Quality Issues for Multiregional Clinical-Trial Materials - Pharmaceutical Technology

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Quality Issues for Multiregional Clinical-Trial Materials
The authors examine risk management relating to the quality issues of clinical-trial materials and discuss areas that would benefit from additional consideration and harmonization.

Pharmaceutical Technology
Volume 35, Issue 10, pp. 124-132

The timing for GTI assessment and testing also must be considered. During the early phases of development leading up to and including initial clinical trials, drug-candidate attrition is significant. Adding to the challenge of addressing GTIs is the fact that the chemical synthesis may be rapidly changing as it progresses toward a commercial synthetic route. Taking into account the limited availability of information on the impurity profile, especially in early development, and in the likelihood that the route of synthesis may change in the course of process optimization, a staged evaluation of reasonably expected GTIs or potential genotoxic impurities (pGTI) should be performed throughout development.

A Pharmaceutical Research and Manufacturers of America's (PhRMA) whitepaper proposes a staged TTC approach based on clinical stage of development, dose, and duration of administration (13). The draft FDA guidance also proposes a staged TTC approach, however, at stricter levels as compared with the PhRMA white paper (11, 13). Following a staged TTC approach, drugs can contain higher levels of GTIs if they are given for shorter periods of time, with the level staged to the duration of exposure.

For pharmaceutical companies, the staged TTC greatly eases the burden on characterizing and controlling impurities during the drug-development process. In early-stage work, impurity information is limited, and analytical methods are undeveloped. As candidates advance and synthetic processes are optimized, impurities are routinely assessed, and plans are made for avoiding or controlling them. A risk assessment of the synthetic process, including starting materials, intermediates, solvents, byproducts, and impurities identifies GTIs that are or might be present.

Regulatory agencies may accept in silico structure-activity relationship (SAR) methods instead of laboratory tests to conclude that the impurity is not genotoxic even if it has an alerting structure. Using in silico evaluations and expert opinion, GTI alert structures are identified among the compounds for which no data are available. Examples of commercial software applications used for this purpose include Casetox (MultiCASE and Derek (Network Sciences Corp.) (14, 15). Certain chemical functional groups or structures associated with DNA reactivity are considered alerts for genotoxicity. If an impurity has a structural alert, a bacterial mutagenesis screen, such as the Ames test, can be run to confirm its genotoxicity. A negative Ames test result will overrule a structural alert, and the impurity can be considered nongenotoxic.

Although seemingly clearcut, pGTI evaluations have become a significant issue because there is no standard, agreed-upon process as to how to do an SAR evaluation. Some European regulatory agencies do not use any in silico methods because the systems are too costly to run and maintain. These agencies rely instead on simple structural alerts. On the other hand, FDA has multiple systems, some of which are proprietary and inaccessible to drug developers.

Although this staged approach provides significant clarity to controlling pGTIs, there are still several areas where further guidance would be beneficial. These areas are the use of scientific justification in lieu of actual testing for pGTIs, the scope of search for pGTIs in the synthetic scheme (i.e., raw materials, intermediates, byproducts, the synthetic steps before the final drug substance), testing methodology, and level of validation of these methods.

An online PhRMA survey was created to serve as a benchmark of industry standards and practices regarding genotoxic impurities (16, 17). The survey was sent to 22 different pharmaceutical companies with 15 companies responding to the survey. Some key results included:

  • 85% of respondents said they evaluate the synthetic process for pGTIs at the preclinical stage.
  • 74% of respondents develop analytical test methods for all identified pGTIs.
  • 82% of respondents stated they control pGTIs in nongenotoxic oncology drugs.
  • 96% of respondents that follow a risked-based assessment for deciding not to test for a pGTI consider the number of steps back from the final API where the pGTI originates.
  • 91% of respondents used the staged TTC approach from the PhRMA white paper for setting specifications for pGTIs during clinical development.

The most common rationale for not testing for a pGTI was consideration of where the pGTI was introduced into the synthesis and whether the pGTI is reactive enough to be eliminated in downstream chemistry or processing, for example, acyl chlorides. Differences in approaches to controlling pGTIs exist in several areas: the point identified in the synthetic process to begin monitoring for pGTIs; the use of limit tests versus quantitative reporting of pGTIs; validation of methods to control pGTIs; and, in cases, where more than one pGTI is possible, the use of individual or collective limits. In addition, due to time constraints, when a pGTI has been identified, analytical methods may have to be developed, and controls implemented before confirmation through mutagenic testing.

Assessment and control of pGTIs in drug development is challenging because of the evolving nature of the synthetic process, variable points of entry of pGTIs in the process, and the need for analytical measurements with adequate selectivity and sensitivity. When applying the staged TTC approach, consideration should be given to the drug product's clinical-development stage, the maximum duration of drug administration at that stage, the proposed indication (e.g., a life-threatening condition versus a less serious condition), the patient population (e.g., adults versus children), and the structural similarity of an impurity to a compound of known carcinogenic potency.


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