Chronic Disease Priorities, Biomarker Breakthroughs, and CGT-RLT Synergies

Behind the Headlines, Episode 22

ICH Q12 and Post-Approval Changes

The quickly evolving development of biopharmaceuticals is impacting innovation in the industry overall.

Advancements in Biopharma Spur Innovation

What Pharma Manufacturers Need to Know

Every Pharmaceutical Manufacturing Professional Should Know

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

IRVINE, CALIFORNIA - 16 APRIL 2020: Student Center and Visitor Center Building on the campus of the University of California Irvine, UCI. | Image Credit: © Steve Cukrov - stock.adobe.com

The laboratory of University of California, Irvine (UC Irvine) Charlie Dunlop School of Biological Sciences assistant professor Reginald McNulty has published research on the current drug candidates that target the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, a protein complex that plays a central role in causing inflammation in response to infection or tissue damage. The research team has stated that it has discovered the first and only known drugs that bind directly to the pyrin domain (1).

No such drug has yet been approved by FDA despite years of investigation, according to a UC Irvine press release (1). And when left unchecked, the McNulty lab said, NLRP3 can contribute to chronic inflammatory diseases affecting millions globally—everything from arthritis to Alzheimer’s disease to rare genetic disorders—or otherwise damage the body rather than protecting it.

“The NLRP3 inflammasome is a key mediator of the innate immune response to pathogen infection or tissue damage,” McNulty said in the press release (1). “Some humans have mutations in NLRP3 that make them more susceptible to the plethora of disorders and diseases NLRP3 is involved in, ranging from autism and arthritis to liver disease. Yet there are currently no FDA-approved drugs that target it.”

McNulty’s team concluded that the present crop of candidates to treat it, their discovery excluded, falls short in numerous areas, such as poor targeting or unwanted side effects (1).

“A significant challenge is to design an NLRP3 inhibitor that doesn’t bind domains previously shown to have ill-desired off-target effects,” McNulty said (1). “We showed that the pyrin domain has a similar structure to human glycosylase, and that inhibitors targeting one could be repurposed to inhibit the other.”

 describes its design of molecules that resemble damaged pieces of DNA, using oxidized guanine, which were deployed to block NLRP3 at the pyrin domain, preventing it from jump-starting a series of reactions that result in inflammation (1,2).

With an eye on next-generation anti-inflammatory therapies, the lab is now using cryo-electron microscopy to visualize the binding of the molecules to the pyrin domain, with safety and efficacy testing in a clinical setting being the next step (1).

“Progress in clinical trials will be key in advancing our understanding of mitigating inflammasome-based diseases,” McNulty said (1).

Investigation into the NLRP3 inflammasome can be lucrative. In September 2022, 

 for exclusive, worldwide rights to develop and commercialize candidates from Ventus Therapeutics’ portfolio of peripherally restricted NLRP3 inhibitors (3). At that time, Ventus’ lead NLRP3 inhibitor program had been indicated for nonalcoholic steatohepatitis, chronic kidney disease, and several other cardiometabolic conditions. Ventus retained the right to develop NLRP3 inhibitors for certain systemic diseases, including specific inflammatory and respiratory diseases, as well as worldwide rights to the company’s brain-penetrant NLRP3 inhibitor program.

UC Irvine Researchers Explore Promising New Pathway for Treating Inflammatory Diseases.

 Press Release. May 15, 2025.
2. Cabral, J. E.; Wu, A.; Zhou, H.; Pham, M. A.; Lin, S.; and McNulty, R. Targeting the NLRP3 Inflammasome for Inflammatory Disease Therapy. 

Ventus Therapeutics Enters Exclusive Development and License Agreement with Novo Nordisk for NLRP3 Inhibitor Program.

Articles

Researchers say they have discovered the first drug mechanism that binds to the pyrin domain to block NLRP3 and prevent a series of reactions resulting in inflammation.

UC Irvine Lab Studies NLRP3 Inflammasome for Inflammatory Disease Treatment Potential

Darmstadt, Germany - November 10, 2021: A building at the headquarters of science and technology company Merck KGaA. | Image Credit: © Anne Czichos - stock.adobe.com

Merck KGaA (Merck), headquartered in Darmstadt, Germany, and Israel-based Peregrine Ventures have announced a collaboration agreement in which Merck will become a strategic partner in one of Peregrine Ventures’ dedicated investment vehicles, called the Incentive Incubator (1,2). Peregrine is a global specialist in investments in transformative medical technologies. Merck, meanwhile, employs approximately 63,000 people in 65 countries.

A press release issued about the launch of the collaboration said that Merck will gain early exposure to certain opportunities for and development of innovation from pharmaceutical and life science startup companies, helping to foster those companies’ future success (1). The partnership has the goal of initiating early-stage collaborations drawn from Merck’s access to market trend insights, opportunity hotspots, and startups in pharma as well as bioconvergence and biotechnology.

Bioconvergence ventures, as defined in the press release, combine biology, engineering, and materials science, having the capability to integrate into Merck’s three global divisions: healthcare, life science, and electronics (1).

Other partners involved in the Incentive Incubator at this point include Bristol-Myers Squibb, Becton Dickinson, Elbit Systems, Tel Aviv University, Ben-Gurion University, and Shaare Zedek Medical Center, according to the press release (1).

