Current Thoughts on Critical Process Parameters and API Synthesis.

  • Ganzer W
  • Materna J
  • Mitchell M
 et al. 
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This article discusses a science-arid risk-based approach to determining which process parameters and controls are critical to quality. The primary points are: CQAs of APIs must be defined by the requirements of the specific drug product (e.g., dosage form, strength, formulation constraints). Some CQAS are affected by the API synthetic process, and others are controlled by overall quality systems. The steps before the last true solution typically affect the impurity profile of an APE rather than the physical properties. Therefore, the process parameters for these steps are generally chosen to mitigate the effect of critical impurities on the final APE. CPPs must meet two criteria in a risk-assessment evaluation: an established link between the process parameter and its effect on the CQAs of an API and a risk-assessment evaluation conclusion that the operating limit of this process parameter being close to the proven limit increases the probability of going outside the proven range for obtaining an acceptable API. Strategic controls at key points in the synthesis confirm the quality of CQAs. These form the basis of filed controls for the intermediates. Controls exist for reasons in addition to quality. Controls unrelated to the CQAs do not need to be in the regulatory submission. The analysis and application of CPPs presented in this article are entirely consistent with BACPAC I, the PhRMA and PQRI proposals for BACPAC II, and FDA,s Guidance Changes to an Approved NDA or ANDA. Focus on the CQAs will permit registration files to address the quality-critical parameters, steps, and controls consistent with ongoing risk- and science-based initiatives, thereby providing an opportunity to reduce future FDA submissions by clarifying the value of parameters initially registered and avoiding those for which future regulatory consequences are vague. CPPs typically are uncovered during process development. Where possible, the process is optimized to eliminate these critical parameters. This is a key goal during process development and an example of quality by design for drug-substance processes. Thus, it is not unusual to see relatively few critical parameters in a well-designed process. This does not imply that unit operations in the process are not important; all steps in a process are important and must be conducted, hut not all are critical in the context of CQAs. This article has clarified several of the concepts and interdependencies related to CQAs, CPPs, and CIPCs. This discussion should provide a basis for a common understanding in the industry and among health authorities. The authors hope this common understanding can help improve product safety and efficacy while supporting technically sound and historically valid regulatory practices. The authors also hope that by including additional discussion that demonstrates the sponsor's understanding of the CPPs that affect the CQAs of the API in the original CTD submission, there will be some opportunity for streamlining and simplifying the regulatory requirements for postapproval changes to processes. INSET: Definitions. [ABSTRACT FROM AUTHOR]

Author-supplied keywords

  • DRUGS -- Design
  • MEDICAL supplies
  • PRODUCT safety

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  • William P Ganzer

  • Joan a Materna

  • Michael B Mitchell

  • L Kevin Wall

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