Risk Assessment and Mitigation in Biopharmaceutical Manufacturing

Published on: 
BioPharm International, BioPharm International-07-01-2015, Volume 28, Issue 7
Pages: 34–36

The challenges and strategies of assessing and mitigating risk in biopharmaceutical manufacturing are discussed.


BioPharm International spoke with Stephan Krause, director of quality assurance, Laura Jeannel, associate director of quality assurance, and Paul Davis, senior manager of business resilience, at AstraZeneca Biologics to get the latest on performing risk management in biopharmaceutical manufacturing.

Risk Assessment Challenges in Biopharma

BioPharm: What top challenges do companies face when performing risk assessment in biopharmaceutical manufacturing compared with solid-dosage manufacturing?

AstraZeneca: In biopharmaceutical manufacturing, microbial contamination is usually the greatest overall risk. The primary factors that affect the risk of microbial proliferation during hold times are the growth-promoting properties of the in-process materials, initial bioburden level, and storage conditions. In general, when risk ranking is performed for a particular manufacturing site, microbial failure events are only infrequently observed, and similar, future events are difficult to predict. It is challenging when potential risks are scored and then ranked. Available risk scoring tools such as failure mode and effects analysis (FMEA) should be properly modified to allow suitable risk ranking of high-impact risks with respect to other less-impact risks due to the existing uncertainty factor(s) of some of the high-impact risks. 

Management reviews need to capture and aggregate risks across manufacturing campaigns to mitigate potential risks during changeover. In general, a biopharmaceutical manufacturer faces similar business continuity risks as those of traditional pharmaceutical manufacturers. 

BioPharm: Does the use of single-use systems (SUS) and/or equipment present any specific challenges or considerations when performing a risk assessment? 

AstraZeneca: The use of SUS removes some of the risks that would otherwise come with the required cleaning process (e.g., cross-contamination and cleaning residues). Risks that may arise with the use of SUS may be the dependency on the SUS supply/vendor from a business continuity perspective. From a quality risk management (QRM) perspective, the risks are usually around product/material compatibility (e.g., leachables, etc.). While one risk source may effectively be transferred outside, the internal focus then turns toward ensuring comprehensive controls are in place for ensuring vendor quality and continued supply.

Risk Mitigation StrategiesBioPharm: What strategy does your company use to mitigate risk in the manufacture of biopharmaceuticals?

AstraZeneca: To obtain the most valuable risk mitigation plans out of the formal risk-scoring process, we review and manage all risks cross-functionally. Whenever possible, we use the same risk identification, collection, and analysis tools, regardless of whether they may impact product quality and/or business continuity. Once collected, we primarily separate risks based on either potential quality/patient impact or production impact (only). Depending on the risk priority numbers, higher-scoring risks are mitigated and results reviewed and monitored by senior management. Lower-scoring risks, although individually of lesser concerns, can be trended within a given category and/or among different categories as needed.

For business continuity, all risks are assessed and have action decisions made by management, regardless of scoring level. The documented actions are tracked through to completion. Multiple risk identifying methods are maintained on an ongoing basis. To account for changes in the business environment, previously accepted risks are periodically reviewed to determine if mitigation is now required. Risk management should be a continuous process to be effective.

Using the same risk management tool and a standardized process for QRM, and all other business continuity risks, allows employees to communicate risks as they are identified within all functional areas, in a consistent manner. It is part of our quality culture to encourage all employees to submit their perceived risks. It is important that all CAPAs [corrective actions and preventive actions] identified fully address the corresponding risks and failure modes. Within our company, we have a tiered approach, which includes risk registers, for both quality and business continuity, at the site and corporate level. 


Regulatory RequirementsBioPharm: What are the specific regulatory requirements for risk assessment and mitigation in biopharmaceutical manufacturing?