“Merck’s scientific, technological, and business strength will greatly support the growth of startups in the incubator,” Lior Shahory, CEO of Incentive Incubator and general partner at Peregrine Ventures, said in the release (1). “Early-stage Israeli startups that catch Merck’s eye and align with its roadmap will receive a major boost in the global market, including access to investments, scientific expertise, clinical trial resources, and strategic assets. We are proud to welcome Merck and believe it will significantly contribute to the incubator’s success and deliver real value to entrepreneurial teams in the coming years.”

Growing partnerships locally and globally

Merck and Peregrine Ventures said they envision the collaboration as a chance for local and international stakeholders to work together on early-stage developments, benefiting from capital investments, access to professional networks, accumulated guidance and strategic guidance, among other factors, with Merck adding that it saw an opportunity to strengthen the company’s local presence (1). Investments, regulatory and business support, and potentially even the planning of early-phase trials were all predicted by the two partners as outcomes of the agreement.

"This partnership reflects our strategic commitment to fostering early-stage innovation and deepening our footprint in Israel’s vibrant pharma and life science ecosystem,” Ezequiel Garfinkel, head of Merck’s Science & Technology office in Israel, said in the release (1). “It builds on Merck’s long-standing scientific and strategic engagement in Israel, where we have been actively supporting research, technological development, and acceleration of local innovation for many years. By working closely with the startups in the Incentive Incubator, we aim to identify transformative technologies that align with our global R&D and business priorities. We are excited to join this dynamic network of partners and contribute to shaping the next generation of healthcare and technology solutions."

1. Merck KGaA. Merck Becomes a Strategic Partner in Peregrine Ventures’ Incentive Incubator. Press Release (received via email). May 15, 2025.
2. Peregrine Ventures. 

Merck will have early-stage opportunities to help startups set up for future success in the pharmaceutical and life sciences fields.

Merck KGaA Becomes Strategic Partner in Peregrine Ventures’ Incentive Incubator

Gold winners award with three stars | Image Credit: © sergign - stock.adobe.com

At the 2025 edition of the International Society of Pharmaceutical Engineering (ISPE) Europe Annual Conference, held in London from May 12–14, ISPE marked the 20th anniversary of its Facility of the Year Awards (FOYA) by announcing the 2025 winners in six categories, plus the awarding of two honorable mentions (1).

FOYA was established in 2005, according to a press release from ISPE, to recognize state-of-the-art projects that utilize new and innovative technologies to improve product quality, reduce production costs for high-quality medicines, and showcase advancements in delivery (1). Facility design, construction, and operation are also weighed in the judging process.

Touchlight, in Hampton, UK, was named the winner in the Innovation category, for its development and manufacturing of novel synthetic DNA in an effort to enable the future of genetic medicines (1). Johnson & Johnson Innovative Medicine (formerly Janssen Pharmaceuticals) won in two categories under the umbrella of Operations, for Operational Excellence for its flexible bottle packaging line in Latina, Italy, and Project Execution for the BioCork 3.2 Expansion Project in Ringaskiddy, Ireland.

CSL Behring was given the nod in the Pharma 4.0 category for its “Project Aurora—Facility F Base Fractionation,” in Broadmeadows, Australia (1). 

 in 2017, to describe a drug manufacturing ecosystem that represents the evolution and revolution of drug discovery, manufacturing, and supply chain logistics, helping to ensure that drugs are delivered precisely when needed, and improving overall patient care (2).

Awards in two categories related to social impact were given to Bayer Healthcare’s United States cell therapy launch and manufacturing facility in Berkeley, Calif., for “Unmet Medical Needs,” and Sanofi’s wastewater treatment and recovery plant in Toronto, for “Sustainability Excellence” (1).

Erbe Elektromedizin, in Rangendingen, Germany, and United Therapeutics, in Christiansburg, Va. in the US, garnered honorable mentions.

“The 2025 FOYA category winners exemplify innovation and excellence that continues to elevate the pharmaceutical industry,” Parag Sane, assistant vice-president of Global Capital Projects at Amgen and 2025 FOYA judging chair, said in the press release (1). “Their forward-thinking projects not only advance manufacturing standards and champion sustainability but also reflect a commitment to improving human lives around the world. These winners are setting new benchmarks for what’s possible in delivering both operational excellence and global impact.”

One overall winner will be announced during the 2025 ISPE Annual Meeting & Expo in Charlotte, NC. The 2025 FOYA Banquet and Awards Celebration is to be held on Sunday, Oct. 26, the first night of the show; the annual meeting runs through Oct. 29, 2025 (1).

“Innovation propels our industry forward,” Mike Martin, ISPE president and CEO, said in the press release (1). “ISPE is committed to continuing to champion new ideas that are helping to shape the future of the industry.As the ISPE FOYA program celebrates its 20th anniversary year, we look forward to coming together for the 2025 FOYA Banquet and Awards Celebration to honor this year’s highly accomplished category winners and announce the overall 2025 FOYA winner.”

ISPE Announces 2025 Facility of the Year Awards (FOYA) Category Winners, Celebrating FOYA’s 20th Anniversary Year.

 Press Release. May 12, 2025.
2. Roy, C. 

Validating Pharma 4.0 for Smart Manufacturing.

