Taking Stock of Biologic Fill/Finish Best Practices

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Aseptic sterile filling is one of the most critical processes in biomanufacturing and is driven by the highly technical nature of these processes as well as the potential safety impact to the end user (1). For biologics fill/finish operations, process design must take into account the innate properties of proteins and the external factors that can affect a given protein’s behavior and stability, and special processes, procedures, and equipment should be in place to ensure product integrity during fill/finish (2).

Aseptic sterile filling is one of the most critical processes in biomanufacturing and is driven by the highly technical nature of these processes as well as the potential safety impact to the end user (1). For biologics fill/finish operations, process design must take into account the innate properties of proteins and the external factors that can affect a given protein’s behavior and stability, and special processes, procedures, and equipment should be in place to ensure product integrity during fill/finish (2).

Handling biologics

For biologics fill/finish, standard quality control (QC) operations include visual inspection in both the United States and Europe, which relies heavily on the experience, training, and skill of the QC operators. Because regulators expect a well-characterized and robust inspection process, extensive training is required in addition to a robust qualification regimen that ensures operators have the necessary skills to visually detect a comprehensive list of potential drug product and container defects (2). The challenges involved in ensuring product quality in biologic fill/finish operations include:

• having the ability to handle sensitive biologic products

• having the skill to inspect both clear and opaque suspensions

• having the skill to inspect amber vials

• having the ability to distinguish between foreign and product-related particulates (2).

Aseptic filling typically requires close coordination and complex interaction between personnel, sterilized product, the fill/finish equipment system, the cleanroom and support facilities, and sterilized filling components (1).

In addition, the implementation of best aseptic practice methods would provide personnel with the methods, training, and knowledge of qualified procedures to further prevent microbial contamination by giving them the means to govern their movement and function within the cleanroom environment. For example, specific procedures are needed for both gowning and de-gowning processes as well as requirements for hygiene (1).

Ensuring sterility

Sterile fill/finish processes must all be performed in a cleanroom where specific conditions must be met, such as:

• high-efficiency particulate air (HEPA) circulates in a single direction.

• environmental monitoring is carried out on a constant basis throughout the manufacturing process

• cleanroom layout facilitates smooth flow of workers and product among the fill/finish equipment (3).

In ensuring sterility prior to fill/finish manufacturing, it is essential that production processes are robust and work reliably in a timely manner, which is key, especially with manufacturing products that are sensitive to microbial contamination. “There needs to be documented evidence-validation to show that the equipment, utilities, processes, and personnel practice are working as intended and not putting patients at risk,” says Sara Frederick, director-Project Management, Piramal Pharma Solutions, Lexington.

“Process simulations that involve media fills are done on a routine basis as well as after any shutdown or significant maintenance or change. It is imperative that there is a procedure that clearly identifies when such media fills are to be performed. Process simulations should also include routine and non-routine interventions that people make with risk assessments. The risk assessment should include the frequency at which such interventions are to be performed and also assess the proximity to open containers, Frederick says.

During media fill, microbiological growth medium is exposed to product contact surfaces to simulate exposure conditions that the product would likely undergo during manufacturing. Microbial contamination is detected by incubating sealed containers filled with medium at defined temperatures (3).

The need to use validated sterilization methods, such as moist-heat and dry-heat sterilization, is also a critical practice in the cleanroom to ensure the sterility of crucial equipment used during fill/finish operations and equipment surfaces that come into contact with sterilized drug product or sterilized primary packaging materials (3). Furthermore, aseptic processing operations should be tested against media fill for the ability to produce sterile products.

Current aseptic best practices include the minimization of motion and ensuring that the drug product has limited contact with all equipment, notes Frederick. “Operators must never directly touch open containers; sterile forceps and equipment are recommended instead. People movements should be minimized to reduce the generation of particles and microbes.”

She cautions that personnel who are directly involved in aseptic manufacturing are the single largest contributor to contamination of sterile products. “Strict adherence to cGMPs at all times is critical. Good aseptic techniques must be learnt and practiced. It includes procedures like proper gowning (i.e., putting on a sterile gown without contaminating it). Practicing good personal hygiene, such as washing and sanitizing hands, and not wearing makeup or jewelry are all part of aseptic must haves,” she states.

Improving practices

While there have been advances in technology, such as automation and isolator barriers, that are considered best practices for maintaining drug sterility, improvements to fill/finish operations could still be beneficial and potentially prevent recalls of drugs based on quality issues. The problem remains, however, that innovation in fill/finish operations ranks low in priority for manufacturers, despite how crucial this step is in the biologic drug manufacturing lifecycle (4).

Improvements to fill/finish operations include the use of closed aseptic processing systems versus open systems as well as advances in equipment, such as automation and barrier isolators. In addition, creative solutions can also be beneficial, such as streamlining operational workflow between parties (i.e., biopharma company and contract manufacturer, if product manufacturing is outsourced) (4). In this case, disruption in fill/finish operations, such as splitting operations between separate locations, can be problematic as this adds to the number of steps involved in achieving the finished product.

Another major point of consideration, where improvement can go a long way, lies in effective and sufficient communication between all parties involved in fill/finish operations. The more information that can be known and shared between the parties, the better that an appropriate fill/finish strategy can be developed, with the appropriate equipment and well-developed manufacturing and validation plans that ensure safety control over product sensitivity to environmental factors (4).

References

1. D. Stockdale, “Overview of Aseptic Fill/Finish Manufacturing,” BioRealty.com, accessed Jan. 8, 2019.
2. D. P. Kovarcik, “Critical Factors for Fill–Finish Manufacturing of Biologics,” BioProcessintl.com, May 17, 2016.
3. R. Peck, “Sterile Fill & Finish,” ContractPharma.com, Mar. 9, 2018.
4. R. Hernandez, BioPharm International 29 (9) 14–21 (2016).

Article details

BioPharm International
Volume 32, Issue 2
February 2019
Pages: 26–27

Citation

When referring to this article, please cite it as F. Mirasol, “Taking Stock of Biologic Fill/Finish Best Practices,” BioPharm International 32 (2) 2019.