Behind the Headlines Episode 27

Ask the Expert

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

Drug Digest September 2025

Artificial intelligence, machine learning, and novel instruments are helping drug developers.

Enhancing Bioanalysis and Drug Development with Advanced Tools and Technologies

J.P. Morgan Report Lists Biologics, Obesity, China

Top Trends Reshaping Pharma R&D

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

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Imfinzi (durvalumab) and Lynparza (olaparib), two AstraZeneca products, have been approved as treatments for certain people who have primary advanced or recurrent endometrial cancer throughout the European Union (EU), AstraZeneca said in a press release on Aug. 14, 2024 (1). The European Commission’s approval follows a positive opinion by the Committee for Medicinal Products for Human Use based on a subgroup analysis of mismatch repair (MMR) status in a Phase III trial (DUO-E), the results of which were published in the 

The approval covers several conditions: first, Imfinzi plus chemotherapy as first-line treatment, followed by Lynparza and Imfinzi, may be used in patients with mismatch repair proficient (pMMR) disease, and second, Imfinzi plus chemotherapy followed again by Imfinzi alone can be used for patients with mismatch repair deficient (dMMR) disease (1).

“This approval of Imfinzi and Lynparza regimens marks the first-ever approval for a combination of an immunotherapy and PARP [poly-adenosine diphosphate ribose polymerase] inhibitor in endometrial cancer and a major step forward for patients,” Dave Fredrickson, executive vice president of AstraZeneca’s oncology business unit, said in the press release (1,2). “In Europe, endometrial cancer is the fourth-most common cancer in women, and until now, the 70% to 80% of patients who have mismatch repair proficient disease have had few available treatment options.”

Endometrial cancer originates in the tissue lining of the uterus and is most common in women who have experienced menopause, with an average age at the time of diagnosis of over 60 years old. Approximately 125,000 women in Europe were diagnosed with endometrial cancer in 2022.

“This approval is welcome news for patients with advanced or recurrent endometrial cancer in Europe, especially those with mismatch repair proficient disease who have limited options,” Els Van Nieuwenhuysen, gynecological oncologist at UZ Leuven, Belgium, and DUO-E trial investigator, said in a press release. “The olaparib and durvalumab as well as the durvalumab regimens now have the potential to improve outcomes for all patients in this setting in Europe, regardless of mismatch repair status.”

The regimen of Imfinzi and Lynparza investigated in the trial reduced the risk of disease progression or death in patients with pMMR disease by 43% versus a control group, with a median 15.0 months versus 9.7 months (1). While a median number of months was not reached in the portion that tested the Imfinzi regimen in patients with dMMR disease, efficacy was measured at 58% in terms of reducing disease progression or death risk.

Imfinzi plus chemotherapy has been approved for dMMR patients with primary advanced or recurrent endometrial cancer in the United States, and the results of the DUO-E trial are currently being studied in Japan and other countries which are considering regulatory submissions for both Imfinzi and Lynparza, according to AstraZeneca (1).

1. AstraZeneca. Lynparza and Imfinzi Combination Approved in the EU for Patients with Mismatch Repair Proficient Advanced or Recurrent Endometrial Cancer. Press Release. Aug. 14, 2024.
2. Westin, S.N.; Moore, K.; Chon, H.S.; et al. Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab with or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial. 

Articles

Imfinzi may be used alone, or with chemotherapy in tandem with the other approved treatment, Lynparza.

Two AstraZeneca Treatments for Endometrial Cancer Approved in EU

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FDA has approved Yorvipath (palopegteriparatide), an Ascendis Pharma product, for administration by subcutaneous injection to adults with hypoparathyroidism, a press release announced on Aug. 9, 2024 (1).

“We are deeply grateful to patients, clinicians, and advocates for their many contributions to this important milestone,” Jan Mikkelsen, Ascendis Pharma president and chief executive officer, said in a press release (2).

Hypoparathyroidism, which is a rare endocrine disease affecting anywhere from 70,000 to 90,000 people in the United States, is most often caused by damage to parathyroid glands either from autoimmune disease or surgery (notably, the FDA press release said that Yorvipath has not been studied in adults with acute post-surgical hypoparathyroidism) (1,2). A low level of parathyroid hormone (PTH) is a chief characteristic of hypoparathyroidism, and leads to blood calcium levels being too low, which is known as hypocalcemia.

Depending on those blood calcium levels, other symptoms can vary, but include tingling or numbness in lips, fingertips, and toes; muscle cramps or spasms; and seizures.

While patients with hypoparathyroidism are typically treated with active vitamin D and (usually large doses) of calcium, taken multiple times a day, to increase blood calcium into the low-normal range, Yorvipath supplements that with a once-daily administration of a prodrug of PTH (1-34), which provides continuous exposure to released PTH over a 24-hour period (1,2).