AstraZeneca: We are required to follow International Conference on Harmonization (ICH) Q9 for QRM and ICH Q10 (1, 2) for the risk oversight by senior quality management. Regulatory expectations exist that risk assessments are performed as part of individual quality systems including proactive systems (e.g., training programs, self-inspections, change control, validation, etc.) and reactive systems (e.g., deviations, out of specification, supplier complaints, etc.).

It should be in the interest of the manufacturer to invest time and resources into the QRM process as the QRM results may ultimately allow for less testing, auditing, control elements, etc. Although QRM should not be used entirely for the purpose of avoiding work, it can reduce time and work required compared with when QRM is not used and all risks are equally addressed. 




Risk Assessment ToolsBioPharm: What current tools are used in risk assessment and mitigation in biopharma manufacturing? Are there tools in development?

AstraZeneca: We often use a modified version of the FMEA tool, similar to what is published in Parenteral Drug Association (PDA) Technical Report (TR) 44 and PDA TR 54 (for biopharmaceuticals) (3, 4). An FMEA is appropriate for managing risks for processes in late-stage clinical and/or commercial manufacturing. A modification of the standard FMEA table(s) may be required, or a different/simpler QRM tool can be used when assessing risks with an associated high uncertainty component. For example, when assessing initial and post-mitigation risks as part of the manufacturing plant’s control strategy for virus contamination prevention, there is likely no previous occurrence within a specific plant to score likelihood based on history (microbial contamination) and/or detectability. Although the impact score would likely be at its maximum, the occurrence/likelihood can be difficult to scale in a meaningful way. In addition, the detectability score also contains a relatively high uncertainty score as we may not have data for all critical sampling points and/or not all viruses may be detected by the available method(s).

Within development, simpler and less formal QRM tools are preferred. For example, it can be challenging to score and rank meaningfully the critical quality attributes (CQA) when developing a control strategy. Most often, there is not much patient data from the clinical studies or adverse events cannot be directly linked to specific CQA levels. The uncertainty factor often outweighs any available data or knowledge and typically drives the need for a low occurrence rating in manufacturing prior to setting the (final) control strategy.

Regardless of the tools being utilized, the most important element for success is fostering a risk-management culture throughout the organization. Risk management should be seen as the responsibility of every employee. All employees should be empowered and accountable for identifying and mitigating risk. 

The Problem of Drug ShortagesBioPharm: What role does risk mitigation play in drug shortages? Does this role affect biopharmaceuticals more or less than solid-dosage manufacturing?

AstraZeneca: For drug shortages, risk mitigation is important for many drugs, and biopharmaceuticals are no exception. Some of the reasons leading to supply shortages could be increased market demand, poor product quality and/or GMP practice, increasing regulatory expectations, or limited or competing manufacturing capacity. PDA TR 68, Risk-Based Approach for Prevention and Management of Drug Shortages, provides an excellent overview of the QRM process to prevent/manage supply shortages for biopharmaceuticals (and other drugs) (5).

When mitigating the risk of drug shortages, it is important to take a global view of the overall supply chain, in addition to establishing comprehensive risk-management programs at each manufacturing location. Each location and/or critical supply function then becomes a link in the overall supply chain. It is then a matter of developing recovery plans in the event of a disruption.

1. ICH, Q9 Quality Risk Management (ICH, June 2006).
2. ICH, Q10 Pharmaceutical Quality System (ICH, 2009).
3. PDA, Technical Report 44, Quality Risk Management for Aseptic Processes (PDA, 2008).
4. PDA, Technical Report 54, Implementation of Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operations (PDA, 2012).
5. PDA, Technical Report 68, Risk-Based Approach for Prevention and Management of Drug Shortages (PDA, 2014).

Article DetailsBioPharm International
Vol. 28, No. 7
Pages: 34–36

When referring to this article, please cite it as S. Haigney, "Risk Assessment and Mitigation in Biopharmaceutical Manufacturing," BioPharm International, 28 (7) 2015.