Safety, Quality, and Stability Drive Lyophilization

Biologic pharmaceutical products, including traditional monoclonal antibodies and next-generation products, such as monoclonal antibodies, bispecific antibodies, and others, continue to advance through the clinic and are expected to account for a larger percentage of drug approvals in the future.

Manufacturers are faced with the challenge of efficiently and cost-effectively producing safe medicines based on these highly complex molecules with innate lability. Unlike small molecules, biologics can readily aggregate or undergo conformational changes in response to various factors, such as increases in temperature, changes in pH, mechanical agitation, freeze–thaw cycles, or the presence of certain excipients.

Assuring product stability, quality, and safety requires implementation of robust manufacturing control strategies that consider the unique properties inherent to biopharmaceuticals. Such measures should be designed to maintain essential product attributes during manufacture and storage and must align closely with analytical testing to ensure potential issues are detected and addressed promptly.

The manufacture of parenteral biologic formulations, which can include highly potent products, requires specialized processes to maintain product sterility, stability, efficacy, and safety. For highly potent drugs, extra measures are necessary to ensure the safety of both patients and manufacturing personnel.

Many parenteral products are thus subjected to lyophilization, or freeze-drying. In this process, water is removed from the drug product after it is frozen and placed under a vacuum, allowing drying without application of heat. In the frozen state, the stability of biologic substances is significantly increased, and interactions between the product and the vial and stopper are limited. The result is extended shelf-lives and the ability to store biologic drug products for longer periods at warmer temperatures.

Lyophilization Approval Landscape

In 2019, the U.S. Food and Drug Administration (FDA) approved drug applications for 47 lyophilized drugs from 37 companies, of which 41 were generic products, four were NDAs, and two were new biologic drugs. The largest therapeutic category among these lyophilized drug products was oncology (47%), followed by infectious diseases (34%) and surgical use (7%). In the same year, the European Medicines Agency (EMA) approved only four lyophilized drugs: two for oncology and one each for infectious and metabolic diseases. The breakdown of 2019 approvals was consistent with historical approvals, with infectious diseases comprising 36% and oncology comprising 24% of the 519 approved lyophilized drugs, followed by cardiology (9%), metabolic disorders (6%), immune disease (5%), and surgical use (3%).¹

Challenging Scale-Up and Tech Transfer

Lyophilization is a complex, often time-intensive process requiring many hours and investment, creating challenges for scale-up and technology transfer. Traditionally, the optimization of lyophilization processes has been primarily achieved through trial and error. Although pharma companies and contract manufacturing and development organizations (CDMOs) generally accept this costly approach as an expense associated with biologic drug manufacturing, it can disrupt pipeline progression and preclude more profitable and efficient manufacturing.

Data-Driven Development Solutions

Today, fortunately, there are alternative methods for the optimization of pharmaceutical freeze-drying processes, including data-driven advances in steady-state computer modeling and subsequent bench-scale lyophilization practices. CFD and analysis of specific product, process, and laboratory equipment attributes (formulation, critical temperatures, vial dimensions and fill volumes, pressure, heat transfer, sublimation rates, etc.) allow modeling of the entire lyophilization process in both laboratory and manufacturing environments.

The data generated through modeling can then be used to distinguish and compensate for variables in equipment performance and design, thus establishing an educated starting point for the development of lyophilization processes. Bench-scale lyophilization experiments are performed to confirm the modeling data and help to minimize the quantity of expensive drug substance required for development and scale-up.

Thorough characterization of the process and equipment at bench scale reveals critical performance attributes and creates the opportunities for optimization of the lyophilization cycle speed by determining the fastest freeze-drying rate that a formulation will safely and effectively tolerate without causing negative impacts to cake appearance, stability, or other product characteristics. This up-front knowledge accelerates cycle times through subsequent at-scale manufacturing, typically late-phase clinical and commercial runs, while further reducing the risk of failure by verifying lyophilization parameters from the start.

As a result, modeling and bench-scale studies provide higher confidence in the critical process parameters, enabling efficiencies in drug substance utilization, optimized manufacturing capacity, and appropriate allocation of supporting labor resources as the lyophilization process is transferred to commercial production. With so many drug candidates receiving accelerated development designations, modeling and bench-scale lyophilization have become even more relevant, because they provide baseline process characterization data that instill confidence in the likelihood of getting it right the first time, which in turn creates a foundation to meet accelerated clinical and commercialization time frames.

The best time to explore the benefits of modeling and bench-scale optimization studies is during or immediately following phase I clinical trials, to ensure that the pharma manufacturer or CDMO partner can fully engage with and benefit from phase I data.

