Category: Long-Acting Injectables

A truly integrated CDMO with the right structural foundation and top-down commitment can provide tremendous benefits to biopharmaceutical customers.

Rising Demand for Contract Services

The value of the global pharmaceutical contract manufacturing market is expected to reach $95.9 billion by 2025, with the API segment accounting for the largest share but the final drug formulation segment growing at the fastest rate.¹ Growth overall is being driven by rising demand for medications around the world, due to the aging population, increases in chronic diseases and growing wealth in emerging economies. Pharmaceutical companies are increasing their dependence on outsourcing partners to achieve increased efficiencies and gain access to advanced technologies.

Renewed Interest in the One-Stop Shop

Over the past decade, innovation in the pharmaceutical industry has shifted to emerging pharma and biotech companies that lack the infrastructure, capabilities and resources necessary to support the entire drug development and commercialization cycle. For these smaller companies that must rely heavily on outsourcing partners, it is much more efficient to develop strategic relationships with integrated CDMOs.

Larger pharmaceutical companies are also realizing that, by working with a company like Piramal Pharma Solutions, it is possible to take a candidate from post-discovery to commercialization with one point of contact and without the need to manage multiple suppliers or the cost and time delays associated with tech transfer between different service providers. Product knowledge and expertise are retained throughout the project lifetime, facilitating collaboration and process scale-up.

Time is of the Essence

There has never been more pressure for pharmaceutical companies to develop new drugs more quickly and at lower cost. Integrated CDMOs that operate as true one-stop shops help sponsors reduce time to the clinic and the market while also controlling costs and often providing access to unique, advanced capabilities. With one contract, one global master service agreement and one quality agreement, integrated providers help simplify the drug development process.

Integration is Essential

Integrated offerings are only effective, however, if all of the services are harmonized and presented to the customer as a single system. An integrated offering must not simply be different businesses linked together, but a single business at the operational level. Commitment must come from the top down, with establishment of a company philosophy and systems that create a single customer-facing solution that facilitates easy customer interaction.

Piramal does not consider integrated projects as projects, but as programs. We have installed software to manage our integrated programs and hired experts to serve as program managers. All interactions with clients from verbal to written communications follow the same protocols. The technology transfer process is headed by the program manager, who ensures that all necessary documents are exchanged, goals and timelines are agreed upon and met and routine communications, both internal and external, are managed effectively.

Understand Your Value Proposition

Choosing a service provider ultimately comes down to risk tolerance, which is different for every pharma company. It is therefore essential for integrated CDMOs to have a clear understanding of their value propositions and clearly communicate those benefits to potential clients. Commitment to the company’s mission must also be embedded in the hearts and minds of all employees.

Piramal has grown through acquisition, building capabilities in drug substance and drug product development and manufacturing. Our leaders have experience in integrated offerings and leverage our global network to provide maximum efficiency and productivity. We have facilities for the production of drug substances in lower-cost countries and sites in the West with specialized capabilities for drug product manufacturing, including solutions for highly potent products and antibody–drug conjugates. We are one of the few CDMOs able to offer integrated services for oncology candidates, as well as for candidates targeting other indications.

At present, Piramal is evaluating how to further expand upon our existing capabilities, including the addition of oral solid dose development and manufacturing services. We have the necessary organizational structure in place and are excited to build on our early success as a truly integrated CDMO.

References

1. $95.94 Bn Pharmaceutical Contract Manufacturing Market, 2025. Research and Markets. 21 2019. Web.

Originally published on PharmasAlmanac.com on October 28, 2019.

The pandemic has significantly affected the pharmaceutical industry, including the contract manufacturing segment. CMOs with flexibility, agility, and speed combined with the ability to form strategic partnerships have been best positioned to support customers going forward. Avara’s Liscate sterile injectables facility has these attributes and continues to pursue investments in equipment and technology — including digitalization solutions for documentation, remote auditing, training, and more — and is exploring the introduction of development capabilities to enhance its ability to support customers from late-stage clinical trials through commercialization.

Pandemic Impacts

As with most sectors within the pharmaceutical industry, contract manufacturing has been strongly impacted by the COVID-19 pandemic. These impacts have been significant, even unprecedented, and many of the changes that have evolved will remain even after we move on from the pandemic.

