Behind the Headlines Episode 27

Ask the Expert

Small Molecules, APIs, and Excipients—Trends, Challenges, and Opportunities

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Margaret Radford is unlicensed medicine services manager at Almac Clinical Services.

Lyn McNeill is Just in Time Manufacturing Solutions manager at Almac Clinical Services.

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In the era of patient centricity, managed access programs (MAPs) are coming of age. While this program type was previously considered a more reactive tactic, sponsors today are increasingly harnessing MAPs—also known as compassionate use programs or early access programs—to provide patients with an unmet medical need with access to unlicensed medication. Used as a strategic tool, MAPs can facilitate optimized, patient-centric, and cost-effective access to investigational drugs outside of a trial setting.

As use of MAPs matures, the potential they represent is becoming more universally acknowledged. As MAPs are designed to deliver treatment access, rather than facilitate research and commercialization, they can be simpler and more cost-effective to operate. MAPs can also support the expansion of patient demographics, strengthen relationships with patient advocacy groups, increase exposure to more healthcare professionals prior to commercialization, and support corporate social responsibility agendas.

There are, however, several key challenges that can prevent sponsors realizing the full potential of MAPs. Many of which can be overcome by embracing a just-in-time manufacturing (JTM) strategy.

Specific challenges vary depending upon the pathway chosen (named patient or patient cohort) but relate to regulatory oversight, product presentation, and supply chain.

Where regulatory activity is concerned, a patient cohort pathway will place full responsibility on the sponsor. This pathway can increase the burden of operating a MAP, especially in regions like Europe, where each member state has its own legislation relating to how European Medicines Agency recommendations are implemented.

Likewise, the nuanced supply chain challenges relating to MAPs are significant. Due to the reactive nature of the program type, demand forecasting is particularly difficult. This difficulty increases the risk of waste or rework if supplies surpass expiry dates while awaiting patient allocation, which can be particularly costly when dealing with biologics and advanced therapies. It also increases the risk of negative patient impact if insufficient drug is available when the patient need arises. In either scenario, a sponsor’s ability to start-up and respond quickly once demand is known is seriously hindered.

To overcome these challenges, the industry is seeking better solutions for MAPs delivery. Solutions that deliver an improved service to patients and healthcare providers (HCPs), while driving improved operational efficiency. JTM is proving useful in this respect by increasing flexibility for packaging and labeling to meet both geographical and forecasting complexities and providing sponsors with more effective management of supplies across both MAPs and clinical trials.

JTM refers to the late-stage customization of clinical kits. It’s a demand-led production technique designed to put patients first and deliver an adaptive supply strategy to meet expanding challenges, including concurrent clinical trial and MAP delivery. JTM achieves all this by delaying secondary packaging and labeling activity until patient or site need arises.

And it really comes into its own where MAPs are concerned. For instance, late-stage customization means unlicensed medicines can be directed to where they are needed, both in terms of geography and volume, helping to reduce cost by conserving drugs. Supply also becomes more flexible when using JTM, as supplies can be used for any country without the need for booklet labels.

Similarly, JTM supports supply pooling, empowering sponsors to use the same bulk supply across clinical trials and MAPs and, through standardizing key elements across pooled lots, benefit from economies of scale without sacrificing the flexibility required to share the product. And because products are only packaged and labeled when needed, JTM reduces exposure to expiry date events. Not only is there less date labeled stock at risk of expiry update loss in the field, but there is also no depot stock requiring relabeling.

Where patient centricity is concerned, JTM supports MAP sponsors to deliver patient specific packaging, helping to lower overheads and improve patient understanding and compliance.

MAPs are typically subject to significant change. Timelines can shift. Participating countries can alter. Regulation and ongoing clinical trial activity can influence supply requirements. While operating a traditional batch manufacturing approach can leave sponsors restricted in their ability to respond to these kinds of changes, JTM supports sponsors to adapt, achieve earlier start-ups, improve reaction time to demand changes, and realize more sustainable supply chains.

To realize these benefits, reduce waste and optimize supplies, JTM must be approached correctly at the time of MAP development. Proactive planning to incorporate JTM can make the process faster, easier, and increase the likelihood of achieving optimal results.

Furthermore, a robust pre-production phase is needed to establish a quick pack, label, and quality release cycle for unlicenced medication. This means developing blueprints for receipt of unlicensed medication at packaging and labeling facilities, agreeing on pack design details, procuring kit components, and translating label text for initial participating countries.