Six winners and two honorable mentions were revealed at ISPE’s Europe Annual Conference in London.

ISPE Announces Six 2025 FOYA Category Winners

Pharmacy, hands and prescription medicine for customer with paper bag for healthcare, drugs and pharmaceutical. Closeup of a pharmacist or medical worker with person in drugstore for retail service | Image Credit: © Azee Jacobs/peopleimages.com - stock.adobe.com

United States President Donald Trump has signed an executive order designed to reduce prescription drug prices for Americans, bringing the prices in line with those paid by similar nations. Among other stipulations, the order, issued May 12, 2025, directs the Secretary of Health and Human Services (HHS) to establish a mechanism by which US patients can buy drugs directly from manufacturers who sell at a “most favored nation” price, bypassing middlemen (1).

“In case after case, our citizens pay massively higher prices than other nations pay for the same exact pill, from the same factory, effectively subsidizing socialism aboard [abroad] with skyrocketing prices at home,” Trump said in a Fact Sheet provided by the White House (1). “So, we would spend tremendous amounts of money in order to provide inexpensive drugs to another country. And when I say the price is different, you can see some examples where the price is beyond anything—four times, five times different.”

Further directions given in the order include directing the US Trade Representative and Secretary of Commerce to take measures to ensure foreign countries are not unfairly or purposefully undercutting market prices, therefore driving price hikes in the US (1). The Trump administration also plans to communicate price targets to pharmaceutical manufacturers with the goal of securing the best deal for the US, which is both the world’s largest funder and purchaser of prescription drugs.

If drug manufacturers fail to offer most favored nation pricing—within 30 days, 

—the HHS Secretary would be authorized to propose rules that impose such pricing, and take other “aggressive measures” to significantly reduce prescription drug costs and end anticompetitive practices (1,2). What specific measures the Commerce or HHS departments might potentially take under these circumstances were not elaborated upon in the order.

 said that Trump is hoping to cut the prices that US taxpayers pay for prescription drugs by 

 (3,4). According to the Fact Sheet, the executive order builds on actions taken by Trump during his first term in office to reduce domestic drug price disparities but now expands those efforts by including Medicaid in addition to Medicare (1).

However, the order came on the same day that the Republican-led US House of Representatives rolled out a plan to trim $880 billion from Medicaid (5).

Social media reacted swiftly to news of the executive order.

“This is as disastrous as it gets for biopharma,” John Carroll, founder of Endpoints News, 

. “Pure chaos. So, everybody is OK with that? Most favored nation pricing is cyanide to Big Pharma.”

 was BiotechTV founder Brad Loncar: “Pharma [companies] should publicly embrace MFN [most favored nation pricing] generally because getting foreign countries to pay a higher share is obviously a good thing, but more important, pharma is so hated that being viewed as a team player rather than obstructionist needs to be the industry’s new modus operandi.”

In 2022, former President Joe Biden signed the Inflation Reduction Act into law, allowing the government to bypass pharmacy benefit managers and negotiate prices directly for several drugs covered by Medicare Part B and Part D that cost the most to patients living in the US; however, the Trump administration said in its May 12 Fact Sheet that Biden’s efforts to “beat Medicare” resulted in drug prices that were, on average, 78% higher than in 11 comparable countries (1,4).

Fact Sheet: President Donald J. Trump Announces Actions to Put American Patients First by Lowering Drug Prices and Stopping Foreign Free-Riding on American Pharmaceutical Innovation.

, May 12, 2025.
2. Seitz, A. and Kim, S. M. 

Trump Signs Executive Order Setting 30-Day Deadline for Drugmakers to Lower Prescription Drug Costs.

, May 12, 2025.
3. Holland, S.; Erman, M.; and Wingrove, P. 

Trump Executive Order Demands Pharma Industry Price Cuts.

rump Executive Order Could Reduce Pharmaceutical Costs by 59%.

House Republicans Unveil Medicaid Cuts That Democrats Warn Will Leave Millions Without Care.

According to the White House, the order builds on actions taken in the president’s first term to reduce price disparities domestically.

Trump Issues Executive Order Aimed at Reducing Prescription Drug Prices for US Patients

Feb 2, 2020 South San Francisco / CA / USA - Genentech headquarters in Silicon Valley; Genentech, Inc., is an American biotechnology corporation which became a subsidiary of Roche in 2009 | Image Credit: © Sundry Photography - stock.adobe.com

Genentech, a biotechnology company and member of the Roche Group, announced on May 12, 2025, that it will invest more than $700 million in a new, state-of-the-art drug manufacturing facility in Holly Springs, NC, Genentech’s first facility to be built on the East Coast of the United States (1). The Roche Group has several other East Coast properties outside the Genentech brand.

Few details were provided about specific equipment to be included in the construction, but a press release from Genentech said the development of the site would add more than 1500 construction jobs, and then more than 400 high-wage manufacturing jobs when the facility comes online (1). The facility is intended to support Roche and Genentech’s portfolio of next-generation obesity medicines.

In the pharmaceutical and diagnostics divisions, Roche and Genentech’s combined US footprint currently includes 13 manufacturing and 15 R&D sites across eight states, many of which will be expanded or supplemented by a $50 billion investment 

 in April 2025 (2). North Carolina would add a ninth state to the footprint, joining Arizona, California, Indiana, Kentucky, Massachusetts, New Jersey, Oregon, and Pennsylvania.