One of the biggest changes to this segment of the industry was the transition from steadier market demand to a situation characterized by spikes and troughs as the world responded to waves of infections caused by new variants of the SARS-CoV-2 virus. This dynamic and unpredictable situation was challenging for everyone, including contract manufacturers, to manage. Procurement difficulties and significantly extended lead times heightened these challenges.

Customers have responded by seeking to reduce the number of contract manufacturing partners with whom they work, as well as to form deeper and more strategic relationships that are better positioned to respond to such challenges. Meanwhile, lockdowns and limited travel within and across borders created the need for digital solutions to facilitate internal and external communications — from personnel training and remote work to sales and marketing efforts to auditing and inspections. The advent of mRNA vaccines, meanwhile, reflects a general trend in sterile injectables toward more personalized products.

Those companies that were sufficiently flexible and agile to survive the COVID-19 pandemic did so in part because they rapidly adopted new ways of communicating with their stakeholders — employees, suppliers, customers, and regulators.

Importance of Speed, Flexibility, and Agility

The sudden changes in demand that occurred during the COVID-19 pandemic required contract manufacturers to offer a higher level of flexibility and speed, and this has now become a customer expectation. In the sterile injectable sector, flexibility and the ability to respond quickly to the unexpected have become even more important. The supply of critical drugs to patients on time and without interruption is of the highest priority. CMOs with these attributes built in are most able to rise to this challenge, even during crises, as Avara Liscate continues to do.

Strategic Partnerships Increasingly Important

The supply chain issues highlighted by the pandemic have led many branded biopharmaceutical manufacturers to seek ways to reduce the complexity of their supply chains. They are doing so by reducing the number of suppliers they use and concentrating their attention on building solid, stronger relationships with a limited number of strategic partners.

The sterile injectable CMOs with which Big Pharma companies are forming those strategic partnerships are top-performing, customer-oriented organizations that are focused on manufacturing and share three important attributes: they make the right investments, have the right organizational structure (e.g., flexibility, agility, and personalized customer service), and possess the specialized skills and equipment needed to reliably supply high-quality products with assured sterility.

In addition to branded biopharma companies, many small startups — often spinoffs from universities — are seeking partners that can help them advance their candidates from preclinical development to market. These emerging biotechs are a main driver of growth in the sterile injectables market, so successful CMOs must have the capability to form long-term partnerships with these firms.

Trend Toward More Dedicated Sterile Products

An overarching trend in the pharmaceutical industry today is the shift away from blockbusters and toward more niche, targeted, and personalized or precision medicines. That is certainly true in the sterile injectables sector. Autologous cell therapies, gene therapies, and immuno-oncology treatments are all prime examples of patient-specific medicines. The successful development of mRNA vaccines against COVID-19 has also opened the door for future development of novel therapeutics in this space. Most pharmaceutical companies have programs exploring new mRNA treatments against other infectious diseases, as well as many types of cancer and numerous other disorders. CMOs must develop the capabilities — facilities, equipment, processes, and expertise — to support the manufacture and packaging of small-volume precision medicines, as well as new therapies that require specialized production and fill/finish technologies, such as viral vectors for gene therapies and mRNA treatments prepared using lipid nanoparticles or other novel delivery vehicles.

Making the Right Investments is Essential

That ties into the next important trend, which is a growing emphasis on making the right investments in equipment, infrastructure, and personnel. Sterile injectable manufacturing is complex and challenging because the products are injected or infused into the blood of patients. It therefore requires not only the right type of equipment but also the right-sized equipment to ensure the production of sterile drug products of the highest quality. It is absolutely imperative that capital investments be made appropriately and directed toward the right product areas and the appropriate, state-of-the-art equipment that will ensure sterile injectable manufacturing.

Acceleration of Digitalization

Those companies that were sufficiently flexible and agile to survive the COVID-19 pandemic did so in part because they rapidly adopted new ways of communicating with their stakeholders — employees, suppliers, customers, and regulators, among others. Digital technologies made that possible. While digitalization of the pharmaceutical industry did not start during the pandemic, that unexpected and complicated period certainly accelerated the rate at which digital transformation is occurring — a rate that has not and likely will not decline going forward.

Given that speed is of the essence in drug development, efficiency and productivity are two crucial objectives for pharmaceutical manufacturers. Digitalization is an enabler of both. It facilitates the management and analysis of large quantities of data, contributes to increased quality, and helps to reduce the risk of error.

