Establishing an Aseptic Drug Product Manufacturing Process

Introduction

This article focuses on establishing the manufacturing process for a sterile biopharmaceutical drug product at a contract manufacturing organization (CMO). Although in theory, it sounds straightforward, aseptically filling biologic products into a vial is complicated and unforgiving when mistakes are made, and the potential effect on the patient can be catastrophic.

Proteins are by nature colloidal suspensions and inherently unstable, further complicating the process. This combination of making a product free of microbial and particle contamination while maintaining its stability and avoiding damage during the drug product manufacturing process makes filling an aseptic product challenging.

Choosing a Fill Line

Because protein-based products are inherently unstable, care must be taken when choosing a fill line so that the filling process does not damage the product. Most proteins are sensitive to shear and aggregation, so it is best to use a gentler peristaltic pump-based system instead of harsher piston pumps, which can introduce cavitation and shear into the process. If a piston system is used, it is essential to perform studies while establishing the drug product manufacturing process to show that the filling system does not damage the product.

There are three main types of technology to support aseptic manufacturing lines to create a clean filling environment: clean rooms, restrictive access barrier systems (RABS), and isolator barrier technology. When choosing between these three, it is essential to remember that people are the largest source of product contamination.

Clean rooms are the oldest technology and are very manual. The process’s cleanliness depends on the air quality in the room and the workers' gowning. Isolator and RABS systems are different in that they physically isolate the workers from the product. Because of this difference, most regulatory agencies consider clean room-based filling systems to be on the edge of compliance and discourage using them.

The main difference between RABS and isolator systems is that an isolator is fully sealed, whereas air flows out of a RABS system into the surrounding room. RABS systems can be either open or closed and are the most flexible configuration of the three types of fill systems. Because air flows out of the RABS system and into the surrounding room, RABS systems must be cleaned manually. Also, because air flows out of the system into the surrounding space, RABS systems are unsuitable for filling cytotoxic products such as antibody-drug conjugates.

Since isolator systems are fully sealed, the production operators are physically separated from the product, removing the most likely source of product contamination. As such, they are considered to have the highest?level of product protection. Also, isolators are the preferred choice for filling cytotoxic products such as ADCs because they are fully sealed, and air does not flow out of the system.??

When choosing between a RABS or an isolator system, one crucial consideration is whether the product is sensitive to hydrogen peroxide. Isolator systems are completely sealed and generally cleaned through automated decontamination procedures using vaporized hydrogen peroxide (VHP).?After cleaning and before the product enters the isolator, most of the hydrogen peroxide should have degraded to water and oxygen. However, if an isolator is used, it must be confirmed during early drug product process development that potentially low levels of residual hydrogen peroxide will not damage the product.

To reduce the risk of cross-contamination from other products manufactured on the same fill line, it is advantageous to choose a filling system compatible with product-dedicated or disposable product contact components. As well as being gentler to the product, peristaltic-based systems tend to be more amendable to disposable technology than piston-based systems since the product contacts disposable tubing instead of a non-disposable piston as it is pumped through the filling system.

To further reduce the risk of cross-contamination, always use disposable bags or dedicated vessels to contain the product as it is fed onto the fill line.?In addition to decreasing the amount of cleaning validation required, using product-dedicated or disposable components reduces the risk of potential product carryover from a previous customer’s product, which may place a maximum limit on how the clinical studies are designed and the maximum amount of drug that can be given to a patient during clinical trials.

Choosing a Container Closure System

A drug product container closure system is defined as the vial, the stopper, and the crimp that secures the stopper in place. For regulatory purposes, the container closure system is defined as part of the final drug product.

For the container closure system, it is best to choose something already well established at the manufacturing site. This will remove the need for custom parts for the fill line and costly machinability studies. Buying custom components can sometimes add thousands of dollars in costs and require additional studies that complicate the program and can delay the program by months. If possible, it is best to avoid using anything outside the vendor's standard offering.

