Enhanced process and product understanding are the basic tenets of Quality by Design (QbD). Although significant advances
have been made, appropriate characterization and management of raw materials remain a concern for the regulatory authorities.
Because of the large number of raw materials that typically are used in biotech processes, a QbD-based approach for raw material
management must be based on scientific knowledge and risk analysis. This strategy will ensure that adequate characterization
is performed on those raw materials that have the most effect on process consistency and product quality. Part 1 of this article
presented an approach for raw material management following QbD principles. In Part 2, we discuss how to conduct risk assessments
for biotech raw materials, along with examples of risk assessment tools that can be used.
The contribution of raw materials to product quality, safety and process performance is considerable, in part because of the
potential to introduce contaminants. It is therefore important in designing processes and selecting raw materials that careful
thought be given to understanding their purpose and suitability for the intended use. Raw materials also are a major source
of variability, and steps must be taken to minimize any negative effects arising from materials and their sources. There essentially
are two parts to this: prevention through assessment, inspection and control of incoming materials; and intervention, in which
processing conditions are modified to account for variability, sometimes through continued monitoring of materials and their
effect on process performance.
Anurag S. Rathore
Part 2 of this 20th article in the Elements of Biopharmaceutical Production series discusses how to conduct risk assessments, handling risk communication to stakeholders, and give examples of applying
risk assessment tools for analyzing raw materials in biotech processes.
TOOLS FOR RISK ASSESSMENT, EVALUATION, AND COMMUNICATION
There are a number of different risk assessment tools available in a range of detail and complexity, and it is important to
use a methodology suited to the purpose of the assessment. The approach begins with identification of risk factors through
brainstorming, in which ideas are recorded with minimal critical appraisal; or Fishbone or Ishikawa diagrams, which offer
a more structured approach. These can be used either to map the process generally, working backwards from the endpoint and
identifying all possible risks at a given point, or to structure the evaluation around a given sent of questions at each point
(e.g., the 6M's: material, method, measurement, machine, man, and mother nature).1,2 After they are identified, risks can be analyzed by a variety of tools, such as preliminary hazard analysis (PHA), failure
mode effects analysis (FMEA), failure mode effects criticality analysis (FMECA), What-if?, fault tree analysis (FTA), event
tree analysis, cause consequence analysis, hazard and operability analysis (HAZOP), and hazard analysis and critical control
A comparison of some risk assessment tools is given in Table 1. PHA scores risk based on severity and occurrence on a five-point
scale, with the highest scores representing the greatest risk. FMEA adds detection to the scoring system. By adding the extra
scoring category, it is relatively simple to advance a PHA assessment to FMEA, which may become appropriate as more information
is known. Additional criteria may be added to distinguish between risks to more or fewer critical quality attributes (CQAs),
bringing it to a FMECA assessment. HAZOP assessments commonly are used to evaluate risk to operators or environmental risks.
Table 1. Comparison of different risk assessment tools
The next stage of the risk assessment is risk evaluation, in which the calculated risk index rating is compared to established
criteria to determine high-risk items and whether additional information is required, and what mitigation activities are required
to bring risk to an acceptable level.
Finally, communication is an important part of any risk management plan. It is essential that the outcome of the risk assessment
is communicated to stakeholders and management and the recommendations for further mitigation or acceptance of residual risk
are taken at the appropriate level.