Aligning mRNA Progress with Regulatory Streamlining

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Dosage Forms: Roundtable on Oral Solid Dosage Trends

Drug Solutions Podcast: 

Pharmaceutical packaging must advance to adapt to new, complex modalities

Out-of-the-Box Packaging Advancements

From Theory to Reality: Automating Process Development

Drug Digest: 

The Importance of Appropriate Supplier Oversight

Ask the Expert

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

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In a press release on Oct. 24, 2024, the contract research, development, and manufacturing organization (CRDMO) BioDuro-Sundia, headquartered in Irvine, Calif., said it was launching a new, pilot-scale production laboratory that will enable scale-up synthesis for drug substance from 500 grams to kilograms (1). The laboratory is located at BioDuro-Sundia’s R&D campus in the Free-Trade Zone of Shanghai, China.

The kilo laboratory, according to BioDuro-Sundia, is equipped with large-capacity reactors allowing the company to simultaneously conduct multiple synthesis batches, in the interest of improving operational efficiency (1). Other key equipment includes both high- and low-temperature jacketed reactors, low-temperature spherical reactors, and advanced safety evaluation instruments—among them, differential scanning calorimetry, which collects safety data that informs the development of safe, efficient reaction routes, the press release said.

"Our new kilogram laboratory exemplifies BioDuro-Sundia's unwavering commitment to advancing our CRDMO platform and delivering exceptional value to our global partners," said Armin Spura, PhD, CEO of BioDuro-Sundia, in the press release (1). "This state-of-the-art facility enables us to scale up production with greater speed and flexibility, expediting the journey of drug candidates from discovery to the clinic, and ultimately helping to address critical unmet medical needs."

Taken as a whole, BioDuro-Sundia said, the features of the kilo laboratory are designed to support complex, multi-step scale-up reactions of select APIs as well as advanced intermediates (1). The company said that as the demands of its partners continue to grow, the opening of the laboratory enhances BioDuro-Sundia’s ability to accelerate a greater number of drug candidates and, as Spura said, to do so from discovery through preclinical and clinical phases, building a bridge between medicinal chemistry research and process development.

The new kilo laboratory is on the same site as BioDuro-Sundia’s Compound Management Center, the launch of which was announced earlier in October 2024 (2). With real-time temperature and humidity controls, the center has the ability to manage more than 400,000 compounds, either solid or liquid, and is equipped with a liquid handling station for fully automated workflows, while sample management software tracks steps at every point of the lifecycle. Services able to be offered include storage, weighing, dissolution, plating, liquid chromatography–mass spectrometry (LC–MS) analysis, and distribution.

 spoke with Kevin Li, MBA, about BioDuro-Sundia’s role in the area of integrated services, and the benefits such services can provide to pharma companies.

“One side can handle both drug substance and drug product, and one side can handle the pre-formulation, formulation development, until commercial manufacturing, everything in one side,” Li said in the interview, “so that integrated solution can really help customers to accelerate their innovation through multiple benefits” (3).

1. BioDuro-Sundia. BioDuro-Sundia Launches New Kilogram Laboratory to Speed Development from Discovery to Preclinical and Clinical Phases. Press Release. Oct. 24, 2024.
2. BioDuro-Sundia. BioDuro-Sundia Launches New Compound Management Center, Strengthening Drug Discovery Services. Press Release. Oct. 2, 2024.
3. Thomas, F. 

CPHI Milan 2024: Highlighting the Benefits of Integrated Services.

Articles

The laboratory is on the same site as BioDuro-Sundia’s new Compound Management Center, which was launched earlier in October 2024.

BioDuro-Sundia Opens New Kilogram Laboratory at Shanghai Site

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The European Medicines Agency (EMA) announced on Oct. 25, 2024 that international regulators have published a report based on outcomes of a workshop held on Oct. 2, 2024 by the International Coalition of Medicines Regulatory Authorities (ICMRA) (1). The workshop, which was held virtually, included representatives from international medicine regulatory authorities, such as FDA, EMA, and the Japan Pharmaceuticals and Medical Devices Agency, and the World Health Organization (WHO) to discuss access to mpox medicines during an outbreak. WHO declared mpox a public health emergency of international concern in August 2024.

The current epidemiological status and the availability of mpox vaccines in African countries was discussed during the workshop. The use of mpox vaccines in pregnant people and in children was also discussed, specifically efforts to fill the gap of evidence for these patient groups. Attendees also discussed effectiveness surveillance systems and regulatory pathways for mpox vaccine and drug approvals. The need for large clinical trials was emphasized by participants so that the appropriate evidence may be generated to quickly develop and approve these medicines.

“One of the major challenges during these outbreaks has been the unequal availability of medical interventions, such as antivirals and vaccines, with low-income countries in Africa facing the greatest difficulties. While high-income countries were able to access vaccines more readily, African countries, where mpox is endemic, have struggled with delayed regulatory approvals and inaccessible prices,” the report states (2).

According to the report, children are the most vulnerable group in the Democratic Republic of Congo and have the highest fatality ratio. Because of this, the workshop discussion prioritized pediatric treatments. FDA granted emergency use authorization for the MVA-BN vaccine for children; this vaccine has been used in the United States safely. Canada has authorized the vaccine for people 18 or older but has made a discretionary recommendation for use in children. EMA expanded the indication for the vaccine to be used in children 12 to 17 years old.

“There is limited evidence for the use of MVA-BN vaccine in pediatric populations under 12 years of age; the safety profile is however not expected to be different in this population. The WHO Strategic Advisory Group of Experts on Immunization has also recommended that the MVA-BN vaccine can be used in children if the benefits outweigh the risks,” the report states (2). “For these reasons, regulators within ICMRA stand ready to support decisions in countries most affected, including for use in children less than 12 years of age. However, misinformation is of concern and robust communication strategies need to be implemented.”

