White Paper

Minimizing Sterile Filtration Risk Through Quality By Design

By Mark Blanchard, Research Fellow, MilliporeSigma

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Controlling bioburden throughout biomanufacturing processes is critical to assuring drug products are safe for human use. To ensure products are free from microbial contamination, multiple filtration steps are implemented across the biomanufacturing process (Figure 1).  The final sterilizing filtration prior to filling is especially critical, and filtration performance should be confirmed according to industry standards and test criteria.  Other steps in the downstream process, such as the filtration of buffers used in chromatography and TFF applications, are less critical; a filter designed for bioburden reduction may provide a sufficient level of risk mitigation against potential bioburden issues for these applications.

To achieve a robust sterile filtration process, drug manufacturers should follow industry best practices and regulatory guidelines.  For final filtration and other critical steps, filter efficacy must be validated under worst-case processing conditions, and the chosen integrity test must use specifications that are consistent with data generated during validation. 

Figure 1. Sterilizing-grade filtration is used at multiple points
in the biomanufacturing process to minimize the risk of contamination from microbes.

 

 

US FDA aseptic processing guidelines require a sterilizing filter to “reproducibly remove all viable microorganisms from the process stream, producing a sterile effluent” (1). For products that are not terminally sterilized, EMA guidelines state that solutions or liquids “can be filtered through a sterile filter of nominal pore size of 0.22 μm or less, with [a filter] with at least equivalent microorganism retaining properties” (2). In brief, all microorganisms must be removed and the microorganism retention properties of the filter must be well defined.

 

The Role of Your Filter Supplier

Although meeting regulatory and industry requirements is the responsibility of the drug manufacturer, filter suppliers play a critical role.

Filter suppliers must show that a sterilizing filter meets the requirements of the FDA Aseptic Processing Guidelines and other regulations.  These requirements define a sterilizing-grade filer as a filter which, when challenged with the bacterium Brevundimonas diminuta at a minimum concentration of 107 colony forming units (CFU) per cm2 of filter surface area, will produce a sterile effluent.

Caution should be used when evaluating filters that claim to be sterilizing because a number of historical approaches do not meet current minimum requirements. A nominal 0.2 μm filter size rating itself does not ensure sterile filtrate. The bacterial log reduction value (LRV) provides a good starting point, but it does not directly ensure that filtrate will be sterile.

The minimum requirement is reflected in ASTM® F838, which states that a filter must successfully retain all bacteria through the standard challenge test (3). Ideally, a filter will be validated with a defined safety margin above that minimum. A quantitative safety margin ensures low risk of failure.  Drug manufacturers should ensure that the sterilizing grade filter they choose, meet this requirement.

Because sterilizing filters occupy critical control points in downstream purification processes, it is important to know how consistent and reliable a sterilizing filter will be beyond the minimum standard. Filters must be designed with a quantifiably high safety margin for bacterial retention and minimum loss of flow or processing time efficiency. Evidence of design conformance should be available from your filter manufacturer, and the risk of a filter being out of specification must be low.

Applying QbD to Filter Design

At MilliporeSigma, we design and manufacture filtration system components to provide high assurance of sterility for aseptic processes by applying principles of Quality by Design (QbD) to the process.

QbD is a science- and risk-based approach for process development and manufacturing. The approach starts with definition of clinically-relevant product attributes followed by design and implementation of a process to consistently deliver quality product. FDA’s emphasis on QbD is based on the recognition that increased testing does not necessarily improve product quality.  Instead, quality should be built into the product from the beginning, based on knowledge of its characteristics and a thorough understanding of the process by which it is manufactured.

FDA’s initiative on QbD embodies key principles:

  • The product is designed to meet patient requirements
  • The process is designed to consistently meet product critical quality attributes
  • The impact of product components and process parameters on product quality is understood
  • Critical sources of process variability are identified and controlled
  • The process is continually monitored and updated to assure consistent quality over time

Consistent with those principles, a “design space” (the combination and interaction of input variables and process parameters that have demonstrated quality assurance) is defined and validated (4). From that, a “control space” for on-going filter manufacturing is developed. For sterilizing filters, this is applied to three areas:

  • Membrane design and validation during which membranes are developed with a quantified safety margin
  • Device design and validation during which retention performance is verified
  • Manufacturing process control of critical process attributes (CPAs), during which continuous conformance to the design principles is monitored and ensured

The Design Space

Designing a filter for sterility assurance begins with developing a manufacturing process within a well understood design space. The process begins with manufacturing a series of membrane samples with different membrane bubble points.  Bubble point is the minimum pressure required to force an air bubble through the largest membrane pore.  The membrane bubble point is inversely proportional to the size of the pores. Pore size is one of the primary membrane characteristics that define retention based on size exclusion.  

