Lyophilization of Highly Potent Drugs: Key Facility and Equipment Design Elements

Fri Jun 21 13:30:00 EDT 2019

By Jeff Tremain, Associate Director Business Development and Ted Tharp, Associate Director, Parenteral S&T

Lyophilization, also known as freeze-drying, is a pivotal operation in the manufacture of unstable biologic drug products. Used to remove water from a drug product after it has been frozen and placed under a vacuum, it allows drying without the application of heat. Lyophilization ensures drug stability, delivers an extended shelf-life, and enables long-term storage at room temperature. A further advantage of a lyophilized drug product is that it limits the number of interactions between the product and the vial and stopper during the period of storage.

Because scale-up and technology transfer of the lyophilization process is challenging, it is important to develop a comprehensive understanding of critical lyophilization characteristics early on. Partnering with an experienced contract development and manufacturing organization (CDMO) for lyophilization can shorten the drug development process and expedite time to market.

Many high potent APIs require lyophilization

Drug preparations intended for mechanical introduction to the body through the skin or other external boundary tissue are known as parenterals. These bypass the body’s natural defenses to deliver active pharmaceutical ingredients (API) directly to the bloodstream or tissue. Typically administered by injection (small volume parenterals) or via an intravenous infusion (large volume parenterals), parenterals circumvent issues such as gastrointestinal irritation or poor GI bioavailability and can drive a rapid response to treatment when desired.

Due to the highly potent nature of some APIs, parenteral manufacture depends on specialized processes to maintain product sterility, stability, efficacy and safety. To meet strict regulatory requirements, improve stability, and ensure the safety of both patients and manufacturing personnel, many high potent drug products undergo lyophilization during the manufacturing process.

1.      Specialized high containment is important for lyophilization of high potent drug products

Filling of lyophilized parenteral products is performed using one of three main types of facility design, the selection of which is dictated by the nature and potency of the drug product:

  • Isolator – personnel are separated from the product/equipment by physical barriers; the aseptic area is completely enclosed; gloves are used to perform interventions
  • Clean room – all areas can be accessed; personnel are separated from the product/equipment by soft, flexible curtains; contamination is controlled only by operational procedures
  • Restricted access barrier system (RABS) – a hybrid of clean room and isolator; affords greater process flexibility with a level of aseptic quality comparable to that of an isolator

The manufacture of high potent drug products requires specialized high containment isolators to protect manufacturing personnel from the drug product, and to protect the drug product from contamination. It is essential that these undergo regular monitoring and servicing to ensure compliance with strict regulatory guidelines for safety.


2.      A low-loss, fully disposable product path is preferred

The lyophilization process is typically preceded by several key steps, each of which requires thorough characterization to minimize product loss and ensure high yields. Product loss may result in serious implications on the final yield and is associated with significant overall process costs and time delays, highlighting the importance of careful evaluation of every step of the drug product manufacturing process. These include:

  • Thawing the frozen drug substance/API
  • Preparation of the excipient solution (if applicable)
  • Pooling of the bulk drug substance, addition of the excipient solution, and mixing
  • Bioburden reduction filtration
  • Sterilizing filtration (0.2 µm)
  • Aseptic filling into sterile primary packaging

To condense timelines for technical transfer, it is recommended to utilize a fully disposable product path. Disposables 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 for multiple pieces of equipment and can reduce the risk of operator exposure to product.

3.      100% dose control improves overall yields

The vial fill volume determines the concentration, and subsequently the performance, of the lyophilized drug product upon dissolution. 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. It is imperative that fill volume is evaluated thoroughly during process characterization since, following lyophilization, any discrepancies will not be readily apparent by visual inspection.

100% dose control is a superior method to monitor fill volume. It involves weighing every vial both before and after filling to eliminate the possibility for low or high fill volumes and represents a significant improvement over statistical dose control. With statistical dose control, the risk of an out of specification dose increases at the end of the filling process. If such out of specification occurs, the filling process must be stopped resulting in costly, precious drug substance remaining and ultimately lost in the fill lines. 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.

4.      Access to a development laboratory that fully characterizes lyophilization process for successful technology transfer

For technology transfer to be successful, it is necessary to understand the capabilities of the drug product lyophilizers used in the process. This includes characterization of both development scale and commercial scale equipment to enable the formation of a lyophilization cycle that generates acceptable product in both the development laboratory and the commercial plant. Importantly, characterization also allows a suitable design space for the lyophilized product to be established.1

Variable input parameters of the lyophilizer include the chamber pressure and shelf temperature. Fixed input parameters include chamber volume, condenser volume, and condensing area, as well as the duct radius and length. Historically the operational qualification (OQ) of the lyophilizer would be used to confirm the ability of the instrument to control shelf temperature and pressure based upon the lyophilizer design. Today, the qualification can be supplemented with computational fluid dynamics (CFD) to better detect and understand the differences in equipment performance which may arise from distinct designs. This allows a model of the lyophilizer to be created during development that will better predict the performance of the commercial equipment and drug product.2

Following qualification of the lyophilizer, further characterization of the equipment should be completed to determine the heat transfer coefficient (Kv) for each vial that will be used in the lyophilizer. The vial heat transfer coefficient describes the complex relationship between heat flow and product temperature. It is influenced by factors such as shelf temperature, shelf spacing, vial design, and chamber pressure and is essential to the development of optimized design space for the product. Generating this data relies on steady state modeling of the primary drying process in transferring from the development laboratory to the production facility.

A comprehensive understanding of the formulation characteristics of the drug product is also fundamental to a successful technology transfer. Critical product temperatures to monitor include the eutectic temperature (Tg’) and collapse temperature (Tc) of the product. To avoid any adverse effects to the quality of the lyophilized material, the drug product is typically frozen at a temperature well below these. It is also important that the lyophilizer maintains a temperature that is below these specific product temperatures during the drying process.

A final piece of the product characterization is the product resistance. 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

5.      100% headspace analysis ensures product quality

Following lyophilization, the finished vials must be assessed to identify any issues which might compromise product safety. These include cracks in the vials, improperly seated stoppers, or other container closure defects which could impact sterility or stability of the product.

100% headspace analysis is an effective method to eliminate the risk of faulty vials reaching the patient population. Using a laser to interrogate the space above the product, which has been backfilled with nitrogen following lyophilization, any vials which do not meet pre-defined quality criteria can be discarded.

With established platform processes and the necessary high containment infrastructure, AbbVie offers unrivaled expertise to support lyophilization for high potent drug product manufacturing.  Offering expertise in all aspects of drug product manufacturing, AbbVie is your partner of choice for lyophilization. Contact AbbVie Contract Manufacturing to discuss your drug product requirements.

To learn more about how AbbVie CMO can help with your with your project,  contact us at 1-847-938-8524 or visit us at