Master packaging specifications will also need to be created within an enterprise resource planning (ERP) system to define each finished good by country, expiration date known at the time, and unique lot number. The ERP will also need to maintain the components required to make future kits, including the assigned bulk drug lot, the approved master label and label variables.

If appropriate planning takes place during pre-production, JTM production and distribution can be completed rapidly, with orders received, validated, and translated to a label work order and assembly work order via the ERP. Labels can then be printed, checked, and approved by quality control for use in the JTM pack and label operation.

MAPs represent an opportunity for sponsors to uphold ethical and regulatory responsibilities to patients with an unmet medical need. More than this, they have the potential to support sponsors to expand their own horizons by driving cost-efficiencies, capturing real-world data in support of commercialization goals, and building strong relationships with a range of key stakeholders. By harnessing JTM as a supply chain solution for MAPs, sponsors can look to maximize these opportunities and deliver production strategies that support speed, agility, and patient centricity.

Margaret Radford is unlicensed medicine services manager, and Lyn McNeill is Just in Time Manufacturing Solutions manager, both at Almac Clinical Services.

Articles

Challenges that can prevent sponsors realizing the full potential of managed access programs can be overcome by embracing a just-in-time manufacturing strategy.   

Understanding the Benefits of Harnessing Just in Time Manufacturing as a Supply Chain Solution for Managed Access Programs

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On Dec. 23, 2024, the World Health Organization (WHO) provided an update on COVID-19 vaccine antigen composition, pointing to the continued evolution of variants of the virus. A review of data has resulted in the recommendation that the current COVID-19 vaccine antigen composition, monovalent JN.1 lineage variant(NextStrain: 24A, GenBank: PP298019, GISAID: EPI_ISL_18872762), be used to enhance neutralizing antibody responses to JN.1 and its descendants. Vaccine antigens from more recent variants or alternative formulations is also a possible approach.

WHO’s Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) has been monitoring genetic and antigenic evolution of SARS-CoV-2 variants and the performance of COVID-19 vaccines against these variants. WHO then advises manufactures of vaccines and regulatory authorities on implications of updates to the vaccines.

In December 2024, the TAG-CO-VAC met to review the evolution of SARS-CoV-2. Also discussed were the immune responses to the infection and vaccination. Currently approved COVID-19 vaccines were evaluated by the advisory group, which then provided an update on antigen composition. Previously, in April 2024, the group recommended the use of a monovalent JN.1 lineage vaccine antigen in response to JN.1 and its descendants. Manufacturers responded by updating their COVID-19 vaccine antigen composition to monovalent JN.1, with some of these approved by regulatory authorities.

The TAG-CO-VAC reviewed evidence that included the SARS-CoV-2 genetic evolution, antigenic characterization of previous and emerging SARS-CoV-2 variants, immunogenicity data on antibody responses seen in approved vaccine antigens, preliminary immunogenicity data on immune responses, vaccine effectiveness estimates of approved vaccines against XBB.1 and JN.1 lineages, and preliminary preclinical data and clinical immunogenicity data on candidate vaccines. The evidence, according to WHO, show that SARS-CoV-2 continues to circulate globally, resulting in severe disease and death, especially in people 65 years and older and/or with existing conditions, and current variants are all derived from JN.1. Based on data using antisera, it appears thatcirculating JN.1-derived variants (JN.1, JN.1.16.1, KP.2, KP.2.3, KP.3, KP.3.1.1, LB.1 and XEC) are antigenically closely related. Data from vaccination frommonovalent JN.1 or KP.2 antigens showed a significant increase in neutralizing antibody titers that cross-reacted with all JN.1 descendent lineages tested.

“The weekly proportion of XEC sequences among all SARS-CoV-2 sequences submitted to GISAID continues to increase, while the weekly proportions of all other Variants of Interest (JN.1) or Variants Under Monitoring (KP.2, KP.3, KP.3.1.1, JN.1.18 and LB.1) are now declining,” WHO stated in a press release (1). “There are other JN.1-derived variants that are currently in low proportions, but which have mutations that may give them an advantage over XEC: currently LP.8.1, NP.1, LF.7.2 are variants being monitored and/or characterized.”

