How to safely and successfully speed your injectable into the clinic
With household names like Botox and cancer treatment Keytruda, it’s no surprise that the global injectable drugs market is expected to top $1.2 trillion between 2022 and 2030. With a projected 9% compound annual growth rate (CAGR) in that same period, the market is quickly expanding to provide desperately needed treatments in areas like oncology and orphan disease to psychiatric disorders and immunodeficiencies.
For all their promise and increasing popularity – fueled largely by the demand for biologics – injectables commonly face a stubborn challenge: solution stability. Many molecules are less chemically stable in liquid solution than in solid form. Biopharma companies are increasingly pursuing a process called lyophilization – or freeze-drying – that removes liquid to create a shelf-stable solid formulation that can be more easily stored, distributed and safely reconstituted for patient delivery.
Lyophilized injectables are speeding new drugs’ path to clinic and extending shelf life – and growing rapidly. Lyophilized drugs account for about 16 percent of the top 100 pharmaceutical drugs and 35 percent of biologics, according to BCC Research. The majority of injectable drugs may soon require lyophilization. This burgeoning segment requires specialized expertise and equipment to perform effectively, efficiently and in full compliance. Indeed, the lyophilization equipment market alone is projected to more than double in the next ten years to $2.3 billion by 2032, with 8.8% CAGR between 2022-2032.
In this guide, we look at how developers can harness the power of lyophilization to get their small molecule and biologic injectable products into the clinic to help patients even faster.
Getting lyophilization right
A lyophilization cycle consists of three core processes that can span several days. First, a product’s water or solvent is frozen to create ice crystals. Next, primary drying or sublimation occurs, and ice crystals are removed via vacuum. Finally, a secondary drying or desorption step removes residual moisture.
Each step must be performed with exacting precision to avoid compromising the final product. Even the subtlest variations in freezing rate, drying rate, temperature control and levels of vacuum or moisture, for example, can ruin a batch. It takes repeated experimentation to calibrate the right parameters for each unique product, dosage and container used. If the lyophilization cycle is successful, it results in a stable solid or “cake” that may later be easily reconstituted just before patient delivery through injection, infusion or implantation.
Planning for success: Issues to consider
The inherent pressures of drug product development and manufacturing are heightened by patient, provider and regulator expectations for the quality, purity and sterility of injectables and other drugs. The technical rigors of the lyophilization process add another layer of complexity. Crafting an ideal lyophilization cycle for a particular product is both art and science. Extensive testing and validation are required to determine how formulation components respond to the freezing and drying processes.
To move through the journey efficiently, developers must undertake thorough planning and diligent implementation for quality control and sterility assurance. “In our industry, people get caught up in ‘What’s the science? What’s the equipment? What are the cool technologies?’ But really, success comes down to doing the right things every day,” noted Richard Sidwell, vice president and chief scientific officer at Societal CDMO, a leader in lyophilization that serves global clients seeking formulation development, clinical and commercial manufacturing, packaging, logistics and regulatory support.
Lyophilized drug developers must consider:
- Formulation development – Various concentrations of the active pharmaceutical ingredient (API) and excipients should be tested. The right combination will optimize product appearance, stability and efficacy – in both solid and reconstituted forms – and result in long-term cost savings as production scales. Biocompatible excipients such as stabilizers and bulking agents must be selected with attention to their specific properties regarding physical state, solubility and physical and chemical stability.
- Equipment compatibility and safety studies – Studies must assess the compatibility of the drug product and the material with which it comes into contact during production and storage. Finished products must be assessed for sterility, endotoxin content and physicochemical stability of lyophilized and reconstituted material.
- Scaling, manufacturing, and logistics – Future phases of the process should be considered from the beginning to avoid developing a small-scale process that cannot work at a larger scale due to insufficient lyophilization chamber and/or condenser capacity, inadequate heat transduction in the lyophilization chamber, and/or non-uniform nucleation in the samples, sterilization (steam-in-place and clean-in-place) capacity or other technical issues. Developers must demonstrate that their production and facility management protocols can support aseptic manufacturing at scale, including maintaining sterility through rigorous environmental controls and monitoring. Logistical plans must also assure that special conditions, such as low-temperature storage, can be met throughout the supply chain.