“I’m proud that Genentech has chosen North Carolina for its first facility on the East Coast,” North Carolina Governor Josh Stein said in the Genentech press release (1). “This major investment in Holly Springs shows that our state continues to be a leading destination for life sciences and advanced manufacturing. With more than 400 new jobs on the way, this project will strengthen our economy, create opportunities for our people, and advance cutting-edge scientific innovation right here in North Carolina.”

Genentech said that the initial $700 million-plus investment could expand even further based on business needs and the policy environment within the US; many companies are 

 in response to increased tariffs under the administration of President Donald Trump (3).

“Our new facility near Raleigh, NC, an established biopharmaceutical talent hub, will serve as an important new setting within our manufacturing network to help deliver on the promise of our company’s life-changing science and industry-leading pipeline,” Genentech CEO Ashley Magargee said in the May 12 press release (1). “We are thrilled to establish this relationship with the city of Holly Springs, where we expect to have a positive impact on the local economy and community, as we have across the United States since we pioneered the biotech industry nearly 50 years ago.”

Even with its recent commitments in the US, Roche—which is headquartered in Switzerland—is making other investments elsewhere in the world. On May 8, 2025, Roche Pharmaceuticals China announced an RMB 2.04 billion (approximately US $283.2 million) investment into building a new biopharmaceutical production base in Shanghai (4).

The May 12 press release from Genentech did not specify when the North Carolina facility might be completed.

Roche and Genentech Announce New North Carolina Manufacturing Facility.

Roche to Invest USD 50 Billion in Pharmaceuticals and Diagnostics in the United States over the Next Five Years.

 Press Release. April 22, 2025.
3. Lavery, P. 

Tariff Pause Reinforces Uncertainty Among Biopharma Professionals.

, April 10, 2025.
4. Roche Pharmaceuticals China. 

Roche Announces Investment of Over RMB 2 Billion to Build a New Biopharmaceutical Production Base in China.

The proposed $700 million, 700,000-square-foot space will support the companies’ future joint portfolio of next-generation obesity medicines.

Genentech and Roche Expand US Footprint with New North Carolina Manufacturing Facility

Text sign showing Industry News. Business photo text delivering news to the general public or a target public | Image Credit: © Artur - stock.adobe.com

Responding to what it called a trend toward United States onshoring of drug supply, Mumbai-based Piramal Pharma announced an investment plan worth $90 million, developed in conjunction with the 2025 SelectUSA Investment Summit, earmarked for two of its US facilities, in Lexington, Ky. and Riverview, Mich. (1).

In a press release on May 12, 2025, Piramal Pharma said other reasons for the planned brownfield expansions of the existing sites are ongoing demand from US customers and the company’s own belief in the benefits of US-based expansion (1).

The press release recapped the details of the expansion of the Kentucky site, which was previously 

 and accounts for $80 million of the $90 million in the May 12 announcement (2). Piramal said the site will be adding 24,000 square feet of manufacturing space, a new laboratory, and state-of-the-art equipment—including a new filling line, two commercial-sized lyophilizers, a capping machine, and an external vial washer (2). The company said it expects these updates to be completed and online in late 2027.

In Michigan, where the Riverview site has become known for its development and manufacturing of APIs, including those that are highly potent, a commercial-scale suite will be added for the development and manufacturing of payload-linkers, which are used in development of antibody-drug conjugates and other bioconjugate drugs (1). This suite is expected to be operational by the end of 2025.

“Since its inception, Piramal Pharma Limited has invested $570 million in its US drug development and manufacturing capabilities,” said Peter DeYoung, chief executive officer, Global Pharma, in the press release (1). “The US is our largest market, where we currently employ approximately 750 people. Expanding the capacities and offerings in these two plants in the US, along with the prior major investments made in our Sellersville, Pa. drug product facility, and our inhalation anesthesia drug substance and drug product facility in Bethlehem, Pa., will support our customers who value our offerings in an onshore setting.”

The announcement of the $90 million investment in the US comes amid sweeping changes in tariffs enacted by President Donald Trump’s administration, 

 after Trump signed an executive order directing FDA and the Environmental Protection Agency (EPA) to reduce certain regulatory barriers, including urging the EPA to accelerate construction of prescription drug manufacturing sites (3). After that executive order was announced on May 5, FDA said on May 6 that it intended to expand unannounced inspections at foreign manufacturing facilities (4).

® Group’s “Behind the Headlines” video series has been taking a look at US reshoring for several months, since the Trump administration began to roll out its tariff policies shortly into the new presidential term. Access all episodes of “

Piramal Pharma Ltd. Continues to Invest In USA; $90M in Expansions of Two US Sites.

 Press Release. May 12, 2025.
2. Piramal Pharma Solutions. 

Piramal Pharma Solutions Announces $80M Expansion Plan for Sterile Injectables Facility in Lexington, Kentucky.

 Press Release. Sept. 30, 2024.
3. The White House. 

Fact Sheet: President Donald J. Trump Announces Actions to Reduce Regulatory Barriers to Domestic Pharmaceutical Manufacturing.

FDA Announces Expanded Use of Unannounced Inspections at Foreign Manufacturing Facilities.

