Digital Transformation in Pharma Manufacturing

Patent Cliff Deals, Tariff Pressures, and the In Vivo Cell Therapy Bet

Behind the Headlines, Episode 23

ICH Q12 and Post-Approval Changes

Speed, Flexibility Top Large-Molecule Manufacturing Trends

Drug Digest July 2025

Key Insights from Industry Survey Results

Bio/Pharma's Tariff Response

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

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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. 

Articles

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

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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.

Abzena, Angiex Collaborate for Phase I Trial of Solid Cancer Tumor Therapy

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 notice dated Aug. 8, 2024 announced FDA’s Fiscal Year 2025 Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality (OPQ) Experiential Learning Site Visit Program (ELSVP) (1,2).

The ELSVP, according to a press release from FDA, allows staff to observe commercial manufacturing and testing operations as well as pilot plants, with the goal of better understanding standard operations of the pharmaceutical industry and how those impact the developmental programs and commercial life cycles of drugs (1). It does not replace or supplement a regulatory inspection.

 notice identified the ELSVP as part of CDER’s commitment to ensuring that safe, effective, and high-quality drugs are available to Americans, in this case by arranging site visits (2). Companies encouraged to participate include those that engage in the development and manufacturing of either APIs, both small and large molecule, or drug products (1).

Groups of no more than 15 OPQ staff typically come to a site to observe operations over a one- to two-day period. There are a number of areas of interest for these staff members, according to FDA, though it is not an exhaustive list (2):

Solutions, suspensions, emulsions, semisolids, and solids

Modified- and immediate-release formulations

Drug-device combination products regulated by CDER (e.g., inhalation products, transdermal systems, implants intended for drug delivery, and pre-filled syringes)

Design, development, manufacturing, and controls:

Engineering controls for aseptic processes

Process analytical technology, measurement systems, and real-time release testing

The selection process gives priority to facilities on the basis of FDA staff training and a facility’s current compliance standing with FDA, among other considerations (1).

Companies that may want to schedule a site visit, or which simply desire more information, are invited to submit a proposal as of Oct. 1, 2024 to 

. Visits will be made within a year of that date, by the close of the next government fiscal year on Sept. 30, 2025 (2).

FDA said proposals should include the following (2):

Facility Establishment Identifier and D-U-N-S numbers, as applicable

maximum number of FDA staff that can be accommodated during a site visit (maximum of 15, on average)

a proposed agenda outlining the learning objectives and associated activities for the site visit

maximum number of site visits a site would be willing to host by the close of the government fiscal year

proposed time frames for each site visit (i.e., month or quarter).

If a site is selected for a visit, FDA will collaborate with the contact person provided on appropriate visiting dates.

1. FDA. FDA Invites Drug Companies to Participate in Site Visitation Program. Press Release. Aug. 7, 2024.
2. FDA. Office of Pharmaceutical Quality Experiential Learning Site Visit Program; Program Announcement. Notice, 

, 89 FR 64938, 64938–64939, Aug. 8, 2024.

The program, for which visits will be scheduled through September 2025, does not replace or supplement a regulatory inspection.

Drug Companies Encouraged by FDA to Participate in FY 2025 Site Visitation Program

US Specialty Formulations (USSF), a provider of pharmaceutical solutions for healthcare, diagnostics, and new drug developers, has begun a $15 million initiative to expand biopharma operations at its Allentown, Pa., facility, according to a July 31, 2024 press release.

USSF has already secured $4.7 million of its $15 million goal. Under the expansion, the company plans to bring in new facility cleanroom suites and state-of-the-art automated packaging and product inspection equipment. The expansion is expected to increase the company’s cleanroom production capacity by more than 2.5 times. The expansion is expected to be completed at the end of 2025. Once done, the company will have the capability to take on substantially larger projects to support growth for new and current clients.

“This expansion is a transformative step for USSF,” said Kyle Flanigan, CEO of USSF, in the press release. “By investing in cutting-edge technology and streamlining our manufacturing processes, we are raising the bar for ourselves and reaffirming our commitment to delivering innovative pharmaceutical solutions that reduce the risk profile of new drug development or contract manufacturing and ultimately improve patient lives. This expansion empowers our dedicated team to serve our partners and clients worldwide more effectively.”

In addition to raising USSF’s cleanroom capacity, the expansion is also expected to significantly boost the local economy by creating jobs and increasing revenue for the Greater Philadelphia region. When completed, USSF will seek to employ more than 100 staff to support the facility.

