Susan Haigney

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Jacobs, a company that designs, builds, and qualifies life sciences manufacturing facilities, announced on March 6, 2024 that the company is opening a new innovation hub in Denmark. The new hub will scale capacity to support projects for Danish customers domestically and globally.

The hub will offer end-to-end expertise from the company’s global network of 60,000 people from a variety of fields. The company plans to add up to 100 new workers in Denmark over the next three years. Jacobs helps its clients in Denmark deliver sustainable solutions by working with international biopharma companies and supporting design and delivery of large-scale bulk drug substance manufacturing facilities.

“Denmark is home to global leaders in innovation, from health and life sciences to sustainability, advanced manufacturing, and tech,” said Jacobs’ director of Life Sciences Operations, Denmark, Lene Bjerregaard. “This, coupled with its strong economy and highly skilled workforce, make it a natural choice to establish our innovation hub. We will bring the breadth of Jacobs’ global capabilities to support existing clients in the region, and strengthen our presence across energy, water and environment, advanced manufacturing, infrastructure, and government services.”

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The facility producer’s new innovation hub will offer manufacturing, life sciences, and infrastructure services.

Jacobs Announces Innovation Hub in Denmark

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On March 6, 2024, the European Medicines Agency (EMA) announced that the Data Analysis and Real World Interrogation Network, DARWIN EU, has plans to expand capacity for real-world data (RWD) studies in 2024 by adding 10 new data partners. The network currently includes 20 public or private institutions from 13 European countries with access to data from approximately 130 million patients in Europe.

was initiated in 2022 between EMA and the European Medicines Regulatory Network as a coordination center to provide evidence on the use, safety, and effectiveness of medicines in a timely and reliable manner. Data regarding diseases, populations, and performance of medicines are collected from real-world healthcare databases across the European Union. Data obtained by DARWIN EU are converted into a common data model, and the data are kept local and analyzed locally by data partners.

These data are used by EMA and national competent authorities in the EU to make regulatory decisions. DARWIN EU supports EU regulators by establishing a catalogue of observational data sources, by providing validated real-word data, and by carrying out non-interventional studies. The project became fully operational in 2024, which includes involvement from both data partners and regulators as well as the ability to conduct studies and provide answers to EMA scientific committees and national competent authorities. The next goal is for DARWN EU to leverage the data obtained and increase geographical coverage and scope.

The project gathers data from partners in The Netherlands, Belgium, United Kingdom, France, Portugal, Spain, Norway, Finland, Estonia, Denmark, German, Hungary, and Croatia. The initiative projects adding approximately 20 additional partners by the end of 2025. Protocols and results of all DARWIN EU studies are publicly available in the 

In the two years since the project was started, 14 RWD studies have been completed and 11 are ongoing. Topics of studies include drug utilization, vaccine effectiveness, disease epidemiology, and patient characterization. Recent completed studies include (1):

A study examined treatment patters in adults and children with systemic lupus erythematosus (SLE). Results were provided to EMA’s Pediatric Committee for the potential use in clinical trials and to see the similarities between adults and children.

Another study looked at more than 30,000 patients diagnosed with multiple myeloma between 2012 and 2022 in Europe. The study was the first of two pilots to gather data on patient characteristics, treatment patters, and chances of survival for these patients.

A utilization study was conducted to understand the use pattern of endothelin receptor antagonists and phosphodiesterase-5 inhibitors in pulmonary arterial hypertension.

An investigation on the annual incidence and prevalence of the use of opioids in seven countries was conducted to determine duration of prescription opioid use, characterization of users, and prescribing and dispensing indications. A study on the use of Take-Home Naloxone to treat opioid overdose was also conducted.

A cohort study to estimate background rates of serious adverse events and causes of death in severe asthma was conducted.

Study results for these and other studies will be shared with relevant EMA committees and stakeholders. Results will be scaled up with onboarding of data from new partners added in 2024 and 2025. The project aims to conduct 70 RWD studies in 2024 and other 140 studies per year from 2025 onward.

Big Data Steering Group (BDSG): 2023 Report.

EMA plans to add 10 partners to its real-world data initiative, DARWIN EU, in 2024.

