CDER Head Talks Quality Management Maturity

CDER director Patrizia Cavazzoni says agency inspectors are highlighting during inspections the importance of having in place effective risk-based change management and risk-based quality control. Speaking at the Parenteral Drug Association’s annual regulatory conference 9/27, Cavazzoni said this is part of FDA’s push for quality management maturity, she said, adding that it helps ensure that patients get quality drugs all the time, but also because quality problems are at the root of almost 60% of drug shortages. “So we really need to make sure that manufacturers have more mature quality management systems that really proactively focus on performance and outcomes that affect the patient, rather than only being focused on ticking boxes, and process metrics, which are of course are important as a foundation,” she told the conference.

With quality problems behind so many drug shortages, Cavazzoni said FDA is developing a draft guidance entitled Risk Management Plans to Mitigate the Potential for Drug Shortages in response to new authorities mandated in the recent Coronavirus Aid, Relief, and Economic Security (CARES) Act. She said the guidance addresses a CARES provision requiring manufacturers of drugs, active pharmaceutical ingredients (API) or any associated medical device to develop, maintain, and implement a redundancy risk management plan that identifies and evaluates risks to the supply of the drug for each establishment in which the drug or API is manufactured

According to Cavazzoni, quality management maturity is an umbrella that covers a number of domains, including quality metrics, business continuity plans, top leadership quality buy-in, quality culture, sustainable compliance, quality culture, manufacturing strategy and operations, advanced analytics, and continual improvement. She said it is a journey that begins with the foundation of current GMPs and progressing through the International Conference on Harmonization’s Q10, which outlines effective pharmaceutical quality system applied throughout the product lifecycle to facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities.

“Quality management maturity,” Cavazzoni continued, “is really the ultimate step, which measures the consistency, reliability, and robustness of the business processes established and maintained to achieve quality policies and objectives, including a focus on achieving continual process and system improvement. And the quality management system certainly pays dividends when it comes to post approval changes. We know that post approval changes represent a significant burden for manufacturers, and that the need for regulatory submissions may dissuade some manufacturers from making needed CMC [chemistry, manufacturing and controls] changes and this also has an impact on innovation.”

Quality management maturity also has an impact on manufacturers’ ability to be flexible and to adapt to changing conditions on the ground and this has not been any more apparent than during the pandemic where manufacturers had to make a lot of changes in order to ensure the continuity of the drug supply, Cavazzoni explained. “It's really an enabler for easier and greater flexibility in making manufacturing changes, because a strong quality management system will really provide more latitude for manufacturers to take sort of thoughtful risk-based approaches to CMC changes and I would refer you to ICH Q12 for more information.”

FDA has begun two pilot programs, one for finished dosage forms and the other for APIs, that will use the quality management maturity framework to obtain and incorporate stakeholder input to refine quality management implementation, according to Cavazzoni.

During her presentation, Cavazzoni also highlighted FDA concern about manufacturers of non-sterile water-based drug products and increasing contamination from Burkholderia cepacia complex (BCC). A recent agency notice says BCC is a significant pharmaceutical contaminant that has been linked to multiple instances of opportunistic infections. “Inadequate design, control, or maintenance of pharmaceutical water systems have led to contamination with BCC and other water-borne opportunistic pathogens,” the agency says…. “It is essential that manufacturing facilities, equipment, and processes are designed to prevent contamination and strict sanitary standards are continually followed. There is a long history of product recalls due to BCC contamination traced back to deviations from current good manufacturing practice requirements.”

Cavazzoni closed with recent trends seen in Warning Letters. They are:

• Low process capability or lapse in state of control (process validation)
• Deficient investigations of production or laboratory problems
• Excessive variability in component quality (supplier reliability concern)
• Chemical or microbial contamination of drug products
• Deficient facilities or equipment
• Failure to meet quality unit responsibilities, including batch release requirements