There are limitations to the data that were available for review, however, according to WHO. Gaps have been seen in the reporting of cases, hospitalizations, and deaths from WHO Member States. It is also hard to predict the timing of mutations and emerging variants, the organization said in the statement. Immunogenicity data against current variants are also not available for all COVID-19 vaccines. In addition, there are limitations in the number and geographic diversity of studies.

“Although neutralizing antibody titers have been shown to be important correlates of protection from SARS-CoV-2 infection and of estimates of vaccine effectiveness, there are multiple components of immune protection elicited by infection and/or vaccination,” said WHO. “Data on the immune responses following JN.1 descendent lineage infection or monovalent JN.1, KP.2 or XBB.1.5 vaccination are largely restricted to neutralizing antibodies. Data and interpretation of other aspects of the immune response, including cellular immunity, are limited.”

The TAG-CO-VAC is encouraging the generation of more data and the further development of COVID-19 vaccines. “The TAG-CO-VAC will continue to closely monitor the genetic and antigenic evolution of SARS-CoV-2 variants, immune responses to SARS-CoV-2 infection and COVID-19 vaccination, and the performance of COVID-19 vaccines against circulating variants,” WHO stated in the release. “The TAG-CO-VAC will also continue to reconvene every six months to evaluate the implications for COVID-19 vaccine antigen composition.”

1. WHO. Statement on the Antigen Composition of COVID-19 Vaccines. Press Release. Dec. 23, 2024. 

https://www.who.int/news/item/23-12-2024-statement-on-the-antigen-composition-of-covid-19-vaccines 

Pointing to the continued circulation and evolution of COVID-19, WHO published a statement on the COVID-19 vaccine antigen composition to respond to variants of the virus.

WHO Provides a Statement on COVID-19 Vaccines

Feliza Mirasol is the science editor for 

Roche has launched its cobas Mass Spec solution upon receiving the Conformite Europeenne (CE) mark approval for the product, including its cobas i 601 analyzer and what the company noted in a Dec. 18, 2024  press release is the first Ionify reagent pack of four assays for steroid hormones (1). The CE mark represents the first milestone in the global launch of the cobas Mass Spec solution. The offering aims to bring automated, integrated, and standardized clinical mass spectrometry testing to routine laboratories globally.

Following the launch, Roche will roll out a cobas Mass Spec solution menu offering that comprises more than 60 analytes for testing steroid hormones, vitamin D metabolites, immunosuppressant drugs (ISD), therapeutic drug monitoring (TDM), and drugs of abuse testing (DAT). The new offering will handle sample preparation through to result interpretation, and with it, Roche will be consolidating four technologies—ion selective electrode (ISE), clinical chemistry, immunochemistry, and mass spectrometry—onto a single platform, which the company expects will maximize efficiency and deliver enhanced medical value. The solution is designed to enable smart testing by leveraging physical and digital connectivity with other analytical units (2).

“The cobas Mass Spec solution will fundamentally change the field of clinical diagnostics,” said Matt Sause, CEO of Roche Diagnostics, in the press release (1). “The solution would make fully standardized clinical mass spectrometry more broadly available with the potential to improve patient care worldwide. For example, in breast cancer patients receiving hormone therapy, mass spectrometry can help physicians detect subtle changes in therapeutic response earlier, allowing for timely adjustments to treatment.”

Because mass spectrometry offers high specificity, sensitivity, and accurate analysis, it is considered the diagnostic “gold standard” for various clinical applications, such as measurements of steroid hormones in endocrinology, vitamin D testing, and the monitoring of immunosuppressants and therapeutic drugs, according to Roche in the press release. Mass spectrometry can benefit healthcare systems by, for example, monitoring the effective and responsible use of antibiotics as well as ongoing monitoring of disease progression and treatment. In addition, the high specificity of testing can provide greater levels of clarity to physicians, which would enable them to make more timely treatment decisions for patients.

In the meantime, Roche’s development of new, proprietary chemistry technology makes commercial automation possible and enables a workflow that is much more environmentally sustainable than current methods. “Until now, mass spectrometry has only been offered by specialist laboratories due to the low level of automation, integration and standardization, and the high complexity of the workflows that require highly skilled operators. This has resulted in great variability between different laboratories and long processing times,” the company stated in its release (1).

The cobas Mass Spec solution will be included in Roche’s established cobas pro integrated solutions product line, which enables full integration into clinical chemistry and immunochemistry testing as well as lab automation and IT.