Europe's DARWIN EU Data Program Adds Capacity

On March 7, 2024, FDA published two final guidance documents regarding analytical procedures in order to facilitate regulatory evaluations and flexibility in postapproval change management of analytical procedures. The documents were developed in collaboration with the International Council for Harmonisation (ICH). Q2(R2)

outlines principles of analytical procedure validation, including the analytical use of spectroscopic data. 

harmonizes scientific approaches for analytical procedure development and provides principals for risk-based postapproval change management.

The Q2(R2) document is directed to common uses of analytical procedures and applies to analytical procedures used for release and stability testing of commercial drug substances and products. It includes information on validation studies, validation during the life cycle of an analytical procedure, reportable ranges, stability-indicating procedures, and multivariate analytical procedures. Specifically, it covers specificity/selectivity, ranges, accuracy and precision, and robustness. The document has two annexes: one provides a selection of validation tests; the other provides illustrative examples of analytical techniques.

“This guidance presents elements for consideration during the validation of analytical procedures included as part of registration applications. Analytical procedure validation forms a part of the analytical procedure life cycle, as described within [ICH] guidance for industry Q14 

 (March 2024) (ICH Q14). This ICH guidance for industry, Q2(R2) 

 (ICH Q2), provides guidance on selection and evaluation of the various validation tests for analytical procedures. This guidance includes a collection of terms and their definitions, which are meant to bridge the differences that often exist between various compendia and documents of the ICH member regulatory authorities. The objective of validation of an analytical procedure is to demonstrate that the analytical procedure is fit for the intended purpose. Further general guidance is provided on validation studies for analytical procedures,” the guidance states. “Approaches other than those set forth in this guidance may be applicable and acceptable with appropriate science-based justification. The applicant is responsible for designing the validation studies and protocol most suitable for their product,” it further stresses.

The Q14 document discusses minimal versus enhanced approaches to analytical procedure development. Specifically, it addresses analytical target profiles, risk management, parameter ranges, procedure control strategies, multivariate analytical procedures, and real-time release testing. It also provides guidance on submission of analytical procedure information. The documents Annex gives examples of application of ICH Q14 principals and an example of multivariate model life cycle components.

“Using the tools described in the ICH guidance for industry Q12 

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

 (May 2021) (ICH Q12), the guidance describes principles to support change management of analytical procedures based on risk management, comprehensive understanding of the analytical procedure, and adherence to predefined criteria for performance characteristics. Knowledge gained from application of an enhanced approach to analytical procedure development can provide better assurance of the performance of the procedure, can serve as a basis for the analytical procedure control strategy and can provide an opportunity for more efficient regulatory approaches to related postapproval changes,” the guidance states.

The two final guidance documents replace draft guidance documents published in August 2022.

FDA has published final guidance documents regarding validation and development of analytical procedures.

Final Analytical Procedures Guidance Published

CordenPharma announced on March 6, 2024 that it is expanding capacity at its Frankfurt, Germany site to accommodate the manufacture of early clinical-phase peptide APIs for its pharmaceutical and biotech customers. The company is planning for the expansion to be operational in the second quarter of 2024 with authorization by German authorities completed in the second half of 2024.

As part of the expansion, 1000 square meters of manufacturing space will be added to the Frankfurt site. The site will add two fully equipped lines comprised of a solid phase peptide synthesizer, high-pressure liquid chromatography, liquid phase isolation equipment, and quality control laboratories. The quality control labs will feature in-process control, starting material batch release, and good manufacturing practice (GMP) stabilities. The GMP manufacturing area will produce peptide APIs from gram to kilogram range for clinical Phase I and Phase II requirements with later transfer to the company’s late-phase and commercial manufacturing Boulder, Colo., site in the United States.

The GMP expansion will support the launch of the integrated services between the company’s CordenPharma Frankfurt site and CordenPharma Caponago, which offers services for injectable drug products. The integrated peptide-injectable services will be tailored to the individual customer and will deliver technical, manufacturing, and regulatory support for investigational new drug (IND)/investigational medicinal product dossier (IMPD) filings and first-in-human (FIH) clinical trials. Customers will benefit from working with one contract development manufacturing organization with a single contract, quality agreement, and project management. The offering also features API route selection, salt and solubility studies, API characterization, and reference standard qualification. Formulation development, analytical method development, and validation will also be provided. Assistance with technical writing for IND/IMPD submissions will also be available.

