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Trump policies create uncertainty for biopharma
Greg Slabodkin Editor-in-Chief
What a difference five months makes. In January, soon after Donald Trump’s inauguration as the 47th president of the United States, stakeholders and analysts were saying his second term in the Oval Office could be a net positive for the biopharma industry.
At the time, Trump’s presidency was met with a sense of optimism in the sector. At the J.P. Morgan Healthcare Conference in January, Thermo Fisher Scientific CEO Marc Casper said he expected a “better business environment” in the new Trump administration, including less stringent regulatory oversight of mergers and acquisitions and a “progrowth” environment from a taxation perspective.
However, fast forward a few months and a sense of anxiety looms over the biopharma industry, thanks to Trump’s threatened tariffs on pharmaceuticals and his executive order reviving his controversial “most favored nation” drug pricing policy. While as of this writing little is known about what either presidential action might ultimately entail, the potential impacts are weighing heavily on the sector and creating an environment of uncertainty and dread.
The Pharmaceutical Research and Manufacturers of America (PhRMA) warned in May that Trump’s most favored nation executive order would “jeopardize the hundreds of billions our member companies are planning to invest in America — threatening jobs, hurting our economy and making us more reliant on China for innovative medicines.”
The Biotechnology Innovation Organization also criticized the executive order calling most favored nation a “deeply flawed proposal that would devastate our nation’s smalland mid-size biotech companies,” while lambasting Trump for treating patients and families as bargaining chips in his trade war “first through proposed tariffs on our nation’s medicines, now with foreign reference pricing.”
Although pharmaceuticals have long been spared from trade wars due to the potential harms, Trump has repeatedly threatened a 25% tariff on drug imports. PhRMA, the main lobbying group for drugmakers, has made the case that tariffs would undermine the White House’s efforts to boost U.S. domestic manufacturing.
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The CEOs of biopharma companies are in the unenviable position of trying to navigate the chaotic situation and potential disruptions to their businesses. With the Trump administration’s cuts across federal health agencies, the biotechnology industry — which has been weathering a prolonged downturn — is particularly vulnerable.
Jefferies analysts in a May 16 note to investors said that the biotech sector “remains volatile” amid the recent most favored nation executive order and “lingering concern” about the FDA’s stability and tariffs. However, the analysts said they “expect negative sentiment to ease as details and clarity emerge (the recent trend has been that these events turn out better than feared).”
Currently, hoping for the best and preparing for the worst appears to be the only thing the biopharma industry can do in the face of such economic turmoil. According to Jefferies analysts, the good news, if you can call it that, is biotech and pharma “outperform in recessions; this remains important amid broader uncertainty on the economy.”
Andrea Corona Senior Editor
INTERPHEX 2025: CDMOs and tech take lead
This year’s show focused on innovations in biopharma
Pharma Manufacturing was on-site at INTERPHEX 2025, where nearly 10,000 professionals from across the pharmaceutical and biotechnology sectors gathered at the Javits Center in New York City from April 1–3.
With over 550 exhibitors and three days of targeted programming, the event offered a concentrated look at current technologies, production strategies, and regulatory approaches across drug development and manufacturing.
This year introduced Show Floor Tours developed with CRB Group and the Parenteral Drug Association (PDA). These included both guided and self-directed options and focused on key operational areas such as aseptic filling, cleanroom practices, continuous manufacturing, RABS, and cell and gene therapy.
The tours helped attendees navigate the show by connecting them with vendors and technologies aligned with their areas of responsibility. PDA also hosted mini-training sessions, while CRB organized informal discussions at its hospitality suite.
The INTERPHEX Conference in the Learning Lab, sponsored by Lisure Science, returned for its second year with over 45 sessions developed in coordination with AAPS and an advisory committee. Session topics covered production efficiency, tech transfer, regulatory expectations, clinical-to-commercial scale-up, digital process control, and supply continuity.
The Learning Lab also offered career support features, including resume and LinkedIn profile reviews, along with a headshot booth sponsored by Endress + Hauser.
New additions to this year’s event included the Community Talks Theater, which joined the Contract Stage and Technical Theaters to deliver presentations spanning workforce topics, market access, and policy.
Sessions in the Community Talks Theater included “Puerto Rico: A Strategic Hub for Business, Global Trade, and Expansion Opportunities” and “Embracing Diversity: LGBTQIA+ Inclusion and Allyship in the Life Science Workplace.”
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The CDMO/CMO Pavilion continued to attract attention, with content focused on contract manufacturing strategies, selection criteria for outsourcing partners, and risk-based approaches to validation and control.
Sessions covered subjects such as AI in continued process verification, container closure integrity, and regulatory readiness. The pavilion featured companies including Aprecia Pharmaceuticals, Aizon, CMIC CMO USA, Glatt, Hikma, INCOG BioPharma, PharmaPhixx, and Simtra BioPharma Solutions.
INTERPHEX TV broadcast live interviews with attendees and exhibitors throughout the show. Discussions covered new equipment launches, facility upgrades, regulatory priorities, and the impact of automation on workforce planning. Videos are available for on-demand viewing on the INTERPHEX website.
INTERPHEX also hosted its annual Exhibitor Awards, judged by editors from American Pharmaceutical Review, Pharmaceutical Outsourcing, Cell & Gene Therapy Review, and Tablets & Capsules. This year’s winners included:
• Best in Show: MilliporeSigma’s Mobius® ADC Reactors, designed for scalable single-use bioconjugation
• Best New Product/Service: Apprentice.io’s Humanin-the-Loop AI and Autonomous Agents
• Editor’s Choice: Tema Sinergie’s ZEROC – RTP Integrity Testing System
• Best Technologies Innovation: Asahi Kasei Bioprocess’s Cleavage & Deprotection (C&D) and Tangential Flow Filtration (TFF) unit
• Efficiency Champion: AST’s Digital Twin for Fill-Finish process modeling
• Biotech Innovation Award: IMA Group’s Tile-X, a gloveless aseptic fill-finish system
Programming across all three days was anchored by real-world application. Companies shared use cases for implementing advanced controls, reducing batch failure, accelerating release timelines, and managing data handoff across teams. Quick Fire and Late-Breaking sessions allowed for timely updates on inspection priorities, facility upgrades, and product pipeline strategies.
Attendees represented a broad mix of functional areas, including process engineering, QA/QC, regulatory affairs, automation, fill-finish, and raw material sourcing. Many sessions emphasized cross-team collaboration, with particular focus on shortening the time between early-phase trials and commercial readiness, while maintaining GMP compliance and cost control.
The show also highlighted a shift in how drugmakers are integrating digital tools — not only for documentation and equipment control but also for training, predictive maintenance, and scenario planning. Several presentations demonstrated how digital twins and AI-supported models are now being used to simulate production runs and prepare for inspections.
With global regulatory scrutiny increasing, INTERPHEX 2025 served as a venue where manufacturers, equipment suppliers, and service providers could exchange methods for maintaining inspection readiness while optimizing throughput and resource allocation.
The show emphasized how companies are addressing production delays, workforce shortages, and multi-site coordination with both new systems and revised workflows.
Greg Slabodkin Editor-in-Chief
Ashift to continuous technologies is gaining momentum
As a concept, continuous manufacturing — which relies on a fully integrated process that runs uninterrupted from beginning to end —has been around for many years, providing an alternative to traditional batch manufacturing in which drug production is segmented into a series of slow-moving steps.
Despite the potential efficiencies and the FDA encouraging manufacturers to make the switch from batch processing, the pharmaceutical industry has been slow to adopt continuous manufacturing due in large part to general conservatism and the cost implications of such investments. However, a shift to continuous manufacturing technologies appears to be gaining momentum.
According to the results of CRB’s Horizons: Life Sciences survey released in October 2024, 75% of respondents are using or plan to use continuous technologies almost exclusively within the next five years, based on a survey of 500 industry leaders including therapeutic developers and CDMO executives.
Batch processing involves sequentially loading a fixed amount of material into the first part of the manufacturing process, processing it, and then discharging the material in preparation for the next phases of manufacturing. However, continuous manufacturing involves material constantly being loaded, processed and unloaded without interruption through the various phases of the process.
“By operating continuously, the manufacturing process becomes intensified, and the specific productivity of the facility is improved, with increased efficiency in use of space, time, labor and raw materials,” CRB contends. “Most importantly, continuous operations can improve both product yield and quality.”
When it comes to sustainability, CRB notes that continuous facilities offer significant energy savings per unit of production.
“Most cGMP manufacturing cleanrooms and some labs require HVAC systems to run 24/7, regardless of whether other systems are operating or not,” CRB states. “Since a continuous facility runs a more intensified process with higher system utilization, continuous facilities reduce energy costs per production unit. According to an energy model, a continuous manufacturing facility can operate 33% more efficiently than a comparable batch process.”
However, Atul Dubey, senior principal scientist at US Pharmacopeia,
contends that continuous manufacturing is not a one-size-fits-all approach. While it can be valuable for certain drug substance and drug product manufacturing processes, it’s not suitable for every situation, he asserts.
Dubey estimates that there are only a little more than 15 drug products in the market today that are being manufactured using continuous manufacturing.
“Those are through the FDA,” he said. “The ones that don’t go through the FDA are made for local markets in India and China. There are companies who are doing it, but we don’t know about them because they don’t come here.”
By operating continuously, the manufacturing process becomes intensified, and the specific productivity of the facility is improved. improve, with increased efficiency in use of space, time, labor and raw materials.”
Piecemeal adoption, solid dose
While continuous technologies have been adopted for individual processes, CRB noted in its report that the implementation of end-to-end continuous manufacturing in the pharma industry remains elusive.
Dubey asserts that end-to-end continuous manufacturing is “very rare” and frankly not needed, pointing to the International Council for Harmonization (ICH) Q13 guidance, Continuous Manufacturing of Drug Substances and Drug Products
The ICH Q13 guideline “says if you want your process to be designated as a continuous manufacturing process, all you need to have is a minimum of two unit operations that are connected together and are running in continuous mode,” according to Dubey.
Continuus Pharmaceuticals, a spin-out company from a multiyear collaboration between MIT and Novartis, specializes in end-to-end integrated continuous manufacturing. The company’s mission is to transform the pharmaceutical manufacturing industry, which it says loses over $50 billion annually due to wasteful processes, by moving it away from “outdated” batch systems to state-of-the-art continuous processes.
Bhakti Halkude, associate director and head of drug product at Continuus who fucuses on oral solid dosage, contends that what is needed in the industry is a major shift — both ideologically and technologically — driven by the need for greater efficiency, cost reduction, and improved product quality.
“I think the biggest change needs to be unlearning — that is one big hurdle that we all have been struggling with,” Halkude said. “Letting go of the older practices is critical because the industry has been set on certain practices and we all have been just following them.”
At the same time, industry has adapted with “bits and pieces of continuous manufacturing, mostly a lot of development has happened on the drug product manufacturing side,” Halkude said. “However, the drug substance or the API, the chemistry
part has been a little slow with actual adoption, actual acceptance and bringing anything in the market.”
Continuus is working with multiple clients to convert their existing process into continuous manufacturing lines. While developing a drug substance continuous manufacturing process is more complicated than a drug product one, Halkude claims that when it comes to the company’s end-to-end offering, theirs is the only technology which integrates drug substance and drug product.
“It is a higher quality, higher kind of technology so that entails higher capital investment, which is definitely not an easy step for any company,” Halkude said. “Companies that are adopting [continuous manufacturing] much faster are actually saving and seeing the benefits, helping them get over that capital investment issue.”
However, Dubey contends that when it comes to generic drugs — which make up 90% of the prescription volume in the U.S. — there is a resistance to adopting continuous manufacturing.
“If you have a working [batch] process and the equipment and everything is lined up, it does not make sense to switch financially especially when you have razor-thin margins for your products,” Dubey said.
Additionally, Dubey makes the case that other challenges for implementing continuous manufacturing include workforce training for a unique skillset of highly specialized workers.
Nonetheless, Halkude argues that among the advantages of Continuus’ technology is it is compact in size without the need for massive solvent and waste tanks, while operating with reduced power consumption. “Smaller equipment equals easier maintenance — our technology for drug product manufacturing is the size of a dining room table, literally five feet by nine feet.”
Halkude contends that another major advantage of continuous manufacturing is the lead time required for production.
“Our tablets, for example, the one that we made come out in a matter of minutes,” she said. “From the time I get an order, I can get the tablet out in 20 minutes versus it takes months with batch manufacturing or at least weeks in certain cases.”
Time is money and continuous manufacturing reduces costs by condensing processes that used to take months into days — and even minutes. The use of automation and robotics can also cut labor costs, while improving quality controls and minimizing waste.
Another significant difference between batch and continuous manufacturing is how materials are fed into their respective processes.
Feeder designs are “an advantage for continuous manufacturing because you’re feeding lesser quantity at a time,” according to Halkude. “It’s easier on the operator to feed smaller quantities and you can have more control over what you’re feeding, and you have more control over what raw material went into what final product.”
While Halkude is a self-described oral solid dosage expert, she contends that “there is a lot that can be adopted from the small molecule side, which is already quite well developed in terms of continuous manufacturing — a lot of these technologies can be extracted and applied to bioprocessing.”
However, a significant amount of technological development is required for biologics processing, according to Halkude.
When it comes to oral solid doses, Dubey points out that a chemical process converts raw materials into active pharmaceutical ingredients, and then those APIs are converted into solid
Pilot plant that produces tablets starting from raw materials
Process Analytical Technologies (PAT) skid
downstream processes, such as continuous chromatography, as evidenced by current purification trends.”
While perfusion-based biologics manufacturing has been around for many years, the biopharma industry has traditionally favored fed-batch processes. However, continuous bioprocessing is getting a second look, according to CRB.
At the same time, CRB found that while continuous technologies are developed in individual processes such as chromatography and perfusion, they remain elusive for end-to-end continuous processing of the entire biomanufacturing process.
Enzene Biosciences, a CDMO with patented technology for continuous manufacturing, says it has manufactured commercial monoclonal antibodies and converted biologics from fed-batch production to fully-connected continuous manufacturing.
The technology, called EnzeneX, has enabled Enzene to integrate the full production process from bioreactor to downstream purification in a seamless flow. EnzeneX leverages a combination of intensified perfusion and multi-column chromatography.
“We have a technology that has not only been developed but deployed and validated,” according to Russell Miller, vice president of global sales and marketing at Enzene. “It has been demonstrated to support programs all the way through the path from development to commercial.”
Miller contends that Enzene’s platform has been demonstrated on more than 40 development programs, and the company uses the technology to manufacture three products on a commercial basis.
dosage form. With biologics, he notes that you typically have cells or organisms that produce materials which are ultimately converted into drugs — a much more complex and challenging process.
Biologics on the rise
Although global sales of all drugs continue to heavily favor small molecules — by as much as a factor of 9:1 — the demand for biologics keeps rising, according to CRB’s Horizons: Life Sciences survey.
CRB found that manufacturers are eager to embrace new innovations in the production of biologics, including the move away from batch processing in favor of continuous technologies.
“There’s a growing consensus that continuous processing during production enhances productivity through process intensification,” according to CRB. “This advantage extends to
Manufacturers are eager to embrace new innovations in the production of biologics, including the move away from batch processing.
Among the benefits of its fully-connected continuous manufacturing platform are a reduction in the cost of goods, an increase in productivity, and the ability to handle complex biotherapeutics using a flexible design, according to Miller. Productivity is a critical metric when it comes to biologics manufacturing, he said, as mammalian-based processes can take 18, 20 and 25 days to execute.
Given its advantages, Miller predicts that ultimately continuous manufacturing will “eclipse and remove fed-batch on a commercial process basis as the platform of choice — is that going to happen in two years? Absolutely not.”
However, over the next 30 years, Miller foresees a time when 90% of products will utilize some continuous-based process and only 10% of products will be tied to a fed-batch process.
RNA continuous manufacturing
ReciBioPharm, the biologics division of CDMO Recipharm, is looking to have a nearterm impact on the industry when it comes to RNA continuous manufacturing.
Vikas Gupta, president of ReciBioPharm, sees continuous manufacturing as the “Holy Grail” and a challenge to the industry that “remains somewhat utopian” in its approach. However, the company is focused on a lofty goal, which it views as an achievable humanitarian mission: making potentially lifesaving technologies more accessible to underserved regions of the world.
In January 2025, ReciBioPharm was awarded a three-year grant from the Bill & Melinda Gates Foundation to support the global deployment of RNA continuous manufacturing technologies to low- and middle-income countries (LMICs).
The grant will enable worldwide implementation of an RNA continuous manufacturing platform and Process Analytical Technologies
he mark ecades th g conditio dthatt
(PAT) — developed through an $82 million MIT project funded by the FDA — as well as predictive analytics software.
A portion of the MIT project was subcontracted to ReciBioPharm to implement an end-to-end process developed by researchers in a pilotscale manufacturing facility.
“We reduced the time it takes for the entire mRNA process, which typically takes about 21 to 25 days. We were able to take it down to five days,” Gupta said, while noting that the company’s goal is to reduce the process to just one day.
As part of the project, ReciBioPharm has created a modular PAT skid with six different analytical tools/ assays integrated into one unifying software platform to make it easier for users to operate.
“The Gates Foundation wants to see this work happen with the PAT skids,” Gupta said. “This is a plug-and-play solution and we can train people in our facility if it was to be deployed in Indonesia, India, or Africa. We can even run this remotely because of all the software development and features we have built into it.”
ReciBioPharm believes that its miniaturized platform will improve the scalability, quality, and accessibility of RNA-based medicines in LMICs, while helping to advance the company’s goal of developing fully integrated, continuous processes across the biomanufacturing industry.
“Eventually, if this whole platform takes off, we might partner with a bioprocessing firm to actually start manufacturing it at a commercial scale,” Gupta said.
omen However, its widespread use was then linked to severe birth defects in thousands of babies, prompting its withdrawa om the market in the early 1960s. While the tragedy significantly impacted drug regulation and safety protocols worldwide, the decades that followed, thalidomide found a remarkable second life in medicine. Research uncovered its effectiveness in eating conditions like leprosy and multiple myeloma, due to its anti-inflammatory and anti-angiogenic properties, and it was scovered that the drug belonged to a special new class of therapeutics: molecular glue degraders. This revelation, centered ound thalidomide’s interaction with cereblon and other target proteins, catalyzed the exploration of similar molecules for rgeted protein degradation. Since then, advances in the understanding of protein-protein interactions and the ubiquitin-proasome system have propelled the development of new molecular glue degraders to target a variety of diseases. Despite the cky origins, molecular glue degraders represent a landmark advancement in drug development, offering a novel approach to rgeting and eliminating disease-causing proteins. These small, monovalent molecules, typically less than 500 daltons in size perate by inducing or stabilizing protein-protein interactions (PPIs) between an E3 ligase and a target protein. This interaction rms a ternary complex that triggers protein ubiquitination (where a ubiquitin molecule attaches itself to the protein), leading its subsequent degradation by the proteasome (the cell’s protein recycling system).Distinguished from PROTACs (proeolysis rgeting chimeras), molecular glues do not rely on bifunctional molecules linked to guide protein interaction. Instead, they wor y fitting snugly between protein-protein interfaces, enhancing the affinity between an E3 ligase and a target protein to initiat egradation. This crucial difference in mechanism highlights the unique advantage of molecular glues, which include their maller size, higher membrane permeability, and superior pharmacokinetic properties. These attributes not only make molecu r glues highly druggable but also offer a more versatile platform for developing new treatments. The seemingly sudden surge interest and research surrounding molecular glue degraders can be traced back to their potent ability to target previously ndruggable’ proteins, a longstanding challenge in the pharma industry. This capability opens up new avenues for drug develpment, particularly in the treatment of complex diseases such as cancer, where traditional small molecule drugs and biologics ave fallen short. Currently, only thalidomide and its analogues have been approved by the FDA. But with key players entering e ring and many clinical trials underway, the molecular glue garden is bound to bloom soon. From ancient tales of an elixir life with the power to confer immortality, to stories of a mythical fountain of youth recounted around the world for thouands of years, to modern-day billionaires biohacking their bodies in an attempt to stave off death, humans have always had n obsession with longevity. For the pharma industry, the quest to live forever or stay eternally young has largely been viewed
In the 1950s, thalidomide was introduced as a sedative and quickly became popular for treating morning sickn in pregnant women. However, its widespread use was then linked to severe birth defects in thousands of babie prompting its withdrawal from the market in the early 1960s. While the tragedy significantly impacted drug re lation and safety protocols worldwide, in the decades that followed, thalidomide found a remarkable second lif medicine. Research uncovered its effectiveness in treating conditions like leprosy and multiple myeloma, due t anti-inflammatory and anti-angiogenic properties, and it was discovered that the drug belonged to a special n class of therapeutics: molecular glue degraders. This revelation, centered around thalidomide’s interaction with
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Data integrity standards in automation
Robust data integrity ensures you can trace, verify, and act before a minor issue becomes a major recall
Your product finally made it to market, but after a few months, it’s determined that a recall is needed.
Do you know which product line the material came from or what dates it was manufactured? How much product needs to be recalled? From a financial standpoint, you don’t want to recall more than is required.
Ultimately, data integrity is good record-keeping for your entire product life cycle.
From raw material input, through processing, through shipment of the final product, you need to know, with certainty, the who, what, where, and when.
Heath Stephens, PE
Controls & Automation (CSIA)
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Key tenets
Nine key tenets for data integrity in the pharmaceutical industry were established by the International Society of Pharmaceutical Engineers (ISPE).
These key tenets state that data must be attributable, legible, contemporaneous, original, accurate, complete, consistent, enduring, and available.
While it may seem daunting, many of these tenets will naturally emerge from your process if you have a properly automated system, including your process control system, your data historian, and often, a manufacturing execution system (MES) to consolidate data outside of the control system environment.
Properly automated systems
Properly automated systems consist of more than just a PLC/DCS control system. You must follow current industry best practices for the pharmaceutical industry, such as adhering to S88 batch programming standards, following ISA99 cybersecurity principles, and observing ISO 9001 quality standards practices for operations.
Since a well-automated system depends on the interaction of human operators and production personnel, they need to be able to properly interpret and command the control system to carry out tasks. If there are problems, operations personnel need to be trained to resolve them. The idea of a well-automated system is that it improves the repeatability of your processes, eliminates personnel exposure to hazardous activities, and reduces menial tasks, but it doesn’t replace your operations personnel.
Redundancy and availability
Your plant’s operation is done according to a predetermined, validated script. Your control system records its
interface
A well-automated system depends on the interaction of human operators
inputs and outputs in real-time. All that data is historized and stored securely in a process historian, either from your control system vendor or a third-party provider. If your data is not readily available, traceability is compromised at any given time. As part of good automation practices, you should consider redundancy and availability both in initial system design and as an ongoing operational focus – in communication, control, data collection, and data storage.
How much online redundancy do you require? How long can data be unavailable, but a process be allowed to continue to run? Can data be buffered, or will the data be missing after normal operation is resumed?
When designing an automation system, each link in the data creation and storage chain must be considered. You must also consider the operational aspects, and how you will handle various failure scenarios.
Human-Machine
The answers to these questions will depend on your process, company policies, customer requirements, and regulatory requirements. These needs may also change over time, so periodic re-evaluation should be anticipated.
Sources of data
The data you care about when producing pharmaceutical products is more than the data generated from your control system.
Offline laboratory testing data used to confirm product quality is most typically entered into a separate system from the control system, often called a LIMS (Laboratory Information Management System), and needs to be merged to connect a certain batch, a particular product run, or a specific time slice of information. Data from your production processes, control
system, and laboratory system need to be linked to a common dashboard or platform.
In addition, your maintenance records, kept in a separate CMMS (Computerized Maintenance Management System), have relevant information. Knowing when things broke, when they were serviced, and what equipment changes were made to a process, can be vital contextual information to explain and timestamp process deviations.
With the use of an MES solution, you can access data from multiple systems including your control system, which is typically a secure environment with only limited access by authorized personnel. The MES can pull important data out of your lab system, your maintenance system, and even your enterprise resource
planning (ERP) system and into a common dashboard to view and correlate all your data. Your MES is also often a platform that your production personnel in the field will use to enter data from their operator rounds or manual processes.
Challenges ahead
Cybersecurity — We must treat cybersecurity more seriously than in the past due to today’s substantially more challenging threat environment. Ransomware attacks have already hit many manufacturers, and those who have not been hit yet can expect that an attack will be attempted at some point. Also, while ransomware attacks may be the most prevalent cybersecurity attack, they are not the only cybersecurity risk. Data theft, or cyber espionage, meaning the theft of
EQUIPMENT CLEANING VALIDATION YOUR
proprietary information, is also a common risk. If cyber threats can access your data, they may also have the ability to alter your data, which is another threat to your data integrity.
Are you keeping good backups? The first step is to do everything you can to defend against and mitigate threats. But, as a last resort, if the worst-case scenario happens, you should ensure you have established a good recovery plan. This is necessary for malicious threats, accidental mishaps, and system failures.
How do you get data back if you have a catastrophic failure? How long will you be down? What’s your restoration procedure? All of these considerations should determine how you meet the outlined tenets and should be established ahead of time. The time to devise or test a restoration procedure is not after the failure.
A good recovery plan is based on the premise that you never keep only one copy of your data. Unforeseen things happen. The best practice is to keep a copy of that data in another physical location, such as your corporate cloud inside your IT infrastructure, a third-party cloud, or even an offline backup.
The backup methods you choose will be based on the importance of your data and how quickly you will need to recover it. Other considerations include the frequency of your backups and the outcome of your last test restoration.
Traceability — You want to ensure that you have good data and know where it comes from. What instruments generated that data? What people generated that data? Who had access to that data after it was received? You need to be able to trace any sources that could alter that data throughout its journey to its final destination.
People make mistakes, so when that happens, you need the ability to determine which operator entered the wrong setpoint or command.
Years ago, operator commands and inputs were printed in real-time on formfeed printer paper. It was not uncommon when an incident occurred that there was an “issue” with the printer – out of paper or a paper jam. Thankfully, a backup electronic log usually mirrored the output to the printer, so you could determine if a setpoint was entered incorrectly or a restart command given, etc. Still, you could often not narrow it down to a particular person, only a console, because operators typically shared the same account. Over the years, traceability has improved with individual logins and authorizations. It’s still common practice in many industries to have shared accounts for your control room personnel.
People make mistakes, so when that happens, you need the ability to determine which operator entered the wrong setpoint or command. This is not for disciplinary purposes, but to investigate the cause and improve training procedures. Operators hold much responsibility, so they should be trained well and given the opportunity to learn from mistakes.
Traceability also includes the instrumentation and equipment generating process and laboratory testing data. Was an equipment change made recently corresponding to a change in product characteristics? Which temperature transmitter was used to determine when the reaction was complete? Were the VFD settings on the agitator motor changed?
How are you tracking your raw material inputs? Do you get deliveries via rail car or 10 lb sacks? Are your raw materials kept segregated or combined in a large holding tank or feed hopper? What are your raw material testing and sampling procedures? How long do you keep raw material samples for additional testing? When product quality issues occur and nothing has changed in the process, unknown changes in your input materials may be to blame. Can you pinpoint when specific lots of raw materials entered the process?
If you follow proper protocols related to traceability, these questions should be verifiable. While some answers may be in your automated control system, others will be found in your MES or other connected systems.
Accuracy — It’s often taken for granted that, looking at a reading in the process historian, the value you see is the actual value. However, that data reading comes from physical instrumentation in the real world, and instrumentation is only as good as its design and maintenance. You can have an excellent instrument for that process, installation, or location, but if you aren’t maintaining it well, you can’t trust that instrument.
At the same time, you can maintain the instrument well, but if it’s the wrong instrument or mounted in the wrong location, it can give you bad readings.
Readings may be consistently off – low or high – so that it’s skewing your data, or readings may be fluctuating or erratic. If a temperature probe is mounted in the wrong location, it may read higher or lower than the reaction mass inside. If a flow meter is installed in the wrong location in a pipe, air bubbles can rise through it, throwing the reading off.
Data is not always trustworthy. Are there other complementary or redundant signals to help verify the readings? Are redundant temperature transmitters giving similar readings? It’s common practice in safety systems to program voting arrangements to determine how a decision will be made when multiple sensors don’t agree. From a quality standpoint, if a process sensor reading is critically important, you want some redundancy in your readings. If you can’t trust the readings coming off of your instrument, then you’re putting inaccurate or unreliable data into your process control system and into your historian.
AI’s impact on data integrity
AI depends on the key tenets of data integrity as a foundation. If you have accurate, complete, and consistent data, you can implement AI to help you make better decisions, run your systems more efficiently, give predictions for reliability events, or give subsequent predictions about your process. If you feed faulty data, AI will either be too confused to give you a prediction, or it will give you a false prediction because it assumes the faulty data is accurate. So, the more you adopt these tenets and meet data integrity standards, the easier it will be to adopt AI.
Conversely, AI can impact data integrity. Since AI-generated responses can be hard to trace back or replicate, the data AI generates is often at odds with good data integrity principles. This means that even if AI feedback and recommendations are useful to your process or operations, more traditional data should be maintained to document the results.
So, it’s fine if AI recommends that it is time to service a pump based on a mysterious combination of process readings. However, it is somewhat more complicated to let AI call a batch reaction complete based on a multi-variate assessment with a statistical probability score. In the end, it may be acceptable if traditional laboratory analyses of the finished product are sufficient to determine that the product meets all customer specifications.
Good data integrity depends on many things, but it all centers on a properly automated system, where most of the data is generated and stored. That automated system consists of not just the PLC/DCS control system, but the process historian, the MES, and multiple other platforms that feed into it.
It also depends on the people who interact with that system, their training, and their procedures. It can be challenging to bring all those components together effectively, but good automation practices can help you achieve your goals.
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Gene therapy moves to the ballroom
Pros, cons and process modeling
U.S. Director of Novel Technolofies, Arcadis
Ballroom design is common in pharmaceutical facilities, particularly in biologics. In this design concept, process closure permits upstream and downstream operations to be performed in a
Consequently, ballroom designs allow for more flexibility than in segregated designs. For example, if business plans change, a larger ballroom offers the flexibility to incorporate different products and equipment (rather than using smaller suites, which can be limiting
Although gene therapy manufacturing is primarily closed, utilizing single-use equipment, most gene therapy manufacturers have been reluctant to move away from a segregated layout. Instead, upstream and downstream activities typically are divided between different suites.
Next generation gene therapy facilities, however, are evaluating ballroom design – specifically for the flexibility advantages such design offers. In this article, we will discuss the pros and cons for moving from segregated suites into the ballroom. We’ll also explain why process simulation modelling is essential for organizations considering whether a shift to ballroom design may be right
Gene therapy and single use equipment
The equipment used for gene therapy manufacturing is essentially the same as the equipment used for all biologics manufacturing, just on a smaller scale – single use bioreactors and single use depth filtration are used for upstream processing. Once you get into downstream considerations, single use chromatography and single use Tangential Flow Filtration (TFF) skids are common.
Gene therapy manufacturers have been reluctant to move away from a segregated layout essentially for reasons of throughput. In biologics, three different batches (for example) may be set up in three different bioreactors in the same ballroom. Gene therapy, on the other hand, is more highly segregated. Until batch A leaves the room, you can’t bring in batch B.
MICHAEL ANNINO
The rationale for this difference in design lies in a concern about cross-contamination. With bulk biologics, where proteins are being manufactured, there is less of a risk of contamination from one batch to another. With gene therapy, where the product is viral vectors, it’s harder to eliminate the risk of contamination from the equation.
