Beyond Sterility Testing: What Sponsors Should Expect from a Sterile Injectables CDMO

When selecting a contract development and manufacturing organization (CDMO) for sterile injectable products, drug sponsors must understand that the manufacture of sterile products is subject to special requirements to minimize risks of microbial, particulate and endotoxin/pyrogen contamination. The complexities of manufacturing sterile medicines mean that there is a plethora of additional controls necessary, above and beyond what is standard for non-sterile pharmaceutical manufacturing.

“Parenteral” is a term commonly used in the pharmaceutical industry. Technically, it refers to any medication with an intended delivery route that does not involve the digestive system. This can include delivery mechanisms such as topicals (creams, lotions, balms, etc.), dermal patches, inhalations, eye drops, etc. However, most commonly when parenteral medication is discussed, it is one that is injected in some manner (intravenous, intramuscular, subcutaneous, etc.).

These delivery mechanisms can have tremendous benefits for patients, including:

• Dramatically reduced time to effect
• More targeted area of effect
• Minimized risk of drug breakdown in the digestive system

However, this route of administration does carry risk. When the delivery route is injection, one of the body’s primary defenses against infection, its skin, is bypassed. This can lead to a large increase in the risk of infection, either localized or systemic (i.e., sepsis). For this reason, drugs intended to be delivered by injection must be completely free of microbial (i.e., bacterial or fungal) contamination, or sterile.

In general, sterility is not a characteristic that can be proved by testing. Although a portion of every batch of sterile medication will undergo sterility testing, this destructive testing cannot be done for the entire batch. Therefore, the principles of sterile (or aseptic) processing must be designed into the manufacture of the product and must be adhered to throughout the entirety of the manufacturing operation.

This critical principle is captured in regulatory guidance, which states that “sole reliance for sterility or other quality aspects should not be placed on any terminal process or finished product test.” In other words, quality and sterility cannot be “tested into” the product, they must be incorporated into every step of product manufacturing.

The manufacture of sterile products requires special consideration across all aspects of the manufacturing process:

Facility Design and Operation

• Sterile products should be manufactured in cleanrooms or other equivalently non-contaminated spaces, such as isolators or reduced access barrier systems (RABS)
• These environments must be designed to minimize contamination, primarily airborne contaminants
• Cleanrooms must be made of appropriate materials that are smooth and impervious to minimize particle shedding and providing crevices in which micro-organisms may collect and grow
• Air flow in cleanrooms should be filtered to remove airborne contaminants, and should be adequate to flush any potential contaminants out of the room

Equipment Requirements

• All equipment must be able to reliably perform the necessary function without introducing any potential for product contamination
• Equipment functionality must be verified and qualified
• Critical equipment should have in-built monitoring systems to alert operators to potential malfunctions
• Equipment used in aseptic processes must be able to be sterilized

Personnel Training and Qualification

• Only the minimum number of operators necessary to complete the required activities should be present inside a cleanroom
• All operators entering, whether for processing operations or for cleaning/disinfection, maintenance, monitoring, or other functions, must be trained and qualified on both proper gowning and proper behavior in the cleanroom
• Data should be regularly collected on operators, and a process for disqualifying them in the event of a trend of negative monitoring results should be in place
• In a modern cleanroom, it is recognized that human beings are by far the largest source of potential contamination, especially microbial contamination, to the product

Critical Process Areas

• For aseptic processing, critical operations (where the product stream is exposed – e.g., filling, stoppering, etc.) must be performed in at minimum Grade A areas
• Grade A is the cleanest (“critical”) zone, where the highest-risk operations (open container filling, stoppering, etc.) occur
• Barrier systems such as RABS or isolators are recommended to minimize the risk of contamination from human operators in a cleanroom

Quality Risk Management (QRM) must be built into the processes, facilities, and manufacturing activities. A Contamination Control Strategy (CCS) must be implemented across the facility and must be actively reviewed and updated where needed. Elements of the CCS include:

• Plant and process design
• Equipment
• Personnel
• Materials
• Vendor approval
• Risk management
• Monitoring systems
• Continuous improvement

For aseptic preparation and processing, a higher risk process, wherein all components and process materials are separately sterilized, and the fill is performed under conditions that minimize the potential for contamination after sterilization, QRM and CCS are especially important.

Monitoring represents the continuous gathering of data to support manufacturer’s claims that all process steps and environmental conditions remain within the range established by process validation. This is necessary to ensure that the manufacturing process continues to operate under the conditions it was designed to function within and therefore will result in drug products that meet the required levels of quality and sterility.

The environmental and process monitoring program represents a part of the manufacturer’s CCS. No individual element of the monitoring program should be considered an indicator of sterility, rather, the entire data set should be reviewed as a standard part of product batch manufacturing and release. Trends in process monitoring data can be analyzed to detect potential areas of concern or process breakdown.

For sterile drug manufacturing, the environmental monitoring (EM) program should at minimum contain the following elements:

• Total airborne particle levels
• Viable (microbial growth) particle levels, airborne, surface, and operator
• Temperature, humidity, and other specific characteristics (e.g., differential pressure between cleanrooms and the surrounding environment)
• Process simulations (media fills) can be considered part of the monitoring for aseptic manufacture

Process Simulations (Media Fills)

Process simulations, commonly referred to as “media fills,” are a requirement for aseptic processing. During these qualifications, an appropriate microbial growth medium is used as a proxy for the drug product and is put through the same process as the normal product, then incubated appropriately. This is done to demonstrate that the process is effective at the prevention of product contamination, a container that exhibits microbial growth after incubation is a strong indicator that there is a major flaw in the process.

The target for all media fills should be zero growth. Any filled unit that is determined to be positive for growth following incubation should be treated as a process simulation failure and should be investigated appropriately.

In a well-functioning relationship between a CDMO and the relevant drug sponsors, the CDMO must meet regulatory provisions, and the sponsor must ensure that this is the case. Sponsors should perform suitable audits on their CDMO partners sufficiently to ensure that they are fully compliant with all regulations.

When evaluating sterile injectable CDMO, sponsors should verify that the partner has:

Validated Infrastructure and Systems

• Cleanrooms qualified to appropriate grades with routine requalification programs
• Equipment designed, qualified, operated, maintained, and monitored to ensure proper function
• Utilities systems (water, steam, gases) of adequate quality for sterile manufacturing

Robust Quality Systems

• A Pharmaceutical Quality System (PQS) specific to manufacturing sterile products
• Risk management is integrated into all areas of the product life cycle
• Adequate knowledge of the products manufactured and the ways in which product quality can be impacted
• Investigation procedures for excursions with appropriate corrective and preventative actions (CAPAs)

Comprehensive Monitoring Programs

• Environmental monitoring performed during all critical steps in the manufacturing operation
• Comprehensive data review with trending analysis
• Process simulations conducted regularly with zero-growth targets
• Investigation capabilities for any deviations that may represent a risk to product quality

At Afton Scientific, we understand that sterility must be designed into the manufacture of the product and must be adhered to throughout the entirety of the manufacturing operation. Our facilities, equipment, personnel, and quality systems are designed specifically to minimize risks of microbial, particulate and endotoxin/pyrogen contamination, with Quality Risk Management and Contamination Control Strategies built into every aspect of your sterile injectable product from development through commercial supply. Contact us to learn how our sterile manufacturing expertise and infrastructure can support your product development and commercial manufacturing needs.