But there are subtle differences between the two. The EMA guideline does not divide process validation into stages. It also allows for a hybrid approach that combines the new process validation guidance with the traditional approach; FDA requires that the new guidelines supersede the traditional practice. Risk assessments should be based on sound science, process characterization information, and data collected from both scaled-down models of the manufacturing process and actual product batches produced during clinical development and scale-up.
The data should include information about the source and quality of all materials used in the manufacturing process, as well as the effect of each material or procedure used in the process on the quality, efficacy, and safety of the final product. Risk assessments should be conducted throughout the product life cycle, starting with process design and continuing through ongoing assessment of commercial manufacturing operations. Risk assessment approaches used initially to determine product critical quality attributes CQAs include risk ranking and preliminary hazard analysis PHA.
These are illustrated in a case study for a monoclonal antibody bioprocess development, which is a practical guide on how to use both QbD and life cycle approach to validation. Risk assessments should be conducted at phase-appropriate intervals, and any time that changes are made to the manufacturing process. Depending on situation and need, they can, and should be, both formal and informal. As the product matures and additional process knowledge accrues, risk assessment and analysis will become more comprehensive, helping to determine the potential effects of even subtle manufacturing process changes on product quality.
The glycosylation of recombinant proteins, for example, can be altered by a range of factors associated with cellular metabolism and metabolic flux as well as the efficiency of the glycosylation process.
The potential risks associated with raw materials, process equipment, and manufacturing processes on biopharmaceutical product quality should also be part of the evaluation. The criticality of these risks should be determined, as should methods or policies designed to eliminate, mitigate, or control them. A quality risk management program will define and prioritize the operating parameters that must be controlled during a manufacturing process. In alignment with QbD, quality risk management acknowledges that it is not possible to achieve control of product quality by final product testing alone.
These CQAs should then be maintained throughout the product life cycle by carefully controlling and monitoring those CPPs that may affect them. This approach allows a manufacturing process to be optimized or changed as long as design space parameters are maintained. Staying within the process design space will eliminate the requirement for revalidation of the manufacturing process, encourage innovation, and allow process changes to be implemented with minimum regulatory delay and expense.
An additional useful tool in conducting an initial risk assessment is the Ishikawa or fishbone diagram, which can be used to identify all possible causes for a given effect. Such an analysis is helpful, for example, in evaluating how different process parameters might affect certain process attributes. In the A-Mab case study mentioned earlier, 9 a fishbone diagram was used to identify equipment design, control parameters, processing conditions, and starting materials for a production bioreactor and its seed reactor that might have posed a significant risk to the quality attributes of a monoclonal antibody product.
This analysis, shown in Figure 2, helped assess the potential effect of each process parameter on product yield and cell viability of the culture. It also identified soluble aggregates, variability in glycosylation, deamidation, and levels of host cell protein or DNA at harvest. Before initiating any risk assessment the scope must be defined, the risk assessment tool chosen, an appropriate team selected, and any potential decisions that will be based on the assessment clearly stated.
Defining the scope of the risk assessment will also help determine the proper team composition. Risk assessment teams should include all individuals required to bring the necessary expertise to the assessment; they may include representatives from validation, process development, quality, and manufacturing. This risk assessment tool can be used to rank quality attributes based on the probability and severity of failure by leveraging prior knowledge to identify future risks to the patient.
FMEA is a methodology for identifying potential failure modes for a product or process; it is designed to assess the risk associated with those failure modes and to classify the severity of failures on the product or process. FMEA analysis ranks potential failure modes and identifies corrective actions to address the most serious concerns.
FMEA considers three factors in evaluating the effect of a failure: These factors are assigned scores determined by the scale assigned for each one. The scores are multiplied to calculate the RPN, which ranks the failure mode, prioritizes risks, and evaluates risk mitigation. This systematic preventive approach to product safety addresses hazard identification, evaluation, and control rather than finished product inspection.
Used for years in the food industry, 14 HACCP can be applied to biopharmaceutical product development and manufacturing as a means of identifying the points in a process at which specified critical control points may be controlled, the limits of control available, monitoring requirements, and required corrective actions.