1. Roche. Roche Transforms Mass Spectrometry Diagnostics with Launch of Cobas Mass Spec Solution. Press Release. Dec. 18, 2024.
2. Roche. cobas i 601 Analyzer. 

The launch of Roche's cobas mass spectrometry solution will bring fully automated mass spec analysis to the clinical lab. 

Roche Introduces New Mass Spectrometry Analyzer

The European Medicines Agency (EMA) announced on Dec. 18, 2024 that the agency, along with the Heads of Medicines Agencies (HMA) have revised their guidance on identification of commercially confidential information (CCI) and personal data used in marketing authorization applications as part of their commitment to transparency in the disclosure of information in response to access-to-document requests and the publication of data for authorized medicines.

The original 2012 guidance document offered, for the first time, a common approach for European regulators to use in order to identify parts of an application dossier that can or cannot be released publicly. EMA and national competent authorities have gained experience since then in the handling of access-to-documents requests and have applied more transparency when data is released. Therefore, EMA stated in a press release that it was necessary to review the 2012 guidance to align with current day-to-day practices and harmonize those practices across authorities. The revised guidance also applies to EMA’s 2014 proactive clinical data publication.

“As a general rule, the overwhelming majority of data in marketing-authorization applications is not considered CCI,” EMA stated in the press release (1). “The exceptions mainly relate to information about the manufacturing of a medicine, as well as information about facilities or equipment and some contractual arrangements between companies. While considered CCI at the time of the initial guidance, general information related to quality is now mostly considered releasable.”

The revised guidance considers information as “releasable by default” instead of applying a yes or no rule to an entire section of a dossier when determining which data can be released. Detailed practical orientations are provided for specific points that may be redacted or made anonymous within each section of the dossier. The guidance’s annex has also been updated to include examples of information that may be considered CCI or protected personal data.

How personal data are to be protected when it might lead to identification of a person is also detailed in the guidance. The revised guidance considers recent data protection legislation in the European Union, including the EU General Data Protection Regulation and Data Protection Regulation for the European Union. Identifying personal data of experts, staff, or patients that should be made anonymous is also addressed in the guidance.

The revised guidance went through public consultation in 2024 and report of the analysis from that consultation will be published in 2025.

The EU has been proactive over the past several years regarding data protection. In September 2024, EMA and HMA published recommendations for staff in the European Medicines Regulatory Networks about the use of generative artificial intelligence in large language models (LLMs), stating it could create potential data security risks (2). These guidelines are part of the HMA/EMA Multi-annual AI Workplan 2023–2028, published in December 2023, to be a guide for the use of AI in managing risk and maximizing benefits of AI.

1. EMA. A Common EU Approach to Data Transparency in Medicine Regulation. Press Release. Dec. 18, 2024.
2. Barton, C. Responding to the Increased Use of Generative AI. 

https://www.pharmtech.com/view/responding-to-the-increased-use-of-generative-ai

Revised guidelines published by EMA and HMA update the rules on identification of commercially confidential information and personal data used in marketing authorization applications.

Protection of Personal Data in European Medicine Regulation

Roche announced results on Dec. 19, 2024 from a Phase IIb study (PADOVA) where prasinezumab, an investigational monoclonal antibody (mAb), failed to achieve statistical significance, missing the study’s primary endpoint. The study involved 586 patients with early stage Parkinson’s disease (PD) who were treated for a minimum of 18 months while on stable symptomatic treatment. Prasinezumab demonstrated potential clinical efficacy in the primary endpoint, which was time to confirmed motor progression, with a hazard ratio (HR)=0.84 [0.69-1.01] and p=0.0657, missing statistical significance, according to a company press release (1). The effect of prasinezumab, as evaluated in a pre-specified analysis, was more pronounced in the patients (75% of the participants) who were treated with levodopa, with results showing a HR=0.79 [0.63-0.99]. It was also observed that consistent positive trends occurred across multiple secondary endpoints as well as exploratory endpoints.

Prasinezumab also remains well tolerated and no new safety signals were observed in the study. Roche is evaluating the data further and will work together with health authorities to determine what steps to take next.

“Parkinson’s is complex and devastating with no disease modifying treatment options available for the millions of people impacted,” said Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, Roche, in the press release (1). “We believe the consistent efficacy trends from the Phase IIb study of prasinezumab merit further exploration. We will continue our close collaboration with the Parkinson’s community as we further evaluate the data to determine next steps.”