- Supply chain issues – Long lead times are frequent in today’s supply chain environment, requiring purchase decisions to be made quickly to keep projects on track. Societal helps clients by maintaining a stock of common excipients and components and by leveraging vendor relationships for timely fulfillment. The company’s new second-source service model enhances clients’ preparedness for and responsiveness to supply chain vulnerabilities by executing the necessary sourcing and planning phase activities of a standard technical transfer process in advance of the physical technical transfer activities, well before product supply is needed. Clients not only save time and money but also safeguard the continuity of vital drug supply.
- Documentation – Accurate documentation for all steps of the process is essential to support filing and approval.
A qualified contract development and manufacturing organization (CDMO) working as your partner can help assess these factors to mitigate risk and tailor practices to your product profile.
Finding the right partner to advance your drug candidate
Many developers are seeking external support for lyophilization activity given its complexity and the significant cost to acquire and maintain the necessary equipment. You must evaluate both a potential partner’s technical capacity and cultural fit.
CDMOs must have highly specialized expertise and equipment to handle formulation, aseptic fill-finish, lyophilization, packaging and logistics services at scale. Societal’s state-of-the-art filling line, with fill rates up to 2,000 vials per hour, and extensive experience in formulation development, aseptic fill-finish and lyophilization of sterile solutions, polymer-based sustained-release and/or long-acting nanosuspensions or microspheres, enable it to flexibly support customers throughout drug development. A presence on both east and west coasts of the United States facilitates the logistics of domestic and global projects.
The company’s novel lyophilization equipment, with ControLyo® lyophilization technology, uniformly and instantaneously induces nucleation within the entire freeze-dryer space, permitting advantageous processing of a variety of injectable products, such as small molecules, biologics, liposomes, sterile suspensions, emulsions and diluents. Benefits include reduced drying times, lessened freezing stress on complex products, and shorter reconstitution times – thereby preserving functionality and increasing the stability of high-value drug products and saving valuable time.
Developers should verify that a potential CDMO partner has the experience to get the job done. For example:
- Does the company have a successful track record with injectable products across key dimensions including formulation, process, analytics, quality assurance, materials management and regulatory compliance?
- If the company has produced a technically sound and well-documented formulation similar to your product profile, did it satisfy regulatory requirements, or were there data gaps and costly delays?
“Lyophilization is the most proven technology to improve the shelf life and handling of complex injectable products, but it is not simple,” noted Igor Nikoulin, senior director of pharmaceutical development and manufacturing at Societal. “Working with a partner who has done it successfully for multiple complex products will dramatically increase the chances of success.” The company has solved an array of development and manufacturing hurdles for its diverse client base, helping clients develop a variety of lyophilizable formulations along with product-tailored freeze-drying cycles that improved product appearance, reconstitutability and increased product stability from months to years.
Engaging a collaborative CDMO
Equally important to the selection process is evidence of a CDMO’s collaborative approach that allows more meaningful, sustained engagement and client support across a partnership spanning months or even years. As a midsize CDMO, Societal is well positioned to serve smaller specialty pharma companies who require responsive, expert-level support to navigate the high-stakes later stages of clinical, scale-up, process qualification or pre-commercial and commercial launch activities – but who don’t get the focus they need from larger CDMOs.
With a mission to “bring science to society,” Societal focuses on relationship-building to form a high-functioning project team built around openness, transparency, accountability and regular communication. This approach helps teams overcome the inevitable challenges that can sink or delay a project.
“It’s our goal to partner with biopharmaceutical companies to help turn their great ideas into approved, scalable, safe and effective products. Doing so fulfills our mission of helping the patients our industry ultimately serves live longer, healthier lives,” said David Enloe, the company’s chief executive officer. “We help bring our clients’ drugs to life.”