"With our new early clinical GMP peptide manufacturing investment in Frankfurt and the launch of seamlessly integrated peptide API to injectable drug product services, CordenPharma is uniquely positioned to deliver customized CMC [chemistry, manufacturing, and controls] support for biotech customers and facilitate their successful IND/IMPD submissions and start of FIH clinical trials. We believe the offer will bring added-value and increased efficiency to our customers, and ultimately enhance the well-being of their patients,” said Stéphane Varray, CordenPharma’s Global Peptide Platform director, in a press release.

previously expanded the Frankfurt site in 2020

 to include an increase in available lab space by 25% and the addition of a dedicated explosion proof area.

the company invested €9.7 million (US$10.9 million) i

nto the design and installment of a new clinical trial development facility for manufacturing oral solid dosage drug products at its Plankstadt facility near Heidelberg, Germany.

 the company also launched its new Lipid NanoParticle (LNP) Starter Kits 

for the formulation of messenger RNA (mRNA)-based therapeutics, such as mRNA vaccines or gene therapies. The starter kits are designed to provide researchers and developers with the essential components needed to create and optimize their own LNPs for mRNA delivery. The kits allow users to fine-tune the LNP formulation process and achieve production of nanoparticles with the desired physicochemical characteristics, such as polydispersity index ≤0.2 and a size range between 30–150 nm, depending on specific LNP reaction conditions, lipid composition, and cargo used.

The company is expanding GMP capacities at its Frankfurt site to manufacture early clinical-phase peptide APIs.

CordenPharma Expands Clinical Peptide Capacity

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The landscape of treatment for medical conditions and illnesses has become tailored and rich thanks to advances in personalized medicine, artificial intelligence (AI), and emerging modalities. Cell and gene therapies have been joined by messenger RNA (mRNA) vaccines in pushing innovation in the field of drug dosage forms. New manufacturing trends have also spurred the drive for new ways to deliver life-saving medicines.

“A confluence of innovative technologies is reshaping the healthcare market. Among these cutting-edge approaches, [AI], data analysis and management, blockchain technology, real-world data utilization, cybersecurity, and continuous manufacturing processes stand out as driving this paradigm shift,” says Jnanadeva Bhat, vice president at ACG Capsules (R&D). “These technological catalysts are not only bolstering medication delivery but also propelling forward the entire spectrum of development, packaging, and final product distribution to end consumers. Pharmaceutical industries are making up these newer technologies for innovation in healthcare.”

Tailoring dosage forms to individual patient needs is becoming a reality, confirms Ramesh Subramanian, chief commercial officer at Aragen Life Sciences. Treatment efficacy can be improved by customizing formulations based on genetic profiles and patient-specific requirements, which may minimize side effects, he emphasizes.

A shift in patient attitudes is also influencing innovation in dosage forms, according to Arnaud Verhaeghe, marketing director Pharma Oral Dosage at Roquette. “Compared with 10, or even five years ago, consumers are far more discerning about the types of drugs or individual ingredients they allow into their bodies,” says Verhaeghe. “This [change] is reflected in the demand for improved digestibility and convenience, personalized treatments in fields such as oncology, endocrinology, and infectious diseases, and especially in the recent ‘vegan revolution.’ The latter, in particular, has had implications for established drug formats like softgels. [Because] the traditional excipient of choice—animal-derived gelatin—is unsuitable for vegan or vegetarian applications, brands have turned to cutting-edge technologies, like first-of-its-kind hydroxypropyl pea starch…Such excipients are unlocking the potential to create high performance, planet-friendly plant-based drugs that are easy for consumers to swallow—both literally and metaphorically.”

Patient adherence is also making an impact on the development of dosage forms. “For decades, patient groups, including children, the elderly, and people who experience issues swallowing, have had no choice but to use medications that are inconvenient, difficult, or even dangerous to take. At best, this can lead to pill fatigue, and at worst complete non-adherence,” says Verhaeghe.