“FDA approval of Yorvipath is such an important milestone for our community,” said Patty Keating, executive director of the HypoPARAthyroidism Association, in an Ascendis press release. “We are thankful that the seriousness of our condition has been understood and our voices heard. We look forward to having this new treatment option to help us move beyond the limits and risks of conventional therapy.”

“The consequences of hypoparathyroidism on the health and quality of life of our patients can be extraordinarily debilitating,” said Lynn Kohlmeier, MD, endocrinologist at Spokane Osteoporosis & Endocrinology, chair of the Medical Advisory Board of the HypoPARAthyroidism Association, and an investigator in the PaTHway trial that led to the FDA approval (2). “The ability to address the underlying cause of this disease is crucial and will be an important advancement for our patients with hypoparathyroidism.”

Ascendis said it anticipates an initial commercial supply of Yorvipath will be available in the US in the first quarter of 2025, and furthermore, is planning to request FDA approval to commercialize existing manufactured product, which could be ready for market by the fourth quarter of 2024 (2).

FDA granted Priority Review to Yorvipath, with the goal of taking action on an application within six months as opposed to the standard 10, and designated it as an orphan drug, which qualifies sponsors for incentives including tax credits for qualified clinical trials, exemption from user fees, and the potential of up to seven years of market exclusivity following approval (3,4).

1. FDA. FDA Approves New Drug for Hypoparathyroidism, A Rare Disorder. Press Release. Aug. 9, 2024.
2. Ascendis Pharma. FDA Approves YORVIPATH (Palopegteriparatide) as the First and Only Treatment for Hypoparathyroidism in Adults. Press Release. Aug. 12, 2024.
3. FDA. Priority Review. 

, updated Jan. 4, 2018 (accessed Aug. 14, 2024).
4. FDA. Designating an Orphan Product: Drugs and Biological Products. 

, updated Aug. 12, 2024 (accessed Aug. 14, 2024).

Yorvipath is a prodrug of parathyroid hormone (PTH) (1-34), designed to be administered once daily to provide continuous exposure to released PTH.

New Drug for Rare Disorder Hypoparathyroidism Gets FDA Approval

Enhertu (trastuzumab deruxtecan), a human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate jointly developed and commercialized by AstraZeneca and Daiichi Sankyo, received conditional approval from the National Medical Products Administration of China for monotherapy treatment of adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GER) adenocarcinomas, provided those patients have received two or more prior treatment regimens, AstraZeneca announced in a press release on Aug. 13, 2024 (1).

The approval decision was based on positive results of a Phase II trial (DESTINY-Gastric06), indicating that Enhertu “demonstrated clinically meaningful efficacy” in patients in China, which is home to more than one-third of all global cases of gastric cancer—359,000 new cases and 260,000 deaths having been reported in 2022 (1,2). About 65% of patients in China present with advanced disease by the time of diagnosis, and approximately one in five gastric cancers around the world are HER2-positive (1).

“HER2-positive metastatic gastric cancer can be particularly aggressive and difficult to treat,” said Lin Shen, MD, director of the department of gastrointestinal oncology at Peking University Cancer Hospital in China, in the AstraZeneca press release. “Patients often face poor outcomes following disease progression on first-line treatment and subsequent chemotherapy. With the approval of Enhertu, patients in China with HER2-positive metastatic gastric cancer will now have an important anti-HER2 treatment option that has demonstrated clinically meaningful efficacy following progression on previous therapies.”

In the Phase II trial, a 6.4 mg/kg dose of Enhertu yielded a confirmed objective response rate of 28.8%, as assessed by independent review, and the median length of progression-free survival was 5.7 months (1).

“This approval of Enhertu brings a much-needed, new targeted treatment option to patients with HER2-positive metastatic gastric cancer in China and underscores our commitment to bringing this innovative medicine to more patients across the globe living with HER2-expressing cancers,” Dave Fredrickson, executive vice president of AstraZeneca’s oncology business unit, said in the release.

AstraZeneca and Daiichi Sankyo agreed to develop Enhertu in March 2019, and since then, the therapy has been approved in some form for various patient groups in more than 65 countries (1,3).

“This milestone marks the third approval in China for Enhertu in less than two years, following approvals for HER2-positive metastatic breast cancer and HER2-low metastatic breast cancer,” Kiminori Nagao, head of the Asia, South & Central America Business Unit of Daiichi Sankyo, said in the release. “Our DESTINY clinical trial program continues to reinforce Enhertu as a practice-changing treatment option for patients with HER2-expressing cancers, and this latest approval in China further illustrates the global impact of this innovative antibody drug conjugate.”

1. AstraZeneca. Enhertu Approved in China for Patients with Previously Treated HER2-Positive Advanced or Metastatic Gastric Cancer. Press Release. Aug. 13, 2024.
2. National Library of Medicine. Study of T-DXd Monotherapy in Patients with HER2-expressing Locally Advanced or Metastatic Gastric or GEJ Adenocarcinoma Who Have Received 2 or More Prior Regimens (DG-06). 

