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Patrick Stone

FDA Compliance

Quality by Design Pilot Presents Industry with New Challenges

The FDA will not let you have your cake and eat it, too

Published: Monday, September 19, 2011 - 09:36

What products will be affected by the Food and Drug Administration’s (FDA) quality by design (QbD) stipulation, as outlined in its report, “Pharmaceutical Quality for the 21st Century: A Risk-Based Approach”?

It will apply to new marketing authorization applications, new drug applications, Type II variations, and prior-approval supplements. It will apply to scientific advice requests and chemistry, manufacturing, and controls formal-meeting requests that include QbD or process analytical technology elements and are submitted to the FDA and European Union as new applications. And it will apply to marketing authorization applications and new drug applications where the sponsor or applicant has agreed to a parallel evaluation by both agencies.

Upon request from the sponsor or applicant, and where procedural timelines will allow, Type II variations and new drug applications may also be considered on a case-by-case basis. Right now this is a voluntary pilot, although some pharma companies are being tapped or nudged by the FDA and the European Medicines Agency (EMA) to join in.

Our geographically diverse health-product market involves more contracting and outsourcing for many product components. Finished-product, real-time, testing-and-design space requirements will be crucial for implementing QbD. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) third-party quality assurance mandates will result from this pilot program.

QbD products will be as unique as the individuals who receive them (personalized medicine). This new model may affect two-thirds of all new health-care products in the pipeline (e.g., cell therapies, gene therapies, and molecular entity therapy). There will be many approaches to higher order characterization, and some are not cost effective at present. Many of the details will take years to sort out. Collaborations between the FDA, Japan’s Ministry of Health, Labour, and Welfare, and the EMA will require funding along with mutual scientific trust.

Emerging technologies and laboratory techniques will be required to accomplish the QbD paradigm shift. The FDA can’t continue using the chemistry approval model for biotechnology products. This paradigm shift may increase development times and cost structures. The ICH model will also bring mandatory third-party quality assurance reviews, so prepare your models for this as well.

Here are the essential points to focus on for QbD products:
• Target the product profile
• Determine critical quality attributes
• Link raw material attributes and process parameters to critical quality attributes
• Perform risk assessment
• Develop a design space
• Design and implement a control strategy

The biotechnology-sector QbD product development focus will be on design space and real-time release testing. The pilot discussion focus for both regulatory agencies will be on ensuring consistent implementation of ICH Q8, Q9, and Q10 guidelines in the assessment process and to facilitate sharing of regulatory discretion and new regulatory concepts. Manufacturers of small-molecule generic drugs have concerns the initial lag-time in course correcting for the QbD initiative may exponentially delay the application file time for their products.

It appears some generic-drug manufacturers are not willing to implement any QbD concepts until closer to final harmonization and discussion time frames.

Why do you need higher order structure modeling? Higher order structure product applicants will have to provide protein-folding kinetics models with characterization integration into the application and annual report. Your research models and early development modeling may be progressed for this function. Personalized medicine with batch-to-batch consistency, including a stability of one to 90 days, is recommended. There are also talking points about including variants and aggregates of your products in the higher order structure models. Intra- and inter-chain disulfide bonding, aggregation, and complete polypeptide modeling may be requested application material.

This may prove to be more cost effective while the two juggernauts (FDA and EMA) iron out the red tape that will flow from this type of global initiative. If the funds necessary to make this effort progress are not available for the FDA or EMA, side delays in the process are inevitable.

Molecular and personalized medicine can’t continue to be reviewed with the FDA chemical entity systems approach and approval model. Effective cancer therapies and molecular medicine may not have the statistical significance necessary when only a handful of patients are treated with the cell or gene therapy.

Warning to industry: the FDA will obviously not let you have your cake and eat it, too. Innovate change by sending comments to the FDA or accept the QbD change that is inevitable. Your comments to the FDA will be monitored on the FDA’s Facebook page and current open comment requests. Contact your respective FDA liaison or center contact for discussion points directly related to your product.

This article first appeared on the AssurxBlog.


About The Author

Patrick Stone’s picture

Patrick Stone

Patrick Stone works toward a future where disease cures and prevention are the main goal of all new test articles. Stone is president and lead consultant at TradeStone QA LLC, which serves the global public by protecting the supply and quality of healthcare products before entering the market place. Stone specializes in Institutional Review Board (IRB) compliance and quality assurance audits; computer system validation and 21 CFR Part 11 compliance; LIMS/data management system compliance; and 21 CFR, GCP, cGMP, and ICH compliance. Stone is the author of Bubble Gum Badge—An FDA His-Story (Xlibris Corp., 2011). You can follow Stone on Twitter.