Both a Phase II study (PASADENA) and this Phase IIb study (PADOVA) will continue to give Roche a chance to explore the observed effects in both studies. Full results from the Phase IIb (PADOVA) study are expected to be presented at an upcoming medical meeting.

Prasinezumab is part of a licensing, development, and commercialization agreement that Roche entered into with Prothena, an Ireland-based late-stage clinical biotechnology company with expertise in protein dysregulation. Under the agreement, formed in December 2013 (1), the companies aim to develop and commercialize mAbs that target α-synuclein, a presynaptic neuronal protein that is genetically and neuropathologically linked to PD (2). Prasinezumab targets the build-up of α-syn protein in the brain, which can potentially prevent further accumulation and spreading between cells. This action can slow down the progression of the disease (1).

“The results from the Phase [IIb] PADOVA study are a significant step forward to potentially bring the first disease-modifying treatment option to the millions of individuals living with Parkinson’s disease and their families,” said Gene Kinney, PhD, president and chief executive officer, Prothena, in that company’s press release (3). “As pioneers in developing the first anti-alpha synuclein targeting antibody, we look forward to Roche presenting the results from the PADOVA study at an upcoming medical conference and sharing with health authorities to determine the most appropriate path forward.”

1. Roche. Roche’s Phase IIb Study of Prasinezumab Missed Primary Endpoint, but Suggests Possible Benefit in Early-Stage Parkinson’s Disease. Press Release. Dec. 19, 2024.
2. Stefanis, L. α-Synuclein in Parkinson's Disease. 

 (2), a009399. DOI: 10.1101/cshperspect.a009399.
3. Prothena. Roche’s Phase IIb Study of Prasinezumab Missed Primary Endpoint, but Suggests Possible Clinical Benefit in Early-Stage Parkinson’s Disease. Press Release. Dec. 19, 2024.

Results from a Phase IIb study missed the primary endpoint by failing to achieve statistical significance. 

Prasinezumab Misses Primary Endpoint in Roche’s Phase IIb Study, but Has Potential in Treating Early Stage Parkinson’s Disease

Nicolas Pivet Cytiva discusses automation benefits process development analytics

Process Development Benefits from Automated Analytical Technologies

In an interview with the PharmTech Group, Nicolas Pivet, vice-president and general manager, Technology Solutions at Cytiva, notes that among the challenges in developing a biomanufacturing process is the process analytical technology (PAT) used in that process. Pivet discusses how automation benefits process development, especially when applied to analytics.

“I would say digital documentation is always helping with fast regulatory filing and tech transfer,” Pivet says, adding that, “What we've been experiencing in Cytiva is that many of our customers actually use a platform approach for process development, which is great for speed, but sometimes is not optimized for everything.”

“The introduction of recipe-driven equipment in process development has really enabled 24/7 utilization of labs, so, it's really enhancing the throughput of your lab staff,” Pivet says. The scientist, therefore, with the help of automation, can program lab equipment to rapidly execute experiments and collect samples. “What we've been seeing as well is that SCADA—the supervisory control and data acquisition system—is a layer that allows equipment information to be viewed together. That's why, in Cytiva over the past seven years, we've been developing our Figurate automation offering, which is a wide range of automation solutions and libraries, from historian to control systems with Unicorn [a control software] to SCADA with Wonderware [an automation platform] and to DCS [distributed control system] with Delta V and PlantPAx [types of DCS].”

In the area of PAT, Pivet feels that the bio/pharma industry needs to move faster. In the sensors space, for example, P80 sensors have been seeing an emergence of improved sensing technology. “Measuring CQAs [critical quality attributes], for instance, inline or online is really the holy grail of the biopharma industry right now,” Pivet says. “…The industry needs to get there in being able to measure CQAs inline and helping with real-time release, or right-time release, of the drug product.”

Nicolas Pivet, Vice-President and General Manager, Technology Solutions, Cytiva

Nicolas Pivet is vice-president and general manager, Technology Solutions, at Cytiva, where his ability to find the right creative solution—whether for customers, or when writing songs—is at the root of his delivery-focused mindset. Innovation is second nature to Pivet, which allows him to bring fresh approaches to meeting customer needs. He is a seasoned leader, with laser-sharp customer focus and experience across software and hardware R&D, program management, strategy, service operations, and commercial. Since 2023, Pivet has led Cytiva’s global Automation, Digital and Learning Solutions Business Unit, developing digital solutions enabling fast, flexible, and reliable process development and manufacturing for the biopharma industry. He also leads the Manufacturing Capacity Solutions unit, where Cytiva supports customers with powerful and innovative end-to-end solutions that transform biomanufacturing.