During the workshop it was recommended that a dose-sparing strategy using the intradermal route of administration be considered due to the gaps in the vaccine supply and the number of doses that are needed for high impacted countries. It was also recommended that a different vaccine, LC16m8, be considered, as it is currently approved for use in all age groups in Japan.

New vaccine development discussion brought to attention the different regulatory pathways for approval and that alternatives to placebo-controlled studies should be considered, as well as alternative methods of administration.

“ICMRA unanimously agreed that fragmentation in clinical research, as has happened so far with mpox, must be avoided, as studies need to be conducted rapidly and efficiently in the best interest of patients. More collaboration towards merging efforts from investigators into larger unified clinical trials is advocated,” the report states.

EMA. Fostering Regulatory Collaboration to Improve Access to Mpox Medicines. Press Release. Oct. 25, 2024.

ICMRA. Summary Report of the International Coalition of Medicines Regulatory Authorities (ICMRA) Workshop on Mpox, October 2, 2024. 

https://www.icmra.info/drupal/news/mpox_news_announcement_25oct2024/mpox_ws_report_2oct2024

The report highlights international regulators’ plans for the development and availability of vaccines to prevent and drugs to treat mpox.

Regulatory Collaboration on Mpox Treatments Summarized in Report

FDA has approved the AbbVie treatment Vyalev (foscarbidopa and foslevodopa) for use in adult patients with advanced Parkinson’s disease, AbbVie announced in a press release on Oct. 17, 2024 (1). The approval makes Vyalev the first and only subcutaneous, 24-hour infusion of levodopa-based therapy for treatment of motor fluctuations in these patients in the United States.

"People living with advanced Parkinson's disease experience daily challenges as a result of uncertainty in managing motor fluctuations, especially as their disease progresses," said Roopal Thakkar, MD, executive vice president, research & development, and chief scientific officer, AbbVie, in the release (1). "We are proud to bring this innovation to patients who may benefit from motor symptom control through continuous 24-hour administration of Vyalev."

Onset of motor complications, according to AbbVie, can be due to neuronal degeneration as well as fluctuating levodopa levels in plasma, with 50% of patients reporting these symptoms anywhere from two to five years after diagnosis, and from 80% up to 100% presenting with them after a period of 10 years (1). Dyskinesia, or involuntary movement, is another hallmark of Parkinson’s disease attributable to these factors.

A 12-week, Phase III trial that studied continuous, subcutaneous infusion of Vyalev against oral immediate-release carbidopa/levodopa (CD/LD IR), the findings of which were disclosed in 

 in 2022, informed FDA’s decision, according to AbbVie (1). Patients were measured in “on” time, when symptoms are generally well controlled, to “off,” when tremor and stiffness may reappear, and in the study, the increase in “on” time without troublesome dyskinesia was 2.72 hours at week 12 with Vyalev, and 0.97 hours with CD/LD IR (2).

Adverse reactions were shown to be mostly mild to moderate and non-serious, with the most frequent being infusion site events, hallucinations, and dyskinesia (1).

"For too long, the Parkinson's community has had limited treatment options for advanced disease. Due to the progressive nature of the disease, oral medications are eventually no longer as effective at motor symptom control and surgical treatment may be required," said Robert A. Hauser, MD, professor of neurology and director of the Parkinson's and Movement Disorder Center at the University of South Florida, in the press release. "This new, non-surgical regimen provides continuous delivery of levodopa morning, day and night."

Vyalev is also marketed under the brand name Produodopa and has been approved in 35 countries, with AbbVie saying it is continuing to work with regulatory authorities around the world to broaden the therapy’s scope to more adults with advanced Parkinson’s disease. So far, the company says, more than 4200 patients globally have begun treatment with Vyalev (1).

In the US, coverage of Vyalev for Medicare patients is expected to start in the second half of 2025 (1).

1. AbbVie. U.S. FDA Approves VYALEV (foscarbidopa and foslevodopa) for Adults Living with Advanced Parkinson's Disease. Press Release. Oct. 17, 2024.
2. Soileau, M.J.; Aldred, J.; Budur, K.; et al. Safety and Efficacy of Continuous Subcutaneous Foslevodopa-Foscarbidopa in Patients with Advanced Parkinson's Disease: A Randomised, Double-Blind, Active-Controlled, Phase 3 Trial. 

Vyalev, also known as Produodopa, has been approved in 35 countries, with more than 4200 patients having started treatment.

FDA Approves AbbVie Therapy for Adults with Advanced Parkinson’s Disease

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Modifi Biosciences, a company formed in 2021 as a spinout of technology developed at Yale University, announced on Oct. 23, 2024 that it is being acquired by Merck, known as MSD outside of the United States and Canada (1). Modifi Biosciences develops direct DNA modification enabled cancer treatments. The novel class of small molecules target a DNA repair protein called O6-methylguanine methyl transferase (MGMT). The company’s research was published in 

in 2022 (2) and has had pre-clinical data amassed through a number of tumor models, including patient-derived xenograft models of gliomas.

“In founding Modifi Biosciences, we sought to radically change the oncology treatment paradigm for cancer patients with glioblastoma and other tumors,” said Ranjit S. Bindra, MD, PhD, Modifi Biosciences co-founder, Harvey and Kate Cushing, professor of Therapeutic Radiology at Yale School of Medicine, and scientific director of the Yale Brain Tumor Center at Smilow Cancer Hospital, in a press release. “We are honored to have Merck recognize the potential of our science, and as an oncology company, they are perfectly positioned to advance our innovations through clinical trials and commercialization.”

