Mitigating Risk for Single-Use Assemblies in Sterile Filling

Print 12 March 2015
Sue Walker / BioPharm International

Single-use technologies can offer significant benefits compared with traditional stainless-steel systems. The key driver is overall time savings. There are risks associated with single-use technologies, however, that can include product loss and questions around sterility assurance and product safety. These risks are magnified in the filling operation because of its closeness to the product in its final form. A thorough evaluation of the assembly design process, manufacture, and use can assist in identifying and mitigating these risks. By mitigating these risks, single-use assemblies can be successfully implemented in all process steps including formulation, filtration, and filling.

Assembly design
In a traditional stainless-steel system, the end user has significant control over the design, construction, use, and maintenance of the system. When implementing a single-use system, the dynamics of the situation change and the relationship between the supplier and the end user needs to be a partnership. The design of the "system" becomes a collaborative effort between the two parties within the manufacturing capabilities of the supplier. In this article, design is defined as the selection of each individual component, how the components connect to create an assembly, how the assembly performs in the process, and ultimately how the assembly impacts the final drug product.

The design guidelines should follow good engineering practices, such as ASTM E2500, with consideration for items such as reduction in the number of parts, error-proofing assembly design, avoiding tight tolerances, ease of assembly, and using modular products. It is also beneficial to apply quality-by-design concepts during specification and assembly design, including critical process parameters (CPPs) and any prior production experience. As typical assemblies are custom designs that may include custom components, project timelines can range from 9 to 18 months depending on scope and complexity. Often, a good portion of this time is required for drawing revisions, prototype testing, and drawing finalization in conjunction with equipment testing and validation. These requirements need to be accounted for in the project planning process.

During assembly design, ease of operator use, product yield, sterility assurance, and product safety should be considered to help minimize the risks associated with single-use assemblies. By combining these attributes with key needs for formulation, filtration, and filling, a technically sound design can be created by the supplier and the end user. Key needs for formulation include:

• Efficient component introduction for both solids and liquids
• Robust and operationally appropriate mixing
• Minimization or elimination of bioburden
• Representative sampling with ability to perform an aseptic disconnect
• Temperature control (if required).

Key needs for filtration include:

• Effective filter flushing and/or wetting
• Maintenance of downstream sterility
• Well-characterized materials of construction
• Ability to perform a pre-use post-sterilization integrity test (if required)
• Ability for single or redundant filter design, as dictated by the end user 
• Filter placement inside or outside of the isolator, as dictated by the end user (see Figure 1).

Figure 1: Comparing filter location inside or outside of the isolator. SUS is single-use system; RABS is restricted access barrier system. All figures are courtesy of the author.

Key needs for filling include:

• Well-characterized materials of construction
• Ability to make a sterile connection between the outlet of the final sterilizing-grade filter and the filling assembly
• Optimized header bag and manifold design
• Dose accuracy.

By creating a sound initial design together, fit for intended use will not be based solely upon verification after installation but will be designed into each assembly.

Assembly manufacture
The partnership between the supplier and the end user shifts drastically during single-use assembly manufacture because the supplier is the responsible party, unlike traditional assembly manufacture in which the end user controls this step.

There is an additional level of complexity in single-use manufacture because each assembly is a custom design that is manually assembled. By systematically evaluating the assembly manufacturing and quality control processes, the risks can be highlighted and properly addressed to the satisfaction of both parties. The first step is to complete a process map or risk assessment to identify all activities and to highlight those activities with the highest risk, as illustrated in Figure 2.

Figure 2: A risk-based approach to assembly manufacture and use involves process mapping of design, manufacturing, and end-use to identify high-risk activities, listed above. The process failure mode and effects analysis (FMEA) includes assembly, testing, packaging, and shipping. The end-use FMEA includes unpackaging, handling, installation, and processing. QC is quality control; AQL is acceptable quality limit.

Based on a typical assessment for assembly manufacture, topics to consider include product certification, manufacturing area classification and cleanliness, gamma irradiation qualification, packaging and shipping qualification, and leak and/or integrity testing.

Product certification
Product certification should be based on 100% quality-control release testing or an acceptable quality-limit sampling plan. Assemblies for this application will usually require the highest level of certification. Items on a product certificate can include shelf life, sterility, endotoxin, particulate, reactivity, and leak testing.

Classification and cleanliness
Typically, the assembly process takes place in a Class 10,000 (ISO Class 7 or European Union Grade C) cleanroom. Maintenance of cleanrooms should include daily monitoring under dynamic conditions for routine performance verification with annual checks and preventative maintenance programs.