, May 7, 2024 (accessed Aug. 13, 2024).
3. AstraZeneca. AstraZeneca and Daiichi Sankyo Enter Collaboration for Novel HER2-Targeting Antibody-Drug Conjugate. Press Release. March 28, 2019.

AstraZeneca and Daiichi Sankyo first entered into an agreement to develop Enhertu in March 2019, and the antibody-drug conjugate has since been approved for various groups in more than 65 countries.

AstraZeneca Monotherapy for Gastric Cancer Gains Third Approval in China

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

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

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

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

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

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

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

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

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

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

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

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

First Nasal Spray for Anaphylaxis Approved by FDA

Results of a Phase III study (LEX-209) of the safety and efficacy of Balfaxar (prothrombin complex concentrate, human-lans), a blood coagulation factor replacement product made by Octapharma, have been published in 

, according to a press release from Octapharma USA on Aug. 12, 2024 (1,2).

The study investigated Balfaxar’s performance in the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (VKA, e.g., warfarin) therapy in adults in need of urgent surgeries and other invasive procedures.

Warfarin, as the press release stated, is prescribed to millions of patients in the United States to prevent blood clots from forming after a heart attack, stroke, heart valve surgery, deep vein thrombosis or pulmonary embolism, or certain types of irregular heartbeat (atrial fibrillation) (1). However, because of its anti-coagulant properties, warfarin carries with it an increased risk of bleeding in patients undergoing related procedures.

In the study, Balfaxar was tested against another four-factor prothrombin complex concentrate (4F-PCC), Kcentra, evaluating just over 200 patients in total, almost exactly evenly split between the two products (1,2). (Balfaxar contains vitamin K-dependent factors II (prothrombin), VII, IX, and X, as well as antithrombotic proteins C and S.) Balfaxar demonstrated effective hemostasis in 94.3% of patients, compared with 94.2% for Kcentra. The safety profile, the study said, was in line with previous studies.

 has published the results of this important study,” said Ravi Sarode, MD, the study’s principal investigator. “Balfaxar met the primary endpoint of hemostatic efficacy and was non-inferior to the comparator, Kcentra, in patients on a vitamin K antagonist undergoing urgent surgery with significant bleeding risk.”

Results of the LEX-209 trial to date have supported FDA’s approval of Balfaxar, according to the press release (1). The product is available as a lyophilized powder for reconstitution, which is then provided with sterile water as a diluent for injection and a transfer device.

“Octapharma launched Balfaxar in the US earlier this year and the response from the medical community has been outstanding,” said Octapharma USA president Flemming Nielsen. "The journal article provides further reinforcement of the great value this life-saving therapy has for patients. Octapharma is committed to ensuring a consistent Balfaxar supply for hospitals and medical providers now and in the future.”

Octapharma cautioned that reversing VKA therapy could lead to thromboembolic events, particularly in patients who have experienced such events in the past—in fact, Balfaxar is not recommended for people who have had a thromboembolic event in the previous three months. Fatal and non-fatal arterial and venous thromboembolic complications have been reported both in clinical trials involving Balfaxar, and post marketing surveillance (1). Patients who receive Balfaxar are recommended to be monitored for signs and symptoms of thromboembolic events.

 Publishes Study Results Demonstrating Efficacy & Safety of Balfaxar for Warfarin Reversal in Urgent Surgery & Invasive Procedures. Press Release. Aug. 12, 2024.
2. Sarode, R.; Goldstein, J.N.; Simonian, G.; et al. Vitamin K Antagonist Reversal for Urgent Surgery Using 4-Factor Prothrombin Complex Concentrates: A Randomized Clinical Trial. 

The 94.3% efficacy of the Octapharma product was just a shade ahead of the 94.2% measured in a comparative product, Kcentra.

Phase III Results Show Balfaxar Non-Inferior to Kcentra in Reversing Warfarin Therapy

Pfizer’s Abrysvo, currently the only approved vaccine for respiratory syncytial virus (RSV) in both older adults and infants through maternal immunization, yielded positive top-line safety and immunogenicity results in a substudy of an ongoing Phase III clinical trial (MONeT, or RSV Immunization Study for Adults at Higher Risk of Severe Illness), Pfizer announced in a press release on Aug. 12, 2024 (1,2). Two doses of Abrysvo were given to immunocompromised individuals age 18 and older who are at risk of developing severe RSV-associated lower respiratory tract disease (LRTD).

“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. “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.”

As Pfizer said in the press release, RSV—which is responsible for up to 160,000 hospitalizations and 13,000 deaths each year in the US alone—is contagious and a common cause of respiratory illness (1). It can impact the lungs and breathing passages of those affected, raising particular risk to certain younger and older age groups as well as people with some chronic medical conditions.

