The Evolution of FDA's Role in Ensuring Product Quality - Pharmaceutical Technology

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The Evolution of FDA's Role in Ensuring Product Quality
The quality of a drug product is an essential element of drug safety and efficacy. With a statutory mission to provide safe and effective medications to the public, the US Food and Drug Administration has always focused on drug quality. The authors summarize the history of FDA's role in ensuring product quality and its role in shaping risk-based approaches to this goal.


Pharmaceutical Technology


The next significant milestone was the first extension of the Prescription Drug User Fee Act (PDUFA II) in 1997, originally enacted in 1992 (PDUFA I), which allowed for the addition of review staff to enable a considerable reduction of approval times for new drugs (9). It is estimated that the approval time for a new molecular entity went from an average of 33 months to 13 months. PDUFA III, revised in 2002, was enacted with the aim of shrinking that time to a median of six months for a priority NDA and 10 months for a standard NDA (10).

The Pediatric Research Equity Act (PREA) that became effective in December 2003 called for a mandatory pediatric study (or deferral or waiver of the requirement) for new active ingredients, dosage forms, dosing regimens, route of administration, and indications (11). The act was effective retroactively for products approved after 1999. Finally, the Best Pharmaceuticals for Children Act enacted in 2002, provides six months of marketing exclusivity for certain voluntary pediatric studies (12).

Determining a risk-based approach for CGMPs

Despite all the strides in regulatory measures, producing drug products with built-in quality remains a challenge due to formulation and process variability. In 2004, FDA launched its white paper on current good manufacturing practice (CGMP) for the 21st century to highlight challenges in manufacturing processes and end-product quality for drugs and biologics (13). The CGMP initiative sought to focus on the greatest risks to public health in manufacturing procedures, ensure that the process and product quality standards do not impede innovation, and apply a consistent approach to these issues across the agency (1). The primary component was to modernize quality management techniques, including implementation of quality systems approaches, in all aspects of pharmaceutical production and quality assurance (13). As described below, FDA launched the process analytical technology (PAT) initiative to address some of the manufacturing issues for controlling and confirming product quality.

Quality by design and PAT. FDA discussed quality by design (QbD) and PAT for a long time, but the first draft guidance on the subject was not published until 2003. The idea behind the QbD approach is for manufacturers to use processes that consistently generate products of predetermined quality. With this in mind, improved quality and efficiency are expected from reduction of cycle times using on-, in-, or at-line measurements and controls. Other positive impacts include the prevention of rejected product and waste, real-time product release, increased use of automation, and facilitation of continuous processing using small-scale equipment, resulting in improved energy and material use as well as increased capacity.

PAT is an integral component of QbD. It is a system for designing, analyzing, and controlling manufacturing processes based on an understanding of the scientific and engineering principles involved and identification of the variables that affect product quality. The PAT initiative is consistent with the belief that quality cannot be tested into products, but should be built-in or by design. According to the FDA draft guidance, there is a desired state of pharmaceutical manufacturing:

  • Product and process specifications are based on a mechanistic understanding of how formulation and process factors affect product performance
  • Quality assurance is continuous and real time
  • Relevant regulatory policies and procedures are tailored to accommodate the most current level of scientific knowledge
  • Risk-based regulatory approaches recognize both the level of scientific understanding and the capability of process control related to product quality and performance (14).

Effective QbD implementation is based on the scientific understanding of the chemical and mechanical properties of all elements of a drug product. A prerequisite for process design, QbD provides for consistent quality of a drug product by ensuring that all characteristics of the product's components are well determined. The next step is to identify the processing variables that control the relevant properties of the drug. From a manufacturing perspective, QbD implementation involves the design based on a thorough scientific understanding of the solid-state properties and stability of the components of the drug product at critical quality attributes throughout manufacturing. Then, measurement and control of the critical parameters integrate a broad spectrum of analytical technologies interfaced to production plant controls and incorporate them into standard procedures.


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