The company stated in its press release that cleanrooms are required to meet most pharmaceutical manufacturing standards. “They provide a highly controlled environment essential for product quality, safety, and compliance with CGMP [current good manufacturing practice] standards. These rooms provide a sterile environment for the production of injectables, including small molecules, botanicals, and vaccines.”

USSF offers a range of services, including drug R&D, contract manufacturing, private label formulations and packaging, and small-molecule pharmaceuticals. The company has developed the oral vaccine platform, QYNDR, and a self-administered drinkable vaccine, the first, according to the company. This drinkable vaccine completed a Phase I clinical trial in 2023 (1).

QYNDR is a next-generation protein-based oral vaccine (mucosal vaccine) developed to addresses the challenges seen with the current COVID-19 vaccines. According to a company press release, the results of the Phase I clinical trial showed that the vaccine demonstrated longevity and cross-variant protection from multiple COVID-19 strains. In addition, the study may possibly have identified a correlation of protection against the virus and other strains, which is to be further investigated in a Phase II clinical trial (1).

“The [P]hase I clinical data showed strong evidence that this oral platform and vaccine is a revolutionary industry disruptor and will become the preferred method of vaccination in the future,” Flanigan said in a press release issued at the time that the Phase I trial was completed. “As we proceed into Phase II and III, we are confident this next-generation vaccine will be more effective than other mucosal vaccines in current development and testing.”

1. US Specialty Formulations. US Specialty Formulations Completes Phase I of Clinical Trials for the Qyndr Vaccine. Press Release, Sept. 7, 2023.

 US Specialty Formulations plans to invest $15 million to expand biopharma operations at its Allentown, Pa.,facility.

US Specialty Formulations to Modernize Biopharma Operations with $15 Million Investment

 is Industry Market Manager Biopharma, Pharma EMEA - Brenntag GmbH.

Benzoyl peroxide powder, chemical compound used in the preparation of cream, lotion or gel in the treatment of acne and mild to moderate forms of dermatitis. | Image Credit: © RHJ - stock.adobe.com

For more than a century, chemically synthesized medicines such as aspirin and paracetamol have helped treat fever, pain, and inflammation (1,2). The constantly improving understanding of the genetic roots of many diseases has led to the development of a new generation of biological active agents (3). The ongoing development of so-called biopharmaceuticals is linked to the establishment of new development processes and new specific challenges in the choice of starting materials. The manufacturing technology for biopharmaceuticals can be divided into upstream and downstream process steps (4). The upstream biopharmaceutical production of APIs refers to the first stages of the production of biopharmaceuticals (5). This includes several processes, including cell line selection, culture media selection, growth parameters, and process optimization to achieve optimal conditions for cell growth and biopharmaceutical production (4). Processes used in the production of biopharmaceuticals rely on diverse basal medium formulations containing more than 50 essential nutrients, such as amino acids, vitamins, trace elements, and additional chemicals. Compared to chemical drugs, biopharmaceuticals are more difficult to produce, and have more than one route of application and unique pharmacokinetics. Their advantages are high selectivity and efficiency, target specificity, and low toxicity. It is especially these advantages that make them particularly interesting for use in personalized medicine (5).

APIs can be produced traditionally (chemically) and have a high degree of stability. Here the molecules are exposed to extreme conditions (high pressures, high temperatures, solvents, etc.). The production of biopharmaceuticals is based on living systems, which only tolerate narrow temperature and pH windows to produce the API. Protein-based biopharmaceuticals are produced using genetically modified cells. Viral vector-based biopharmaceuticals are infectious viruses that can be used to express the desired API recombinant via 

) cells. Patient cell synthesized biopharmaceuticals are typically produced using human cells and transduced via a lentivirus. Figure 1 summarizes the four different starting points for producing APIs (6).

 Four starting points for API production.

The challenge in biopharmaceutical production of ensuring safety and quality

The lessons of the past, in which a few biopharmaceuticals were contaminated, have led to the current best practice, which relies on three pillars: the selection of appropriate starting and raw materials with a low risk of containing adventitious virus; testing of cell banks and in-process materials to ensure they are free from detectable viruses; and finally, the incorporation of steps to remove and inactivate potential undetected adventitious and endogenous viral contaminants during purification of the product (7). Regulatory guidelines are essential for patient safety. There is no “one-size-fits-all” approach for the different types of pharmaceutical drugs. Biopharmaceuticals are absolutely different from classical chemical APIs.

