrogens) have the capacity to induce a high fever,” said John Dubczak, general manager, Microbial Solutions, Charles River Laboratories (1). “A large enough dose of endotoxin can lead to lung and kidney failure, intravascular coagulation, and a systemic inflammatory response that can lead to septic shock and death.”

Therefore, endotoxin testing is an important part of the quality and safety steps taken in the manufacture of certain sterile pharmaceutical products. Techniques for bacterial endotoxin testing using non-animal derived reagents are provided in the new chapter. Specifically, the new chapter discusses methods using both recombinant cascade (rCR) and recombinant Factor C (rFC) reagents. It also gives information on how to incorporate the methods into quality testing.These new techniques are in addition to those found in Chapter <85> Bacterial Endotoxins.

“Chapter <86>is intended to provide manufacturers with the information needed to use non-animal derived reagents. Manufacturers that currently use limulus amebocyte lysate (LAL) for endotoxin testing can continue to do so and Chapter <86> has no impact on them,” USP said in a press release (2).

One of the main endotoxin tests, LAL assay “works via the reaction of the LAL reagent-an aqueous extract of blood cells from the horseshoe crab-with bacterial endotoxins and lipopolysaccharides” (1). While the LAL test is an animal-derived test, and the animal itself is not tested upon, the desire to reduce animal use in testing has influenced the pharma industry, which resulted in the LAL test replacing the previous standard Rabbit Pyrogen Test. The LAL test is an animal-derived test, meaning the animal itself is not tested upon (1). This change prevented the use of hundreds of thousands of rabbits per year. There has also been a commitment to conserve the horseshoe crab. “Work has included sustainability partnerships to enhance the horseshoe crab population along the mid-Atlantic shores,” said Victoria Watson, laboratory manager, Microbiology at Wickham Labs. “Such projects have focused on increasing the survival rate of the horseshoe crab in early stages of life. Eggs are collected, and the crabs are grown in predation-free, controlled environments then released into their natural environment when older and stronger” (1).

Thomas, F. Putting Endotoxins to the Test. 

https://www.pharmtech.com/view/putting-endotoxins-test

USP. Expert Committee Approves Endotoxin Testing Using Non-animal Derived Reagents. Press Release. July 26, 2024.

The US Pharmacopeia’s Microbiology Expert Committee approved the inclusion of a chapter into the United States Pharmacopeia–National Formulary that allows the use of non-animal-derived reagents for endotoxin testing.

USP Permits Use of Non-Animal-Derived Reagents for Endotoxin Testing

Quality Considerations for Using AI in Bio/Pharma

Ask the Expert Episode Two

The use of artificial intelligence (AI) is seeing a surge in a variety of industries. But does the regulated nature of bio/pharmaceutical development, manufacturing, and commercialization serve up unique challenges for incorporating AI into processes? According to Siegfried Schmitt, vice-president, Technical, at Parexel, using new technology will most likely require the assistance of experts in that technology. And if you’re contracting a third party for that help, you need to do an assessment of that vendor.

“[T]he thing with AI, it being a computer-based technology, there is sometimes the issue of, do you have sufficient or good documentation practices applied? It's all too easy to play around with computer code and settings and so on, but you do need to have appropriate documentation, and because you're applying it to process development … It is something that can get inspected, so be ready for an inspection,” Schmitt cautions.

Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, stresses that a robust quality management system and document control are necessary when adding AI to a process. “I also worry about if there's the expertise to interpret what the data [are] telling you. You're going to be collecting a lot more data than you've collected before, and data that's new, and how it impacts your organization. And the data you're collecting may prompt you to want to make a change in the coding, [but] you need to follow that stream through your quality management system,” Schniepp says.

Click the video above to watch Sue and Siegfried answer the question: “My company is researching the possibility of using AI in the formulation of a new product. Are there any quality considerations we should be aware of?”