Particulates are a specific area of concern that can be successfully managed with the proper control strategy. The first step is proper cleanroom maintenance and controls, along with the cleanliness of any incoming materials, controlled flow of materials and personnel, appropriate cleanroom gowning procedures, an operator training program (both initial and continuous), the appropriate in-process inspection and final product testing, as well as follow-up on non-conformances and preventative/corrective actions. 

Subvisible particulates are monitored by testing according to United States Pharmacopeia (USP)<788> (1), but visible particulates can be more challenging. Visible particulates are grouped into two categories: intrinsic and extrinsic. Intrinsic particles can be reversible or irreversible aggregates or precipitants. Extrinsic particles can be environmental or shedding/flaking from materials used in the process such as plastics or glass. Any extrinsic particles found must be characterized and eliminated. USP <1> indicates that products for injection should be essentially free from visible particulates but does not dictate zero particulates (2). Currently, in-process visual inspection is the method for finding visible particulates. Particulates can be created throughout many of the manufacturing steps including film cutting, bonding, and sealing; assembly; assembly inspection; and final inspection. Operators must meet training and visual acuity requirements. The visual inspection process uses the TAPPI standard test method chart to estimate the size of any particulates found (3). 

Gamma irradiation qualification
Since assemblies are custom, a monster (or representative) assembly is created to perform a quarterly qualification. This assembly will contain a range of components based on a number of factors, such as materials of construction and type of component. It is used to substantiate a sterilizing dose of gamma irradiation required to achieve a sterility assurance level of 10-6. The guidance of ANSI/AAMMI/ISO 11137:2006 (4) and AAMI TIR33 (5) are followed.

Packaging and shipping qualification
This testing is performed using ISTA2a drop and vibration testing with package integrity, sterility, and/or functional testing (6).

Leak and integrity testing
For the purpose of this article, a leak test is defined as a test capable of detecting gross leaks in a system. An example is the pressure hold test performed after sterilizing in place on a stainless-steel vessel. This type of test can also be performed on a single-use assembly, but the test pressure needs to be less than one psi. This low pressure hold test can be used as a check during assembly manufacture, after installation and before use by the end user.

For the purpose of this article, an integrity test is defined as a test capable of detecting a defect of a known size or a correlation to a known parameter using a specific test methodology such as aerosolized bacteria or liquid ingress. A manufacturing integrity test has been specifically designed for single-use final fill assemblies using a pressure decay test based on ASTM F2095 (7). It has the ability to detect a 20-µm defect by measuring pressure decay at a higher pressure. The increased test pressure is possible through the use of a restraint plate system, though the test system is normally limited to standard configurations. 

The use of the two different tests at the site of manufacture in conjunction with the use of the test by the end user post-installation can lead to an overall reduction in risk by assessing for damage throughout the life of the assembly.

Assembly use
The final consideration is successful assembly implementation performed by the end user at the point of use. This can include:

• Confirmation of the design through applications testing
• Operator training for unpacking, handling, and transportation around the facility
• Review of all relevant product information such as validation guides, technical notes, white papers, and product dossiers.

Conclusion 
With a thorough evaluation of the assembly design process, manufacture, and use, risks associated with single-use assemblies for final sterile filling can be identified and mitigated. By mitigating these risks, single-use assemblies can be successfully implemented in all process steps including formulation, filtration, and filling operations.

References
1.  USP General Chapter <788>, "Particulate Matter in Injections," (US Pharmacopeial Convention, Rockville, MD, July 2, 2012).
2.   USP General Chapter <1>, "Injections," (US Pharmacopeial Convention, Rockville, MD, Dec. 2001).
3. TAPPI Standards: Regulations & Style Guidelines, (Norcross, GA, March 2013).
4.  ANSI/AAMMI/ISO 11137:2006 Parts 1, 2, 3, "Sterilization of Health Care Products--Radiation," Association for the Advancement of Medical Instrumentation, (Arlington, VA, 2006).
5.  AAMI TIR33, "Sterilization of Health Care Products-Radiation-Substantiation of a Selected Sterilization Dose Method VDmax," (Association for the Advancement of Medical Instrumentation, Arlington, VA, 2005).
6. ISTA2a, "Partial Simulation Performance Tests, 2A Packaged Products Weighing 150 lb. (68 kg) or less," (International Safe Transit Association, East Lansing, Michigan, 2011).
7. ASTM F2095, "Standard Test Methods for Pressure Decay Leak Test for Flexible Packages with and without Restraining Plates,"(ASTM International Subcommittee F02.40, Conshohacken, PA, July, 2013).

About the Author
Sue Walker is a global product manager for Mobius Final Fill at  EMD Millipore, Bedford, MA,

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