Abrysvo was approved by FDA for the prevention of LRTD caused by RSV in those 60 and older in May 2023, in infants from birth to six months by immunization of pregnant women at 32 to 36 weeks’ gestational age in August 2023 (both of those followed by approval actions from the European Commission, also in August 2023), was recommended as a maternal immunization by the US Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices in September 2023, and approved by Health Canada for both older adults and expectant mothers in January 2024 (3–7).

Prior clinical trial data of Abrysvo versus placebo suggested higher rates of low birth weight (5.1–4.4%) and jaundice (7.2–6.7%) in infants whose mothers had been given the vaccine at the targeted gestational age (1). Most common side effects in adults included fatigue, headache, nausea, muscle pain, and pain at the injection site.

1. Pfizer. Pfizer Announces Top-Line Results of Abrysvo for RSV in Immunocompromised Adults. Press Release. Aug. 12, 2024.
2. National Library of Medicine. A Study to Assess the Safety, Tolerability, and Immunogenicity of RSVpreF in Adults at High Risk of Severe RSV Disease (MONET). 

, April 9, 2024 (accessed Aug. 12, 2024).
3. Pfizer. US FDA Approves Abrysvo, Pfizer’s Vaccine for the Prevention of Respiratory Syncytial Virus (RSV) in Older Adults. Press Release. May 31, 2023.
4. Pfizer. US FDA Approves Abrysvo, Pfizer’s Vaccine for the Prevention of Respiratory Syncytial Virus (RSV) in Infants Through Active Immunization of Pregnant Individuals 32-36 Weeks of Gestational Age. Press Release. Aug. 21, 2023.
5. Pfizer. European Commission Approves Pfizer’s Abrysvo to Help Protect Infants through Maternal Immunization and Older Adults from RSV. Press Release. Aug. 24, 2023.
6. Pfizer. Pfizer Broadens Portfolio of Respiratory Vaccines Recommended by CDC Advisory Committee with Abrysvo for RSV. Press Release. Sept. 22, 2023.
7. Pfizer Canada. Health Canada Approves Pfizer's Bivalent Respiratory Syncytial Virus (RSV) Vaccine for Older Adults and Infants Through Maternal Immunization. Press Release. Jan. 4, 2024.

The virus, which is contagious and a common cause of respiratory illness, hospitalizes up to 160,000 people and is responsible for as many as 13,000 deaths in the United States every year.

RSV Vaccine Shows Positive Results in Substudy of Phase III Trial of Immunocompromised Patients

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

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A swelling population that is aging and increasingly suffering from chronic conditions is leading to a greater demand for bio/pharmaceutical products. However, developing a bio/pharmaceutical therapy is a long and expensive journey that does not always end in commercial success or even, for many drugs in the pipeline, commercial viability at all. In fact, according to research, attrition rates for drug candidates remains stubbornly high, sitting at around 90% for those drugs that have reached the Phase I trial stage (1).

Some key trends impacting many industries worldwide, including the bio/pharmaceutical industry, are digitalization and robotics. These trends are also expected to positively impact drug formulation by improving efficiencies and, hence, lowering the potential risk of failure.

“Digital enablement, in general, is gaining momentum, with around 75% of business-to-business customers preferring engagement with digital platforms over in-person interactions,” remarks Shahrzad Missaghi, senior manager, Product Development at Colorcon. “Intuitive digital platforms empower companies to make the right decisions at the start of the process and reduce formulation iterations.”

According to Sibaji Biswas, executive director and chief financial officer at Syngene International, machine learning (ML) and artificial intelligence (AI) have the potential to provide the bio/pharmaceutical industry with significant opportunities to enhance the formulation process and avoid potential failures. “For example, AI and ML technologies are already being increasingly used to predict drug–excipient interactions, which allows for the rapid selection of optimal formulation compositions,” he says. “These predictive models are also employed in the pharmaceutical space to forecast the properties of drug products, such as tablets, based on data sets generated during development.”

In concurrence, Himanshu Gadgil, CEO, Enzene, notes that ML and AI are proving to be transformative for many industries and offer significant formulation advantages by way of improved efficiency and effectiveness. “ML leverages vast amounts of historical data to predict outcomes and identify trends,” he says. “By analyzing [these] data, AI can anticipate the properties of new formulations and validate them before they undergo costly laboratory testing. This capability not only streamlines the development process but also reduces costs by identifying potential issues early on, thus minimizing the risk of failures.”

Some customized generative pre-trained transformer or open-access platforms, such as FormulationAI, are being developed specifically around formulation development, asserts Vincent Levet, director, Formulation Development and Production, Ardena. “[These platforms are] offering solutions that can enhance the creativity of scientists, for instance by helping to review literature very quickly, evaluate compounds through predictive models, or support the actual formulation process by generating design of experiments (DoEs) studies and help to analyze the data,” he says. “However, as it is still in its early stages, it’s important to mention that the adoption of AI also brings concerns regarding IP [intellectual property] protection and potential data breaches, which is particularly crucial as companies must protect their pipeline to survive.”