“DNA repair defects are a frequent hallmark of tumor cells and a major cause of resistance to cancer therapy,” said David Weinstock, MD, vice-president, discovery oncology, Merck Research Laboratories, in the release. “The talented Modifi Biosciences team has developed an innovative approach that we believe has potential for treating some of the most refractory cancer types.”

“We designed our small molecules to have the ability to uniquely overcome clinical resistance mechanisms that have been known for decades but until now have been non-actionable. Additionally, we created the molecules in a manner which allows them to be rapidly progressed from bench-to-bedside,” said Seth Herzon, PhD, Modifi Biosciences co-founder and the Milton Harris ’29 PhD Professor of Chemistry in Yale’s Faculty of Arts and Sciences and professor of Pharmacology and Therapeutic Radiology at the Yale School of Medicine, in the release.

The acquisition agreement has Merck, through a subsidiary, taking possession of all outstanding shares of the company for $30 million with potential milestone payments up to $1.3 billion.

In other news by Merck, the company entered into a license and collaboration agreement in October with Mestag Therapetuics, a Cambridge, UK-based biotech company to identify novel targets for inflammatory disease treatments, using Mestag’s reversing activated fibroblast technology platform. The proprietary platform models the pathogenic role of fibroblasts in human disease.

“Mestag was founded on … insights into fibroblast–immune biology, and as an early innovator in this area of research, we have built a robust pipeline of antibody programs and created a unique and productive target discovery platform,” said Susan Hill, PhD, chief executive officer of Mestag, in a company press release (3). “We are acutely aware of the significant unmet needs faced on a daily basis by patients suffering from inflammatory diseases. We are thrilled to collaborate with [Merck], together driving continued innovation for the benefit of patients.”

Modifi Biosciences. Modifi Biosciences Acquired by Merck. Press Release. Oct. 23, 2024.

Lin, K.; Gueble, S.E.; Sundaram, R.K.; Huseman, E.D.; Bindra, R.S.; Herzon, S.B. Mechanism-based Design of Agents that Selectively Target Drug-resistant Glioma. 

Mestag Therapeutics. Mestag Therapeutics Announces License and Research Collaboration with MSD to Identify Novel Targets for Inflammatory Diseases. Press Release. Oct. 8, 2024.

Merck is acquiring the Yale-spinout, which develops direct DNA modification-enabled cancer treatments. 

Merck Acquires Modifi Biosciences

Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

Leaders in pharmaceutical industry discuss the latest news making waves in the pharmaceutical industry. 

Behind the Headlines, Episode 5: GLP-1 Shortage, Nobel Prize, RNA Editing, and More

 is a bi-weekly panel discussion examining the latest trends, readouts, and other factors that drive pharmaceutical news and innovation. Each episode features consultants, venture capitalists, scientists, patient advocates, and journalists discussing the prior weeks’ top news while seeking to highlight the more enduring lessons that hide behind the headlines.

In episode 5, panelists Laks Pernenkil, Principal Life Sciences at Deloitte; Brian Feth, CEO at Xcell Biosciences; and Alex Philippidis, Senior Business Editor at Genetic Engineering & Biotechnology News, go behind the headlines to understand why FDA felt it was time to remove 

 from the drug shortages list (1) and how Catalent’s sale of a small molecule manufacturing facility (and incidentally its own headquarters) to expanding European company Ardena might affect future drug availability (2).

The panel also discussed Nobel Prize awards being given in the 

 field (3) and what that might mean in terms of growth, given a series of false starts and hurdles including the shelving of a hepatitis C therapy due to fears that microRNA might not compete commercially with traditional therapeutic approaches (4). The Nobel Prize in physics awarded to recognize advancements in artificial intelligence (5) was likewise considered from the perspective of how AI will bolster drug discovery and drug formulation, as well as help optimize drug manufacturing. 

Lastly, panelists discussed the emerging potential for novel protein replacement therapies on the heels of Wave Life Sciences’ positive clinical data for RNA editing to combat AAT protein deficiency (6), and how temporary and reversible RNA-editing approaches may confer additional benefits that further support this novel approach in the marketplace.

FDA clarifies policies for compounders as national GLP-1 supply begins to stabilize. FDA Drug Safety and Availability. October 2, 2024. 

https://www.fda.gov/drugs/drug-safety-and-availability/fda-clarifies-policies-compounders-national-glp-1-supply-begins-stabilize

Catalent signs agreement to sell Somerset, NJ oral solids facility. Catalent. October 14, 2024. 

https://www.catalent.com/catalent-news/catalent-signs-agreement-to-sell-somerset-nj-oral-solids-facility/

The Nobel Prize in physiology or medicine, 2024. 

https://www.nobelprize.org/prizes/medicine/2024/press-release/

Sparmann A and Vogel J. RNA-based medicine: from molecular mechanisms to therapy. 

https://www.nobelprize.org/prizes/physics/2024/press-release/

Wave Life Sciences Announces First-Ever Therapeutic RNA Editing in Humans Achieved in RestorAATion-2 Trial of WVE-006 in Alpha-1 Antitrypsin Deficiency. Press release. Wave Life Sciences. October 16, 2024. 

https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-first-ever-therapeutic-rna-editing

Videos

Laks Pernenkil, Brian Feth, and Alex Philippidis go behind the headlines to discuss the impact of recent news, including FDA’s drug shortage list update, Nobel prize winners in microRNA and AI, and a big-potential research win for RNA editing. 

