Advanced Pharmaceutical Manufacturing

With growing demand for advanced therapies, improved manufacturing processes are needed to provide flexibility and increase speed and scale-up. Leveraging innovative product manufacturing technologies and approaches, advanced pharmaceutical manufacturing (APM) aims to improve drug quality, address shortages, and speed time-to-market. Technologies include continuous manufacturing, additive manufacturing or 3D printing, and digital integration, among others. These technologies, which can be applied across a diverse range of drug products and therapies, offer potential improvements in drug quality, process reliability, and the supply chain.

While APM offers significant advantages, challenges such as high upfront costs, implementation hurdles, and regulatory barriers remain. However, industry initiatives aim to address these challenges to promote broader adoption of APM. 

The U.S. Food and Drug Administration promotes APM through initiatives such as Emerging Technology Program (ETP), where industry representatives can meet with FDA to discuss, identify, and resolve potential technical and regulatory issues regarding the development and implementation of a novel technology prior to filing a regulatory submission.

Also, the Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) and the Advanced Manufacturing Technologies Designation Program (AMTDP), aim to facilitate the adoption of new manufacturing technologies by the pharmaceutical industry, particularly for essential medicines or drug shortages. 

CDMOs play an important role in supporting advanced manufacturing technology and capability. Contract Pharma provides insight from SMEs at CDMOs specialized in this innovative space. 

APM Technologies

Three-dimensional printing (3DP) technologies, single-use systems equipped with real-time process analytics and automation platforms, and high-throughput processing and analytical technologies with data-driven development approaches, are among the latest tools CDMOs are employing to improve manufacturing processes.

3D screen printing is advancing manufacturing by enabling scalable production of complex dosage forms and delivering high-quality, personalized medicines faster and more efficiently. Steven Facer, Senior Vice President, Global Sales and Marketing at Adare Pharma Solutions, explains, “Unlike traditional 3D printing, 3D screen printing uses a gentle, cold, flatbed screen-printing process that preserves API integrity while allowing precise layer-by-layer control over drug release profiles, including immediate, extended, and delayed release in a single tablet. This flexibility supports novel combinations, unique geometries, and multi-compartment designs, helping to address drug shortages by enabling efficient scale-up from R&D to commercial production (up to 1.5 million units per day) without major process changes.”

This technology, according to Facer, minimizes waste, reduces API requirements, and supports rapid prototyping for dose-finding studies. Additionally, its ability to create differentiated formulations provides new IP and regulatory pathways.

Furthermore, 3DP technologies can offer significant benefits in clinical development as well as across the pharmaceutical lifecycle leveraging platforms designed to deliver speed, flexibility and precision in drug product manufacturing and distribution. Kyle Smith, President and Chief Operating Officer, Aprecia Pharmaceuticals, says, “Through rapid formulation prototyping and real-time quality control evaluations, Aprecia’s platforms allow for efficient formulation screening to eliminate non-viable drug product candidates, thereby enhancing clinical trial efficiency, precision dosing and reducing development costs and risk.” 

For example, Aprecia’s Z-Form Flex platform allows for rapid formulation prototyping, real-time quality control assessments and seamless transition from clinical to commercial manufacturing using integrated Process Analytical Technology (PAT) and precisely layered 3DP manufacturing capabilities.

Smith adds, “These capabilities are especially valuable for complex oral solid dose products, including high-dose Orally Disintegrating Tablets (ODTs) that disperse immediately — ideal for pediatric, geriatric, and dysphagia patients. With the ability to tailor dosage, drug product release rates, and tablet structure, Aprecia’s 3DP is well-suited for personalized medicine, clinical prototype development, and lifecycle management of approved products.”

Other technologies driving APM include the integration of single-use systems, real-time process analytics and modern automation platforms. Together, these technologies offer greater control, efficiency and responsiveness from early development through commercial manufacturing. According to Salvador.

Alvarado-Olivo, Sr. Manager, Product Management, Thermo Fisher Scientific, “A key driver of evolution in APM is the adoption of single-use bioreactor platforms, which are helping accelerate scale-up while maintaining consistency across development and production. By removing the need for cleaning steps and offering a wide range of flexible production volumes – from 1-liter benchtop reactors to 5,000-liter commercial vessels – the DynaDrive portfolio helps reduce turnaround times and make facility fit and tech transfer much simpler.”