Videos

Cytiva's Nicolas Pivet, vice-president and general manager, Technology Solutions, emphasizes how automation benefits process development, particularly in the analytical space.

In her end-of-the-year message, Emer Cooke, executive director of the European Medicines Agency (EMA) promoted the agency’s successes in 2024, including the recommendation of 114 drugs for approval, collaborations with EU Member States and regulators from other regions, and efforts to combat drug shortages.

The marketing authorization recommendations made in 2024 by EMA included 48 new active substances, 16 of which were for rare diseases. “It is the first time since 2009 that we have been able to deliver more than 100 positive opinions,” Cooke stated in the press release (1). “This is good news for patients, but also a very encouraging indication of the competitiveness of the European pharmaceutical sector.”

Noteworthy marketing authorization recommendations went to the first Alzheimer’s disease medication in the European Union to slow progression of the disease and the first Chikungunya vaccine for adults. A new antibiotic was also approved to fight infections caused by multidrug-resistant bacteria, which is a positive development as antimicrobial resistance continues to be a threat to public health.

EMA collaborated with a variety of partners in 2024 to deal with multiple industry challenges. The agency worked with EU Member States to transition ongoing clinical trials to the Clinical Trials Information System. “Ten thousand applications have been submitted in the system since January 2022. This marks the end of a three-year transition period that began when the Clinical Trials Regulation became applicable,” Cooke stated in the release. The agency also worked with the African Medicines Agency to share experience and knowledge and to support a pilot program for joint evaluation of drugs in Africa.

To combat the ever-present problem of drug shortages, EMA worked with EU Member States in 2024 to ensure medicines were available to patients. Efforts included recommendations to keep the supply of critical vulnerable drugs strong. Communication was increased regarding key drugs, such as glucagon-like peptide-1 receptor agonists. In addition, the European Shortages Monitoring Program was established so that information regarding drug shortages can be exchanged quickly and efficiently between regulators and pharma companies. The Task Force on Availability of Authorised Medicines for Human and Veterinary Use, established in 2016, also concluded its work in 2024. “Fast forward to today, and one pandemic later, the activities started by the group have been enshrined in law and added to our public health mandate. The Task Force can be incredibly proud of what it has achieved, including the just published second version of the Union list of critical medicines,” Cooke stated.

“In 2025, EMA will continue its mission to protect public and animal health—with determination, with enthusiasm and passion. We are tirelessly working on reinventing and improving ourselves,” Cooke said in the release. “Next year, the Agency will maintain its focus on accelerating and optimizing the assessment of key medicines, improving both accessibility and availability of medicines, as well as working on approaches to future-proofing medicines regulation in the EU [European Union] in preparation for the new pharmaceutical legislation. I am expecting 2025 to be another exciting year for medicines regulation.”

1. EMA. Emer Cooke, EMA’s Executive Director: 2024 Achievements in Medicine Regulation. Press Release. Dec. 17, 2024.

Emer Cooke, executive director of EMA, is encouraged by the competitiveness of the European pharmaceutical market.

Innovation, Collaboration, and Performance Were Highlights for EMA in 2024

In a press release posted on FDA’s website on Dec. 20, 2024, Endo USA, Inc. announced it was voluntarily recalling all lots of Adrenalin Chloride Solution (EPINEPHrine nasal solution, USP) 30 mg/30 mL (1 mg/mL) 30 mL vials. The recall was issued because the product, which is a vasoconstrictor for topical application that predates the 1938 Federal Food, Drug & Cosmetic Act, was never approved by FDA. The product was also found to be misbranded by FDA with a misleading label that is similar to one for an FDA-approved drug, Adrenalin (epinephrine injection, USP) (1 mg/mL) 30 mL vial, which is also produced by Endo. The approved Adrenalin (epinephrine injection, USP) (1 mg/mL) 30 mL vial has not been recalled.

According to FDA, the labeling similarity makes telling the difference between the non-sterile topical product and the sterile injectable product difficult. This could lead to administration errors.