The company said the investment is in response not only to customer demand and a belief in the value of US-based innovation, but also because of the trend toward US onshoring brought about by new tariff policies.

Piramal Pharma to Invest $90 Million at Kentucky & Michigan Sites

A laboratory technician performing a quality control test on a batch of pharmaceutical tablets, highlighting the importance of ensuring drug safety. | Image Credit: ©MAY -stock.adobe.com

The API is, one might say, the most important element in a pharmaceutical product. Poor-quality APIs that do not meet potency levels and/or those that harbor impurities can create safety risks for the patient. Drug formulations may be destabilized by poor-quality APIs, which could shorten the drug’s shelf life. Poor-quality APIs may result in regulatory actions or recalls that can create production delays for the manufacturer that can impact the supply chain, therefore, keeping drugs from the patients that need them. Poor API quality may also leave the door open for counterfeit drugs to reach the market.

“From a supply chain perspective, poor-quality APIs increase the likelihood of production interruptions, which disrupt the supply to the market,” says Qixuan Lu, vice-president of Process Chemistry at BioDuro. “Because of the poor-quality API, additional quality control measures become necessary, driving up costs and diminishing profit margins. If such issues arise repeatedly, they can harm a company’s reputation and undermine market confidence in its products. Beyond these commercial setbacks, manufacturers also face considerable legal and regulatory risks if they fail to meet the standards required for pharmaceutical quality and patient safety.”

Impurities may result from a lack of a robust process and inadequate quality control, which often evolves from a lack of understanding of critical quality attributes (CQAs). This can manifest in poorly defined design spaces and analytical methods that fail to detect impurities, according to Dirk-Jan van Zoelen, Drug Substance Business Unit director, Ardena. “Moreover, when new impurities are identified, out-of-specification (OOS) results can lead to production delays, affecting the stability and reliability of the supply chain,” van Zoelen explains.

“Poor quality API presents several risks to the drug product, supply chain, and ultimately patients. These risks range from a lack of efficacy to the possibility of toxicity. Poor efficacy may result from low potency API, whereas toxicity may be related to the presence of uncontrolled impurities,” Richard Castledine, head of Drug Substance Operations at Quotient Sciences, says. “Additionally, simple batch-to-batch variability of quality attributes such as particle size and residual solvent concentration may result in differences in downstream manufacturing processes.”

Having strict quality checks, supplier audits, and strong compliance measures are important to maintain a safe and smoothly run system, according to M. Damodharan, chief quality officer, Sai Life Sciences.

A comprehensive control strategy is key for ensuring API quality, according to van Zoelen. This strategy should address an in-depth understanding of the processes involved (e.g., chemical, physical, and cleaning) with defined critical process parameters (CPPs) and acceptable ranges. These processes should then be validated. The critical material attributes of raw materials and starting chemicals should be evaluated using comprehensive fit-for-use assessments to determine impurity clearance. A rigorous supplier qualification process should be put in place to ensure material quality and regulatory compliance. Analytical methods should be developed and validated in accordance with International Council for Harmonisation (ICH) guidelines, and a quality assurance department should be created that has an established quality management system to monitor regulatory compliance, van Zoelen says.

“A strong quality management system, aligned with good manufacturing practice (GMP) requirements, should define detailed production processes and quality control procedures to ensure that every stage of manufacturing is consistently supervised,” Lu agrees. “By actively monitoring the manufacturing workflow, manufacturers can guarantee that each critical step meets the required specifications and prevents potential quality deviations.”

Once parameters are set, they must be understood within the manufacturing process, says Castledine. “By understanding the edge of failure of any given process checks and controls can be implemented to ensure the process remains within the target ranges to produce high quality drug products,” he says. “Establishing a high-quality supply chain for all materials used in the manufacturing operation reduces the risk of introducing substandard materials to the process. Finally, the manufacturing process should be supported by internal analytical capabilities to assess critical quality attributes.”

“When designing a synthetic route for an API, process route design involves finding and selecting a pathway with favorable characteristics to maintain high quality CGMP [current good manufacturing practice] production when the API is manufactured at larger scale,” Castledine continues. “Modification or redesign of the process is often required to prepare for larger batch sizes and ensure that API can be produced in a compliant, efficient manner. Early on, drug developers should be mindful of identifying and developing control strategies for process and degradation impurities which may otherwise remain in the API. Additionally, avoiding niche or expensive starting materials and reagents for API synthesis is recommended; these can result in supply chain difficulties later and possibly lead to poorer quality substitutions being made.”

Sourcing from GMP-certified suppliers can help ensure API quality, according to Subbareddy Inta, vice-president and head of Quality, Dr. Reddy’s Laboratories North America. “Regular audits and inspections of supplier facilities ensure compliance with safety and quality standards,” Inta says.

“To secure high-quality APIs, manufacturers should implement a rigorous supplier evaluation system that carefully selects qualified raw material providers and conducts periodic audits. Incoming raw materials must undergo thorough inspections to confirm compliance with specified standards,” Lu stresses.

“Suppliers should be seen as an extension of internal manufacturing controls and standards, aligning with the drug manufacturer’s quality and compliance goals/objectives,” Timothy Buckley, vice-president of Global Quality, SK pharmteco, says. “Supplier qualification is critical, not only from a quality perspective, but also to ensure reliable supplies to eliminate potential drug shortages and supply interruptions.”