Behind the Headlines: GLP-1 Shortage, Nobel Prize, RNA Editing, and More

Felicity Thomas is Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Retrofitting Facilities for Cell and Gene Therapy Production

In his episode of Ask the Expert, Peter Walters, Fellow of Advanced Therapies at CRB Group, discusses the retrofitting of older and/or solid-dosage facilities into sustainable cell and gene therapy manufacturing facilities. According to Walters, cell and gene therapy facilities can be made very lean and sustainable, with some being 100% electric.“A lot of that has to do with the fact that there isn't a huge utility draw for that process,” says Walters. “A lot of those materials are going to be typically purchased and either made off site and brought in, or are made on site, but are low water usage, low utility usage.”

Walters says that, when retrofitting a facility, air handling, air locking, and personnel flows are factors to consider. “Cell therapy facilities tend to have at least a handful of spaces that want to be very high classified, and so you're [going to] need not only the air handling—ability to push a lot of air through those spaces in a very clean manner—but the air locking to get the material segregation movements [and] the personnel flows to get into those highly classified spaces. As we talk about gene therapy, sometimes viral vector spaces want to be BSL [biosafety level] spaces. They want to have certain levels of segregation. It's not uncommon to see vector facilities that have [a] two-corridor system; one dedicated to the supply of materials and one dedicated to outgoing waste and outgoing materials, and that helps drive segregation of flows and materials through your facility. It can be difficult to find a facility that's set up in such a way [as] to facilitate an easy retrofit.”

Click the video above to watch Walters answer the following question:

We wish to retrofit our solid-dosage facility into a sustainable facility for cell and gene therapy commercialization. What kind of cost should we expect?

Peter Walters is Fellow of Advanced Therapies at CRB Group.

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

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

In this episode of the Ask the Expert video series, Peter Walters, Fellow of Advanced Therapies at CRB Group, discusses how facilities used for solid dosage manufacturing may be retrofitted into sustainable cell and gene therapy production facilities.

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EquipNet, a leading provider of surplus asset management solutions based in Canton, Mass., has announced in a press release that it has entered a reseller agreement with California-based Agilent Technologies to support the sale of select certified, pre-owned instruments (1).

An initial listing of 14 instruments—including mass spectrometers compatible with either liquid or gas chromatography, high performance or ultrahigh-pressure liquid chromatography stacks, and UV-visible spectrophotometers—was made available on EquipNet’s website via 

, with price tags ranging from $14,000 to $85,000 (2).

All of the pre-owned equipment is backed with original equipment manufacturer (OEM) warranties, according to EquipNet (1). The listing page promises a one-year manufacturer's warranty with “brand-new software, expert installation, and direct ship from the OEM” (2).

EquipNet said that Agilent’s hardware portfolio is deployed in a variety of applications, including environmental testing, life sciences, and pharmaceuticals, and that collectively, Agilent equipment is known for its analytical capabilities and capacity for high-performance testing.

“Agilent is globally recognized for its innovation, precision, and reliability in the lab instrumentation space,” the press release stated (1).

“Collaborating with Agilent allows us to deliver the best of both worlds—affordable, pre-owned laboratory equipment, coupled with the assurance of an OEM warranty,” said Greg Feinberg, managing director of biotech business development at EquipNet, in the press release (1). “This reseller agreement demonstrates our commitment to enhancing the buyer’s experience and expanding our offerings to meet the growing demands of the scientific and industrial markets.”

Further expanding on the customer perspective, the press release said that offering the OEM-backed pre-owned instruments would allow buyers to be confident the items they are purchasing have the same reliability as brand-new products (1). EquipNet said the agreement underscores the company’s objective to provide customers with cost-effective solutions with an additional focus on sustainability due to the resale of surplus assets.

For Agilent, the agreement with EquipNet follows several months after a $925 million acquisition of BIOVECTRA, a contract development and manufacturing organization (CDMO) based in Canada, which was announced by Agilent on July 22, 2024 (3). In a press release, Agilent said it stood to benefit from that transaction by being able to build upon its offerings in three key areas: expansion of the company’s portfolio of services through adding sterile fill/finish services, plasmid DNA and messenger RNA capabilities, and lipid nanoparticle formulation services; growth in modalities including antibody-drug conjugates, highly potent APIs, and glucagon-like peptide-1 segments; and capabilities to support customer’s gene-editing needs as a single-source provider.

Meanwhile, EquipNet has been marking its 25th anniversary in 2024, a marker that the company recognized in a May 2024 press release.

“Reaching this 25-year milestone is a testament to our team’s dedication, innovation, and hard work,” said Roger Gallo, CEO of EquipNet, in that release (4).

1. EquipNet. EquipNet Announces Collaboration with Agilent to Offer Select Certified Pre-Owned Instruments. Press Release. Oct. 22, 2024.
2. EquipNet. Certified Pre-Owned Analytical Instruments from Agilent Technologies. 

 (accessed Oct. 23, 2024).
3. Agilent Technologies. Agilent to Acquire North American CDMO BIOVECTRA. Press Release, July 22, 2024.
4. EquipNet. EquipNet Celebrates 25 Years in Business. Press Release. May 2024.

The agreement follows Agilent’s acquisition of Canada-based CDMO BIOVECTRA in July 2024.

EquipNet, Agilent Enter Reseller Agreement for Certified Pre-Owned Instruments

Aloka Srinivasan, PhD, is Principal and Managing Partner, Raaha LLC.