For most biopharmaceutical product manufacturing processes, FMEA is generally used to determine risks associated with the manufacturing process. For those manufacturing processes where controlling hazards is a critical issue, however, HACCP may be more appropriate. This is because HACCP focuses on critical control points to prevent or eliminate hazards and risk, while FMEA focuses on the potential effects of any identified failure mode.
An HACCP analysis, for example, may be better suited than an FMEA analysis for determining risks when a filling process for a biopharmaceutical molecule conjugated to a toxic compound relies heavily on environmental and manufacturing controls to ensure not just product quality, but patient and operator safety.
Risk ranking is used to assess product quality attributes and determine which must be controlled as CQAs. Risk ranking evaluates quality attributes based on their potential to affect the patient adversely multiplied by the level of confidence in the knowledge used to determine that effect. Scoring for each category should be established using a numerical system commensurate with the criteria for each category. The numerical scale used is considered arbitrary, provided it gives appropriate to the impact score.
Risk ranking does not take into consideration the detectability or controllability of a failure; as a result, the criticality score will not change as product and process knowledge evolve.
It will change, however, as understanding of the product increases. Risk ranking should be used during the initial assessment of product quality attributes and reevaluated over the course of the product life cycle at phase-appropriate intervals. An example of the type of risk analysis and ranking that can be used to assess the impact of raw materials or process parameters on product quality attributes and the assignment of CQAs is provided by Boychyn and Hart, who applied this approach in assessing the risk of adventitious agent contamination of raw materials used in cell culture media.
These factors had a risk potential several orders of magnitude greater than the next-highest set of raw material risks evaluated. As a result of this analysis, cell culture media containing the highest-risk raw materials should be subjected to viral inactivation processes before they are used in product manufacturing.
A similar analysis by Kiss concluded that the highest-impact risk mitigation strategy was to provide an efficacious virus barrier at the point of use in the manufacturing facility.
In this modernized approach, manufacturing processes are continually reviewed during routine manufacture to ensure that adverse trends are identified and corrected before the product fails to meet its final specifications. These new process validation guidelines promote designing quality into the product rather than simply testing for quality in the finished product.
As defined in the FDA January guidance, the life cycle approach specifies that traditional process validation, which typically relies on three consecutive successful full-scale conformance runs, should be replaced by a deliberate design process, commercial process qualification, and ongoing review of processes with increased use of continuous process monitoring.
As knowledge about the safety and efficacy of a product increases during its clinical development, so too does the knowledge of its manufacturing process. Now the CQAs of the product and CPPs of the manufacturing process, initially defined during process validation Stages 1 and 2, are continuously monitored and verified during Stage 3.
This requirement for continued process verification remains throughout the commercial life of the product. During process design, the manufacturing process is developed, characterized, and then scaled up to commercial levels as outlined earlier in this paper. During Stage 1, product CQAs should be identified and the critical and key process parameters for the manufacturing process defined.
As described below, much process design and process development work can be done using scaled-down process models and high-throughput development techniques. FDA guidance recommends using statistical design of experiments to study the interaction of different process parameters using multivariate experiments.
During Stage 1, a standardized approach such as that outlined in Figure 4 allows all unit operations, analytical methods, and product specifications to be scrutinized carefully and developed properly. Each CPP in the manufacturing process should also be classified. These additional classifications, while not an absolute regulatory requirement, can be helpful during routine manufacturing to determine acceptable responses to process deviations or excursions.
Non-CPPs may be divided into two discrete categories, key and non-key process parameters, in accordance with the definitions established by the Parenteral Drug Association. Non-CPPs that do not affect product quality, but may affect process performance such as yield, are classified as key process parameters KPPs.
Non-key process parameters non-KPPs are those that have no effect on process performance or product quality. However, it is possible to define categories of process parameter criticality to meet individual program requirements. By agreeing to these rules you permit FaaDoOEngineers. You also permit FaaDoOEngineers. Also we would share you promotional emails and SMS from our advertisers, on your registered email ID and registered mobile number. By agreeing to these rules you also permit FaaDoOEngineers.
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