“AI is [only] as good as the data used to train it,” warns Hanns-Christian Mahler, CEO and board member of ten23 health. While AI is a tool that has the potential to provide value in formulation development, it is important to start off with expert knowledge and an understanding of specific liabilities and challenges of molecules or therapeutic modalities—the critical quality attributes (CQAs), he adds.

“Adequately large data sets of molecules that are characterized in depth and where differences and similarities are well understood, in combination with expert knowledge, can effectively guide and train AI,” Mahler says. “Sadly, most companies do not have such large data sets by themselves, so some cross-company initiative may be needed to support such developments.”

The large datasets, such as those seen in other AI applications used in other industries, are simply not available yet within the bio/pharmaceutical field, agrees Bernard Sagaert, CEO, etherna. “However, making sure that your data [are] structured in a way that makes [them] accessible to perform the first steps in AI and ML has helped [the industry] already in limiting screening efforts and predicting certain pathways to follow,” he says.

For Vinay Patil, product development manager at Sharp Services, the focus for AI and ML tools will be placed upon gaining efficiency in target identification. “[Because] formulation development can only begin once a target compound has been identified and characterized, I expect that more AI/ML efforts will be made in the drug formulation process as the technology matures, and once the industry gains additional experience and, more importantly, success in the use of AI for drug discovery,” he affirms.

At Abzena, an integrated biologics contract development and manufacturing organization (CDMO) and contract research organization (CRO), AI and ML are being leveraged to create a model that is capable of predicting formulation stability over long-term storage using early-stage data, adds Gary Watts, senior manager in Analytics, Abzena. “This model has been validated with multiple formulations of various therapeutic molecules and is particularly beneficial in projects with tight timelines driven by client needs,” he says.

“With the use and evolution of ML and AI, companies have a greater ability to prototype quickly and in a more cost-effective way,” continues David Ferrizzi, director of New Product Development, Colorcon. This ability affords companies opportunities to tackle challenges that may have been insurmountable previously. “For example, certain diseases that were not a focus before are now coming into focus,” he says. “Personalized medicine and a focus on speed and lower total cost are also enhanced as a result of ML and AI.”

“Patient-centricity plays a crucial role in formulation design and the final product’s market success,” says Biswas. “An integrated strategy is often more effective to create an optimized product for the patient, keeping in mind the clinical conditions and individual therapy requirements.”

While patient-centric approaches were traditionally centered on transitioning from immediate-release to modified-release products and creating therapies suitable for patients with a given clinical condition, the landscape is now changing to more personalized approaches, Biswas explains. “One emerging trend is patient-customized medications, where formulations are tailored to meet individual needs, reflecting a shift towards individualized therapies,” he specifies. “New chemical entities are also being formulated with advanced technologies including devices to minimize side effects and reduce dosing frequency, further enhancing patient convenience and compliance.”

Sagaert points out that there are numerous factors to consider to obtain a patient-centric formulation. “Companies need to constantly have all aspects of the platform and the product in mind,” he states. “For RNA-LNP [RNA-lipid nanoparticle]-based products, this is clearly making sure the RNA is non-immunogenic and highly expressed in the target cells, and not expressed in other cells to reduce dose and side effects. The LNPs need to target the right cells and organs to avoid off-target expression as much as possible, and the route of administration needs to be as convenient as possible for the patient in his disease setting.”

The primary consideration, however, is the patient population, adds Mahler. “Studying patient preferences and patient needs for a given indication and use case is key,” he says. “For the various modern therapeutics, such as biologics, ADCs [antibody-drug conjugates], CGTs [cell and gene therapies], oligos, all of these require sterile injection of infusions. For some indications and modalities the answer is probably to aim for subcutaneous (SC) administration using syringe or cartridge solutions with adequate (possibly high concentration) formulations, in combination with a device such as [an] autoinjector, pen, or on-body injector (OBI). Even in the case of cancer therapies, developing products for SC use offers significant benefits for patients.”

“‘Personalized’ medications are a hot topic in current times, and there have been greater efforts to understand the differences in sub-groups of patients such as different ethnicities and those prone to certain conditions,” continues Watts. “Until the science is clearer, formulation strategies must continue to focus upon the target patient population for each drug individually and ensure that this aligns with the design of the final drug format.”

Focusing on pediatric patients, Asma Patel, vice president, Integrated Development Services, Quotient Sciences, remarks that patient centricity is a growing need as these patients require age-appropriate and palatable dosage forms. “In pediatrics, liquid and solid dose formulations that are easier for infants and children to swallow are preferred, including solutions, suspensions, powder for reconstitution, and minitablets, and the taste and palatability challenges of these forms need to be overcome and confirmed by taste assessment studies,” she says. “There are also applications for these dosage forms for other patient populations, such as the elderly and those with disabilities, where easier-to-administer or easier-to-swallow dosage forms can ensure ease of administration, patient compliance, and efficacy.”