“Intravenous administration of the unapproved non-sterile topical Adrenalin Chloride Solution (EPINEPHrine nasal solution, USP), instead of the approved sterile Adrenalin (epinephrine injection, USP) (1 mg/mL) 30 mL vial for injection, would result in non-fatal serious and/or severe, health outcomes related to delayed or inadequate treatment of the underlying condition (anaphylaxis, hemodynamic instability, hypotension) or infection due to intravenous administration of a non-sterile product,” the press release stated (1). “In addition, there is a high probability that intravenous administration of the nasal product will result in patients receiving the wrong dose of epinephrine in emergency situations for serious, life-threatening conditions such as the treatment of anaphylaxis, blood pressure support, and cardiac arrest. If these events are not treated with the correct dose of epinephrine, patients may be at risk for death.”

The recalled lots are packaged as 30 mL vials in individually packed cartons under national drug code number (NDC) #42023-103-01 that say, “Nasal Solution USP” and “For Topical Application” on the package. The following lots of Adrenalin Chloride Solution (EPINEPHrine Nasal Solution, USP) for topical application 30 mg/30 mL (1 mg/mL), which were distributed nationwide from Oct. 10, 2023 through Dec. 11, 2024, are recalled:

NDC 42023-103-01. Lot 82809. Expiry date: 03/2026

NDC 42023-103-01. Lot 79637. Expiry date: 11/2025

NDC 42023-103-01. Lot 77776. Expiry date: 07/2025

NDC 42023-103-01. Lot 74716. Expiry date: 05/2025

NDC 42023-103-01. Lot 71835. Expiry date: 01/2025

NDC 42023-103-01. Lot 72916. Expiry date: 01/2025.

Notification is being provided by the company to direct consumer accounts. Wholesalers are advised to discontinue the recalled lots immediately. Endo states in the press release that the company has not reported adverse events associated with the product in the past five years. Adverse reactions may be reported to FDA through its MedWatch Adverse Event Reporting program.

This is not the first recall for Endo in 2024. In July, the company recalled 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 mg tablets 60-count) because an incorrect strength appeared on the cartons of some packs (2). The product strength was listed as 0.125 mg and not 0.25 mg. The inside blister strips, however, had the correct strength of 0.25 mg noted. The error was made by a third-party packager.

1. FDA.Endo USA, Inc. Issues Voluntary, Nationwide Recall of Adrenalin Chloride Solution (EPINEPHrine Nasal Solution, USP) Due to the Potential for Administration Errors. Press Release. Dec. 20, 2024. 

https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/endo-usa-inc-issues-voluntary-nationwide-recall-adrenalinr-chloride-solution-epinephrine-nasal


2. 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

The company is voluntarily recalling all lots of Adrenalin Chloride Solution (EPINEPHrine nasal solution, USP) 30 mg/30 mL (1 mg/mL) 30 mL vials due to misleading labeling and its status as an unapproved drug. 

Endo Recalls Adrenalin Chloride Solution 

Dr Rupa Pike, Sr. Director & Global Head Strategic Alliances and Field Scientists for Cell Therapy, Catalent, shares insight on de-risking cell therapy programs using streamlined development and manufacturing platforms.

From Early Development to Commercialization: Strategies for Successful Cell Therapy Manufacturing

Manufacturing is a critical component in the development of cell therapies, and implementing de-risking strategies early in the process is essential to ensure product safety, efficacy, and alignment with regulatory requirements. De-risking encompasses identifying and addressing potential safety and manufacturing challenges, such as variability in raw materials or inefficiencies in processes, to reduce technology transfer issues and clinical development setbacks. Early-stage strategies like Quality by Design (QbD) principles, gap assessments for regulatory compliance, and thoughtful planning around vendor selection, raw materials, and manufacturing technologies contribute to smoother clinical progression and commercial readiness. These measures also lead to time and cost savings, ultimately improving the likelihood of successful IND approval and clinical manufacturing initiation.

To address manufacturing challenges specific to CAR-T therapies, Catalent has developed the UpTempo℠ CAR-T platform, a flexible and customizable solution built from experience with over 500 manufactured batches across 20+ cell therapy programs. This platform leverages GMP-compliant manufacturing equipment, ready-to-use raw materials, and a robust suite of analytical tools to streamline processes and ensure quality. It supports two approaches: transferring existing processes into the UpTempo℠ ecosystem for optimization or utilizing Catalent’s standardized workflows for efficient manufacturing. The platform's flexibility and instrument-agnostic design enable integration of the latest technologies, reducing costs, accelerating timelines, and enhancing therapy accessibility.

