Biopharmaceutical companies undertaking Quality by Design (QbD) initiatives find themselves in the quandary that accompanies any significant advance in life sciences manufacturing: If we implement a far-reaching change in the way we operate, what will it mean to our compliance status? In the case of QbD, the question is even more confounding because QbD represents a profound change in the nature of compliance itself.
Chester A. Meyers, PhD
The increased scientific understanding of products and processes that lies at the heart of QbD makes it possible for manufacturers and regulatory agencies to focus on critical control points and parameters necessary to ensure that products meet quality attributes. They can then base compliance on risk—the probability that as long as the multi-dimensional combination of input variables and process parameters remains within the validated design space, or are otherwise controlled to achieve specified product attributes, then product quality is ensured.
For manufacturers, that will mean establishing an integrated quality system designed to accommodate the far more holistic and flexible approach to compliance that QbD requires. For regulators, it will mean understanding the decisions that manufacturers make when manufacturing their products instead of relating current good manufacturing practices (cGMPs) to a set of rigid and highly complex requirements.
QUESTIONS OF COMPLIANCE
Unfortunately, there is no template that biopharmaceutical companies can follow to establish their approach to compliance under QbD. The step 2 draft of the ICH Q11 guideline, Development and Manufacture of Drug Substances, which is intended to bring together and clarify issues related to quality systems raised in previous ICH guidelines, will not be released until late 2010. Even then, it is likely to provide only a framework for compliance, not a step-by-step guide to creating the organization, policies, and processes that are most likely to take best advantage of the opportunities promised by QbD: greater assurance of quality, reduced costs through less rework and rejected batches, and a lighter regulatory burden.
Furthermore, QbD tools will continue to evolve. Today, documentation of a design space is the preferred approach to risk-based quality assurance (QA) because we have the tools and technology to determine it. However, process analytical technology (PAT) will continue to improve and eventually could become capable of controlling a manufacturing process in real time. When that occurs, there may no longer be the need to document a wide, multidimensional design space. As long as we know how the process relates to the product output, PAT would be able to ensure product quality at all times.
With no compliance template and the continued evolution of QbD tools, biopharmaceutical companies face a host of questions about the specifics of compliance, including:
- How will implementing QbD and quality risk management (QRM) strategies affect my current cGMP compliance status? How will I know about a change in that status?
- Will agency audits be looking at traditional GMPs (i.e., deviation reports) when we've incorporated risk-assessment decisions and processes? If so, for what purpose?
- If there is movement trending within the design space, when do we implement a change? Who decides? How is this decided?
- What are the regulators' expectations about how we "regulate" our operating parameters or design space? Are full-scale batches required for that purpose, or will qualified scale-down models be sufficient? (An FDA draft guidance document from November 2008 indicates the intent to reduce the need for re-establishing validated parameters at scale, but there is still uncertainty surrounding the specific compliance requirements for a validated design space.)
- When we make changes in our defined design space, do we still conduct investigations and write deviation reports?
- What trends and changes have to be part of batch records? What changes are for information only and what has to be a part of required batch documentation?