Although there are no definitive answers to these questions, newer perspectives on risk management, knowledge management,
continuous verification, and real-time feedback, analytics, and control (including PAT) can be understood as extensions of
general GMP principles: State what will be done, by whom, and when. Define acceptable performance and outcomes. Document the
actual execution and outcome and make the whole process traceable.
Basic GMPs also provide a framework for lifecycle process management, but under QbD they need to accommodate important new
scientific justifications and data. For example, the addition of design qualification to basic equipment qualification (IQ/OQ/PQ)
requires the organization to justify that the equipment design is appropriate for its intended use. Similar justifications
must be considered for process and product profile decisions.
With these principles in mind, a biopharmaceutical company can bring together cross-functional teams to consider three key
activities central to implementing QbD: QRM, knowledge management, and change control. These activities encompass the four
elements that define products and processes as validated and compliant: critical process parameters, critical quality attributes
(CQA), critical material attributes, and relevant target product profile attributes.
By undertaking these considerations and approaches, the cross-functional teams can better frame and address the questions
arising from these activities. After they develop and prioritize the answers, they can begin to integrate the new practices
into the existing quality system and start to find the way forward.
QUALITY RISK MANAGEMENT
Traditional GMPs are a means of establishing traceability—the assurance that processes have been carried out and that the
end product conforms to specifications. But they offer no mechanism for adding scientific insight and accumulated experience
or knowledge, as there is in quality risk management.
ICH Q9 defines QRM as "...a systematic process for the assessment, control, communication and review of risks to the quality
of the drug (medicinal) product across the product lifecycle." The advantages of the lifecycle management of risk are obvious—the
continuous improvement of product and process based on continually increasing knowledge. The industry has long been comfortable
with the idea of phased-in compliance during development but has not been as good at integrating development, clinical, and
commercial data; and traditional GMPs provide little guidance.
Biopharmaceutical manufacturers cannot eliminate risk altogether. Risk-based quality management aims to reduce risk as much
as possible through continuous science-based and data-driven evaluations. In this way, QRM provides the means to achieve the
continuous improvement and integration of data that is expected from QbD implementation.
Consider, for example, the statistical evaluation of the design space or process capability. Multivariate statistical analysis
tools are required for this exercise. Effective execution requires personnel with expertise in both the process and statistical
analysis (but not necessarily in GMP compliance). The tools and data that are used may vary with the specific process under
analysis, and also with the risks associated with that process. Further, acceptance criteria may not always be prescribed
with this approach, as they are for such items as a Certificate of Analysis or validation criteria. Rather, acceptance criteria
may result from the risk analysis and the evaluation exercise.
Because these analyses do not follow a traditional GMP/SOP format, compliance in a QbD environment is better suited to evaluating
how the exercise was carried out, for example, by asking:
- Were the right individuals involved in the risk analysis and statistical evaluation?
- Were all appropriate sources of data considered?
- Were the analyses conducted and documented appropriately?
- Were the outcomes and mitigations consistent with the risk profile?
- Do the decisions (changes) better ensure that the target product profile is achieved?
- Were the decisions communicated effectively?
With these characteristics of QbD, QA scrutiny should be concentrated at the level of process, not outputs. And, statistical
analyses of process and analytical data will now become justifications for further process controls and changes. They also
become the platform of knowledge for other products.
Furthermore, traditional QA metrics revolve around days to review records and closing deviations and corrective and preventive
actions. In many companies, the sheer volume of records has created the need to do only spot checks. Better metrics might
gauge whether problems were actually solved or proposed mitigation plans actually work. In other words, compliance needs to
be measured in terms of the effectiveness of quality systems. Further, because deviation within the design space is acceptable,
risks must be calculated in real time for the company to decide whether to continue processing when an excursion is encountered.
Therefore, those who are doing real-time assessment must have access to the knowledge and tools they need to do the job—elevating
knowledge management to more than a mechanism of record-keeping for purposes of traceability.