“Patient compliance and convenience are key elements in the design and development of formulations,” says Missaghi. “Gaining a deep understanding of patient preferences is the first step in informing the design of the dosage form.” For solid oral dosage products, formulators must consider factors, such as taste, size, shape, color, dosing frequency, and swallowability, which can all help with patient satisfaction and lead to compliance, she confirms.

“Companies can ensure that they’re developing formulations with the patient in mind by soliciting patient input throughout the development process,” adds Patil. “When possible, the proposed drug should be developed as a flexible dosage form. And on the clinical side, drug sponsors should ensure that the protocols are written in such a way that minimizes the burden on participants to the most reasonable degree possible, such as reducing the number of visits, offering home-based assessments, and using virtual consults when possible.”

According to Levet, by employing quality-by-design principles, formulators can define target product profiles matching the needs of the patients, and they can also identify CQAs that focus on patient safety and clinical efficacy from the outset of development. “Choosing excipients that are safe and can enhance drug stability and patient tolerance also plays a big part in being ‘patient-centric’,” he says. “Finally, fast-tracked and phase-appropriate development approaches, designed to get the right level of information to be able to reach the next clinical trial phase and evaluate (but also reject) new therapies as fast as possible allow, in the end, a better focus of the resources available, and ultimately quicker patient access to the most efficient treatments.”

“Selecting the right development partner with a proven track record can be a deciding factor in clinical and eventually commercial success,” asserts Patel. “When selecting a CRO/CDMO partner, the availability of integrated CMC [chemistry, manufacturing, and controls] and clinical research services from one company can be invaluable to streamline drug development processes, along with having a strong foundation of formulation development expertise.”

Partners play a crucial role in drug formulation, particularly during early development, confirms Missaghi. “Some key areas a partner can enhance the process include: offering technical capabilities and competence, including development and troubleshooting experience; knowledge of regulatory and quality standards, aiding in compliance; and a full understanding of the formulation landscape including patient adherence, common pain points, and industry challenges,” she says.

Levet points out that the broad skillset and experience offered by outsourcing partners is invaluable for drug formulation. “[Outsourcing partners] guide customers towards efficient and cost-effective formulations without overextending resources on a compound’s development before its potential is fully realized over the clinical phases,” he says. “With a ‘phase-appropriate’ development, they can help expedite the development process, which is essential, particularly for small and virtual companies to secure funding for subsequent phases.”

“Phase appropriateness is [essential] because it is a very important lever in expediting the screening and evaluation of drug candidates,” concurs Biswas. “This approach helps expedite drug candidate evaluation, allowing rapid assessment in Phase I but without compromising necessary quality. Smaller biotech’s operating on milestone-driven development, require CDMOs’ expertise for quick, risk-based decisions. Outsourcing partners with their extensive and diverse experience can provide a solid and effective platform for quicker delivery of these milestones through deployment of phase appropriate systems and processes.”

Sponsor’s look for a range of integrated development services when selecting an outsourcing partner, therefore, a capable partner should offer comprehensive solutions that include the breadth of the drug development process, asserts Gadgil. “Moreover, in today’s digital era, it is increasingly important for outsourcing partners to embrace innovations like AI and real-time data integration,” he concludes. “An effective outsourcing partner will not only showcase expertise across these domains but also leverage modern technologies to offer integrated, forward-thinking solutions for drug development.”

1. Sun, D.; Gao, W.; Hu, H.; Zhou, S. Why 90% of Clinical Drug Development Fails and How to Improve It? 

Felicity Thomas is associate editorial director for 

®
Vol. 48, No. 8
August 2024
Pages: 10–13

When referring to this article, please cite it as Thomas, F. Integrating Strategies for Formulation Success. 

Employing novel technologies and more patient-centric approaches can help to reduce the potential of formulation failure.

Integrating Strategies for Formulation Success

Donald Singer is principle microbiology global consultant at Ecolab Life Sciences.

Tony Cundell is principal consultant at Microbiological Consulting.

Unlike batch manufacturing, where drug substances or finished products are made with separate unit manufacturing steps with intermediate storage and testing between steps that sometimes take place in different global manufacturing locations, continuous pharmaceutical manufacturing allows each element of manufacturing to take place in a continuous process in a single facility. This compresses the manufacturing time, improves quality, reduces costs, and increases overall efficiency.

As highlighted in FDA’s March 2023 continuous manufacturing guidance (1), the concept of continuous manufacturing is particularly well suited for downstream processing for biopharmaceutical production and the manufacture of solid oral dosage forms. As the order of 60% of the sales volume of drug products continues to be solid oral dosage forms, this technology review will concentrate on the manufacture of compressed tablets and powder-filled capsules, where the batching, milling, mixing, tablet compression, or filling of dry powders in capsules applies more to dry (water-free) process equipment cleaning over the more common wet cleaning.

