Role of Risk Assessments in Viral Safety: An FDA Perspective

Available guidance documents, such as the International Conference on Harmonization (ICH) Q5a: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin, delineate principles to consider when assessing the viral safety of biotechnology products (1). The risk of viral contamination is a feature common to all biotechnology products derived from cell lines. Such contamination could have serious clinical and/or manufacturing consequences, and if a facility is shut down for prolonged periods, a potential stock-out situation may ensue. Viral contamination can arise from the contamination of the source cell lines themselves or from adventitious introduction of virus during cell culture production. It is expected that the safety of the products with regard to viral contamination can be reasonably assured only by the application of an effective virus testing program and the assessment of virus removal and inactivation achieved by the manufacturing process. Because of the complexity and diversity of sites, processes, and products, a systematic risk assessment, management, and response program is extremely helpful. Here we present a model failure mode and effects analysis (FMEA) example for assessing risks for viral contamination of biotech manufacturing processes. This approach is based on the principals and process of the Quality Risk Management guideline ICH Q9 (2). Such a comprehensive approach is warranted for evaluating the impact of potential viral contamination at different points in the product lifecycle and for communicating this understanding across different disciplines and organizations.

The purpose of the approach is to utilize risk management tools to assess and evaluate the overall potential risks associated with viral safety in drug substance (DS) sites for monoclonal antibodies and related products. For the purposes of this exposition, the scope of our featured model risk assessment will mainly focus on occurrence (related to DS manufacturing) of the potential risks associated with viral contamination. It should be noted that a full FMEA will also have factors in severity and detectability as well.

According to ICH Q9 Quality Risk Management, risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. Quality risk assessment is a systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risk associated with exposure to those hazards. Quality risk management is a systematic process for the assessment, control, communication, and review of risks to the quality of the drug (medicinal) product across the product lifecycle. FMEA is one of several potential risk assessment tools listed in ICH Q9, and as such a systematic method of identifying and preventing product and process problems before they occur. Here in our model risk assessment, the failure mode (unwanted) is any potential viral contamination and the effects analysis is the potential impact to the product's safety/efficacy profile, potential harm to the patient, as well as resource drains associated with facility cleaning and down time.

There are three factors in the FMEA tool: severity, occurrence, and detectability. Severity is the potential negative impact of a risk factor on product safety and/or efficacy profile. For any potential viral contamination, the severity is difficult to precisely gauge, but should be assumed to be high. This is because while not all viruses are necessarily pathogenic to humans, any contamination could prompt a facility shutdown and decontamination, a resource draining situation. Occurrence is the frequency or the likelihood that the cause of the failure and/or contamination will happen. Historically, this has been low, but not zero as evidenced by periodic reports of contaminations (Garnick, 1996 (3); Khan et al., 2012 (4)), etc.). Detectability (detection with an appropriate control strategy) is the likelihood that the cause will be detected prior to product release. Detectability is important because it facilitates the identification and correction of failures before they cause harm to the patient. Detection can occur at any point of the process (e.g., in raw materials, in cell culture, etc.), but is enhanced by a strategy where multiple points of the process is tested.

One important point regarding the detectability is that the ranking system for detectability is the reverse of the severity and occurrence ratings, which means a high detectability has a low ranking. The overall risk can be defined by a risk prioritization ranking (RPR) or a risk prioritization number (RPN) in which RPR or RPN is the combination of severity, occurrence, and detectability. RPR is a qualitative method for determining the level of risk by combining severity, occurrence, and detectability rankings of the failure or event, while RPN is a quantitative method for determining the level of risk by multiplying the severity, occurrence, and detectability rankings of the failure or event. Severity is always potentially high when considering risk assessment for viral contamination, therefore it remains constant. In the RPN system, a high constant number, such as 10, could be assigned. Then the RPR and/or the RPN become a combination of occurrence and detectability. Table I shows an example of the proposed model risk assessment. Both the RPR and the RPN can be used; however, lack of granularity in a RPR system may make the ranking more subjective. Therefore, this model assessment would prefer to use the RPN rating system.

The potential sources of risks on the manufacturing of DS are listed as follows:

1. Difficult-to-screen raw materials (control, source, and origin)

2. Susceptible expression/production system (in vitro or in vivo)

3. Open upstream process system (process difficult to control, e.g., ascites, roller bottles)

4. Inadequate downstream purification process

5. Inadequate ICH Q5a-compliance of the manufacturing process

In our model, a risk assessment is performed for each potential source element listed above, and our proposed scores are shown in Table II.Table III shows the proposed overall risk assessment with the sum of RPN from each individual risk assessment to evaluate the overall potential risk. At this point, we have not established a threshold value for directed follow-up, but this will be determined through gained experience, and an on-going dialog with invested parties.

Risk of adventitious agent contamination including viral contamination in biotech products is always complex. Overall potential risk of adventitious agent contamination including viral contamination in biotech products could include the following: the risk to patients/personnel from direct infection, the risk to product availability for patients with life-threatening illness, and the risk to other products in the facility and/or the risk to product quality. Therefore, when we perform any risk assessment and management, we need to evaluate the all consequences associated with the risk adventitious agent contaminations. Listed in Table IV are three examples regarding risk management factors related to alternative products (availability) and good manufacturing practice (GMP) compliance history, including inspection history and GMP compliance status.

In conclusion, our model FMEA measures the impact of viral contamination on DS manufacturing sites. This is potentially useful in evaluating and controlling the potential risk of the viral safety. However, any risk assessment and management must ultimately be considered on a case-by-case basis using the best available science and previous experience. CDER chemistry, manufacturing and controls (CMC) reviewers will welcome feedback regarding our model virus safety FMEA, including proposals for refining ratings, setting thresholds, and continuously monitoring and improving the virus safety evaluation process. We believe that through knowledge and experience through the on-going risk- and scientific-based review process, and data from some retrospective studies, product safety will be improved going forward.

• © PDA, Inc. 2014