Increasingly, however, next generation facilities are evaluating ballroom design for future flexibility. Our organization recently concluded a project for a company debating whether or not to employ ballroom design. After some collaborative planning sessions we arrived at two separate layouts – one with individual suites and a second with ballroom design. A process simulation model was developed, and based on their targets, the company concluded they were able to meet their capacity needs with a ballroom layout, while also retaining an option for individual suites, based on their clients’ preferences.
Process simulation modeling is an essential step in determining whether ballroom design is right for your organization. In the sections that follow, we’ll weigh the pros and cons of this design approach.
Pros of ballroom design
There are several advantages to ballroom design for gene therapy, including reduced square footage for facilities, operational efficiency and cost reduction, and the ability to share equipment. Let’s consider each. Reduced square footage. Here we’re primarily considering reduction in the number of airlocks.
Consider a facility with Grade D corridors and Grade C suites. In that case, there are potentially four airlocks to access each suite: PAL IN, PAL OUT, MAL IN, and MAL OUT. By combining
upstream and downstream operations into a single suite, the facility planners can save the square footage of a minimum of four airlocks – perhaps even more, depending on the HVAC strategy being employed.
Operational efficiency/cost reduction. Here we’re particularly focusing on the substantial cost reductions that accrue from reducing gowning expenses.
Gowning expenses are surprisingly significant from the perspective of operator costs.
Most gene therapy facilities are “unidirectional,” meaning that operators working in a given suite must return to the locker room before being able to move to a different suite. This means that an operator working in the upstream suite who needs to move to a downstream suite must fully de-gown through the PAL OUT, return to the locker room, then re-gown before entering the downstream suite.
So, every time someone takes a lunch break, every time they use the restroom or any other activity, they have to completely de-gown, go to the locker room, change out of their scrubs, and then come back in and repeat that process. This expense is especially significant when considering maintenance personnel or individuals collecting samples. Operating expenses can mount quickly under those circumstances. By moving to a ballroom approach, operational efficiency is improved, and gowning costs are reduced. Access for maintenance personnel is also improved with a ballroom design.
Ability to share equipment. In a segregated design, it is difficult and time-consuming to move equipment between upstream and downstream suites. A ballroom approach allows for single use mixers of a similar size, for example, to be shared between upstream and downstream unit operations. This in turn leads to a reduced capital cost investment.
This is not to say, however, that ballroom design is all upsides. There are some distinct disadvantages that companies also must weigh when considering this approach.
By moving to a ballroom approach, operational efficiency is improved, and gowning costs are reduced.
Cons of ballroom design
The downsides to ballroom design include potential for higher HVAC classifications, facility throughput issues, and biosafety level considerations. Let’s take each in turn.
Potentially higher HVAC classifications. Many gene therapy manufacturers maintain their upstream suites and downstream suites with different HVAC classifications. It’s common to see upstream suites classified as Grade D, and downstream suites as Grade C.
With a ballroom approach, the higher HVAC classification (Grade C) must apply. This can lead to increased cost for HVAC energy loads, environmental monitoring, and gowning.
Facility throughput. As mentioned earlier, throughput remains the primary reason manufacturers are reluctant to combine upstream and downstream operations into a single ballroom.
Unlike biologics, where multiple batches of products can be manufactured in the same ballroom, gene therapy products are subject to more regulatory scrutiny. According to the EMA GMP Guidelines for ATMPs, “Concurrent production of two different ATMPs/batches in the same area is not acceptable.”
This restriction, by definition, limits manufacturers to one batch per suite. Consequently, a process simulation model is recommended to evaluate the throughput differences between a ballroom approach versus segregated suite design.
As an option to improve efficiency, viral negative cell expansion steps prior to the production bioreactor may be shifted to inoculum prep to improve throughput.
Biosafety level considerations. Some facilities classify their production cleanrooms as Biosafety Level 2 (BSL-2). This ensures maximum flexibility, allowing for retroviral and lentiviral production. On the other hand, however, many manufacturers are dedicated to Adeno-Associated Virus (AAV) production.
With AAV, only the upstream suite needs to be classified as BSL-2 to account for the Human Embryonic Kidney (HEK) host cell line. Downstream suites may be classified as BSL-1.
Shifting to a ballroom design means the entire suite – and therefore all waste, both liquid and solid, from the room – may have to be managed as BSL-2. This can, of course, lead to increased costs. Given the reality that resources are constrained in the case of existing facilities, these concerns can become operationally significant.
Process simulation modeling is key
For readers wrestling over whether the decision of using ballroom design in their facility, process simulation modeling is essential. Understanding the pros and cons described above, when weighed against the organization’s business model, help drive the decision of whether or not ballroom design is appropriate.
This is an especially important part of the decision-making process when an organization is realigning its business goals. In the case of the example cited at the outset of this article, the company is expanding. Their current layout is segregated. They made the decision to add ballroom design, with both configurations in the same facility.
That actually became an internal point of debate: Would there be concerns among prospective clients that half of the facility was upstream/ downstream, and half ballroom? From the company’s perspective, that flexibility actually became a benefit. If one of their clients wants segregation, that is possible. If they want a ballroom approach, that option also is available.
It’s important to note that while facility throughput is an essential consideration, so too are the implications of a particular facility design on staffing and equipment sharing.
If all processes will be combined into a ballroom design, will upstream and downstream staffing be shared? Will there no longer be a need to duplicate personnel because of the ballroom approach?
The same consideration applies for equipment. In segregated design, moving equipment between suites may be cumbersome and time-consuming, especially when compared with ballroom design. On the other hand, perhaps given a manufacturer’s particular production requirements, it might be most cost effective to buy additional equipment altogether.
These considerations are particularly relevant for organizations that may be shifting their lines of business – adding some product types, or removing others. And that may be the tipping point when considering ballroom design. If the area of the facility will be expanding, there is greater flexibility in design. A larger piece of equipment may work better in a ballroom, for example, than in an individual suite.
Regardless of where an organization may be in the process of choosing between ballroom design or segregated suites, process simulation modeling is essential in making the choice that will best support its business needs.
Aimee Hodge VP Business Operations Development & Manufacturing PCI Pharma Services
Avoiding common PPQ pitfalls
How overlooked details in process validation can derail commercial readiness
For just a moment, let’s imagine we remove our pharma engineering hats and slip into… running shoes. Let’s swap out our dedication to drug development and manufacturing and replace it for weeks, months and even years of physical training all for one goal: completing a marathon.
To say you’ve put in the work is an understatement. Long hours in the gym, longer hours on the track.
Trading pizza for protein
shakes and carrot cake for, well, carrots. Running through pain, rain and strains to gain that extra advantage on the lengthy, 26.2-mile road to a remarkable physical feat. Rounding the final corner, the checkered banner of the finish line comes into view. What a welcome sight.
So welcome that you stare into the distance long enough to veer off the roadway and headfirst into a lamppost. Goodbye marathon, hello hospital. Now, pharma development hats back on. In our neck of the woods, such snatching of defeat from the jaws of victory closely resembles a drug development journey that travels
great distances before stalling out in the process performance qualification (PPQ) stage.
Up to that point, the drug project has passed several key milestones. For new small molecules and biologics, rigorous multi-phase clinical trials are wrapping up. For ANDAs, a complex reverse engineering process has led to a generic product that stands up to its brand name big brother. Everything seems ready for the final push to commercialization, the crossed T’s and dotted I’s of a resource-rich project years in the making.
And then it isn’t. And worse, the reasons were, like that lamppost, entirely avoidable. Let’s explore a few case studies where the path to commercialization took unfortunate detours at the least tenable time: the final runup to approval and launch. In the process, we’ll discuss best practices that can help keep drug approvals on course for the winner’s circle.
MICHAEL ANNINO + SHUTTERSTOCK-AI
Too generic
Our first example is a hard lesson in being hyper-selective and detail-oriented when it comes to both vendors and processes. Specifics matter, and a lack of them can lead to a formulation recipe for disaster.