Advanced Analytics Invaluable

In addition to establishing a thorough understanding of process parameters and thus ensuring rapid and successful scale-up and tech transfer, it is also essential to understand the capabilities of the development and commercial-scale drug product lyophilizers used in the freeze-drying process. This information is necessary to establish the appropriate design space and determine a lyophilization cycle that generates acceptable product in both the development laboratory and the commercial plant.

The ability of the lyophilizer to control shelf temperature and pressure is typically confirmed using operational qualification (OQ) results, but this information can also be supplemented with CFD data to ensure greater understanding of the differences in equipment performance that may arise from distinct designs. A model of the lyophilizer can then be created during development that will better predict the performance of the commercial equipment and drug product.

Understanding the heat transfer coefficient for each vial, the product formulation characteristics, and the product resistance are also essential for optimizing the design space. The vial heat transfer coefficient describes the complex relationship between heat flow and product temperature and is influenced by the shelf temperature, shelf spacing, vial design, and chamber pressure. Generating this data relies on steady-state modeling of the primary drying process when transferring from the development laboratory to the production facility.

Formulation attributes of prime importance include the eutectic temperature (Tg) and collapse temperature (Tc) of the product. Freezing is generally performed at a temperature well below these to avoid any adverse effects on the quality of the lyophilized material, and it is important that the lyophilizer temperature remains below these specific product temperatures during the drying process.

Product resistance is a function of the dried product or cake and influences the maximal permitted shelf temperature and primary drying time. The interaction of the vial heat transfer coefficient and product resistance with variables such as shelf temperature and chamber pressure are used to build a robust cycle that can be optimized for time and scale-up with minimal development work.

Leveraging Single-Use Technology

Condensing times for tech transfer can also be achieved through the utilization of single-use systems to create a fully disposable product path. Single-use systems are available for all product contact operations, from pooling and mixing of the drug substance through filtration and filling of the product into vials. This approach eliminates requirements for cleaning equipment and cleaning validation, minimizes risk of cross-contamination, and reduces the risk of operator exposure to product. This approach is particularly recommended for highly potent biologics.

Importance of 100% Dose Control and Headspace Analysis

Knowledge of the fill volume and headspace content in each vial is essential to ensure patient safety for each lyophilized vial. A low fill volume can result in sub-potency, while a high fill volume may deliver to the patient an unacceptably high quantity of the drug product. Similarly, following lyophilization, any cracks in the vials, improperly seated stoppers, or other container closure defects may impact product sterility or stability.

Controlling dosing is critical, and 100% dose control, which involves weighing every vial both before and after filling, is a superior method for monitoring fill volume that presents a significant improvement over statistical dose control. Statistical dose control carries higher risk for the occurrence of out-of-specification fill volumes at the end of the filling process, which requires line stoppage and loss of expensive drug substance. When combined with a filling line that can run each filling needle individually to complete fillings, 100% dose control provides assurance that the proper dose is filled throughout the batch, improving the overall yield for the product.

Similarly, 100% headspace analysis is an effective method for eliminating the risk of faulty vials reaching the market. At the end of the lyophilization, the vials are backfilled with nitrogen to remove oxygen from the headspace. A laser is then used to analyze the headspace for lack of oxygen in each vial to confirm container closure integrity. Any vials that do not meet pre-defined quality criteria are discarded.

Experienced Global Network Focused on Lyophilization Optimization

To successfully manage the unique challenges presented by lyophilization scale-up and tech transfer requires extensive expertise in lyophilization process development and the use of advanced modeling and production systems. Partnering with a CDMO for lyophilization can shorten the drug development process and expedite time to market.

AbbVie is well-versed in lyophilization process development, optimization, and scale-up, with facilities worldwide benefiting from best-in-class equipment operated by highly experienced personnel. From lab-scale lyophilization with manual or peristaltic vial filling to dedicated equipment for lyophilization process optimization, scale-up, and tech transfer, AbbVie’s expert team leverages state-of-the-art technologies across multiple global sites and has formulated numerous drug products over several decades. Access to this experienced global network of resources encompassing many in-demand technologies and a broad, up-to-date working knowledge of worldwide regulatory requirements is a real advantage for pharma companies.

We are also committed to staying current on industry tools and technologies. Leading-edge capabilities include CFD for modeling development and state-of-the-art GMP equipment. These and other technologies are pivotal to AbbVie scientists’ continued demonstration of consistency and improved lyophilization cycle / lyophilization quality to minimize engineering runs at scale. With all fill/finish manufacturing studies backed by significant analytical capability – including development and investigative testing, headspace analysis, container closure integrity test development/validation, and HPLC and sub-vis particulate analysis – AbbVie is widely recognized as a global leader for operational excellence.

For more information, visit abbviecontractmfg.com.