Digital tools leveraged during the pandemic included software for data sharing to enable remote working, video conferencing, and online meeting software; solutions for the remote monitoring of production operations with real-time data access from mobile phones, laptops, and other devices; and video streaming for remote audits, to name just a few.

Going forward, these technologies, and many more — such as artificial intelligence, robotics and other automation solutions, cloud computing, and so on — will be used to further boost efficiency and productivity and allow for a good balance of on-site and remote work to support the needs of manufacturers and their employees.

De­spite the extraordinary situation that the COVID-19 pandemic present­ed, Avara was able to build on our strong rela­tionships with customers and stay on track with the delivery of needed medicines.

Rapid Pandemic Response at Avara

The COVID-19 pandemic placed everyone in the pharmaceutical industry in a dramatically unfamiliar environment unlike anything previously experienced. Everything was new and in flux, with sudden changes that had to be managed. Contract manufacturers that could adapt to those sudden changes and then continue to meet customer needs not only kept those customers happy but often built stronger relationships with them.

Avara took many measures to ensure the ongoing supply of sterile injectable products for our customers. These products included several drugs used to treat intensive-care patients, such as anesthesia medications. We focused resources on increasing the manufacturing of existing products while also accelerating the transfer of critical new products for the treatment of patients with COVID-19 and other diseases.

New product transfer activities were made possible by implementing the latest communication technologies that enabled close interaction with our customers despite lockdowns and travel bans. For instance, real-time video streaming during audits and during pilot and engineering batch runs ensured business continuity and adherence to very tight timelines.

To overcome equipment shortages, Avara identified opportunities to use — after requalification — existing equipment and components to support product transfers. We were also very open and transparent with our customers about other supply chain issues. In particular, there have been shortages of vials and stoppers, with lead times of 9–12 months. For these materials, we worked closely with our customers to develop specific assessments in support of the use of equivalent commodities.

The preparation of GMP documentation was accelerated by creating parallel work streams and simplifying document storage and access, all while maintaining full compliance with quality and other regulatory requirements. Our project management system was also modified, with the key change being a move to quick, daily meetings with customers to address the various constraints and problems that continually arose and had the potential to impact timelines.

At Avara, we always keep in mind that the final customer is the patient and that our products help alleviate suffering. That was true during the pandemic as well, and, despite the extraordinary situation it presented, we were able to build on our strong relationships with customers and stay on track with the delivery of needed medicines.

A good example of a collaborative effort with a Big Pharma customer involved an Italian hospital. The hospital identified Avara as the manufacturer of an important product used for intensive-care patients for which they were out of stock and needed to receive more immediately. We dedicated a team to this issue, who worked closely with the pharmaceutical company for which the product is made. It was very gratifying to see the aircraft leave our site and head to the hospital with that much-needed medicine. Ultimately, our customer and Avara elected to donate a portion of the volume of this product that we had in stock to the pandemic effort. This was an experience that not only underscored the types of partnerships Avara has with its customers but touched all of us working at the Liscate facility.

As a medium-sized CMO, Avara is appreciated for the focus and dedication that we offer our partners. We are a very customer-centric CMO, with each customer valued highly and appreciated individually. At Avara Liscate, operating in this mode gives confidence to customers with respect to the customer service they receive and the quality of the sterile injectable products we manufacture.

Investing in Stronger Relationships

To meet the increasing needs of customers who require support earlier in their projects — at clinical rather than commercial phase — is a key strategic objective for Avara Liscate. Supporting customers with their clinical trial, product and process development, and dossier creation efforts will allow for the establishment of stronger customer relationships and the building of trust, both of which are crucial as a project advances to the commercial phase. The goal is to help develop the right processes and the right products that will find success in the pharmaceutical market.

To that end, Avara Liscate is investing in the construction of a new department within the facility that will be fully dedicated to product process and development, as well as clinical trial material production.

A Customer-Oriented CMO Partner

As a medium-sized CMO, Avara is appreciated for the focus and dedication that we offer our partners. We are a very customer-centric CMO, with each customer valued highly and appreciated individually. At Avara Liscate, operating in this mode gives confidence to customers with respect to the customer service they receive and the quality of the sterile injectable products we manufacture.