Ensuring that all components of the biopharmaceutical manufacturing process are free of impurities is one of the pillars to produce a high-quality and clean API product.

It is widely acknowledged that risk-assessment strategies play an important role in the successful implementation of manufacturing processes for biopharmaceutical API production. They assist in the establishment of appropriate specifications for raw materials and help ensure the implementation of effective testing approaches. The development of test methods to verify the identity and quality of materials used in biopharmaceutical manufacturing can help to prevent the use of unsuitable raw materials, thereby providing a solid foundation for a successful process. Whereas pharmacopeial standards may not be a 100% perfect solution, they do provide valuable tools for users of these materials. They can save them time and expense that would be required if they were to develop and validate test methods themselves. Raw materials that have been processed under good manufacturing practice (GMP) conditions and meet the requirements set out in compendial monographs have established a certain level of quality. Nevertheless, it is still necessary to prove their suitability for use in the process. For instance, pharmaceutical-grade citric acid is available for use as a cell culture supplement (process step upstream), and its quality could be tested against existing monographs. However, to establish its quality, it may be helpful to also assess the impact of the albumin’s lot-to-lot variability on cell growth, its stability in the process, and possible interactions with other processing components. Many regulatory guidelines indicate that raw materials should be included in the manufacturing strategy, but they do not describe exactly how to do this. The question arises as to why there are still no exact conditions and standards in known guidelines regarding the choice of raw materials in the upstream process. As there is no exact definition of what quality a raw material should have, theoretically any quality of raw material from Table I can be used for production of a biopharmaceutical API.

 General grades and their characteristics (8).

The European Medicines Agency publishes scientific guidelines on human medicines that are harmonized by the International Council for Harmonisation (ICH). The ICH publishes harmonized scientific guidelines for pharmaceuticals, accepted by regulatory authorities and industries in Europe, Japan, and the United States (9,10).

There are two ICH guidelines in the “Specifications” chapter, one for chemical drugs (ICH Q6A) (11) and one for biopharmaceuticals (ICH Q6B) (12). However, none of the ICH guidelines describe what quality a material should have that is to be used in the upstream process to produce an API. In ICQ 7, the decision to select the quality standard is left to the manufacturer of the API.

The raw materials used (media, buffer components) may provide the potential for growth of microbiological contaminants. Depending on the source, method of preparation, and the intended use of the API or intermediate, control of bioburden, viral contamination, and/or endotoxins during manufacturing and monitoring of the process at appropriate stages may be necessary

Impurities influence product quality, stability, and efficacy, so their levels need to be minimized (14). The use of pharmacopeial standards can bridge the gap between the lack of guidelines and the minimum requirements of the raw materials for the upstream process, as they can be tools for traceability and compliance. Reference standards can be used as calibrators to ensure that substances are used in a consistent manner, meet the same specifications, and are then transferred to consistent production.

Downstream manufacturing processes remove two types of impurities: product-related, such as unwanted molecular variants, and process-related, such as residues of cell culture components and substrates. These must be reduced to acceptable levels to ensure product safety (15).

Not all methods used in the downstream process lead to the removal of all contaminants that arise during the upstream process. This is one of the reasons why it is important to ensure that the starting materials are of high quality and purity right from the start, to reduce contamination to a minimum. The removal of lipopolysaccharides and endotoxins, for example, is complicated and causes high costs in the downstream process when removing these. It would therefore make sense to choose purely endotoxin-free starting materials, set out in an ICH guideline, to improve this process and minimize the risk (16). Downstream process costs, which currently account for the majority of costs, could be reduced by using higher quality products that do not contain endotoxins from the outset (17). Today, about 80% of the cost to produce and purify a biopharmaceutical active molecule is found in the downstream process section (18).

Quality through strategic partner selection and tailor-made services

Various regulatory guidelines emphasize the importance of including raw materials in manufacturing strategies. However, they often lack specific instructions on how to achieve this. Pharmacopoeia standards can fill this gap by providing compliance tools. For example, reference standards can serve as calibrators to ensure consistent material usage and adherence to specifications, promoting uniform manufacturing practices.