Materials used that are obtained from a third-party vendor must be rigorously qualified to ensure quality. This can be done through spike/fate and purge studies conducted on multiple lots, according to van Zoelen.

The physical and chemical characteristics of these materials, including crystal form, particle size, solubility, purity, residual solvents, and heavy metals, must be tested for CQAs to determine that they meet requirements. “Moreover, understanding the synthetic route used by the vendor is crucial, since the reagents, reaction conditions, and by-product removal methods should be compatible with the downstream manufacturing process,” Lu states. “This alignment ensures efficient conversion of starting materials or intermediates and minimizes impurities that might otherwise compromise the finished product’s quality.”

Tests performed on third-party-sourced materials, according to Ragavendran Vasudevan, director and head of Operations C2 Pharma India Ltd., include identity testing, purity and impurity profiling, assay testing, physical and chemical characterization, microbial and endotoxin testing, and stability and storage condition studies.

“Identity testing using FTIR [Fourier transform infrared spectroscopy], NMR [nuclear magnetic resonance], HPLC [high-performance liquid chromatography], or GC–MS [gas chromatography–mass spectrometry] confirms chemical structure. Purity and impurity profiling detect unwanted byproducts, while potency is measured through titration, UV-Vis [ultraviolet-visible], or HPLC. Residual solvent analysis via GC-HS [headspace-gas chromatography] ensures no toxic solvents remain,” Damodharan explains. “Water content is checked using Karl Fischer titration, and microbial testing screens for bacteria and endotoxins. Particle size and polymorphism studies assess bioavailability impact. Stability testing evaluates degradation risks, and elemental analysis using ICP-MS [inductively coupled plasma mass spectrometry] checks for toxic metals. These steps ensure the API meets safety and regulatory standards.”

Validation is a crucial step in ensuring the quality of APIs and applies to the regulatory compliance requirements of facilities, equipment, and infrastructure, according to Lu. “Stability testing should also be carried out to track changes in the physical and chemical properties of the API, as well as the formation of any degraded products or impurities over time,” Lu says. “These tests help determine appropriate shelf life and storage conditions, ensuring that the API retains its intended quality and efficacy until it is used.”

Other validation exercises, according to Vasudevan, include supplier qualification, raw material testing, process validation, analytical method validation, and regulatory documentation.

“Validating test methods, such as chromatography and spectrometry, ensures accurate purity and potency analysis,” Inta says. “Conducting stability studies under various storage conditions ensures the API remains stable over time. Ensuring compliance with pharmacopeial standards and regulatory requirements maintains high-quality standards.”

“Confirmation of the manufacturing process used is also essential to ensure that methods used for testing are suitable,” Castledine says. “For example, some manufacturing processes have the potential to generate potentially mutagenic impurities (PMI) which need to be controlled to PPM [parts per million] levels, often requiring the development of specialized HRMS [high-resolution mass spectrometry] methods.”

Quality validation of APIs should be a phase-appropriate approach, according to van Zoelen, with analytical methods getting partial validation in early phase development that focuses on process-related impurities and safety data. “As development progresses to later clinical phases, a more comprehensive validation is required, including full validation of the analytical methods for the API, starting materials, and intermediates,” van Zoelen says. “Impurity profiles are set during early-stage development, with tox-batch validation and process validation as essential milestones. Throughout this process, supplier qualifications should also be conducted to ensure consistency and reliability of materials.”

A transparent supply chain is achieved by good distribution practices, according to Damodharan, and helps prevent counterfeit drugs. “Regulatory compliance is a must, including accurate documentation and real-time monitoring. Staying updated on compliance changes and maintaining data integrity [can] ensure long-term quality,” Damodharan says.

Maintaining accurate CGMP records for APIs is necessary to assure regulators of compliance, traceability, and product quality. However, according to Vasudevan, many companies lack complete and accurate documentation and have poor record keeping practices. They also have data integrity violations and insufficient training on compliance with CGMPs.

Poor documentation, including incomplete records or backdating, violate CGMPs and data integrity requirements. “Illegible batch records, unverified calculations, and outdated SOPs [standard operating procedures] lead to errors,” Damodharan says. “Failing to record deviations, corrective actions, or equipment calibrations weakens oversight. These slip-ups can trigger compliance issues, recalls, or even regulatory shutdowns.”

It is important to avoid gaps in impurity data in CGMP records. A mistake some manufacturers make, according to van Zoelen, is not aligning analytical methods with an API’s impurity profile in clinical phases. “As development progresses, particularly through the clinical phases, new impurities may emerge, such as genotoxic or mutagenic impurities,” van Zoelen says. “Multiple analytical methods may be employed at different stages, and these may change as the development advances. It is critical to ensure continuous alignment of these methods with impurity data to avoid gaps or discrepancies in CGMP records, especially as the product progresses through clinical phases.”

“Failing to capture batch-specific information or variations in production conditions can compromise data integrity,” Inta says. “Inadequate documentation of deviations or corrective actions can leave issues unresolved. Lastly, not adhering to proper data integrity protocols, such as avoiding falsification or improper handling of electronic records, can severely compromise data quality.”