Most protein-based biologic products use type 1 glass vials paired with coated stoppers. Barrier and lubricity are the two types of stopper coatings. Barrier coatings help reduce the interaction risk between the drug and the stopper, protecting the product from contamination. Lubricity films can enhance performance on filling lines by preventing the stoppers from getting stuck and jamming during filling operations.

Glass vials are generally used because they are inert to most chemical reactions and relatively easy to clean, depyrogenate, and sterilize. However, some companies are migrating from glass to molded plastic vials because of the potential for glass delamination. If molded plastic vials are used, it is essential to take steps early to ensure that leachable chemicals and shed particles from the plastic do not end up in the product. It is also important to ensure the plastic vial is clear so its contents can be visually inspected after the fill.

In recent years, glass delaminating from the vial and adulterating biopharmaceutical drug products has become a major regulatory concern, causing millions of dollars in commercial product recalls, and delaying development programs. These recalls have been reported in the popular media and have caused product shortages. Because of the potential for glass delamination, assessing the product's compatibility with the container closure system early in the process is essential.

Product Introduction Studies

Most projects at drug product contract manufacturing sites begin with a product assessment. In this assessment, the manufacturing site will ask about product attributes such as sensitivities to light, shear, and temperature. The site will also request a product material safety data sheet (MDS). With this information, the vendor will work with you to choose an appropriate fill line and container closure system.

Cleaning verification studies are usually the first experimental work performed. These studies must still be performed even in fully enclosed isolator systems with product-dedicated and disposable fluid paths. As controlled as the filling process might be, there will be times when leaks in the fill line occur, and the product is spilled. These studies ensure that if the product spills, it can be cleaned up.

Once cleaning verification is performed, product-specific qualifications of the microbiology assays are performed. These include tests for endotoxin, sterility with bacterial and fungal stasis testing, and bioburden. When performing these tests, they must be qualified using the product in its final formulation. During these studies, it is necessary to prove that the product does not interfere with endotoxin testing and is not bactericidal or fungicidal. If these microbiology assays are not fit for purpose, they could lead to false-negative results masking an actual contamination event.

Downscale studies are often performed with the product to confirm that the filling process will not cause the product to aggregate, degrade, or introduce particles. Since most biologic products are filled at room temperature but stored at frozen or refrigerated temperatures, it is best to qualify product hold times at room temperature for both the duration of the drug product manufacturing process, for when the vials are inspected after fill, and for any expected downstream packaging and labeling operations.

Depending on the batch size, 24–48 hours or more may be required at room temperature to stage, fill, and inspect the final product. Building in these studies early helps ensure the product is suitably stable to make it through the drug product manufacturing process without changing the product’s quality.

Manufacturing

At this stage, a suitable manufacturing fill line and container closure system have been chosen, and the studies to support successfully filling the product should be in place. If materials are available, performing an engineering run before filling the first clinical batch is recommended. This gives the drug product manufacturing site practice filling the product before committing the clinical supply to the drug product manufacturing process. It also confirms the data from the downscale model studies, further providing confidence in the robustness of the drug product manufacturing process. Filling an engineering batch before the GMP batch also allows for generating additional drug product stability data, which the authorities will want to see in any regulatory filing.

Conclusion

This paper provides only a high-level overview of establishing a drug product manufacturing process for an aseptic biopharmaceutical product. However, it informs readers about the different types of fill lines available and how to approach choosing a container closure system. The paper also provides an overview of the typical product introduction studies required to demonstrate that the filling process does not damage the product and how to ensure that the microbiology assays are suitable for supporting the manufacturing of a sterile drug product.

Since drug product is usually injected directly into the patient, these processes must be in place to avoid microbial contamination and introducing foreign particles, which would adulterate the product. Also, if the filling process damages the product, it may lose efficacy or create an immune response in the patient. As damaging as it may be to the company if issues arise from drug product manufacturing, in the end, it is the patient who loses out.?