Applying Quality by Design to Sterile Manufacturing Processes - Pharmaceutical Technology

Latest Issue

Latest Issue
PharmTech Europe

Applying Quality by Design to Sterile Manufacturing Processes
The author reviews the draft guidance on process validation, its QbD applications, and its potential impact on sterile manufacturing operations.

Pharmaceutical Technology

In November 2008, the US Food and Drug Administration issued a much needed document titled, Draft Guidance for Industry on Process Validation: General Principles and Practices. The draft guidance clarifies the quality-by-design (QbD) approach to processing human and veterinary drugs, including biologics, active pharmaceutical ingredients (APIs), and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).

Quality-by-Design overview
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 This article provides an overview of FDA's draft guidance on process validation and QbD's impact on sterile manufacturing operations.

Manufacturing process

The following sections discuss how the draft guidance may influence the manufacturing process and product development.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).

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.


blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
| Weekly

What role should the US government play in the current Ebola outbreak?
Finance development of drugs to treat/prevent disease.
Oversee medical treatment of patients in the US.
Provide treatment for patients globally.
All of the above.
No government involvement in patient treatment or drug development.
Finance development of drugs to treat/prevent disease.
Oversee medical treatment of patients in the US.
Provide treatment for patients globally.
All of the above.
No government involvement in patient treatment or drug development.
Jim Miller Outsourcing Outlook Jim MillerOutside Looking In
Cynthia Challener, PhD Ingredients Insider Cynthia ChallenerAdvances in Large-Scale Heterocyclic Synthesis
Jill Wechsler Regulatory Watch Jill Wechsler New Era for Generic Drugs
Sean Milmo European Regulatory WatchSean MilmoTackling Drug Shortages
New Congress to Tackle Health Reform, Biomedical Innovation, Tax Policy
Combination Products Challenge Biopharma Manufacturers
Seven Steps to Solving Tabletting and Tooling ProblemsStep 1: Clean
Legislators Urge Added Incentives for Ebola Drug Development
FDA Reorganization to Promote Drug Quality
Source: Pharmaceutical Technology,
Click here