A Perspective from FDA on ICH Q10 Pharmaceutical Quality System for Contract Manufacturers

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.

PharmTech: 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?

McNally: 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.

PharmTech: 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?

McNally: 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.

PharmTech: In evaluating implementation of ICH Q10, certain questions may arise for both the sponsor company and a contract manufacturer. Can you offer insight into some of these issues, looking first at how a company might demonstrate implementation of a pharmaceutical quality system in accordance with ICH Q10?

McNally: Under CGMP, companies should develop procedures governing their quality system. Evidence that process performance, corrective actions and preventive actions, and changes are appropriately evaluated and implemented are typically requested during an inspection. Evidence of management reviews should also be available.

FDA's own inspection guidance (7356.002) to investigators requires coverage of the quality system during every inspection. We expect the quality unit to establish procedures and ensure that effective oversight and monitoring mechanisms are in place to detect actual or potential quality problems and react in timely manner. We expect management to fully empower the quality unit with the responsibility and authority to be effective.

PharmTech: What information and documentation of development work would be required at a manufacturing site?

McNally: The contract manufacturer should have all necessary drug formula, component, process information, and knowledge to enable the site to capably perform the manufacturing operation under contract, including any quality-assurance activities associated with the manufacturing operation. Contract manufacturers should have information on site or readily available to facilitate appropriate response to new or unexpected product results or process experiences, as well as proper handling of intended or unintended changes.

The agency expects sponsors and contract manufacturers to establish clear communications and effective collaboration to ensure product quality.

PharmTech: Will ICH Q10 certification be required?

McNally: No.

PharmTech: Will the inspection process be changed either in terms of the inspection itself or related documentation?

McNally: FDA already had a quality-systems inspection program in place that is closely aligned with basic principles found in ICH Q10. There is no current plan to revise the CGMP surveillance inspection manual or change the need for all routine inspections to cover the quality system.

For further perspectives on ICH Q10 and quality by design for outsourcing, see PharmTech's January 2010 cover story, Quality by Design: Adding Another Dimension to Outsourcing.