US FDA Views on QRM in Design, Control, and Maintenance

Rick Friedman

Deputy Director, Office of Manufacturing Quality

FDA/CDER

Friedman began by emphasizing the importance of compliance as it applies to pharmaceutical manufacturing regulations and defined compliance as “the act or process of complying with a regimen” and “the degree of consistency and accuracy with which a prescribed regimen is followed.”

He said that US FDA’s Current Good Manufacturing Practices (CGMPs) provides a foundation for compliance and also a continuing state of control in quality pharmaceutical manufacturing as the CGMPs both prescribe and provide a proactive and preventive-focused quality system.

He listed the risks associated with CGMP non-compliance to include:

• Inadequate practices in supplier management and facility design and maintenance
• Contamination and cross-contamination
• Lack of robust systems and data integrity
• Poor excipient quality

In contrast, good compliance can provide:

• Quality risk management
• Data integrity
• Supplier oversight
• Patient safety

Friedman maintained that it was the responsibility of senior management to ensure high manufacturing capabilities by utilizing robust manufacturing processes that will, in turn, yield high quality output, as compared to low manufacturing capabilities that will yield unacceptable products.

Friedman presented a case study in which a company’s primary focus shifted to reducing both capital expenditures and operational costs – even as production and time pressures increased –which decreased investment in their facilities and reduced the number of employees, including subject matter experts (SMEs). He blamed senior management’s poor decisions for the overall negative impacts, which included increased product variability and reduced product quality.

In contrast, he cited a company that was driven by quality risk management (QRM). This company consistently reinvested in their facility and made timely upgrades in equipment, thus yielding long-term cost savings, fewer production delays, and fewer supply interruptions.

Friedman spoke on how QRM and maintaining data integrity could better facilitate hazard identification and also help map vulnerabilities leading to reduced risk. He also discussed digital transformation as a tool to help a firm better comply with regulatory standards.

He listed three aspects of digital transformation that could provide efficiency advantages:

• Suitability (appropriateness) for intended use
• Data integrity
• Facility capability

Citing ICH Q9(R1), Friedman said that a technology’s fitness for use was critical for reducing risks related to emerging technologies, adding that the application of digitalization and emerging technologies can lead to risk reduction, but only when the technologies are fit for their intended use; otherwise, they may introduce other risks that need to be controlled.

Friedman drew attention to the production of industries other than the pharmaceutical industry, such as agriculture, aviation, health care, and the electronics/semiconductors industry – all of which have demonstrated the business value and advantages of employing higher capability technology. The advantages include better yield, faster turn-around, earlier detection of unexpected downtime, faster market launches, and increased product quality.

Friedman also suggested that paying daily attention to CGMP and using QRM could lead to robust processes, continual improvement, and dependable supply. He added that CGMPs are not reducible to a checkbox approach but, instead, require a commitment to quality assurance through facility and systems design, as well as vigilant product lifecycle oversight.

He concluded by saying that high manufacturing capability determines output quality, and that highly capable technology is essential to assuring pharmaceutical quality, He added that employing CGMPs and QRM can lead to robust processes and continual improvement and high capability. However, he warned that companies with low manufacturing capability will receive extra US FDA scrutiny.