By taking this approach, we continually work to make our company stronger within the CMO world and to ensure the growth of the company. With the right investments, organization, and quality, we can ensure ongoing regulatory compliance, on-time delivery, and excellent customer service.

Creating partnerships with customers involves much more than establishing basic relationships with them. Partners work closely together to resolve any issues that arise and leverage innovative technologies to improve all aspects of performance — flexibility, efficiency, productivity, quality, and pricing.

Ultimately, the most important element that emerges from successful strategic partnerships is trust. Trust is fundamental to the deeper relationships needed for both suppliers and customers today. By engendering trust with our customer partners, Avara Liscate helps them accelerate the commercialization of their sterile injectable products, which translates to greater access to medicines for patients. At the same time, it supports Avara’s goal of becoming a CMO recognized for meeting the current and future expectations of all of our stakeholders.

Originally published on PharmasAlmanac.com on June 16, 2022.

With mutual respect and a shared commitment to high quality standards and sustainable value creation, Vetter and Rentschler Biopharma began exploring ways to build upon our respective service portfolios and draw from synergies between our companies to provide valuable market foresight. In mid-2020, Vetter and Rentschler Biopharma announced a strategic collaboration aimed at achieving long-term value for clients through the alignment of manufacturing approaches, combining Vetter’s drug product manufacturing expertise with Rentschler Biopharma’s drug substance manufacturing expertise, to optimize time-to-market and simplify processes. The relationship allows Vetter and Rentschler Biopharma to leverage complementary skills and experience along the biopharmaceutical value chain, with the aim to better serve our clients and, by extension, their patients, more efficiently.

A Dynamic Global Market

The global pharmaceutical market and larger global healthcare ecosystem continue to experience rapid and expansive growth, albeit with increasing costs and complexities. Contract development and manufacturing organizations (CDMOs) must continually find new ways to better support their clients as they work to develop new therapies to treat patients with serious and rare diseases. In order to maintain safety and efficacy standards while simultaneously reducing costs and time to market, CDMOs must innovate while demonstrating flexibility and adaptability to maintain competitive advantages and provide first-class client service. Biopharmaceutical companies must streamline their products’ path to market and optimize efficiency and simplicity. To do so, CDMOs must think outside the box to set new standards and benchmarks as they continue to refine best practices. The collaborative alliance between Vetter and Rentschler Biopharma aims to mutually enhance our respective services to provide our clients and their patients with the best possible outcomes.

Defining and Refining — Progress in the Framework

Vetter and Rentschler Biopharma have marked an important milestone since the initial collaboration announcement, taking key steps forward to further strengthen and define our collaboration through validation of previously identified opportunities to simplify structures and processes, as well as sharing visibility into manufacturing requirements early on. This has led to an active exchange of best practices that may benefit both companies and our respective clients.

The alliance has progressed with the establishment of a governance structure in addition to the implementation of guidelines for a joint approach across functions. The framework for contributions from both organizations was established in a collaboration agreement, including operational agreements and guidelines between various departments spanning quality, development services, and logistics. These guidelines delineate key standards for joint approaches and core inputs, aligning interfaces and optimizing services for client convenience and long-term planning.

The formation of the mutual agreements and alignment on a client approach were foundational steps that both Vetter and Rentschler Biopharma identified early in our exploration of this strategic alliance. We look forward to the new progress that this step will facilitate.

Having more narrowly defined some of the finer details of the alliance, Vetter and Rentschler Biopharma anticipate the possibility of reduced project timelines, adding value to our respective clients and their patients around the world. Some of the joint measures include the orchestration of logistics processes to minimize efforts for active pharmaceutical ingredient (API) shipments, thereby reducing transportation risks. Additionally, joint organization and client-audit management should help coordinate a seamless exchange of information and client requests and the creation of an aligned client questionnaire for early information sharing. The collaboration is further enhanced through the coordination of processes and materials from Rentschler Biopharma on the drug substance side and Vetter on the drug product side. We have also been working to fast-track various options and boost technology concepts. 

Our efforts include collaboration across our business development teams, where we have clearly defined target markets with a focus on Europe, the United States, Asia-Pacific, and emerging markets. The teams are working closely to identify clients who would likely benefit from our collaboration, with each organization introducing the other to our respective clients to demonstrate the collaborative benefits. We have successfully initiated our first joint-client projects, with additional projects in various phases of discussion; however, each company will remain fully independent without an obligation for clients to work with both organizations.

“We are very interested to see how the experience gained in these initial projects will further enhance our strategic alliance,” commented Dr. Frank Mathias, CEO of Rentschler Biopharma. “These client engagements will provide valuable insights for our teams to leverage in refining the alignment of our processes and approaches.”

Both organizations remain steadfast in their commitment to simplify and accelerate product path-to-market for propitious new therapies for patients, and we will continue to pursue strategies and initiatives aimed at supporting the continued refinement of this collaboration.

About Vetter

Headquartered in Ravensburg, Germany, Vetter is a global leading CDMO with production facilities in Germany and the United States. Currently employing 5,500 individuals worldwide, the company has long-term experience in supporting biotechnology and pharmaceutical customers both large and small. Vetter services range from early-stage development support, including clinical manufacturing, to commercial supply and numerous packaging solutions for vials, syringes, and cartridges. As a leading solution provider, Vetter appreciates its responsibility to support the needs of its customers by developing devices that contribute to increased patient safety, convenience, and enhanced compliance. Great importance is also given to social responsibility, including environmental protection and sustainability.

About Rentschler Biopharma SE

Rentschler Biopharma is a leading CDMO focused exclusively on client projects. The company offers process development and manufacturing of biopharmaceuticals as well as related consulting activities, including project management and regulatory support. Rentschler Biopharma’s high quality is proven by its long-standing experience and excellence as a solution partner for its clients. A high-level quality management system, a well-established operational excellence philosophy, and advanced technologies ensure product quality and productivity at each development and manufacturing step. In order to offer best-in-class formulation development along the biopharmaceutical value chain, the company has entered into a strategic alliance with Leukocare AG. Rentschler Biopharma is a family-owned company with about 1,000 employees headquartered in Laupheim, Germany, with a second site in Milford, MA. In Stevenage, UK, Rentschler Biopharma has launched a company dedicated to cell and gene therapies, Rentschler ATMP Ltd.

Originally published on PharmasAlmanac.com on June 9, 2021.

Complex injectable products, including those based on liposomes, microspheres, micelles, and submicron crystals, are attractive formulation solutions for many challenging new active pharmaceutical ingredients (APIs) and for unique life cycle management strategies. Few CDMOs have the knowledge, expertise, and appropriately designed manufacturing facilities to support these highly advantageous drug delivery technologies. New Jersey–based ForDoz Pharma is changing that.

Growing Interest in Complex Products

Complex products under the Generic Drug User Fee Amendments (GDUFA II) are defined as products with complex active ingredients; complex mixtures of APIs; complex formulations, including liposomes, suspensions, emulsions and gels; complex routes of delivery, such as locally acting dermatological and inhalation drugs; complex dosage forms including long-acting injectables and implantables; and complex drug–device combinations.

Water-insoluble APIs, which make up a growing percentage of drugs in development, may be highly potent or cytotoxic, and many have solubility issues. Particle-based drug delivery systems, such as liposomes, microspheres, and micelles and submicron crystals in suspensions or emulsions, can address these issues and facilitate delivery to target sites.

The emerging technologies for complex and innovative drug delivery have wide applications in the design of sustained-release dosage forms, such as long-acting injectables, improving therapeutic index by reducing toxicity and enhancing efficacy of APIs and facilitating reformulation of existing pharmaceutical products with limited clinical utility. As a result, the demand for complex products is particularly high in drug delivery technologies for complex injectable products, due to the rapidly expanding market for biologic drugs, which are often unstable and are prone to degradation in vivo and thus require stabilization and delivery to specific target organs.

Many Types of Complex Injectable Products

Complex injectable products include liposomes, microspheres, micelles and submicron crystals in suspensions, and emulsions.

Liposomes are microscopic vesicles comprising an aqueous solution core surrounded by a hydrophobic membrane of carefully selected phospholipids. Both hydrophobic and hydrophilic small molecule and biologic (e.g., proteins, plasmids, nucleic acids) drug substances can be carried in liposomes and delivered to targeted sites of action by modifying the surfaces of the vesicles. They are also useful for sustained-release drug delivery, reducing toxicity, improving efficacy, enhancing drug solubility, and improving the activity of vaccine adjuvants.^1–6

Microspheres range in size from approximately one to several hundred micrometers and consist of the active drug substance dispersed in a matrix comprising biodegradable synthetic polymers, most commonly PGLA or PLA. They can be delivered via several routes of administration, including parenterally. Microspheres are ideal for delivering drugs at a sustained and controlled rate, which can significantly improve patient compliance.^7–10

A polymeric micelle, which typically exists on the nanoscale, is a supramolecular assembly of surfactant molecules dispersed in a liquid with the hydrophilic “head” regions in contact with surrounding solvent, sequestering the hydrophobic single-tail regions inside the micelle center. Unlike microspheres, they can adopt a number of different shapes, including rods, tubules and filaments, as well as vesicles and spheres. Various polyamides, polyesters, and lipids are employed for micelle generation. Micelles are typically attractive for the delivery of poorly soluble drug substances. Many water-insoluble drugs, including proteins and gene therapy drugs, can be encapsulated in the hydrophobic core during the formation of the micelle core. Many micelle pharmaceuticals demonstrate favorable stability and pharmacokinetics properties.^11–14

Emulsions are thermodynamically stable isotropic systems in which two immiscible liquids are mixed to form a single phase by means of an emulsifying agent, and are suitable for the delivery of both hydrophilic and hydrophobic drugs. The droplets in the emulsion have a large degree of dispersion and a large total surface area, which can promote the absorption of drugs and improve the bioavailability.^15,16

A suspension is a coarse dispersion of insoluble solid particles in a liquid medium with a particle size in the low micron range. Suspension dosage forms can incorporate significantly higher concentration of poorly water-soluble and lipid-soluble drugs.^17–19 Submicron crystals in suspension also provide a method for enhancing the bioavailability of poorly soluble drugs, but do so in a carrier-free manner. The drug substance is formulated in a colloidal delivery system with a particle size ranging from 100 to 1000 nm. Compared with traditional formulations, submicron crystals in suspension can significantly improve drug solubility and prolong adhesion and the retention time of the drug in biological tissues. When injected into the muscle, submicron crystals can be slowly released over a prolonged period, reducing dosing frequency.^20,21

ForDoz Pharma is a technology-based company focusing on the evelopment and commercialization of complex injectable products.

Benefits of Complex Injectable Products

Encapsulation provides greater control over the pharmacokinetic and pharmacodynamic properties of the API, leading to one or a combination of positive improvements, including reduced toxicity, increased solubility, enhanced bioavailability, and improved activity against intra- and extracellular pathogens. Additional benefits include targeted delivery, which is achieved through careful design of the liposome, microsphere,  micelle, or other system. Controlled release over extended periods of time, which allows for reducing dosing frequency, is also possible with these systems.

Specialized Expertise Required for Drug Development and Manufacturing

The therapeutic efficacy of complex injectable products is directly correlated with their stability during manufacturing, storage, and delivery, as well as their ability to deliver the active drug substance to the right target. If these special particles are not produced properly, they will disassociate and not function as intended, and the drug substance may leach out into the bloodstream, potentially causing toxic side effects.

It is therefore necessary to understand the chemistry and physics of the formation processes involved for each specific type of complex injectable form and the biochemical processes contributing to their biodistribution and to be able to translate that knowledge into formulations that are manufacturable and scalable.

Specialized equipment and manufacturing systems are required to ensure that complex injectable products are produced with the desired properties. Careful selection and pre-processing of raw materials can reduce the likelihood of physical and chemical degradation. For particulate forms that are difficult to maintain in suspension, lyophilization (freeze-drying) is often used to extend shelf stability.

Sterilization for some complex injectables, notably liposomes, can also be challenging, due to the sensitive nature of the components with respect to exposure to high temperatures and radiation. Typical sterile filtration methods may also not be applicable for complex injectables based on larger particles. For some products, the entire production process must be performed under aseptic conditions.

It is also essential to develop production processes that provide high encapsulation efficiencies for liposomes and micelles, uniform distribution of APIs for microspheres, and the appropriate crystalline form for submicron crystals.

Production of liposomes, microspheres, and submicron crystals involves very high-energy processes to ensure that the right particle sizes are obtained. High entrapment efficiency must also be achieved. Off-the-shelf equipment is generally not suitable; specially designed, purpose-built systems combined with deep knowledge of processing parameters are needed to ensure that processes are established that consistently and reproducibly generate particles of the correct size. For microspheres, it is also important to remove the organic solvent used to solubilize the starting polymers without impacting the particle integrity.

Characterization of these different particle types is also challenging and requires specialized analytical technologies. It is also necessary to conduct in vivo studies to understand how these particles behave in the body.

Specialized Particle Technology Platform at ForDoz Pharma

ForDoz Pharma is a technology-based company focusing on the development and commercialization of complex injectable products. Our proprietary particle-based drug delivery technology platforms enable us to develop and manufacture innovative and superior complex products with particle sizes ranging from 10 nm to several hundred µm that improve patient care. These technologies include, micelles (~10–30 nm), liposomes (~100 nm), nanoemulsions (~200 nm), submicron crystals in suspension (~100–1000 nm), micron suspensions (~1000–3000 nm) and microspheres (~100 µm).

New State-of-the-Art Facility

In 2016, ForDoz Pharma acquired LaviPharm’s campus in East Windsor, New Jersey. At this 27-acre property, we established our own R&D labs and cGMP analytical labs. From 2017 to 2019, we successfully constructed, validated and qualified a complex product manufacturing facility that complies with U.S. cGMP standards. Overall, we have invested significant funds in this new, state-of-the-art, purpose-built facility.

The plant includes two unique, specially designed suites dedicated to liposome processing, one of which can handle cytotoxic APIs. The third process suite is reserved for microspheres, designed to operate at up to the 1000-L scale (1000 kg output).

Our filling line for liquids can process up to 100 vials per minute for vial sizes ranging from 2 to 100 mL. The completely automated line is installed within an isolator to minimize the risk of contamination. No direct human contact occurs from vial loading, vial washing and depyrogenation, filling, stoppering, and crimping; any manual interventions take place using a glove box. In the future, we will be adding a second filling line for powders and pre-filled syringes.

At ForDoz Pharma, we also have the capability for lyophilization, with two large-scale (10 m²) lyophilizers. Vial loading, washing and depyrogenation, filling, loading, and unloading of the two units is fully automated and is performed inside the isolator.

Extensive Generics Pipeline of Complex Injectables

ForDoz Pharma has established a diversified product pipeline of investigational drug products to benefit patients and ensure continuous growth of our company. We are actively pursuing additional growth opportunities for our pipeline through a combination of internal development and external licensing.

Our proprietary technologies include NanolipoDoz™ Technology, a phospholipid-based nanotechnology designed to improve therapeutic index and enhance solubility, and NanopolyDoz Technology™, a polymer-based nanotechnology in which APIs are encapsulated in polymeric matrices to control drug delivery rates and enhance drug stability.

These technologies are being used to develop generic versions of the complex existing injectable drug products. In all but one case, the drug is produced only by the innovator. By offering a generic alternative in the future, we are reducing supply chain risk and providing a more cost-effective option for important medicines. Currently, we have four products in our pipeline for which we are ready to produce FDA submission batches for the clinical trial bioequivalence stage, including anticancer and antifungal agents and a treatment for schizophrenia and emesis. The first two approvals are expected in 2022–2023, with additional approvals expected in 2024–2025.

We also have seven additional products in different stages of development in our pipeline: three are microsphere injectable products, which are used for treatment of pain, Alzheimer’s disease, and infertility; one micellar anticoagulant product; and one submicron suspension anti-inflammatory product. Patents for the five products have been filed, and regulatory submission will be filed via the 505(b)(2) route. Further, we are currently developing processes for two ANDA products based on submicron crystal technology.

Now Offering CDMO Services

We have always provided contract services for partners with whom we have had long-standing relationships. With our facility in place and our pipeline of late- and early-stage candidates well established, we are in a position to begin offering CDMO services to the pharma community at large.

ForDoz Pharma is looking to evolve by offering our platform liposome, microsphere, micelle, and submicron suspension technologies to customers seeking differentiating drug delivery technologies for their NCEs. We hope to work with customers that have candidates at the IND phase or that are in early-phase clinical development and can benefit from improved drug delivery solutions.

As projects scale, we have room to expand our production capacity and are willing to invest to meet growing demand. We are also happy to sign a no-compete agreement for all our CDMO clients; ForDoz has no interest in developing similar products that would be direct competitors of our customers’ products. We are, however, committed to partnering with pharmaceutical companies in the fight against serious illness with improved formulations.