Permeability is also causing an impact on dosage form choice, according to Lisa Caralli, senior director, Scientific Advisory at Catalent. “Addressing permeability limitations for peptides and biomolecules has been an area of intense focus in recent years, with the modulation of tight junctions with excipients remaining a key approach,” she says. “First pass metabolic loss for small molecules will also drive the use of the injectable route, whereas pregastric delivery through the mouth with dosage forms such as orally disintegrating tablets remains an under-explored area to address this metabolic concern.”

Ishani Maharaj, application development specialist, pharma ingredients at Univar Solutions, also points to issues with API solubility and permeability as pushing the demand for improved formulation strategies. The use of solubility and permeation enhancing excipients allows for APIs with improved bioavailability and increased efficacy, she explains.

“To formulate these APIs as solid dosage forms, there have been promising strategies such as amorphous solid dispersions (ASDs), co-processed APIs, and lipid-based formulations (LBF),” continues Maharaj. “With the use of a lipid base delivery system consisting of a solvent, surfactant, and co-surfactant, a self-emulsifying delivery system can be formed in the digestive tract. This
[delivery system] allows improved dissolution of the drug within micelles and for better systemic absorption of the water-insoluble API. Choosing the right components of a lipid-based delivery system for a particular API can be complex. To address this, excipient manufacturers are now delivering ready-made lipid-based pre-concentrates to simplify this process for formulators.”

New technologies are also making an impact on dosage form development. Manali Dalvi, lead–White Papers & Publications at ACG, points to the integration of three-dimensional (3D) printing as one of the innovations creating new capsules that can be tailored to individual patients. “This breakthrough empowers manufacturers to effectively address the unique therapeutic needs of each patient,” says Dalvi. “Moreover, capsules also offer fresh perspectives on fixed dose combinations, introducing flexibility in the composition of capsule inner content. This versatility opens the door to a wide range of potential constituents—ranging from powders and pellets to semisolids and various liquid forms (solutions, suspensions, emulsions)—to be encapsulated within,” she notes. “As the field continues to advance, it has become imperative for pharmaceutical manufacturers to stand at the forefront of this transformative shift, driving innovation and personalized care forward.”

Developments in advanced and complex therapies have seen a surge in recent years. Bhat points to advances in genetics, molecular biology, and biotechnology as the drivers of these new treatments.

“Many researchers are eager to capitalize on these scientific breakthroughs,” asserts Bhat. “Complex therapies such as gene and cell therapies have the potential to offer advance treatment for the diseases that have been challenging to address with conventional medication. For example: cancer, heart disease, and cystic fibrosis. Many pharmaceutical companies have successfully developed and commercialized complex therapies, gaining the competitive edge in the sector, positioning themselves as leaders in medical innovation.”

Complex and advanced therapies often come with manufacturing and patient adherence challenges. How can industry meet these challenges?

The challenge of bioavailability is often seen in newly developed APIs, which exhibit poor solubility and where adequate dosing in a convenient dosage form is difficult, according to Verhaeghe. “This presents significant challenges, both in terms of manufacturing and end-user compliance,” he says. “But drug developers are fighting back with some truly ingenious approaches. One of the most exciting examples has been the expanded interest in specialized and co-processed excipients as processing aids and final-formulation ingredients. Cyclodextrins, for instance, have delivered great results in this area—their molecular encapsulation properties and affinity with complex molecules helps simplify formulations, increase solubility, and assure stability.”

Nick DiFranco, MEM, Global Market Manager, Novel Pharmaceutical Technologies at Lubrizol, agrees. “Complex therapeutics often involve challenges such as poor solubility or a high dose of drug. These challenges require efficient excipient technologies to solubilize compounds, control drug delivery without resulting in a tablet that’s too big to swallow, or avoid injections with extensive infusion times,” he says. “For example, if an oral tablet formulation is not optimized, patients may need to take tablets three or four times a day to achieve a desired therapeutic effect. Using excipients that enable high drug loading and/or control over release can increase the amount of drug per tablet while minimizing side effects, which reduces pill burden and offers huge benefits to patients. These excipient technologies don’t necessitate complex manufacturing techniques either.”