In this case, the project originated several years ago and involves the abbreviated new drug application (ANDA) regulatory pathway. This segment typically comprises generic drug development, and carries inherent benefits and drawbacks.
On the plus side, ANDAs almost always have a pre-approved predecessor: a brand name drug whose safety and efficacy have already passed regulatory muster. However, since these original brand name drugs often involve exclusive APIs and other substances, at least some degree of reverse engineering is typically required to develop an optimized formulation and process.
With ANDAs, then, it stands to reason that among the most crucial aspects of formulation development is drug substance sourcing. In this case, as in most, the brand name manufacturer had an exclusive relationship with its API supplier, so an alternate source was required. Ultimately, the vendor chosen by the generics company underwhelmed – to put it kindly – and these shortcomings didn’t come to light until well after the process had moved forward along the pre-commercialization pipeline.
Highlighters out, because this scenario showcases a pre-commercialization must: proper, thorough supply chain and raw material risk assessments. Part and parcel to a comprehensive drug development process is designing a robust validation strategy that considers a product’s critical quality attributes (CQAs) – those properties that must be controlled within a certain range to ensure a product meets a set of predetermined standards.
Unfortunately, the issues with this project stretched well beyond the drug substance supply chain. Indeed, neither the product properties nor the production process was well-defined, two factors that sit atop a “problem tree” and can branch out
Getting it right
Without a clear idea of optimal mixing times, the liquid product is likely to suffer
to cause any number of unforeseen, unwanted issues.
Simply put, in pharma development and manufacturing a dearth of adequate critical process parameters (CPPs) is a fatal dose of failure. Without a thorough checklist of attributes that must be known, honed and reliably repeatable, something is bound to go awry. Take, for example, a drug produced in liquid form and subsequently lyophilized for its distribution journey. If a manufacturer doesn’t have a clear idea of optimal mixing times, the liquid product is likely to suffer; from there, without a knowledge base about hold time limitations (the critical period between the product’s production and its filling, sealing and lyophilization), the product’s efficacy or even safety may be adversely affected.
Any number of these shortcomings can lead to a drug submission not meeting contemporary regulatory requirements, including those pertaining to the Manual of Policies and Procedures (MAPP), a collection of directives and internal procedures insisted upon by the FDA’s Center for Drug Evaluation and Research (CDER). To stay in the lyophilized lane, one issue can revolve around conformity to concentration requirements, since such drugs are typically diluted prior to the freeze-drying process.
In this case, the result was predictable: the initial drug submission was confronted with numerous information requests and complete response letters (CRLs), chiefly due to concerns about overall product quality. The time and resources lost were considerable –and avoidable.
Details matter
Our second scenario involves a Biologics License Application (BLA) that was initiated several years ago. As with the ANDA project, unforced errors led
Step by step
Developing and manufacturing a pharma product is a delicate, multistep dance
to CRLs along with several questions from regulatory authorities about drug product manufacturing.
Developing and manufacturing any pharmaceutical product is a delicate, multistep dance, but producing biologics medicines is especially exacting. Some of the pitfalls in this project mirrored those in the first example, including a lack of sufficient mixing studies to satisfy regulatory requirements. Others were specific to the next-level challenges posed by sterile injectables; in this category, the project’s setbacks included incomplete filter validation, a reporting gap that can call into question a biologic’s mission-critical sterility. For understandable reasons, a biologic product’s sterility must be both assured and provable, and any inadequacies concerning filter validation process will not be overlooked by the discerning eyes of regulatory officials.
Again, the process starts crashing through branches on the “problem tree.” As with the ANDA example, the BLA project suffered from ill-defined in-process controls (IPCs), with CPPs that were not understood in sufficient depth to satisfactorily produce the formulation in a consistently predictable fashion. A shortage of so-called micro-validations – including reinforcing the drug’s fine print attributes, such as endotoxin methods – completed the incomplete picture.
The simple truth was that the process hadn’t been completely thought through. And the truth hurt far more than feelings: the litany of issues wasn’t discovered until after the initial PPQ batches, leading to sunk costs for both precious API and valuable partner engagement time and infrastructure usage.
These case histories highlight just a few of the disheartening detours that can occur along a drug’s pathway to commercialization during the PPQ stages. Depending on the regulatory category, these stages may comprise activities occurring after Phase III clinical trials but before full market readiness. Other PPQ pitfalls can arise stemming from insufficient or incomplete communications with regulatory agencies regarding a product’s expectations, or not conducting detailed risk assessments and corresponding remediation plans. And of course, none of the above matters unless both the pharma company and its selected CDMO are fully prepared to handle one of drug approval’s final hurdles: on-site inspections.
Adhering to a tried-and-true set of best practices during the PPQ-stage can prevent a drug approval from stalling out on the final lap. For starters, you should seek to establish an ironclad protocol for commercial supply agreements that sets clear parameters for drug substance continuity and, most importantly, quality. Only with the proper product ingredients in hand can a manufacturer make informed decisions on the next step: finalizing CQAs and, relatedly, a buttoned-up process failure mode and effects analysis (PFMEA).
Next, stick the landing on a final process validation campaign. Such a systematic procedure is crucial to ensure a manufacturing process can consistently produce quality products. Subsets of this step include drug product stability registration, continuous process verification and, furthest downstream, packaging and shipping validation.
Collaboration is key
The final item in our best practices collection should be bolded, CAPPED and scrawled across the top of the checklist for any pharma company engaging a contract development and manufacturing organization: COLLABORATE WITH YOUR CDMO.
The due diligence that you undertake when selecting the right CDMO takes outsized effort; the process should, at least, consider prior experience with similar formulations, the ability to support both short- and long-term needs, depth of development capabilities and, per our purview here, process for onboarding new products and assisting with regulatory submissions. Now, put that sound decision to hard work.
Above all, this means bringing that CDMO as fully into the process as possible. Details matter.
Michael Schmitz VP Logistics, Vetter
Sterile injectable supply chain trends driving global CDMO growth
CDMOs face shifting demand, tighter g
growing complexity in sterile py injectable supply ppy chains
shifting tighter regulations, and complexity in sterile injectable supply chains
Pharma has long relied on a complex global flow of raw materials, manufacturing resources, and logistic information to supply the global market with injectable drug products. While this system has weathered many challenges over time, it’s also one that has repeatedly proven its robustness and resilience.
Today, however, stakeholders across the parenteral product value chain find themselves navigating many fast-changing challenges and unpredictable developments. Some are familiar but evolving quickly, especially challenges related to the regulatory, financial, and technological frameworks that increasingly shape the global sterile injectable supply chain. Others, like new injectable modalities and growing geopolitical friction, are creating both new strains and opportunities.
Leading, global CDMOs specializing in sterile injectables operate at the forefront of these dynamics. This article offers an expert, experience-based perspective on how parenteral product supply chains are evolving, what these changes may mean for value chain stakeholders, and how manufacturers can optimize their operations for a new era.
Today’s new normal
Several years after the pandemic’s acute disruptions have passed, we can see our industry’s global logistic system reaching a new equilibrium. In most areas of the value chain, the security of supply established before COVID has been successfully restored. At the same time, this return to stability has brought new challenges: substantially more operational scrutiny, heightened expectations for proactive preparation, and unsettled geopolitics keeping supply chains at continual risk.
At warehouses and logistics centers, this new reality is already being felt in day-to-day operations — often through shifting customer expectations for on-hand “security stock.”
While some CDMOs may have pursued cost-saving “zero inventory” strategies before COVID, most manufacturers have historically hedged against unexpected shortages and disruptions by keeping a certain amount of customers’ raw materials, supplies, and resources in stock. Today, following the industry’s scarring pandemic experience, many drug owners are not only mandating on-hand inventory but also substantially increasing the amount of stock they expect CDMOs to hold in reserve.
MICHAEL
As a result, commercially available inventories of both raw materials and some finished products are often reduced by just-in-case purchasing, while CDMOs face pressure to expand their storage footprint to accommodate far more on-hand resources. The zero-inventory approach has also largely been abandoned.
