In November 2008, the US Food and Drug Administration issued a much needed document titled, Draft Guidance for Industry on Process Validation: General Principles and Practices. The draft guidance clarifies the quality-by-design (QbD) approach to processing human and veterinary drugs, including biologics,
active pharmaceutical ingredients (APIs), and medical devices. Although the document may have been better titled "process
design," it has addressed many industry concerns regarding how to take a life-cycle approach and how to meet regulatory expectations
with regard to validation. Many questions still remain, however, and industry must grasp and integrate the proposed guidance
concepts along with the International Conference on Harmonization's guidelines Q8 Pharmaceutical Development and Q9 Quality Risk Management (1, 2).
Individuals working in pharmaceutical sterile development and manufacturing will undoubtedly be the most affected by regulations
associated with QbD because of the unique associated technologies, processes, and products currently in use and development
(see sidebar, "Quality-by-Design Overview"). Many of these technologies require new manufacturing processes that support existing
traditional fill-finish operations. Many facilities, utilities, processes, and equipment may need to be modified (e.g., improving
controls to reduce variability). This article provides an overview of FDA's draft guidance on process validation and QbD's
impact on sterile manufacturing operations.
The following sections discuss how the draft guidance may influence the manufacturing process and product development. Processes
addressed include manufacturing, aseptic manufacturing, lyophilization (freeze drying), and others that depend on multiple-unit
operations (see Figure 1).
Figure 1. (ALL FIGURES ARE COURTESY OF THE AUTHOR)
Process design is typically the biggest challenge for a company's process development team and has tremendous impact on the
success of the product. Sterile manufacturing has become increasingly more complex because of the increase in the number of
poorly stable compounds, new technologies, unit operations, and controls. Numerous biotechnology companies, for example, use
unique freeze–thaw systems to support dispensing and bulk-drug storage at temperatures often ≤ –80 °C that provide complete
control of bulk-drug thawing, dispensing , freezing, and storage.
FDA's draft guidance suggests that the process development team design a process suitable for routine commercial manufacturing
that can consistently deliver a product that meets its critical quality attributes (CQAs). The team's objectives are to: understand
the sources of variation, detect presence and degree of variations, understand the impact of variation on the process and
product attributes, and control variation in a manner that is commensurate and proportionate to the risks presented to the
process and product. FDA further recommends an integrated team approach, with members representing multiple disciplines. The
team should have solid project-management skills and archiving capabilities, be able to capture scientific knowledge and maintain
project plans, and have full senior-management support. The latter may involve regular reports or presentations to senior
management (3, 4).
In addition, the draft guidance calls for process decisions and justifications of control to be documented, internally reviewed,
and preserved for later use in the product life cycle. Verification and mapping of the process design through to commercial
documentation is required and planned changes should be documented and justified. Finally, after the performance qualification
(PQ), a report documenting and cross-referencing results, data, issues, nonconformances, corrective actions, and overall conclusions
regarding whether the process is in an adequate state of control must undergo management review and approval.