Alvarado-Olivo, adds, “Process analytical technologies (PAT), including in-line Raman spectroscopy, are enabling real-time monitoring of key parameters such as glucose, lactate, and titer. These tools provide actionable insight that helps ensure product quality and reduce risk of batch failure. Digital twins replicate the physical bioreactor and its process behavior virtually, allowing engineers to simulate process changes, predict bottlenecks and optimize production before executing on live equipment.”

To address common biopharma industry challenges, such as supply chain disruption, shortages caused by potential quality issues, and increased costs due to delayed timelines, Camille Segarra, Head of Strategy & Innovation, Integrated Biologics, at Lonza, says, “Lonza is introducing programs that shorten time-to-clinic, where minimizing risk remains a top priority for drug developers. For example, we’ve accelerated timelines for toxicology material supply to enable earlier initiation of tox studies while maintaining highly competitive drug substance GMP release timelines. Additionally, we have considerably expedited timelines to complete IND-enabling Chemistry Manufacturing and Control (CMC) studies to generate required data. To further de-risk an accelerated development journey, we recently introduced a new offering with consistent titers and stability across a range of molecule types,” according to Segarra.

Opportunities 

With the host of benefits these technologies offer, the best opportunities lie in complex biologics, personalized therapies, highly potent products, as well combination therapies and those with complex release profiles.  

Salvador Alvarado-Olivo at Thermo Fisher Scientific, says, “APM offers particular value for a diverse range of therapies. Complex biologics, such as monoclonal antibodies, fusion proteins and next-generation biologics, benefit from the precise control over upstream and downstream parameters that APM provides. Advanced modalities like mRNA vaccines, viral vectors and gene therapies also see significant gains, as they require speed, agility and high-quality standards.”

Personalized therapies, with their small batch sizes and compressed timelines, are especially well served by flexible automation and rapid scale-up capabilities, according to Alvarado-Olivo. Highly potent products are another area where single-use systems shine, reducing the need for extensive cleaning validation and minimizing cross-contamination risk. “As product pipelines diversify, these technologies are helping manufacturers support both large-scale and niche therapies under one roof,” says Alvarado-Olivo.

Additionally, drug products that require complex release profiles, combination therapies, or highly customized dosage forms are best positioned to benefit from APM technologies like 3D screen printing, according to Steven Facer at Adare Pharma Solutions. Facer notes, “3D screen printing enables immediate, extended, and delayed release functions within a single tablet, making it ideal for therapies that require precise pharmacokinetic control.” 

Products with multiple APIs, especially those that are chemically incompatible or require separate compartments, can be efficiently produced without complicated multi-step manufacturing, according to Facer. “Furthermore, delicate APIs such as peptides, poorly compressible powders, or moisture-sensitive compounds benefit from the cold, gentle process that maintains stability and potency,” Facer adds.

Additional opportunities lie in process intensification technologies and advanced analytics for production of a wide range of drug products to enhance speed consistency, and flexibility for complex formats such as biologics.

Camille Segarra at Lonza says, “Process intensification technologies allow us to run high-density fed batches at any scale in our network, enabling cost-effective solutions with consistent product quality throughout the manufacturing process. These technologies can facilitate the production of a wide range of drug products, including biologics, which are especially well-suited to APM due to their inherent structural complexity, sensitivity to process variation, and high value per gram. For example, Process Analytical Technology (PAT) and Raman spectroscopy allow us to provide real-time monitoring of critical process parameters while enabling design control strategies for any process coming through our facilities; these technologies significantly increase batch-to-batch consistency and result in fewer deviations.” 

Additionally, advanced analytics help considerably increase the pace and volume of batch release, speeding time to clinic, adds Segarra. “For developers of conventional monoclonal antibodies (mAbs), our ability to introduce intensified manufacturing techniques late in the development process can help drug developers achieve desired economies of scale. We can also leverage our technologies to manufacture complex formats, including bi- and tri-specifics and non-Fc molecules, guaranteeing superior recovery yields compared to traditional processing methods,” says Segarra.

APM Challenges 

Adopting new technologies and the costs associated with implementing them in a highly regulated industry, are among the chief hurdles associated with APM. This often involves substantial capital, dedicated training and lengthy validation processes before the systems can be fully integrated into existing operations, according to Salvador Alvarado-Olivo at Thermo Fisher Scientific.