Significant new regulations are also a visible and impactful feature of the new post-COVID market scenario. Stung by the pandemic’s global disruptions, authorities in many major markets have either launched or proposed new regulations intended to protect and reinforce their drug product supply chains.
In the US, the Drug Supply Chain Security Act (DSCSA) has substantially raised the bar for supply chain visibility to unit-level tracking of product shipments — a requirement that many forward-thinking CDMOs were already well-prepared for. Authorities in many markets — the US, EU, and Asia included — are also proposing strategies and requirements aimed at strengthening supply chains by moving them closer to home. Much remains to be seen about how these new regulations will develop and be implemented, but their primary intent is clear: securing drug product supply chains by reshoring them.
That goal, of course, reflects the many geopolitical tensions driving administrations to incentivize bringing home manufacturing and logistics — especially for vital products like many medications. This trend will be closely watched by many value chain partners, as it may create both new regional opportunities and more demands which will cause industry leaders to rethink established global supply chains.
Either way, this evolving dynamic is already compounding a pressure
point that has emerged in the parenteral product supply chain in just the last few years: demand for products at two very different ends of the production scale.
Polarized production demands
Until recently, the future of the pharmaceutical pipeline seemed clear: Less reliance on a few flagship therapies produced millions of doses at a time, and more focus on highly specialized products with niche patient populations and vastly small batch sizes. Recently, however, the sterile injectable market has found itself navigating a significant swerve in this trend.
Today, a new generation of blockbuster injectables has emerged to dominate the parenteral product market — while at the same time, the global pipeline of parenteral products continues to fill with many specialized, small-volume products. As a result, supply chain and logistics stakeholders find themselves challenged to manage two very different demands in parallel: creating efficient, consolidated, scaled-up systems to support mass production while also optimizing for the flexibility required for small-volume manufacturing.
Preparing for growth in both scenarios is an increasing challenge for many CDMOs, even specialized manufacturers that already support high-volume and small-batch production. Doing so requires precision orchestration of resources, materials, and personnel across the organization: for example, optimizing logistic facilities to supply both high-speed, high-volume filling lines and clean rooms with regular product-to-product changeovers.
What’s more, patient preferences and competitive forces are also pushing many blockbuster owners to adopt delivery devices like autoinjectors
and injector pens: formats with significantly more demanding supply requirements.
To produce these in-demand products at scale, CDMOs must manage material, resource, and logistics processes for both aseptic filling and device assembly and packaging — two closely integrated but very unique processes that each demand their own supply chain expertise. Further investment in infrastructure is often called for as well.
To support two opposite manufacturing scenarios in parallel, often for products with complex device-based formats, a CDMO may need significantly more storage space for a much greater number and variety of products: From all the individual needs of a portfolio of specialized vial-based products to the commercial-scale supply requirements of a mass-produced, autoinjector-based therapy.
Even CDMOs that focus specifically on smaller-volume products may now find themselves absorbing more projects displaced by facilities optimizing for high-volume batches, therefore needing to swiftly scale their specialized processing resources in response. These specialists are far from alone in needing to evolve their infrastructure. In fact, this kind of investment has become a key priority for many sterile manufacturers working to adapt to this increasingly two-ended market. Two areas are rising as the focus of these strategies: digitizing and automating logistics and expanding cold chain resources.
Digitalization and cold chain
Familiar forces are driving the focus on both of these areas: The need to balance compliance with growing cost pressures across the value chain and sustained growth in demand for complex, sensitive parenteral products.
Today’s CDMOs are downstream from many challenging financial dynamics squeezing the sterile injectable market, from tight capital markets to customer cost-cutting efforts, to impending patent cliffs and national cost-control strategies. Predictably, these pressures have given manufacturing partners the difficult task of fulfilling production contracts as cost-consciously as possible while still achieving the highest possible levels of quality and compliance.
In response, many sterile manufacturers are eagerly adopting efficiency-driving digital technologies across their businesses, including their logistic services.
Within those specialized groups, technological investments are taking many different forms. Digital inventory management systems, logbooks, and shipping records are quickly becoming a new standard for CDMOs seeking to streamline their supply chain operations, reduce administrative overhead, and optimize compliance with tightening data integrity requirements. Elsewhere in their facilities, many supply chain and logistics leaders are also
automating physical inventory handling, leveraging robotics in their warehouses, and further strengthening track-and-trace systems needed to comply with regulators like the DSCSA.
At the same time, growing demand for sensitive parenteral molecules is also driving CDMOs to invest in their cold chain infrastructure. Refrigerated facilities, storage areas, and handling processes, chilled, freezing, and sub-freezing, are all vital for any sterile manufacturer processing complex biologic products, most of which require end-to-end cooling throughout their production cycle.
For advanced manufacturers, however, expanding refrigerated space is only the start: State-of-the-art digital monitoring systems are also an increasingly important feature of the facilities and workflows used to process refrigerated drug products. These systems now play a vital role in both operational and regulatory areas of cold chain management, continually tracking product and environmental temperatures, enabling audit-ready tracking, and verifying that products remain within compliant temperature parameters at all times.
At the same time, however, the importance of these systems also
reflects a bigger compliance trend in aseptic manufacturing. Explicitly supply chain-focused regulations aren’t the only ones that CDMOs’ logistic services are adapting to: They’re also navigating many broader mandates that are reaching deeper into manufacturing organizations than ever.
Regulatory ripple effects
While many recent mandates have taken direct aim at the pharmaceutical supply chain, many more general regulations are now being extended to logistic functions too.
In the U.S., the FDA’s pre-approval inspection (PAI) requirement establishes the general expectation that CDMOs demonstrate “a commitment to quality” across their manufacturing process, both physical and digital.
For logistic service units, that expectation has brought more scrutiny on how products travel not just through filling lines but also facilities, warehouses, and storage areas—with added attention now being paid to how quality is protected from shelf to batch release. The PAI program also has a strong focus on data management integrity, which has created additional urgency to audit-proof digital tracking and reporting systems.
Meanwhile, in the EU, most forward-thinking aseptic manufacturers have already implemented robust Annex 1 compliance programs and proactively addressed many of the regulation’s requirements for their core production facilities. Elsewhere in the organization, however, many finer details are still being worked out in day-to-day operations.
Over time, regulators and logistic service teams will undoubtedly find an alignment on these challenges and arrive at clear compliance expectations for the parenteral product supply chain.
Product expansion CDMOs need more storage space
Eric Bankos Senior CQV Engineer, Genesis AEC
Understanding validation and commissioning
Mistakenly used interchangeably, the terms have crucial differences
In the pharmaceutical, biotech, and life sciences industries, the terms validation and commissioning are frequently — and mistakenly — used interchangeably. These two essential processes often occur side-by-side during equipment startup, leading some to view them as interchangeable. They are not.
Commissioning: Setting the stage
Commissioning ensures that facilities, utilities, and equipment are installed correctly, and function as intended. It includes initial checks, inspections, installation verification, functional and safety testing, calibration, and preliminary troubleshooting and tests such as Factory Acceptance Testing (FAT) and Site Acceptance Testing (SAT). The focus is on operational readiness not regulatory compliance or quality assurance documentation.
Key aspects of commissioning include installation verification, utilities verification, calibration, operational readiness, functional testing, equipment calibration and initial troubleshooting.
Commissioning verifies the “as-built” state, ensuring that all components of a system or piece of equipment work correctly under defined operational conditions.
Validation: Ensuring compliance and quality
Validation, on the other hand, is a documented, systematic process
that demonstrates with a high degree of assurance that a system, equipment, process, or method consistently produces results meeting predetermined specifications. It also requires adherence to standards such as ISO 17025 (for calibration traceability) and 21 CFR Part 11 (for data integrity and electronic records compliance).
Validation directly impacts regulatory compliance and product quality and is mandated by regulatory authorities such as the FDA, EMA, and others. Validation consists of three core phases:
• Installation qualification (IQ): Making sure that equipment is installed per the manufacturer’s and clients specifications and regulatory requirements.
• Operational qualification (OQ): Testing that equipment consistently operates within the established parameters.
• Performance qualification (PQ): Demonstrating that the equipment or system consistently performs reliably under real-world conditions.