N-Nitroso-diethylamine or NDEA carcinogenic molecule. 3D rendering. | Image Credit: ©Studio Molekuul/Wirestock - stock.adobe.com

In September 2024, the much-anticipated update to FDA’s 

Guidance for Industry, Control of Nitrosamine Impurities in Human Drugs

 was published (1). This update is being called Revision 2 by the agency; the original guidance was published in 2020 and updated in February 2021. The most significant change in Revision 2 is the differentiation of nitrosamines into two classes: common, smaller nitrosamines originating from reagents, solvents, etc., and the larger and more complex nitrosamine drug substance-related impurities, referred to as nitroso drug substance related impurities (NDSRIs). This differentiation, when originally mentioned by FDA a few years back, had led to a conundrum in the pharmaceutical industry regarding how and when NDSRIs should be controlled in drugs. Revision 2 of the guidance (September 2024) could be considered a paradigm shift from Revision 1 (February 2021), which implicated the major cause of concern as smaller nitrosamines originating from reagents, solvents, and other extraneous sources and mentioned six nitrosamines with their proposed acceptable intakes (AIs). The current update (Revision 2) has a detailed discussion on several topics related to nitrosamines in pharmaceuticals, the smaller and more ubiquitous ones such as N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), as well as the larger, previously unknown NDSRIs. While not all inclusive, Revision 2 is a beneficial road map to evaluate and control the risk related to nitrosamines in pharmaceuticals.

In this article, the author has attempted to highlight some of the salient features that were not in the original guidance and have been included in Revision 2 and their impact on the industry. The author has also tried to point out some of the gaps in the guidance, which the industry should be cognizant of and address, hopefully in the foreseeable future.

Overview of guidance Section III: Nitrosamine Impurities and Root Causes of Formation

Sections I and II of Revision 2 are general information, and the actual content starts from Section III.

In Section III of Revision 2, FDA has demarcated the difference between the smaller and more common nitrosamines such as NDMA, NDEA, N-Nitrosodiisopropylamine (NDIPA), N-Nitrosodibutylamine (NDBA), N-nitrosoethylisopropylamine ( NIEPA), and N-Nitrosomethylphenylamine (NMPA), which could arise from reagents, solvents, and other sources containing secondary, tertiary, or quaternary amines or amides of secondary amines (e.g., dimethylformamide) from the larger, more complex nitrosamines, which can form based on the inherent structure of the API itself or intermediates, impurities that resemble the API. The latter have been labeled by FDA as NDSRIs(

mpurities), a terminology that FDA has been using for a few years now.

Additionally, in Section III, FDA has also outlined the root causes of presence of small nitrosamines and NDSRIs in drug substance and drug products. The agency has clarified that even if no nitrite is used in a route of synthesis of an API or the manufacturing process of a drug product, due to its ubiquitous nature, nitrite may be present in small quantities in reagents, excipients, packaging material, and equipment. Thus, nitrosamine risk is high whenever vulnerable amines such as secondary, tertiary, and quaternary amines or amides of secondary amines are present either as a reagent, solvent, or by virtue of the structure of the API, intermediates, or impurities/degradants, irrespective of use of nitrite in the process. Henceforth, in this article, the term, “vulnerable amine/s” will be used to describe the secondary, tertiary, quaternary amines, or amides of secondary amines.

 This clarification by FDA is especially significant because the previous version of the guidance was not clear about the ubiquitous nature of nitrite. Thus, many cases, where sponsors and manufacturers had concluded the absence of nitrosamines even if the process or product included vulnerable amines, based on absence of nitrites or nitrosating agents in their risk evaluation, will need to be revisited. The current update has reiterated the well-known fact that nitrite is everywhere, and thus, the absence of nitrosamine should be verified if API and/or drug product have vulnerable amines.

Revision 2 has an interesting footnote (#28) regarding nitrosamines being formed by tertiary amines and amides of secondary amines. It is well known in the public domain (2) that tertiary amines nitrosate at a much slower rate than secondary amines. However, as the nitrosamine saga unfolded, it was obvious that several drugs with APIs that are tertiary amines showed the presence of the corresponding NDSRIs in the API itself as well as the drug product, over shelf life. In this footnote, the agency has confirmed that tertiary amines are a viable risk of nitrosamines. Amides of secondary amines, which are prone to degrade by hydrolysis to secondary amines, are significant risk nitrosamines and should be considered nitrosamine risks.

 The agency clarified their stance related to tertiary amines and amides of secondary amines and indicated that they should be considered as vulnerable as secondary amines, when it comes to nitrosation. This clarification would help in eliminating the discrepancies in nitrosamine risk evaluation of the same product by different sponsors, some of whom took the tertiary amines in consideration and some who did not. This guidance levels the playing field where nitrosamines of all vulnerable amines should be considered.

In Revision 2, FDA put significant responsibility on the drug product manufacturers to make sure that the supplier/vendor qualifications are adequate when it comes to excipients, water, and packaging materials. In Section IIIC, FDA mentions that, in addition to evaluating the presence of nitrosamines, the supplier qualification program should also take into consideration the presence of nitrites. During the leachable and extractable studies, the possibility of nitrosamines as well as nitrites leaching into the drug product should be taken into consideration.

 This advice from FDA has the potential of increasing the workload of the manufacturers and sponsors of drug products, as, in addition to nitrosamines, they may need to test for the nitrite content in the excipients.

The possibility of studying the nitrite as an extractable and leachable from packaging configurations is relatively new and thus should be noted by the industry.

Overview of Section IV: Recommendations for Control and Mitigation of Nitrosamines in APIs and Drug Products

Section IV is the most significant part of the current guidance, which discusses the controls and mitigation strategies for nitrosamines in drugs. The International Council for Harmonisation (ICH) document, 

 has been mentioned as a roadmap to risk management (3).