The use of pharmacopoeia standards can mitigate the risks associated with manufacturing products at multiple sites.A careful selection of suppliers ensures that only the highest quality products are used in the upstream biopharmaceutical manufacturing process. Adhering to strict standards and rigorous testing protocols, can also ensure the quality of raw materials. The investment required for manufacturers of starting materials for the biopharmaceutical process to conduct appropriate tests according to pharmacopoeia standards is significant. Due to the absence of explicit guidelines stipulating that upstream materials must adhere to a corresponding standard, and given that quality is often considered secondary during the laboratory development phase, some manufacturers opt not to produce according to these standards. However, to provide assurance in these instances, testing of these raw materials should be done according to pharmacopoeia standards. This ensures that biopharmaceutical API manufacturers receive the quality required by pharmacopoeia standards, facilitating the production of high-quality APIs. Frequently, raw material manufacturers package their products in a manner that suits their own economics but may not be suitable for the end customer. Repackaging supplier-packaged goods to meet the specific requirements of the API manufacturer, offers a customized solution. The development of new biopharmaceutical APIs through the various clinical phases takes time and therefore attention should be paid at the beginning of the development phase to ensure that high quality raw materials are used in order to ensure that the production of the APIs will continue in the coming years, assuming that exact requirements for the origin of the raw materials in the bioprocess are defined at some point.

1. Zahn, P.K.; Sabatowski, R.; Schug, S.A.; Stamer, U.M.; and Pogatzki-Zahn, E.M. Paracetamol für die perioperative Analgesie. 


2. Deutsches Patent und Markenamt. “120 Jahre Aspirin,” n.d.
3. Kesik-Brodacka, M. Progress in Biopharmaceutical Development. 


4. Jozala, A.F.; Geraldes, D.C.; and Tundisi, L.L. Biopharmaceuticals from Microorganisms: From Production to Purification. 


5. Haider, R. Pharmaceutical and Biopharmaceuticals Industries: Revolutionizing Healthcare. 

The Challenge of CMC Regulatory Compliance for Biopharmaceuticals

, 3rd ed.; Springer Nature, Switzerland, 2019. DOI: 


7. Barone, P.W.; Wiebe, M.E.; Leung, J.C.; et al. Viral Contamination in Biologic Manufacture and Implications for Emerging Therapies. 


8. Schieving, A. The Most Common Grades of Reagents and Chemicals. 

, Feb. 27, 2018.
9. European Medicines Agency. ICH: Quality. 

 (accessed June 18, 2024).
10. Ohno, Y. ICH Guidelines—Implementation of the 3Rs (Refinement, Reduction, and Replacement): Incorporating Best Scientific Practices into the Regulatory Process. 

Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

Good Manufacturing Practice for Active Pharmaceutical Ingredients

, Step 5 version (2000).
14. Oshinbolu, S.; Wilson, L.J.; Lewis, W.; Shah, R.; and Bracewell, D.G. Measurement of Impurities to Support Process Development and Manufacture of Biopharmaceuticals. 


15. Shukla, A.A.; Jiang, C.; Ma, J.; et al. Demonstration of Robust Host Cell Protein Clearance in Biopharmaceutical Downstream Processes. 


16. Melo, C.C.; Fux, A.C.; Himly, M.; et al. Recovering What Matters: High Protein Recovery after Endotoxin Removal from LPS-Contaminated Formulations Using Novel Anti-Lipid A Antibody Microparticle Conjugates. 


17. McNulty, M.J.; Berliner, A.J.; Negulescu, P.G.; et al. Evaluating the Cost of Pharmaceutical Purification for a Long-Duration Space Exploration Medical Foundry. 


18. Almeida, C.; Pedro, A.Q.; Tavares, A.P.M.; Neves, M.C.; and Freire, M.G. Ionic-Liquid-Based Approaches to Improve Biopharmaceuticals Downstream Processing and Formulation. 

Biopharmaceutical production faces the challenge of ensuring the quality of raw materials due to a lack of specific guidelines. By implementing effective risk assessment strategies and working with reliable, selected solution providers, biopharmaceutical manufacturers can minimize these challenges and improve product quality.

The Quest for Quality: Challenges and Strategies in Raw Material Selection for Biopharmaceuticals

FDA has reopened the comment period for a June 14, 2024 Proposed Administrative Order concerning over-the-counter (OTC) monograph drugs that contain acetaminophen. The order (No. OTC000035), “Amending Over-the-Counter Monograph M013: Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use,” would, if approved, eventually require the addition of a warning label to such OTC products, alerting consumers that the use of acetaminophen can cause severe skin reactions (1).

The reopening of comments addresses the addition of a warning to consumers that acetaminophen may cause skin irritation characterized by reddening, blisters, and rashes.

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