 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. 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 want answered, sent it to 

Susan J. Schniepp is distinguished fellow at Regulatory Compliance Associates and a member of 

Siegfried Schmitt is vice president, Technical at Parexel and a member of 

In the second episode of the Ask the Expert video series, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, vice-president, Technical, at Parexel, discuss the quality requirements needed when incorporating AI in bio/pharmaceutical development and manufacturing.

FDA announced on July 17, 2024 that Endo Inc.’s subsidiary, Endo USA, is voluntarily recalling one lot of Clonazepam Orally Disintegrating Tablets, USP (C-IV) 0.25 mg tablets (also seen as Clonazepam Orally Disintegrating Tablets, USP (C-IV) 0.125 tablets 60-count) because an incorrect strength appears on the cartons of some packs. The product strength is listed as 0.125 mg and not 0.25 mg. The error was made by a third-party packager. The inside blister strips have the correct strength of 0.25 mg noted.

The recalled lot, which was distributed through wholesale distributors to retail pharmacies nationwide,includes Clonazepam Orally Disintegrating Tablets, USP 0.25 mg 60-count carton, lot 550147301, expiration date August 2026, and Clonazepam Orally Disintegrating Tablets, USP 0.125 mg 60-count carton, lot 550147301, expiration date August 2026; National Drug Code (NDC) number 49884-306-02. The product is packaged in cartons of 60 tablets.

Clonazepam Orally Disintegrating Tablets are used as an adjunct in the treatment of the Lennoz-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures, as well as panic disorders. Significant sedation, dizziness, ataxia, and confusion may result in children and adults who take a larger dose than prescribed. There is potential for life-threatening respiratory depression, especially in patients with concomitant pulmonary disease, patients prescribed doses near the maximum dosing allowed, and patients taking other medications. “In the event that a patient inadvertently took a 0.25 mg dose rather than the intended 0.125 mg dose, they are advised to consult a physician,” the company stated in the press release (1).

The company stated it has not yet received any reports of adverse events related to the recall. Adverse events may be reported to FDA through its MedWatch program.

Written notification is being sent to wholesale distributors and retailers so that the impacted lot can be returned. “Consumers in possession of any unused prescribed 60 tablet cartons of Clonazepam Orally Disintegrating tablets, USP 0.25mg, which may also appear as Clonazepam Orally Disintegrating tablets USP 0.125mg bearing the lot number 550147301 have been advised to discontinue use of the product,” the company stated in the release.

Recalls can result in quality issues that impact drug supplies. In February 2024, FDA’s Center for Drug Evaluation and Research (CDER) released its report, 

. The report describes the center’s key safety programs and activities involved in promoting and protecting public health (2). Postmarketing surveillance and risk evaluations are performed by FDA on products to identify new adverse events that were not present in the approval process. New information is investigated by the agency and may require changes in prescribing information or modification of a Risk Evaluation and Mitigation Strategy. CDER’s pharmacovigilance efforts in 2023 included reviews of 15 newly identified safety signals (NISS). One of these NISS was related to naloxone hydrochloride product administration. There were attempts to administer a syringe that had no needle. In response, FDA required changes to carton labeling to include a warning that said, “Needle not included.”

FDA. Endo USA, Inc. Issues Voluntary, Nationwide Recall of One Lot of Clonazepam Orally Disintegrating Tablets, USP (C-IV) Lot Number 550147301 Due to Mislabeling: Incorrect Strength on Product Carton. Press Release, July 17, 2024. 

https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/endo-usa-inc-issues-voluntary-nationwide-recall-one-lot-clonazepam-orally-disintegrating-tablets-usp

Haigney, S. FDA’s Drug Safety Priorities for 2023. 

https://www.pharmtech.com/view/fda-s-drug-safety-priorities-for-2023

The company has issued a voluntary recall of one lot of Clonazepam Orally Disintegrating Tablets, USP (C-IV), because of incorrect strength published on product carton.