To start with, FDA has provided advice regarding the prioritization of risk from the regulatory perspective. Example, chronic drugs with high maximum daily dose (MDD) would take priority over low-dose drugs or drugs with short-term use.

. The agency has not included market share as one of the critical prioritization criteria that the pharmaceutical industry should pay attention to. If a sponsor has a significant market share of a product that has low dose or short-term use, the priority should be to work on that product over others with high MDD and high dose, to keep the market share intact and to avoid drug shortages.

The author notes that FDA has information regarding prioritization of nitrosamine risk based on short-term use in footnote #29 of the guidance. It is noteworthy that FDA has until now refused to accept the less than lifetime (LTL) approach of ICH Q7(R2) in setting specifications of nitrosamines (4). There seems to be a contradiction to what is being recommended in Revision 2 and not accepting LTL for nitrosamines. In Revision 2, FDA indicates that when two drugs have comparable amounts of a nitrosamine, the drug with short term use is of lower risk. As an extension of this conjecture, and following the recommendations of ICH M7, allowing higher limits of nitrosamines drugs with short-term use should then be considered low risk and health protective. FDA, however, has repeatedly resisted the LTL approach with nitrosamines. Hopefully, this fallacy of nitrosamine and LTL will be addressed in the near future by FDA as well as ICH M7 updates.

In Revision 2, FDA established the much needed bridge between this guidance and the FDA guidance for industry, 

Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities

 (5), which has been referred to as RAIL guidance, and the information on nitrosamines on FDA’s website (6). It is clear from the current version that FDA would like the sponsors to take a holistic view of controlling nitrosamines based on all the information provided. While the previous version of this guidance had provided the AIs of a limited number of small and common nitrosamines, and, given a blanket comment that all other nitrosamines should be controlled at 26.5 ng/day unless other information are available, Revision 2 has merged the requirements with the RAIL guidance and subsequent communication of the agency regarding the process of setting AIs of nitrosamines with the carcinogenic potency categorization approach (CPCA) and, in special cases using surrogates, 

 methods, mentioned website (6). It has also been suggested that if the total nitrosamines in a drug product is below 26.5 ng/day, additional safety data are not needed.

FDA has steered the industry to CPCA to determine the AI of NDSRIs that are data poor, based on the RAIL guidance. While the agency has mentioned that other in-vivo and in-vitro approaches may be used to set limits above what CPCA recommends and to derisk the nitrosamines, it is apparent from the concurrent updates provided on FDA’s website (6)

that derisking a specific nitrosamine and confirming an AI above 1500 ng/day would be an uphill battle that pharmaceutical companies with limited resources would find expensive and time consuming. The section, “Recommended Safety Testing Methods for Nitrosamine Impurities

in the webpage (6) states the following, “In addition to the enhanced Ames test, the Agency is currently requesting a 

second in vitro mammalian cell mutation assay and in vitro metabolism data

 (including human hepatocyte or microsome) to support an AI limit of 1500 ng/day” (6). Thus, proposing an AI of 1500 ng/day for a nitrosamine based on the negative enhanced ames assay is no longer valid. While the agency has mentioned that higher limits based on “read-across” may be acceptable, it has been a trend in FDA to resist an AI that is higher than 1500 ng/day based on read-across, no matter how good the match is and how well studied the surrogate is.

FDA has indicated that it may not be open to accepting limits based on ICH Q3A

(7) or ICH Q3B (8) founded on negative in-vivo studies, irrespective of the fact that other agencies may have accepted the above. This decision is confusing and may be the cause of hardship to the pharmaceutical industry, which is global in nature; however, it does help dispel the notion that a nitrosamine has been derisked by the European Medicines Agency (EMA) or Health Canada (HC), is derisked by FDA.

From the combined recommendations in the RAIL Guidance, the webpage (6) and the Revision 2, it is amply clear that FDA’s favored approach for setting AIs for NDSRIs is the use of CPCA, followed by a read-across, as long as adequate information is available for the surrogate and the AI proposed does not exceed 1500 ng/day.

The agency has merged the criteria for justifying limits of multiple nitrosamines in a drug product with the EMA and HC recommendations. FDA has completely adopted the flexible approach that EMA, HC, and other agencies have been using for some time now, to establish a specification when multiple nitrosamines are present (information Appendix C of Revision 2).

. The updates to the recommendations related to control of multiple nitrosamines are logical and aligned with other agencies and are a welcome change compared to what was provided in the original guidance of 2020 and 2021. Industry should remember that the control of total nitrosamines should include the smaller nitrosamines as well as NDSRIs arising from the APIs, intermediates, and/or impurities.

In Section IV.C.2 of this version of the guidance, FDA has stated that if the level of nitrosamine is above 10% of the proposed AI, then each drug product batch should be tested at release, stability, and retest dates. This version also states that any lot of API with nitrosamine above the proposed AI should not be released.

. This recommendation varies from the recommendations of EMA and HC, in that these later guidance documents state that an amount of nitrosamines less than10% of AI can justify omission of specification, and an amount less than 30% of AI may justify skip testing. FDA has no option of reduced testing when the nitrosamine is consistently within the range of 10% to 30% of the AI.

Instead, FDA has proposed that if the amount of nitrosamine is above 10% of AI, each and every batch should be tested at release and stability, which could lead to significant increase in workload of the pharmaceutical manufacturers.

In Section IV.D.2.a, FDA placed the responsibility of establishing the reliability of API suppliers on the drug product manufacturers and applicants. The guidance indicates that the information regarding the nitrosamine levels provided by the API suppliers should not be accepted by the drug product (DP) manufacturers without testing significant number of lots and repeating the verification testing from time to time.