Navigating regulatory requirements throughout the manufacturing process requires early and proactive engagement with authorities like the FDA. Interact and pre-IND meetings provide critical feedback on product development expectations, including manufacturing and quality controls. Sponsors benefit from guidance on preclinical models, CMC readiness, and expedited approval pathways, which have been instrumental in bringing commercial cell therapies to market. Maintaining compliance through clinical phases and addressing country-specific regulatory requirements are crucial to ensuring product safety, quality, and consistency. Catalent’s global regulatory affairs team supports sponsors from pre-IND submission through commercialization, ensuring adherence to evolving regulatory standards.

Integrating advanced analytics and data-driven insights into cell therapy manufacturing enhances efficiency and decision-making by enabling real-time monitoring of critical process parameters (CPPs) such as cell health, proliferation, and functional properties. Catalent’s UpTempo℠ platform incorporates innovations like microfluidics-based automated flow cytometry and rapid sterility strategies, reducing analytical testing time and accelerating batch release. Emerging technologies such as non-invasive sample analysis, cloud-connected inline tools, and embedded sensors further optimize monitoring and control. The application of AI and machine learning is also beginning to play a role in predictive modeling, complementing current tools to accelerate product release and improve manufacturing outcomes. This data-driven approach supports process optimization, quality assurance, and commercialization efforts, paving the way for broader accessibility of cell therapies.

Dr Rupa Pike, Sr. Director & Global Head Strategic Alliances and Field Scientists for Cell Therapy, Catalent, shares insight on de-risking cell therapy programs using streamlined development and manufacturing platforms.


David McErlane, Group President of Biologics, Catalent, reacts to trends in cell and gene therapy development and manufacturing and comments on Catalent's ESG strategy to support people, the environment, and communities.

The Evolution of Cell & Gene Therapy: Development and Manufacturing Insights and the Role of CDMOs

Contract Development and Manufacturing Organizations (CDMOs) play a critical role in advancing the field of cell and gene therapies by providing specialized expertise, state-of-the-art facilities, and scalable manufacturing solutions. Their technical knowledge and ability to adapt to evolving regulatory standards enable faster development timelines and ensure compliance, supporting biotech companies in bringing life-changing therapies to patients more efficiently. By leveraging their established infrastructure, CDMOs also offer cost-effective solutions that allow biotech firms to focus resources on groundbreaking R&D while reducing the need for significant investment in in-house production facilities. This combination of expertise, flexibility, and cost efficiency ultimately accelerates the path to market for innovative treatments.

As cell and gene therapies continue to revolutionize the treatment of previously untreatable diseases, key trends are shaping the future of manufacturing in this field. Streamlined regulatory approval processes, such as the anticipated FDA Platform Technology Designation Program, aim to reduce the time and complexity of bringing therapies to market. Advancements in automation, artificial intelligence, and digitalization enhance the efficiency, scalability, and reliability of manufacturing processes, reducing costs and barriers to patient access. Additionally, innovations in supply chain management improve reliability and traceability, ensuring timely delivery of these highly individualized therapies.

Looking ahead, the balance between insourcing and outsourcing in cell and gene therapy manufacturing is likely to shift, with many biotech companies prioritizing funding for core innovation rather than maintaining in-house production capacity. CDMOs with phase-appropriate expertise and facilities are positioned to become essential partners, particularly as companies seek to offset high development costs and manage the complexities of production. Allogeneic cell therapies, with their streamlined requirements, are especially well-suited to outsourcing, further underscoring the growing importance of CDMOs in the industry.

The commitment to Environmental, Social, and Governance (ESG) principles is another area where CDMOs like Catalent can demonstrate leadership. By fostering a diverse and inclusive workplace, minimizing environmental impact through science-based targets, and giving back to local communities, CDMOs align their operations with the broader goals of sustainability and social responsibility. Sustainable manufacturing practices, ethical sourcing, and robust governance frameworks further reinforce their dedication to ethical and environmentally conscious operations. This holistic approach not only builds trust with stakeholders but also supports healthier communities and a more sustainable planet.

Want to learn more? Watch episode 3 of this series 