References

Gigliobianco, M. R., Casadidio, C., Censi, R. & Di Martino, P. “Nanocrystals of Poorly Soluble Drugs: Drug Bioavailability and Physicochemical Stability.” Pharmaceutics 10, (2018).

Yang, T. et al. “Enhanced solubility and stability of PEGylated liposomal paclitaxel: In vitro and in vivo evaluation.” International Journal of Pharmaceutics 338, 317–326 (2007).

Mohammed, A. R., Weston, N., Coombes, A. G. A., Fitzgerald, M. & Perrie, Y.“Liposome formulation of poorly water soluble drugs: optimisation of drug loading and ESEM analysis of stability.“ International Journal of Pharmaceutics 285, 23–34 (2004).

Khadke, S., Stone, P., Rozhin, A., Kroonen, J. & Perrie, Y. “Point of use production of liposomal solubilised products.“ International Journal of Pharmaceutics 537, 1–8 (2018).

Yadav, D., Sandeep, K., Pandey, D. & Dutta, R. K. “Liposomes for Drug Delivery.“ Journal of Biotechnology & Biomaterials 07, (2017).

Sercombe, L. et al. “Advances and Challenges of Liposome Assisted Drug Delivery.“ Front Pharmacol 6, (2015).

Allen, T. M., Hansen, C. B. & de Menezes, D. E. L. “Pharmacokinetics of long-circulating liposomes.“ Advanced Drug Delivery Reviews 16, 267–284 (1995).

Kim, K. K. & Pack, D. W. “Microspheres for Drug Delivery.“ BioMEMS and Biomedical Nanotechnology 19–50 (Springer, Boston, MA, 2006). doi:10.1007/978-0-387-25842-3_2.

“Sustained-release microspheres of amifostine for improved radio-protection, patient compliance, and reduced side effects:“ Drug Delivery: Vol 23, No 9. https://www.tandfonline.com/doi/full/10.1080/10717544.2016.1223222.

K.H, R. “Microspheres: as carrieres used for novel drug delivery system.“ IOSR Journal of Pharmacy (IOSRPHR) 2, 44–48 (2012).

Varde, N. K. & Pack, D. W. “Microspheres for controlled release drug delivery.“ Expert Opinion on Biological Therapy 4, 35–51 (2004).

Ahmad, Z., Shah, A., Siddiq, M. & Kraatz, H.-B. “Polymeric micelles as drug delivery vehicles.“ RSC Adv. 4, 17028–17038 (2014).

Kedar, U., Phutane, P., Shidhaye, S. & Kadam, V. “Advances in polymeric micelles for drug delivery and tumor targeting.“ Nanomedicine: Nanotechnology, Biology and Medicine 6, 714–729 (2010).

Ke, X. et al. “Role of non-covalent and covalent interactions in cargo loading capacity and stability of polymeric micelles.“ Journal of Controlled Release 193, 9–26 (2014).

Xu, W., Ling, P. & Zhang, T. “Polymeric Micelles, a Promising Drug Delivery System to Enhance Bioavailability of Poorly Water-Soluble Drugs.“ J Drug Deliv 2013, (2013).

Jaiswal, M., Dudhe, R. & Sharma, P. K. “Nanoemulsion: an advanced mode of drug delivery system.“ 3 Biotech 5, 123–127 (2015).

Wadhwa, J., Nair, A. & Kumria, R. “Emulsion forming drug delivery system for lipophilic drugs.“ Acta Pol Pharm 69, 179–191 (2012).

Chen, A. et al. “Dosage Form Developments of Nanosuspension Drug Delivery System for Oral Administration Route.“ Curr. Pharm. Des. 21, 4355–4365 (2015).

Patel, V. R. & Agrawal, Y. K. “Nanosuspension: An approach to enhance solubility of drugs.” J Adv Pharm Technol Res 2, 81–87 (2011).

Yadollahi, R., Vasilev, K. & Simovic, S. “Nanosuspension Technologies for Delivery of Poorly Soluble Drugs.” Journal of Nanomaterials https://www.hindawi.com/journals/jnm/2015/216375/ (2015) doi:10.1155/2015/216375.

Gao, L. et al. “Application of Drug Nanocrystal Technologies on Oral Drug Delivery of Poorly Soluble Drugs.” Pharm Res 30, 307–324 (2013).

Originally published on PharmasAlmanac.com on March 19, 2020