. FDA’s opinions indicate that they hold the DP manufacturers and applicants to be responsible for all aspects of controlling the nitrosamine risk. While this could be overwhelming to the drug product manufacturers, they need to take note that not testing the APIs based on the evaluation provided by the API supplier may not be acceptable when the API has vulnerable amines. In addition to being a review issue, this topic could be a compliance-related issue, where the API and raw materials-related vendor validation may need testing of several lots for possible nitrosamines and in some cases, nitrites (see comments in Section III). However, this in no way reduces the responsibility of the API manufacturers, who need to do their own due diligence and propose controls of nitrosamines wherever needed.

When it comes to root cause analysis, in the current guidance, FDA has provided a significant amount of information to cover NDSRIs, which were not discussed in the previous versions. This version clarifies that API control strategies of nitrosamines based on upstream controls could be justified only if there is clear understanding of the process and should be submitted as Prior Approval Supplements (not changes being effected [CBE] 30 or other lower-level supplements).

A signification update in the current version of the guidance is the recommendation regarding reformulation of drug products with nitrosamine scavengers. FDA has named some excipients as antioxidants, which could be used to reformulate products (e.g., ascorbic acid, alpha tocopherol, propyl gallate, cysteine hydrochloride, and sodium bicarbonate [pH modifier]). Interestingly, all these excipients appear in the FDA Inactive Ingredient Database (IID). FDA has referred to the publication Shakleya 

The Shakleya paper includes nitrite scavengers such as caffeic acid and ferulic acid in the study of nitroso bumetanide impurity formation and its inhibition in bumetanide tablets. However, these effective nitrite scavengers are not mentioned in the IID and thus omitted in this guidance. In future, it may be helpful for the industry to appeal to FDA to allow the use of these excipients in new drugs as well as generic formulations, based on sufficient literature available in the public domain to demonstrate their safety of these scavengers, when used in small quantities

A helpful addition in this update are the details of reporting categories of reformulation, based on SUPAC (Level 3) (10–12). It has been stated that for reformulation of Biopharmaceutics Classification System (BCS) Class 1, BCS Class 2, and BCS Class 3 drugs, performing 

 dissolution comparison may be adequate to justify formulation change with nitrite scavengers. For the justification of reformulation, FDA has reference to the publication from Shakleya 

. 2023 (6). FDA in this guidance has mentioned that for new drugs, bioequivalence (BE) proposals should be submitted by either Type C meeting or for generics, via pre-abbreviated new drug application (ANDA) meeting (not a controlled correspondence).

The guidance refers to the nitrite scavengers as antioxidants and, in some cases, pH adjusters. This information is especially helpful for development of generics of parenteral dosage forms where antioxidants are considered as exception excipients which may differ quantitatively and qualitatively from the reference listed drug (RLD).

 The Shakleya 2023 paper deals with oral immediate-release dosage form related reformulation. There are numerous other dosage forms which may need reformulation and are not addressed. FDA has given a valuable hint that labeling nitrite scavengers as antioxidants may be able to resolve the Q1/Q2-related issues for generics of many formulations. But, how generics are expected to be Q1/Q2 to the reference listed drug (RLD) with respect to 

 inactive ingredients with no exception, especially otic and ophthalmic products, may be reformulated is not clear.

This process of formulating or reformulating Q1/Q2 generics may become a challenge if there are patents introduced for products with pH ranges that deter nitrosation or inclusion of nitrite scavengers that the agency has mentioned in this guidance.

Section V of the revised guidance provides advice regarding how the nitrosamine controls may be implemented in drug substance and drug products and the pathways of communication with FDA. The agency has stated that confirmatory testing of three commercial lots of the drug product at different stages of lifecycle or targeted forced degradation studies may be performed to justify the omission of controls of nitrosamines. However, the testing should be repeated during every process validation throughout the life cycle of the product. This information may be either provided to FDA upon request or submitted in the next annual report.

Control of the nitrosamine is required by this guidance when the nitrosamine limit exceeds 10% of the AI limit but within the AI limit. This may be done by a CBE-30 supplement.

The general advice by FDA is to consider the reformulation of approved products when the levels of nitrosamines exceed the AI limit and submit the changes as prior approval supplement (PAS).

The agency has also recommended the supplementation of the application of approved products when an alternative AI (other than CPCA) is being proposed or a AI limit based on CPCA is being proposed for a NDSRI that is not addressed in the FDA webpage (6).

For over-the-counter (OTC) products and products that are not subject to approved applications, the information should be retained in the manufacturing facility.

The updated guidance encourages sponsors to work with the Center for Drug Evaluation and Research’s Drug Shortage Staff at drugshortages@fda.hhs.gov when a distributed product is found to have nitrosamines above the FDA proposed AI. The agency has indicated that if the amount of nitrosamine in the API or distributed drug product are above AI already acceptable by FDA (either based on CPCA or through PAS), a field alert should be filed. For some of these products, interim higher limits may be allowed on a case-by-case basis. It is noteworthy that the FDA has recommended that an API manufacturer should also file a field alert if they find out that the distributed API lots may have nitrosamines above AI.