“While GMP expectations such as data integrity, GDP [good documentation practices], and facility/personnel controls are the same for APIs and drug products, a key issue for API manufacturers is ensuring appropriate documentation and evaluation of supplier changes,” Buckley explains. “Changes in the route of synthesis for critical raw materials, such as regulatory starting materials, can lead to a new or altered impurity profile of existing impurities. This may introduce concerns related to nitrosamines, heavy metals, and/or PEG [polyethylene glycol] residues. Therefore, while there are many GMP considerations, change control and supplier qualification are especially critical in API manufacturing.”

Highly potent APIs (HPAPIs) have increased pharmacological activity and safety risks according to Vasudevan. Safe production and handling of HPAPIs can be done by implementing stringent quality measures. These include dedicated production areas or isolators and closed-system processing. Using segregated facilities that have independent heating, ventilation, and air conditioning (HVAC) systems can prevent contamination. Maintaining negative pressure environments may contain potent compounds, and using automated handling systems reduces manual intervention, insists Vasudevan.

“More drugs in development than ever are classed as highly potent,” Helen Baker, director of Formulation Design, Quotient Sciences, explains. “HPAPIs present additional CMC [chemistry, manufacturing, and controls] challenges due to the containment requirements to protect both the operators and manufacturing facilities. The production processes may also require greater precision and control due to the very small quantities of drug present in the final dosage form.”

Preventing cross-contamination in the manufacture of HPAPIs is the main concern with ensuring quality for pharmaceutical products that contain these types of ingredients, especially when manufactured in multipurpose facilities, according to van Zoelen, who stresses that stringent cleaning protocols must be adhered to. “The maximum allowed carryover (MACO) should be defined based on health-based occupational exposure limits (HBOEL) to ensure safe transitions between high-potency and low-potency APIs,” van Zoelen says. “Additionally, a comprehensive cross-contamination strategy is essential, including facility design considerations, dedicated equipment, and validated cleaning procedures to mitigate the risk of HPAPI contamination in subsequent batches.”

“If potent compounds are produced in the same facility as less potent products, dedicated production lines or segregated manufacturing areas are essential to eliminate the risk of contamination and to uphold stringent safety standards,” Lu agrees.

“EH&S [environmental, health, and safety] audits are critical to ensure that HPAPIs continually meet CGMP compliance standards and regulatory requirements,” Baker says. “The HPAPI manufacturer should also have a robust risk management program that includes ongoing environmental health monitoring and surrogate monitoring to ensure consistent control over our processes, facilities, cleaning procedures, and SOPs is also critical to ensure that HPAPIs are being manufactured consistently.”

Drug shortages can impede access to life-saving medications, and quality issues are one reason drug shortages may occur (1). Regulatory agencies have guidelines that should be followed to mitigate the risk of poor-quality ingredients, such as APIs. By following these guidelines, having a robust quality system, and qualifying API suppliers, drug manufacturers can help keep the supply chain healthy.

 March13, 2025 (accessed April 11, 2025). 

https://www.fda.gov/drugs/drug-safety-and-availability/drug-shortages

When referring to this article, please cite it Haigney, S. Poor API Quality Threatens a Healthy Supply. 

Poor API quality may often lead to delays in production and a shortage of supply.

Poor API Quality Threatens a Healthy Supply

Mississauga, On, Canada - October 24, 2020: Astrazeneca Canada company sign is seen in Mississauga, Ontario, Canada. AstraZeneca plc is a British pharmaceutical and biopharmaceutical company. | Image Credit: © JHVEPhoto - stock.adobe.com

AstraZeneca announced on May 6, 2025 that its Calquence (acalabrutinib), a second-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK), was approved in the European Union in combination with bendamustine and rituximab for treatment of adults with mantle cell lymphoma (MCL) that has been previously untreated, and who are not eligible for an autologous stem cell transplant (1). Acalabrutinib had been previously approved in the EU as monotherapy for treatment of adults with relapsed or refractory MCL.

In a press release, AstraZeneca said the combination of acalabrutinib with bendamustine and rituximab was previously approved in the United States and other countries based on the results of a Phase III trial (ECHO), the findings of which were also used by the European Commission’s Committee for Medicinal Products for Human Use (CHMP) in its positive opinion issued March 31, 2025 (2).

“Treatment with the Calquence combination in first-line mantle cell lymphoma demonstrated a significant improvement in progression free survival and a consistent safety profile for patients in the pivotal ECHO trial,” Dave Fredrickson, executive vice president of the Oncology Haematology Business Unit for AstraZeneca, said in the release (1). “As the first and only BTK inhibitor approved in this indication in the EU, we are proud to provide a much-needed new option to patients living with this difficult disease."

Martin Dreyling, MD, Department of Medicine, University Hospital LMU Munich, and investigator in the trial, added, saying “This approval provides a new first-line treatment option for patients in the EU with mantle cell lymphoma, an aggressive lymphoma with a dismal long-term outcome still today. With a progression-free survival improvement of more than 16 months for these patients, the acalabrutinib combination is a much-needed advance in this challenging disease.”

In February 2025, another MCL treatment, Eli Lilly and Company’s Jaypirca (pirtobrutinib)—a non-covalent or reversible BTK inhibitor—was given a positive opinion by CHMP (3,4). That treatment, according to Lilly, had been approved by FDA in 2023 under an accelerated approval pathway for treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma who have received at least two prior lines of therapy, including a BTK inhibitor and BCL-2 inhibitor, or for treatment of adults with relapsed or refractory MCL after at least two lines of systemic therapy.