A multi-faceted approach can be used to address these challenges, according to Subramanian. “These innovations not only improve patient outcomes but also facilitate the development and commercialization of these advanced therapies,” he says. “Complex therapeutics often require specialized delivery systems, such as liposomes, nanoparticles, or microspheres that can improve drug stability, bioavailability, target specific tissues, and control release rates, enhancing the therapeutic effect.”

By way of example, Subramanian highlights nano-based formulations, 3D printing, and novel excipients as useful tools. “Nano-based formulations can enhance the therapeutic efficacy of complex drugs and reduce side effects,” he remarks. “3D printing is another technology that can help meet the dosage form requirements of complex therapies and bring formulation manufacturing closer to patients. [The technology] allows for precise control over the structure and composition of dosage forms and enables the creation of customized and patient-specific dosage forms, which is particularly valuable for complex therapies. The development of novel excipients can enhance the stability of complex therapeutics and improve their manufacturability. These excipients may be used to protect sensitive compounds or modify drug release profiles.”

Additionally, Subramanian points to quality by design as a tool in the development of complex dosage forms that uses a systematic approach to formulation to meet quality and performance requirements.

Filipe Gaspar, VP of Technology Intensification at Hovione, points to the company’s search for new technologies to deliver new modalities instead of technologies that come with limitations in formulation options, such as freeze drying. “Precise control over particle size and density, coupled with formulation design, is an enabler for high dose and low volume injections maximizing patient compliance,” he says. “At a much more mature phase is the use of respiratory delivery (inhalation and nasal) for biopharmaceuticals using spray drying technology which offers ample formulation options. Developing a highly efficient delivery device and product combination which ensures that an unskilled patient receives the intended effect is as important to address.”

The growth of the biologics market and patient-centric dosage forms have promoted the development of parenteral formulations and long-acting injectable products, according to Maharaj. “Injectable dosage forms are adequate when assessing the balance between benefit and inconvenience. The pursuit of convenient and reliable devices that can simplify injection procedures and give autonomy to patients can be a promising strategy to deliver such complex medicines in a patient-friendly way. Wearable devices such as a microneedle autoinjector could be a good candidate for delivering these larger molecules such as proteins, peptides, and monoclonal antibodies,” she says.

Delivering high-value biologics orally, however, will be a priority for the industry, continues Maharaj, because it is non-invasive. Delivery methods for biologics that are not readily absorbed after oral administration, however, will also be explored, she remarks.

“For example, monoclonal antibodies (mAbs) have a variety of potential therapeutic applications in autoimmune diseases and cancers. The dosage form remains a major obstacle for mAbs as frequent intravenous administration can reduce patient adherence,” says Maharaj. “Subcutaneous administration promises improved patient convenience and compliance due to the possibility of self-administration by patients, less visits to the hospital, and low healthcare costs.”

A push from regulators to develop advanced therapies also gives incentive for sponsor companies to invest in technologies and processes for complex therapies. FDA’s Pilot Program for the Review of Innovation and Modernization of Excipients (PRIME) allows for agency review of novel excipients, which “will foster development of excipients that may be useful in scenarios in which excipient manufacturers and drug developers have cited difficulty in using existing excipients” (1).

“Novel excipients can be the key to producing products with improved bioavailability and reduced side effects,” says Caralli. “For example, surfactant excipients are often used to solubilize molecules with low aqueous solubility, or to form emulsions. However, some of these excipients are known to cause a hypersensitivity reaction in some patients, therefore, by using alternative forms that do not induce this reaction could provide a better and safer patient experience. Another area is innovation in polymers used for amorphous systems: highly crystalline drug substances can be transformed into their amorphous state, and stabilized with polymers to improve in-vivo solubility, and therefore, bioavailability. Novel polymer systems that can be used at lower processing temperatures in hot melt extrusion may reduce drug degradation and improve processability.”

Technologies being adopted in laboratory hardware and data analytics are accelerating the development of dosage forms, according to Gaspar. “[Laboratory hardware] enables fast optimization, and [data analytics] transform the continuous accumulation of data (experience) into knowledge that can be multiplied for every new drug under development,” he says.

