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By Paul Hurley, Associate Director, Product Development and Scale-Up, Alkermes Pharma Ireland Ltd.
The cut-off for progressing items from the risk ranking to the FMECA stage will have been agreed upon before commencing the risk assessment. Typically, all risks ranked as “high risk” will require full FMECA. The risk-ranking process does not assess the probability or severity of a risk occurring or if there are strong controls already in place.
These assessments take place at the FMECA stage. However, particularly for new processes, there are risks that must be ranked high as they directly impact a CQA, but which usually fall down the relative risk ranking when severity, probability or existing control review is applied. A recent example was the risk associated with a power outage during a fluid bed drying cycle on a machine. While a power outage would be a significant risk, the fact that the drying cycle machine had back-up power rendered it a low-risk activity.
To reduce the time associated with working risks through the full FMECA process, we have introduced a sub-process between risk ranking and the FMECA stage referred to as the “silver bullet” step. Here, unanimous agreement of both teams can render the risk acceptable based on existing knowledge. It is important that the justification for applying the silver bullet be thoroughly documented.
Three Paths to Process Quality
To further improve the efficiency of the process, multiple decision-point criteria are provided to allow the FMECA to be brought to closure. Defined in advance, these decision-point criteria allow the FMECA process to be concluded and a recommendation made as to the appropriateness of moving forward to the next stage of the tech transfer. For example, in the case study that is described below (Section B), three paths to proceed to the process qualification stage were agreed to with the donor:
1. Donor and recipient agree that the risk is acceptable.
2. Donor and recipient agree that more data is required. Donor has existing supporting data. Donor determines that risk is acceptable and takes responsibility for the risk.
3. Recipient deems the risk is unacceptable based on limited experience. Donor is prepared to accept risk.
Such decision paths are sometimes required due to the disparity in the process history knowledge between the donor and recipient sites. The key here is that the risk is considered, documented and responsibility for the risk is clearly agreed upon while allowing an efficient closure of the process via a simple declaration by the donor. Such decisions must always be made with the quality of the product and safety of patients as the primary consideration, regardless of the source of the process history knowledge.
IncludE Business Risks
While the joint risk assessment typically addresses technical risks, business or project risks that can potentially impact the tech transfer may also be included. For example, where time or material constraints are impacting the extent of engineering trials that can be performed, a risk may be included to reflect this situation. Allowing for the inclusion of such business risks ensures that both the donor and recipient have a shared understanding of the risks and are moving ahead on an agreed basis.
The inclusion of such risks may also help clarify where areas of process responsibility reside. For example, the donor may be responsible for the quality and delivery of the active ingredient, while the recipient site may be responsible for the sourcing of excipient(s).
Risk Assessment Iterations
It is important to note that the risk assessment process is iterative and is repeated at multiple points during the tech transfer. The initial assessment, including first pass FMECA, is completed after an initial data review when the donor has provided the transfer data pack and the recipient has built a first draft of the process design. These documents are used to generate a list of all possible risks to the transfer. At this point, the list can be extensive with both parties working through a process of identifying risk with a view to eliminating all risks or mitigating all risks. The objective is that no risks remain in the high-risk category as the project moves into the process qualification or registration stage.
In identifying risk controls, the objective is to identify the engineering studies, equipment upgrades and other controls required to execute the tech transfer. Depending on the complexity of the engineering studies required, the next round of risk assessment is performed at the end of the engineering campaign or at logical breaks in a larger, more complex engineering campaign. At this point, the previously identified risks are reviewed to see if they have been eliminated or reduced by the outputs of the engineering campaign. Any new risks identified during the engineering phase are also assessed. The output of this round of risk assessment allows the transfer to move forward to demonstration phase or alternatively may outline what further engineering trials or controls are required before moving on.
At the demonstration batch stage, a demonstration batch is typically manufactured employing the quality systems, facility, equipment, documentation, etc., proposed for use in the process qualification, registration or clinical supply stage, thereby test-driving the process being transferred. On completion of the demonstration batch, the final round of risk assessment is performed. Again, this round of risk assessment aims to conclude that all risks are at an acceptable level and the tech transfer may move into the process qualification or registration phase.
At Alkermes, the various rounds of risk assessments are linked into our project management system and act as important inputs into the technical reviews conducted at key project stages such as End of Engineering and Ready for Validation (and/or Registration, as appropriate) points.
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