Acalabrutinib treatment plus bendamustine and rituximab is currently under review in Japan and several other countries (1).

1. AstraZeneca. Calquence Plus Chemoimmunotherapy Approved in the EU as First and Only BTK Inhibitor for 1st-Line Mantle Cell Lymphoma. Press Release. May 6, 2025.
2. AstraZeneca. Calquence Plus Chemoimmunotherapy Recommended for Approval in the EU by CHMP as First and Only BTK Inhibitor for 1st-Line Mantle Cell Lymphoma. Press Release. March 31, 2025.
3. Eli Lilly and Company. Lilly's Jaypirca (pirtobrutinib) Recommended by CHMP for Approval in the European Union for Adults with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) Previously Treated with a BTK Inhibitor. Press Release. Feb. 28, 2025.
4. EMA. Meeting Highlights from the Committee for Medicinal Products for Human Use (CHMP) 24–27 February 2025. Press Release. Feb. 28, 2025.

Calquence (acalabrutinib) plus bendamustine and rituximab reduced risk for disease progression or death by 27% compared with the current standard of care, according to a phase III trial.

EU Approves AstraZeneca Mantle Cell Lymphoma Treatment

Building relationships with customers who are as focused you are on innovation for a better world is a perfect starting point and premise for a successful project. 

, a global health care company working to deliver innovative health solutions for today and the future, chose 

 to solve an urgent need at their facilities in Rahway, New Jersey.

We spoke to a Global Engineering Services representative at Merck and Stefano Specchia, IMA Life Product Manager

 to explore the details of the project and gain insight into the mutual benefits.

According to the customer, the primary objective was to source a flexible, multi-format RTU 

 that could manage a range of products, from serum-based to freeze-dried formulations, without compromising safety or process integrity. The equipment needed to ensure 

compliance with stringent containment requirements

, given the risk level of the substances.

Given the equipment's role as a replacement in an urgent situation, Merck narrowed its choice to those suppliers that were not only able to provide adequate support to 

address the specific needs of handling both potent compounds and live virus formulations

A solution demanding rapid deployment was needed in order to avoid production delays and uphold commitments to stakeholders. Moreover, there were a number of critical requirements that only IMA Life was able to address satisfactorily.

Stefano Specchia underlines the key reasons why Merck opted for the fill-finish line constructed around INJECTA.

 in handling complex, high-potency products and live virus formulations reassured the customer regarding the 

our ability to ensure safe processing without sacrificing operational efficiency

our solution met the technical specifications

we aligned well with the challenging timeline

we provided high-level digital training for Merck's operators

In particular, training aimed at enhancing operational efficiency and ensuring consistent management of the line using standard working parameters. Seen as a crucial requirement, IMA Life was successful in fulfilling this need. According to the customer, there were “no doubts about their commitment to support and optimize our processes.”

Advanced robotics, which is a core principle in terms of INJECTA and its design concept, facilitated 

effective cleaning and containment when dealing with potent compounds

. This feature is critical for compliance and safety in handling high OEB-level products. The design also supports 

 and improving overall production reliability.

The line is also easy to use. Recipe programming is intuitive and enhanced monitoring capabilities also contribute to potentially fewer rejects.

Faced with a tight timeframe, a building that was not designed to accept the line initially, and a challenging path taking us from the first design phase of the processing line right up to commissioning, training and on-site support, IMA demonstrated “

the true value of working with a trusted and committed partner in the field

At all times throughout the project - from the design phase all the way through to qualification and support – one of the key factors ensuring success had to be the partnership between the companies and especially the people working in each team.

Moving ahead, it is clear that IMA’s commitment will not diminish thereby enabling the equipment to function as an integral part of the production environment across its entire life cycle.

IMA Life has supplied a fully integrated, isolated line that spans the entire process

, from RTU container handling through freeze-drying and downstream operations, including external washing and tray loading. This comprehensive approach ensures seamless compatibility and operational efficiency across all stages of production, meeting the highest standards for containment, precision, and reliability.

INJECTA is the first of a new generation of material handling technologies

, setting new standards in the industry. The dedication of the IMA team, their depth of knowledge, and the support resources they provide are instrumental in ensuring timely and effective project outcomes. While certain areas of task execution and design may benefit from minor adjustments, this partnership has underscored IMA’s adaptability and readiness to push technological boundaries to meet evolving industry needs.

For more information on INJECTA and our aseptic processing capabilities:

FLEXIBLE READY-TO-USE COMPONENT PROCESSING LINE • Pharma • IMA Group

HIGH-SPEED PRE-FILLED SYRINGE PROCESSING LINE • Pharma • IMA Group

Supporting Merck toward a new age of aseptic fill-finish processing of highly potent drugs.

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Scientific, economic, and practical factors should be considered when choosing between the frozen state and lyophilization.

Featured Content

Behind the Headlines, Episode 22

ICH Q12 and Post-Approval Changes

Advancements in Biopharma Spur Innovation

What Pharma Manufacturers Need to Know

Every Pharmaceutical Manufacturing Professional Should Know