Throughout the revised guidance document, FDA has stated that when faced by dilemma regarding the marketing of the products,manufacturers and applicants can contact the Drug Shortage Staff in CDER at 

. To discuss issues involving recalls, manufacturers and applicants can contact the recall coordinator assigned to the product type and location.

 published in September of 2024 could be considered a quantum leap from the original version of 2020 and the update of 2021. In this version, FDA has taken into consideration a significant amount information that it has accrued in the past four years regarding the quality issues that may affect the presence of nitrosamines, especially the NDSRIs, in drugs. The guidance is clear in its directives and has been converged with other contemporary FDA documents such as the RAIL guidance (5) and information on FDA’s website (6). While these clarifications indicate that in some cases the industry members may have to reconsider their risk assessment, confirmatory testing criteria, the information in the guidance would be helpful performing these activities. The disappointing aspect is the non-alignment of AIs of NDSRIs with the EMA and/or HC, which is expected to cause hardship to the industry. Overall, the update shows that FDA has come a long way since NDMA was first detected in valsartan, but also tells us that we, as the pharmaceutical industry, have miles to go before we resolve the concerns of nitrosamines in drugs.

Guidance for Industry, Control of Nitrosamine Impurities in Human Drugs, Final Guidance 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/control-nitrosamine-impurities-human-drugs

Smith, P. A. S.; Loeppky, R.N. Nitrosative Cleavage of Tertiary Amines, 

M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk 

Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) 

FDA. Recommended AI Limits for Certain Nitrosamine Impurities. 

 (accessed Sept. 25, 2024) https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits#compound

Shakleya, D.; Asmelash, B.; Alayoubi, et al. Bumetanide as a Model NDSRI Substrate: N-nitrosobumetanide Impurity Formation and Its Inhibition in Bumetanide Tablets. 

 (12), 3075–3087. DOI: 10.1016/j.xphs.2023.06.013

SUPAC-IR: Immediate Release Solid Oral Dosage Forms: Scale-Up and Post approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation 

SUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale-Up and Post approval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation 

SUPAC-SS: Nonsterile Semisolid Dosage Forms: Scale-Up and Post approval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation 

This article presents an overview of FDA’s recent update to the guidance document, Control of Nitrosamine Impurities in Human Drugs.

What Does the FDA's Recent Update of the Nitrosamine Guidance Convey?

FDA has approved a vaccine to prevent lower respiratory tract disease resulting from the respiratory syncytial virus (RSV) in adults 18 to 59 years of age who are at increased risk, Pfizer announced on Oct. 22, 2024. The bivalent RSV prefusion F vaccine, Abrysvo, has a broader indication to include those younger than 60 and is the only RSV vaccine approved in pregnant people who are at 32 through 36 weeks of gestation, and infants from birth to six months of age, according to the company (1).

“In the prefusion state, the RSV fusion protein (F) is a major target of neutralizing antibodies, serving as the basis of Pfizer’s RSV vaccine. Variations in the F protein sequence among RSV-A and RSV-B subgroups are clustered in a key antigenic site, a target for potent neutralizing antibodies,” stated the company (1).

According to Pfizer, FDA made its decision based on results from a Phase III clinical trial(NCT05842967), MONeT (RSV I M munizati ON Study for Adul T s at Higher Risk of Severe Illness), which looked at the safety and efficacy in adults with certain chronic medical conditions, such as asthma and diabetes.

“Immunocompromised adults, such as patients with cancer or autoimmune disorders, have a substantially increased risk of experiencing severe complications from RSV, yet there are currently no vaccines approved for those aged 18 to 59 in the [United States],” said Annaliesa Anderson, Pfizer senior vice president and chief scientific officer for vaccine research and development, in an August 2024 press release about the results (2). “We are encouraged by the positive top-line data from this study, which provide important evidence that Abrysvo has the potential to address a significant unmet need in this vulnerable population.”

“RSV represents a significant threat to younger adults with certain chronic conditions. After decades of vaccine research by the scientific community and Pfizer, we now have the opportunity to help alleviate the burden of RSV in this high-risk adult population,” said Aamir Malik, chief US commercial officer and executive vice president, Pfizer, in a press release (1). “With this approval, we are proud that Abrysvo is now the only RSV vaccine indicated for adults aged 18 to 49 at increased risk for the disease, expanding on its existing indications for older adults and pregnant women.”

Abrysvo was also granted marketing authorization in the European Union by the European Commission in August 2023 for older adults and maternal immunization (3).

“The approval of ABRYSVO in Europe marks significant progress in the scientific community's efforts to provide meaningful protection against RSV, a common respiratory virus that could potentially be severe and even life-threatening, especially for infants and older adults,” said Anderson, at the time (3). “Last year’s significant number of newborns, children, and adults being hospitalized across Europe demonstrated the immense need for protection against severe RSV cases. The approval of the vaccine for both older adults and infants through maternal immunization is a triumph for public health and we hope to see a tremendous impact for future seasons.”

Pfizer.U.S. FDA Approves Pfizer’s RSV Vaccine Abrysvo for Adults Aged 18 to 59 at Increased Risk for Disease. Press Release. Oct. 22, 2024.

Pfizer. Pfizer Announces Top-Line Results of Abrysvo for RSV in Immunocompromised Adults. Press Release. Aug. 12, 2024.

Pfizer. European Commission Approves Pfizer’s Abrysvo to Help Protect Infants through Maternal Immunization and Older Adults from RSV. Press Release. Aug. 24, 2023.

Pfizer’s bivalent RSV prefusion F vaccine has been approved to prevent lower respiratory tract disease resulting from the respiratory syncytial virus in adults 18 to 59 years of age who are at increased risk.


FDA Approves RSV Vaccine

On Oct. 18, 2024, REGiMMUNE and Kiji Therapeutics announced the two companies are intending to merge, creating a specialty company, REGiMMUNE/Kiji TX, for regulatory T cells (Tregs) targeting drugs for multiple modalities and indications. The two companies’ complementary portfolios will be used to create the new Treg biotech to address unmet needs by the modulation of the Treg function.

The merger will create a specialty company, REGiMMUNE/Kiji TX, for regulatory T cells.

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