Gaspar points to continuous manufacturing of oral dosage forms as an example of a way to utilize data analytics because of the rich data environment and sophisticated process equipment and process analytical technology. “Scientists and engineers can interact with such a broad data environment and build sophisticated models that are normally used in control strategy definition, while also monitoring the manufacturing process not just with a few selected process parameters, but potentially with the full process data that can be analyzed by multi-variate methods to inform potential faults in real-time,” he notes. “During drug product development, it facilitates execution of extremely fast [design of experiments] and exploration of a design space.”

Caralli believes AI will play a pivotal role in drug dosage design. “[AI’s] ability to quickly synthesize current research will dramatically increase the speed of bringing new ideas into reality. [AI] could assess current dose design trends, based on patient populations and indication, allowing the optimization of drug administration, and ultimately increasing the rate at which drugs advance into the clinic,” she says.

However, Caralli cautions that AI-generated information may not be completely reliable. “Firstly, it may be detrimental to true innovation as it becomes easier to build on the ideas of others rather than generate new ones; and additionally, there is a need to override the natural impulse to publish studies showing what has been successful, versus what has not to avoid generating a biased data set. The industry may find itself becoming too trusting in the seemingly confident answers generated by AI, that it may not apply human skepticism, which is an important part of the scientific method,” she summarizes. “However, as the ability to identify trends through AI improves, the safety benefits to patients may ultimately outweigh the risks to innovation.”

1. FDA. Pilot Program for the Review of Innovation and Modernization of Excipients (PRIME). 

®
Vol. 48, No. 3
March 2023
Pages: 12-14

When referring to this article, please cite it as Haigney, S. Reshaping Dosage Forms. 

Advancements in personalized medicine and other innovations are transforming the way dosage forms are viewed.

Reshaping Dosage Forms

Simtra BioPharma Solutions announced on Feb. 28, 2024 that it is investing more than $250 million to expand its sterile fill/finish manufacturing campus in Bloomington, Ind. This expansion follow’s 

Advent International’s and Warburg Pincus’ acquisition of Baxter’s BioPharma Solutions

 business in October 2023, which is now operating under Simtra BioPharma Solutions.

The expansion will include a new state-of-the-art 150,000-square-foot building that will feature two high-speed automated isolator syringe fill lines and a new high-speed isolator vial line equipped with three 30-square-meter lyophilizers. Process suites in the new building will have dedicated formulation/compounding rooms, and a dedicated clinical line will support the company’s development and clinical business.

Simtra expects construction of the new building to begin in June 2024 and be completed in late 2026. The clinical line is expected to be ready for projects by summer of 2025 and will allow the company to accommodate projects that are in Phase I or II development, keeping the projects onsite as they scale up for commercialization.

"We are experiencing a broad increase in demand and need for injectable manufacturing in therapeutic classes such as GLP-1 drugs and product categories such [as] antibody-drug-conjugates as well as overall continued growth of the oncology pipeline," said Franco Negron, CEO of Simtra BioPharma Solutions, in a press release. "Our customers consider our sites in Halle and Bloomington as an extension of their manufacturing network, so we are thrilled to further enhance our capabilities and resources to help them meet their respective goals. This expansion is the latest in a series of strategic, long-term investments to ensure that Simtra continues to grow with and for our customers."

"We are excited to back the exceptional team we have at Simtra to make the first, of what we hope is several, major growth investments as we build the leading, independent sterile injectable CDMO," said Carmine Petrone, a managing director at Advent International, and Ruoxi Chen, a managing director at Warburg Pincus, in the release. "The planned expansion is designed to meet the needs of our customers, and their patients. We're excited for the trajectory of the business, given the dynamic industry backdrop, and aim to enable Simtra's customers to deliver more doses of life sustaining therapies to patients."

Simtra BioPharma Solutions is an injectable contract development and manufacturing organization that provides current good manufacturing practice (GMP) sterile fill/finish and development services. In 2021, the company, operating as Baxter BioPharma Solutions, 

also invested more than $100 million to expand its Halle/Westfalen, Germany site

 to include a high-speed syringe line and a vial line equipped with four lyophilizers. The company expects that the expansion will be GMP ready by the end of 2024.

The company is investing more than $250 million into its Bloomington, Ind. Manufacturing site.