Bacterial retention testing is conducted on the membrane bubble point series to measure organisms in the filtrate using a standard ASTM® test method. A membrane is defined as “fully retentive” if there are no bacteria downstream following a challenge of >107 colony forming units (CFUs) Brevundimonas diminuta per square centimeter of membrane area. This organism is small in size and for most applications, represents a worst-case scenario.

Bacterial retention increases with increasing bubble points, resulting in higher sterility assurance (Figure 2). For sterilizing filters, sterility assurance of >99.9% at 107 CFU/cm2 is desired. The safety margin comes from log(CFU) = –3. With that margin, zero CFU are expected 999 times out of 1000 tests.

Figure 2. Filter specification set with high capability retention at ASTM® F838 conditions

  • Retention assurance >99.9% at 107 CFU/cm2
  • Using log (CFU) vs. bubble point, the specification is established with a safety margin
  • When log (CFU) = -3, average CFU is zero with 99.9% confidence

 

 

The Control Space

Once that safety margin has been established, we set a manufacturing range (the QbD control space) well above the sterility assurance specification. The range must also be beyond the potential measurement error for bubble point testing and the manufacturing capability must be high.

Within those safety margins, filter membranes are routinely manufactured with >99.99% sterility assurance under ASTM® conditions at a bacterial challenge load of 107 CFU/cm2.

Figure 3. Our sterilizing-grade membranes are manufactured with >99.99% sterility assurance at a bacterial challenge load of 107/cm2.

All membrane rolls at MilliporeSigma are bubble point tested during manufacturing to ensure they meet this standard and membrane manufacturing process is adjusted in real time, if necessary. In addition, ASTM® bacterial retention performance is verified for each membrane lot (Figure 4A).

Filter Device Manufacturing

To effectively support a sterile process, a membrane must be coupled with a complete device manufacturing process. For this process, all sterilizing grade devices are 100% integrity tested during manufacturing (Figure 4B). Bacterial retention performance is verified on samples from each lot of devices followed by a full panel of tests for endotoxins, extractables, flow rate, hydraulic stress, and resistance change after sterilization (Figure 4C). 

Figure 4. On-going process monitoring includes membrane lot release testing (A), in-process integrity testing (B) and device lot release testing (C).

Final Validation

Filter validation confirms the filtration device provides sterilizing performance under the user’s process conditions. Process conditions to be validated include temperature, pressure, filtration time, bioburden profile and quantity, and any conditions that may adversely affect filter materials or filtration properties (e.g., sterilization condition). The validation evaluates the filter under worst case processing conditions.

Our Commitment to Customers

Table 1. Elements of MilliporeSigma's comprehensive quality program to minimize sterile filtration risk and assure compliance.

Sterilizing filtration is a critical control point in biomanufacturing. A capable filter and thorough validation at worst case filter and process conditions can provide confidence in sterility assurance. We design sterilizing grade filters to meet regulatory and industry requirements and assure sterility by following a scientifically-based process to develop, validate, and control critical design properties (Table 1). Our membranes are designed with a high and well-characterized safety margin for bacterial retention, with further safety margin, control and monitoring provided during manufacturing. 

We understand the critical importance of aseptic processing to the success of our pharmaceutical customers and patient safety. With more than fifty years of experience and expertise in sterile filtration and industry leading products, our membranes have processed billions of sterile doses.

REFERENCES

  1. CDER/CBER/ORA. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practices. US Food and Drug Administration: Rockville, MD, 2004; www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm070342.pdf.
  2. EudraLex, Volume 4: EU Guidelines to Good Manufacturing Medicinal Products for Human and Veterinary Use. Annex 1 Manufacture of Sterile Medicinal Products. European Commission: Brussels, Belgium, 2008; http://ec.europa.eu/health/files/ eudralex/vol-4/2008_11_25_gmp-an1_en.pdf.
  3. ASTM F838-15ae1: Standard Test Method for Determining Bacterial Retention of Membrane Filters Utilized for Liquid Filtration. ASTM International, West Conshohocken, PA, 2015
  4. ICH Q8(R2). Pharmaceutical Development. US Fed. Reg. 71(98) 2009: www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf.