The US pharmaceutical industry has experienced great advancements in development and control of manufacturing processes in
the recent past. The quality-by-design (QbD) effort has transformed new product development, resulting in more sophisticated
development and manufacturing approaches. Implementation of modern technology that is now commonplace in the pharmaceutical
manufacturing environment has been facilitated by QbD. While celebrating QbD technical process advancements, the industry
has simultaneously experienced several negative well-publicized events, mainly regarding issues with the supply chain and
contamination of products—all deficiencies in compliance. These events were not caused by manufacturing process problems but
rather by deficiencies in compliance. Some events were caused by deliberate criminal actions, such as economically motivated
adulteration (e.g., the heparin substitution by oversulfated chondroitin sulfate in 2008). Other problems, however, were preventable
(e.g., the Viracept cleaning in 2006, in Germany) and certain business factors (e.g., inexperienced and reduced headcount)
may have contributed to these situations.
Basis for approach
The proposed approach to quality systems and compliance throughout the entire drug product life cycle includes the new concepts
of compliance by design (CbD) and a compliance master plan (CMP). This organized approach is based on the following:
Quality by design. Key aspects of QbD include the quality target product profile (QTPP), critical quality attributes (CQAs), formulation and
process design and development, critical process parameters (CPPs), critical material attributes for drug substance and excipients,
risk assessment, design space, scale up, and control strategy (1). The product and manufacturing process is continually monitored
and updated to ensure consistent quality during the product's commercial life cycle. Changes and continuing improvements in
product and process are expected.
Life-cycle approach to process validation.
The life-cycle approach to process validation has significantly expanded the focus of validation to include product design
and development through postvalidation monitoring. The life-cycle approach to process validation guidance has been discussed
for more than five years and was finalized by FDA in January 2011 (2). The three stages of the life-cycle approach to process
validation include process design, process qualification, and continuous process verification.
Validation master plan.
The validation master plan (VMP) is a well-accepted document in pharmaceutical manufacturing (3–5). Auditors almost always
request the VMP in regulatory audits.
Compliance by design
Applications of the QbD approach to pharmaceutical development and manufacturing can be fundamentally conceptualized and simplified
for application to quality systems as follows:
CbD design and objectives.
The CbD design and objectives provide comprehensive expectations and critical attributes for a quality system. Just as a
QTPP and CQAs are determined for a product being developed, compliance objectives and attributes are determined for a quality
system. When implementing this approach, one might ask, Is the system appropriately designed to accomplish quality system
CbD critical parameters.
The CbD critical compliance parameters are essential activities to ensuring that systems objectives and quality attributes
are accomplished. Just as CPPs directly affect the CQAs of a product, crucial compliance parameters may affect the accomplishment
of attributes for the quality system. What parameters may affect successful accomplishment of objectives?
CbD input variation and control.
The CbD input variable control strategy identifies potential changes or variables that might affect the quality system and
provides a proactive method for their control.
CbD ongoing maintenance and management.
CbD ongoing monitoring and maintenance activities contribute to continuing the success of the quality system. What will be
monitored to maintain successful system performance to meet objectives?
Process analytical technology (PAT) and risk analysis.
Just as PAT is recommended for real-time process control and minimizing variation, similar technology should be implemented
as appropriate for quality systems applications. For instance, real-time monitoring and control of a warehouse would be a
practical application, especially for areas where temperature-sensitive products are stored. Priority for implementation should
be assigned to the highest risk applications.