Industry and regulatory obstacles to dry cleaning implementation and risk mitigation

Although regulatory agencies such as FDA support the transition from batch to continuous manufacturing, the pharmaceutical industry has been slow to embrace this change. A self-audit of the sparse history of continuous manufacturing submission, review, and approval point to FDA not being the major obstacle to the transition (2). FDA’s Center for Drug Evaluation and Research (CDER) published a draft guidance in 2019 outlining quality considerations for continuous manufacturing (3). Earlier in 2014, CDER stablished the Emerging Technology Program (ETP), a collaborative program where industry representatives can meet with Emerging Technology Team (ETT) members to resolve potential technical and regulatory issues around the development and implementation of a novel technology prior to filing a regulatory submission. Examples of ETP-accepted emerging technologies in 2022 are continuous manufacturing of small-molecule drug substances and drug products and continuous manufacturing for biological molecule downstream processing.

Among the regulations pertinent to cleaning during continuous manufacturing is 

211.67), “Equipment Cleaning and Maintenance” (4), which states that documentation should include:

responsibility for equipment cleaning and maintenance

a detailed description of the cleaning procedure

In addition, the 2016 FDA Guidance for Industry Q7 

Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients

Equipment maintenance and cleaning (Section 5.2). 

Written procedures should be established for cleaning equipment and their subsequent release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include the following (Section 5.21):

assignment of responsibility for cleaning of equipment

cleaning schedules, including, where appropriate, sanitizing schedules

a complete description of the methods and materials, including dilution of cleaning agents used to clean equipment

when appropriate, instructions for disassembling and reassembling each article of equipment to ensure proper cleaning

instructions for the removal or obliteration of previous batch identification

instructions for the protection of clean equipment from contamination prior to use

inspection of equipment for cleanliness immediately before use, if practical

establishing the maximum time that may elapse between the completion of processing and equipment cleaning, when appropriate” (5).

Submitted: Oct. 9, 2023
Accepted: April 2, 2024

Guidance for Industry, Q13 Continuous Manufacturing of Drug Substances and Drug Products

 (CDER, March 2023).
2. Fisher, A. C.; Liu, W.; Schick, A.; et al. An Audit of Pharmaceutical Continuous Manufacturing Regulatory Submissions and Outcomes in the US. 

, 121778. DOI: 10.1016/j.ijpharm.2022.121778
3. FDA. 

Draft Guidance for Industry, Quality Considerations for Continuous Manufacturing

 Title 21, Part 211.67 (Government Printing Office, Washington, DC) 162.
5. FDA. 

Guidance for Industry, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients

Donald Singer is principle microbiology global consultant at Ecolab Life Sciences, and Tony Cundell is principal consultant at Microbiological Consulting.

®
Vol. 48, No. 8
August 2024
Pages: 22–28

When referring to this article, please cite it has Singer, D.; Cundell, T. The Role of Dry (Water-free) Process Equipment Cleaning in Continuous Pharmaceutical Manufacturing. 

The growing use of continuous manufacturing in the pharmaceutical industry merits a review of the application of dry cleaning and sanitization methods, especially for non-sterile oral solid drug product manufacturing of dry powders.

The Role of Dry (Water-free) Process Equipment Cleaning in Continuous Pharmaceutical Manufacturing

Feliza Mirasol is the science editor for 

Andelyn Biosciences, a patient-focused cell and gene therapy contract development and manufacturing organization, announced on Aug. 6, 2024 that it has entered into a license agreement with the Broad Institute of MIT to include MyoAAV plasmids in its AAV Curator Platform, which expands the platform’s offerings.

Under the agreement, Andelyn will have use of the MyoAAV plasmids to perform research and development services for clients who are developing gene therapies. Andelyn will screen potential candidates and perform scale-up and pre-clinical development work to prepare for investigational new drug-enabling studies. The agreement also gives Andelyn permission to sublicense the MyoAAV plasmids to its clients for internal research purposes.

The MyoAAV plasmids were developed by researchers at the Broad Institute of MIT and Harvard. They are a new family of plasmids that produce adeno-associated viruses (AAVs) ten times more efficient in reaching muscle tissue and targeting the liver than wild-type vectors, according to a company press release. “With more precise targeting of muscle tissue, research shows MyoAAV-delivered therapies may require lower dosing,” Andelyn stated in the press release.

Andelyn will utilize its expertise in translational drug development to bring Broad's new class of engineered AAVs to biotech organizations as they target diseases in therapeutic areas with significant unmet need. The company expects that the new AAVs will ultimately reduce the effective dose demand while improving product safety.