Data integration is another significant challenge, particularly when it comes to bridging information between laboratory and manufacturing environments or across multiple sites and platforms, according to Alvarado-Olivo. “Ensuring seamless data flow demands careful planning and a strong focus on data security and management. In addition, the growing use of chemometric and machine learning models introduces complexities in terms of validation, lifecycle management and regulatory approval,” said Alvarado-Olivo.

Despite their promise, it can be challenging to implement, integrate and adopt new technologies, notes Camille Segarra at Lonza. “On the implementation side, high upfront capital investment must be carefully managed, as ROI is generally realized over a long period of time. At Lonza, we address this challenge using a tailored investment approach. As an example, we have implemented perfusion technologies across our global network based on the specific needs of small and emerging biopharma companies.” 

Integration with legacy systems and facilities is also a major challenge, especially with continuous manufacturing technologies, but also from a pure IT/OT integration standpoint, according to Segarra. “Data integrity and cybersecurity are among our foremost concerns, and we diligently strive to remain fully compliant with regulations and industry standards as we integrate new technologies,” says Segarra.

Meanwhile, some pharma and biopharma companies are hesitant to commit to APM technologies due to the perceived regulatory risk of adoption. This is particularly true of drug developers who seek to improve process efficiency after initial clinical trials, Segarra notes. “Fortunately, early engagement with the FDA’s Emerging Technology Program (ETP) and the EMA’s Innovation Task Force can mitigate uncertainty surrounding adoption of these technologies, and our team of regulatory experts can help the drug developers we partner with accordingly,” says Segarra.  

Regulatory Frameworks and Initiatives

While the FDA has several initiatives aimed at promoting various APM technologies, global regulatory pathways are lacking, hindering adoption. The FDA’s ETP has enabled regulatory guidance for broader 3DP pharmaceutical applications, however many innovative initiatives remain limited, especially for point-of-care manufacturing and agile manufacturing, according to Kyle Smith at Aprecia Pharmaceuticals. 

Recently, the federal government partnered with Battelle Memorial Institute and Aprecia to address a key hurdle: the inflexible and risk-prone supply chain. This collaboration, focused on health preparedness and response, will investigate how Aprecia’s technology, combined with Battelle’s innovative expertise, can accelerate drug production to deliver high-quality medications.

The program aims to create pilot agile pharmaceutical manufacturing sites producing both active pharmaceutical ingredients and finished pharmaceutical dosage forms at the same location—with the aim of shortening the pharmaceutical raw material supply chain while also lessening supply chain risk for commercial product distribution. 

“The collaborative program with the federal government provides the opportunity to facilitate the regulatory process and accelerate adoption of technology suitable for these types of manufacturing applications which can strengthen domestic supply chains and reduce U.S. drug shortage risk,” Smith says.

With respect to the FDA’s ETP and AMTDP, which offer early engagement and technical feedback for companies adopting innovative manufacturing technologies such as continuous manufacturing, digital twins, and PAT, Camille Segarra at Lonza notes that not all global regulatory agencies are at that stage yet. “This situation contributes to fear of regulatory pushback in markets with a less mature regulatory infrastructure. The industry would therefore benefit from greater regulatory convergence to lower compliance barriers across markets. Some barriers, such as those pertaining to leveraging data models and digital twins, still lack defined regulatory pathways,” Segarra says. The industry must therefore work closely with the relevant regulatory bodies to resolve these issues.

Salvador Alvarado-Olivo at Thermo Fisher Scientific agrees, “Global harmonization is still a challenge, as regulatory inconsistency across regions can hinder the widespread implementation of APM strategies. Industry standards for chemometric model transfer and reuse, especially concerning process analytical technologies, are still evolving. Additionally, workforce readiness is a concern, with continued adoption depending on a stronger pipeline of talent skilled in data-driven process engineering.”

Meanwhile, investment in APM is on the rise, according to Alvarado-Olivo. “Public-private partnerships and government incentives are helping to localize and modernize biologics manufacturing, while private capital continues to flow into tech-enabled, flexible CDMO capacity,” says Alvarado-Olivo. These trends are helping to accelerate the adoption of innovative technologies across the industry.