The US Food and Drug Administration's quality-by-design (QbD) initiative emphasizes a science- and risk-based approach to
pharmaceutical manufacturing. A pharmaceutical quality system is a crucial aspect in realizing current good manufacturing
practices (CGMP) as well as in meeting harmonized guidelines for quality. The International Conference on Harmonization (ICH)
Q10 Pharmaceutical Quality System specifies the modern quality system needed to establish and maintain a state of control that can ensure the realization of
a quality drug product and facilitate continual improvement over the product's life cycle. Guidelines also extend to the outsourced
relationship. To gain a regulatory perspective on ICH Q10 as it relates to contract manufacturing, Patricia Van Arnum, senior
editor of Pharmaceutical Technology, discusses these issues with Grace McNally, senior policy advisor in the Division of Manufacturing and Product Quality in
the Office of Compliance at FDA's Center for Drug Evaluation and Research.
As in any outsourced relationship, the quality of a product ultimately resides with the sponsor company. From a regulator's
perspective, as pharmaceutical companies move to a QbD paradigm, what specialized requirements and mindset should sponsor
companies have when working with contract manufacturers? Are there considerations in terms of technology transfer or other
areas unique to the outsourced relationship that are particularly important?
Contract manufacturing does present special challenges. The CGMP regulation requires that manufacturing processes are well
designed, scientifically shown to consistently produce quality drugs, and are maintained in control. Quality by design leads
to better product and process understanding, including how variability in formulations, components, and unit operations impact
the process and the product. This understanding helps companies predict process performance upon scale-up achieve more targeted
and appropriate process controls. As noted in Q10, scale-up then provides more information: 'Monitoring during scale-up activities
can provide a preliminary indication of process performance and the successful integration into manufacturing. Knowledge obtained
during transfer and scale-up activities can be useful in further developing the control strategy.'
In order to more appropriately capture and react to signals that indicate process drift, control problems and/or substandard
product during commercial production, it is useful for the contract manufacturer to have some background on process development,
as this information must be integrated into their strong quality system. A great deal of forethought and planning is necessary
to assure conformance to CGMP and establish a state of control. Knowledge management throughout the life cycle then builds
on this foundation to maintain process control. Companies that outsource manufacturing operations need to consider what product
and process knowledge is necessary for the contractor to fulfill their responsibilities and how to impart that knowledge during
technology transfer, and thereafter how to effectively monitor the performance of the process they are contracting out.
While information from the routine production experience must be communicated back to the owner of the product, and the contractor
also must share responsibility for the process design and process improvements and changes. All drug manufacturers are required
under CGMP to periodically evaluate the quality standards for each drug product to determine the need for changes in specifications,
manufacturing, or control procedures. Both the sponsor and the contract manufacturer share this obligation. Good communication
and establishing clear agreements and expectations between the two parties is essential.
ICH Q10 Pharmaceutical Quality System addresses the outsourced relationship and the attendant quality requirements. Can you
provide some insight into the agency's expectations for a contract manufacturer under ICH Q10?
The agency would expect a contract manufacturer to develop and implement its own quality system complete with the elements
described in this guideline, for example:
- Process-performance and product-quality monitoring system
- Corrective action and preventive action (CAPA) system
- Change-management system
- Management review of process performance and product quality
These aspects of ICH Q10 are considered fundamental to CGMP conformance. The contract manufacturer and the sponsor/product
owner must discuss and mutually agree upon how the quality system elements will be handled during each stage of the product
life cycle, for example, product development, technology transfer, and commercial manufacturing.
The agency expects that sponsors/product owners perform due diligence in qualifying contract manufacturers, and that responsibilities
and information-sharing procedures are well defined in a written agreement including investigations of out-of-specification
(OOS) results, rejects, and deviations.