“Our license from the Broad Institute furthers our goal of providing the industry access to critical tools and capabilities that facilitate the development of innovative therapies to bring more treatments to more patients. With access to the increased specificity of MyoAAVs, our clients now have the opportunity to maximize efficiency in their gene therapy processes and drive down the cost per patient,” said Matt Niloff, chief commercial officer of Andelyn, in the press release.

In May 2023, Andelyn was selected to manufacture AAV therapies using its Curator Platform under the California Institute for Regenerative Medicine (CIRM) Accelerating Medicines Partnership (AMP) Bespoke Gene Therapy Consortium (BGTC) (1).

CIRM established a partnership with Andelyn to advance BGTC’s goal of developing platforms and standards that will drive the development and delivery of customized or “bespoke” gene therapies for rare diseases. BGTC is focused on developing cures for eight such rare diseases. Andelyn’s role will be to optimize and scale the AAV gene therapy processes for treating congenital hereditary endothelial dystrophy–type 1.

“As a long-standing pioneer in AAV gene therapies and historical connection to the clinic, we have great synergies with the CIRM/BGTC. Andelyn is privileged to work with the CIRM/BGTC on its first AMP established specifically for rare disease and leverage our AAV Curator Platform to help overcome the major obstacles related to developing gene therapies,” Niloff stated in a company press release (1).

1. Andelyn Biosciences. Andelyn Biosciences Selected as Viral Vector Manufacturing Partner for the California Institute for Regenerative Medicine (CIRM) Accelerating Medicines Partnership (AMP) Bespoke Gene Therapy Consortium (BGTC). Press Release, May 23, 2024.

With the agreement, Andelyin Biosciences will add MyoAAV plasmids developed by Broad Institute of MIT and Harvard to its AAV Curator Platform.

Andelyn Biosciences and Broad Institute of MIT Enter into License Agreement to include MyoAAV Plasmids in AAV Platform

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

A transmembrane 4 L six family member 1 (TM4SF1)-directed antibody-drug conjugate (ADC) called AGX101 is now being given to patients in a Phase I clinical trial, as announced by Abzena in a press release on Aug. 8, 2024 (1,2). Abzena, a contract development and manufacturing organization (CDMO), is partnering with Angiex, a developer of nuclear-delivered antibody-drug conjugate (ND-ADC) therapies for solid cancers, to conduct the trial (1).

As defined by the two companies, the AGX101 monotherapy targets two different tumor components, its vasculature and cancer cells, and operates via three mechanisms: eliminating tumor blood vessels, killing tumor cells that may be capable of invasion and/or metastasis, and, finally, instructing the immune system to attack the cancer (1).

In preparation for the Phase I trial being run by Angiex, Abzena said it provided linker-payload design and synthesis, bioconjugation, process development, and current good manufacturing practice (CGMP) manufacturing (1). The Phase I study is open-label, with dose escalation and expansion components that are intended to evaluate the safety, pharmacokinetics and pharmacodynamics, and preliminary anti-tumor activity of AGX101.

“We are very excited to have dosed our first patient in our first-in-human study of our novel TM4SF1 ADC, AGX101,” Paul Jaminet, Angiex co-founder and CEO, said in the press release. “Throughout the development of AGX101, Abzena has worked closely with us to achieve successful GMP manufacturing and quality control. We could not have reached this milestone without Abzena’s expertise, cooperation, and support. Both companies have extensive expertise in their respective fields and an aligned mission, and we look forward to continuing our partnership to ensure that AGX101 is available to meet the needs of clinical cancer patients. We are delighted that Abzena shares our vision that no one should die of cancer.”

“The Abzena team is incredibly proud to have helped Angiex achieve this significant milestone,” Abzena CEO Matt Stober added in the release. “Our unique ability to support Angiex with a fully integrated approach allowed us to de-risk and rapidly progress AGX101 into the clinic for patient dosing. We will continue supporting Angiex with our extensive ADC expertise and integrated capabilities to accelerate the development timeline of AGX101, and ultimately get this life-changing treatment to cancer patients faster.”

According to the two companies, the dose escalation portion of the study can assess doses up to 10 mg/kg in the solid tumor patient population, while the dose expansion portion can evaluate treatment at the recommended Phase II dose in multiple indications (1).

The press release did not indicate a timeline for the Phase I study, or when further trials might be scheduled.

1. Abzena. Abzena Supplies Clinical Trial Material for Angiex’s Phase I Study of AGX101, a First-in-Class TM4SF1-directed ADC. Press Release. Aug. 8, 2024.
2. Chen, G.; She, X.; Yin, Y.; et al. Targeting TM4SF1 Exhibits Therapeutic Potential Via Inhibition of Cancer Stem Cells. 

AGX101 targets the cancer cells and vasculature of a tumor, and works to eliminate the tumor blood vessels, kill tumor cells capable of invasion or metastasis, and direct the immune system to attack the cancer.

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