Common pitfalls to avoid
Common errors in validation that should be diligently avoided include:
• Deviations: Even minor deviations can snowball into compliance risks if not properly documented, investigated, and justified.
• Typographical Errors: Minor typos in protocols can lead to significant
misunderstandings, misinterpretation, or regulatory citations. Ensure rigorous proofreading and technical reviews.
• Protocol generation errors: Every protocol must be an accurate reflection of actual procedures. Using generic or outdated templates without sufficient adaptation to the current system or equipment can cause compliance and execution issues.
• Improper training: Personnel executing validation activities must be properly trained and qualified. Documentation of this training is essential.
• Ignoring traceability: Validation must demonstrate traceability to User Requirements Specifications (URS), Functional Design Specifications (FDS), and other design and requirement documents.
Best practices
Define the handoff early: Establish the transition point from commissioning to validation at the beginning of the project to avoid confusion later. Involve QA early: Engage validation and quality teams during commissioning planning to align expectations and deliverables.
Run Mock Qualifications: Conduct dry runs or mock qualifications to identify gaps before execution. Commissioning gets systems ready to run. Validation ensures those systems are compliant and capable of consistently producing quality results. The distinction matters.
Nick Downey Principal Engineer, DGeo
Raising the bar in sustainable packaging
Companies need to start planning for a more sustainable future today to keep pace
In pharmaceutical transport, consistency isn’t a luxury – it’s a necessity. One misstep in temperature control and test samples can easily be ruined or generate false readings. Vaccines can spoil, putting lives at risk. Perfect transport is required, every time.
That’s challenging enough. But, now add another layer into the mix: sustainable packaging that doesn’t languish in landfills for hundreds of years.
Environmental responsibility continues to become a greater focus within the pharmaceutical industry. As regulations evolve – like the proposed Packaging and Packaging Waste Regulation requiring all pharma packaging to be “demonstrably recyclable at scale” by 2035 – smart pharma companies need to start planning for a more sustainable future today to keep pace.
So, how can you marry safe, compliant and consistent cold chain packaging with packaging that’s also sustainable? You might be surprised to learn that modern packaging innovations are already available, designed specifically to meet these dual needs.
Low temps, high stakes, higher testing standards
Let’s start with how to assure both compliance and safety. What works in a warehouse might not cut it in transit, making packaging a crucial part of the cold chain.
That’s why more pharma companies are turning to total packaging solutions that include both UN and comprehensive thermal testing.
These materials are often highvalue, and outsourcing this kind of testing saves time, resources and stress. Thermal testing isn’t one-sizefits-all either – it factors in minimum and maximum load sizes, seasonal extremes and whether cold packs or dry ice are in play. In my experience, this type of testing isn’t just a nice-tohave; it truly validates the security of my products while in transit.
Unpacking environmental impact
As you likely already know, many goods within the pharma supply chain are classified as dangerous goods (DG) requiring specialized packaging.
Unfortunately, traditional DG packaging often doesn’t cut it when it comes to sustainable solutions.
Take expanded polystyrene (EPS) foam, for example. It’s an effective insulator, but it’s an environmental nightmare that lingers for centuries and sheds harmful microplastics. Metal containers? They’re heavy, require more energy to move and are prone to dents.
Traditional EPS coolers also pose logistical challenges – they can’t collapse like corrugated shippers, making them bulky to store and more expensive to transport. While modular cooler options exist, the assembly process is often cumbersome.
But there’s good news.
You don’t have to choose between prioritizing sustainability and green initiatives and protecting your bottom line. The right solutions can give you both.
Pharmaceutical companies embrace change
Innovative materials and designs are reshaping pharmaceutical logistics by offering more reliable and sustainable alternatives to conventional packaging. Since 2021, the pharma industry has made significant strides: Sustainable packaging adoption has increased by 25%, packaging material usage has dropped by 40% and renewable energy in manufacturing has achieved 85% efficiency.
Increasingly, I’m seeing pharma executives expressing interest in biobased, sustainable packaging. In fact, one company was recently looking for a cooler in a new size not currently available. When offered standard EPS instead, they declined – stating they’d only consider switching from their current supplier if the new solution was more sustainable.
A more sustainable cold chain foam cooler is just one new innovation. Several others prove you don’t need to choose between safety and sustainability.
The future of hazmat and pharma packaging is crystal clear: greener, smarter and built to last. The pharma companies that adopt sustainable solutions today will be leaders tomorrow.
Greg Slabodkin Editor in Chief
Biosimilar approvals create ‘golden’ opportunity for CMOs
Companies specializing in biologics can expect to see higher biosimilar volumes, according to GlobalData
Given the FDA’s record-breaking number of biosimilar approvals in 2024, contract manufacturing organizations (CMOs) specializing in biologics stand to benefit from this growing market, finds data and analytics company GlobalData.
“FDA biosimilar approvals reached a record 19 in 2024, with projections indicating that 2025 could surpass this milestone trend,” GlobalData contends. “This presents a golden opportunity for contract manufacturing organizations (CMOs) specializing in biologics, as more blockbuster drugs approach patent expiration and regulatory barriers to entry diminish.”
The global biosimilars market is expected to grow at a compound annual growth rate (CAGR) of nearly 20% through 2030, as patents for blockbuster biologics expire, offering a potentially lucrative pathway for CMOs.
GlobalData argues that the momentum for biosimilars is “set to accelerate” noting that patents for 14 biologics expired in 2024, including major products like UCB SA’s Cimzia and Johnson & Johnson’s Simponi” and that “even more biologics — 18 — will lose patent protection in 2025, paving the way for a new wave of biosimilar entrants, including Amgen’s Prolia and Roche’s Perjeta.”
Currently, 90% of biologics facing patent expiry over the next decade lack biosimilar candidates creating a potential opportunity, according to Samsung Bioepis’ second
quarter 2025 biosimilar market report released last month.
Celltrion vs. Samsung Bioepis
South Korea is home to two dominant biopharma companies. While Samsung Bioepis has the largest number of approved products, Celltrion leads the overall biosimilar deals landscape, according to GlobalData.
“Given Celltrion’s involvement in most of the deals, both globally and locally, the company leads the overall biosimilar deals landscape in South Korea and is expected to have an edge on deal-making strategy over other South Korean players,” GlobalData pharma analyst Nelluri Geetha said in a statement.
Sung Yoo, head of the Bio Platform Center at Edaily, noted in a recent column that the lines between these two companies are “now blurring” with the convergence of their respective strategic targets.
While Samsung Biologics “has long relied on CDMO and biosimilar operations (via affiliate Samsung Bioepis) as its twin engines,” the company is “now seeking to accelerate growth through expansion into novel drug development,” Yoo said. “Meanwhile, Celltrion is executing a strategy to transform into a global biopharma player by building on its biosimilar base, with additional investments in novel drugs and CDMO.”
Celltrion contends it is South Korea’s largest manufacturer and exporter of biosimilars, with an annual
production capacity of 250,000 liters. But in 2024, the company also created a wholly owned CDMO subsidiary, Celltrion BioSolutions. Celltrion BioSolutions plans to break ground on a 100,000-liter production plant in the first half of 2025, with commercial production slated to begin in 2028 and a long-term goal of achieving domestic capacity of up to 200,000 liters.
BRICS countries
With Brazil, Russia, India, China, and South Africa (BRICS) nations exploring barrier-free regulations for biosimilars and biologics, these countries could provide a “counterbalance” to the challenges posed by U.S. tariffs “fostering healthy competition and reducing production costs,” according to GlobalData.
While the intergovernmental organization is a loose coalition of non-Western economies, GlobalData contends that BRICS member nations have emerged as key players in global pharma manufacturing bolstering access to affordable medicines, as President Trump has doubled down on his threat to target the pharma with tariffs meant to bring drug manufacturing back to the U.S.
“By advancing regulatory harmonization for biosimilars and biologics, BRICS nations are positioning themselves to offset the pressures created by U.S. trade policies,” Leyla Hasanzadeh, GlobalData’s senior research analyst for health economics and market access, said in a statement .
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