CPHI Worldwide experts propose new FDA quality metrics system and recommend critical formulation attributes

Continuous processing at a ‘tipping point’, with CDMO implementation over next 3 years, but the industry needs a better definition of what ‘continuous’ means.

The overall findings reveal there are a number of improvements industry and the regulators can and should make to shift the industry from just meeting standards towards instilling continuous improvement and quality cultures across the board, which the panel predict will vastly improve overall quality and reduce manufacturing errors.

Prabir Basu, independent consultant and Prof Thomas Friedli of the University of St Gallen review a new systems-based approach to quality metrics in their article – following the University receiving an FDA grant to undertake this. The goal is to recommend a measurement system based on St. Gallen’s Operational Excellence model, which encourages improved quality rather than lagging indicators that measure symptoms. The team, which also includes the Dublin Institute of Technology, state that these new metrics will "help the FDA to establish a clear standard for review and inspection, allowing for a risk-based regulatory approach, transforming quality oversight from a qualitative to a quantitative risk-based process".

Furthermore, Brian Carlin, Director of Open Innovation at FMC warns that excipient risk cannot be fully assessed during development, as product and process changes, including scale-up, have the propensity to change the risk profile. Excipient criticality may be dependent on variations and process changes that occur during manufacturing, which will be unknown at the time of filing. He added: "Continuous monitoring of impact from all excipients throughout the lifecycle is more important than a one-off arbitrary binary classification during development. The importance of all attributes and parameters should be evaluated for impact, and re-evaluated as new information becomes available."

Emphasising the panel’s concern regarding the need to shift towards quality cultures and away from binary measures of product failure, Ajaz Hussain, CEO at Insight Advice & Solutions LLC states that the “file first, figure it out later” mindset is a fundamental part of the problem. He believes that companies that implement QbD and PAT early in development will see the greatest benefits and have the capabilities to “file first”. He added: "‘Broader adoption of PAT-based continuous manufacturing system by brand and by a couple of major generic and CDMO’s should be more prominently evident in the next 3 years."

Ajaz believes the industry is now at a ‘tipping point’ with the first adopters of continuous processing having been included in NDAs, and an excellent opportunity now exists for the manufacture of injectables and we should expect more progress during the 3 three years. He argues, however, the ability to manufacture continuous, while significant, is, in fact, a business decision.

Similarly, Girish Malhotra, President at EPCOT International, suggests that although there is much excitement around continuous processing, we must better define what it is we mean by continuous – as in terms of APIs, very few products have the scale to be manufactured truly continuously. There simply aren't the volumes needed and the industry's greatest shortcoming is its overall record of manufacturing technology innovation. He commented: "When all's said and done, each company producing APIs or their formulations has to justify and use the most cost-efficient technology (batch, campaigned batch or continuous) to produce products that are economic and deliver the same quality all the time. Regulators can only regulate and assure product quality. They can suggest the technologies and methods companies should consider for their products. However, companies have to justify use of such technologies. Excellence comes from within the companies rather than outsiders.’

Chris Kilbee, Group Director Pharma at CPHI, said: “The findings in this report will be disused further at CPHI Worldwide during the CPHI annual report media debate, but it is clear that although the industry is making significant improvements to overall quality, our experts believe that continuous improvement programmes and on-going analysis are more important to instilling a quality culture than simply striving to achieve minimum regulatory standards. What’s really exciting is that over the next few years we should see a shift towards harmonised standards and more advance manufacturing. By implementing the recommendations from our panel, the pharma industry will advance more quickly, develop better and safer drugs and realise the full potential of lower cost and higher quality manufacturing.”