Pharma

Genotoxic Impurities

Hi Everyone…

Good evening

Today we are going to discuss on the Genotoxic Impurities and its assessments.

The toxicological assessment of genotoxic impurities and the determination of acceptable limits for such impurities in active substances is a difficult issue.

The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessment of acceptable limits.

In the absence of data usually needed for the application of one of the established risk assessment methods, i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed.

A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1 in 100,000 over a lifetime) for most pharmaceuticals.

From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose. Higher limits may be justified under certain conditions such as short-term exposure periods.

For determination of acceptable levels of exposure to genotoxic carcinogens considerations of possible mechanisms of action and of the dose-response relationship are important components. Based on the above considerations genotoxic impurities may be distinguished into the following two classes:

  • Genotoxic compounds with sufficient (experimental) evidence for a threshold-related mechanism

This approach calculates a “Permitted Daily Exposure” (PDE), which is derived from the NOEL, or the lowest- observed effect level (LOEL) in the most relevant (animal) study using “uncertainty factors” (UF).

  • Genotoxic  compounds  without  sufficient   (experimental)  evidence  for   a   threshold-related mechanism

The assessment of acceptability of genotoxic impurities for which no threshold mechanisms are identified   should   include   both   pharmaceutical   and   toxicological   evaluations.   In   general, pharmaceutical measurements should be  guided by  a  policy of  controlling levels to  “as  low as reasonably practicable” (ALARP principle), where avoiding is not possible.  Levels considered being consistent with the ALARP principle following pharmaceutical assessment should be assessed for acceptability from a toxicological point of view.

A TTC value higher than 1.5 µg/day may be acceptable under certain conditions, e.g. short-term exposure, for treatment of a life-threatening condition, when life expectancy is less than 5 years, or where the impurity is a known substance and human exposure will be much greater from other sources (e.g. food). Genotoxic impurities that are also significant metabolites may be assessed based on the acceptability of the metabolites.

The concentration limits in ppm of genotoxic impurity in drug substance derived from the TTC can be calculated based on the expected daily dose to the patient using equation (1).

(1) Concentration limit (ppm) = TTC [µg/day]/dose (g/day]

The TTC concept should not be applied to carcinogens where adequate toxicity data (long-term studies) are available and allow for a compound-specific risk assessment.

REFERENCES

  1. Cheeseman M.A., Machuga E.J., Bailey A.B., A tiered approach to threshold of regulation, Food Chem Toxicology 37, 387-412, 1999
  2. Dobo K.L., Greene N., Cyr M.O., Caron S., Ku W.W., The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development, Reg Tox Pharm 44, 282-293, 2006.
  3. Gold L.S., Sawyer C.B., Magaw R., Backman G.M., de Veciana M., Levinson R., Hooper N.K., Havender W.R., Bernstein L., Peto R., Pike M.C., Ames B.N., A carcinogenic potency database of the standardized results of animal bioassays, Environ Health Perspect 58, 9-319, 1984.
  4. Kroes R., Renwick A.G., Cheeseman M., Kleiner J., Mangelsdorf I., Piersma A., Schilter B., Schlatter J., van Schothorst F., Vos J.G., Würtzen G., Structure-based threshold of toxicological concern (TTC): guidance for application to substances present at low levels in the diet, Food Chem Toxicol 42, 65-83,2004.
  5. Kroes R., Kozianowski G., Threshold of toxicological concern (TTC) in food safety assessment, Toxicol Letters 127, 43-46, 2002.
  6. Müller L., Mauthe R.J., Riley C.M., Andino M.M., De Antonis D., Beels C., DeGeorge J., De Knaep A.G.M., Ellison D., Fagerland J.A., Frank R., Fritschel B., Galloway S., Harpur E., Humfrey C.D.N., Jacks  A.S.J.,  Jagota  N.,  Mackinnon  J.,  Mohan  G.,  Ness  D.K.,  O’Donovan  M.R.,  Smith  M.D., Vudathala G., Yotti L., A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity, Reg Tox Pharm 44, 198-211, 2006
  7. Munro I.C., Safety assessment procedures for indirect food additives: an overview. Report of a workshop. Reg Tox Pharm 12, 2-12, 1990.
  8. Munro I.C., Kennepohl E., Kroes R., A procedure for the safety evaluation of flavouring substances, Food Chem Toxicology 37, 207-232, 1999.
  9. Rulis A.M., Establishing a threshold of regulation. In Risk Assessment in Setting National Priorities(J.J. Bonin and D.E. Stevenson, Eds.) Plenum, New York, 271-278, 1989.
  10. U.S. Food and Drug Administration (FDA), Food additives: Threshold of regulation for substances used in food-contact articles (final rule), Fed. Regist. 60, 36582-36596, 1995.
GMP, Pharma

Root Cause Analysis for Drugmakers

Hi Everyone

Whenever regulatory authorities anywhere in the world perform an audit of a drug manufacturer, one of their most frequent findings remains the inadequate performance of the investigation of deviations.

Authorities expect stakeholders will carefully investigate deviations to identify non-compliance, intervene and then evaluate the effectiveness of that intervention. Without adequate investigation and root cause analysis (RCA), those stakeholders cannot effectively identify and design successful interventions. In fact, organizations waste millions of dollars every year on ineffective interventions.

A tool such as RCA uses a defined critical analysis approach in evaluating the reason for a deviation or non-conformance.

RCA techniques include brain storming, the “5 whys” and the “fishbone diagram.” Any and all may be used to explore and further examine the causes behind an event. Firms may then use the resulting analysis to identify areas for change, as well as any recommendations and solutions that aim to minimize the likelihood of an event repeating in the future.

Some organizations go so far as to create a corrective and preventive action (CAPA) for every event, although it is not always necessary.

A firm’s primary goals in investigating an incident should include both discovering its cause and ensuring it does not reoccur.

Regulatory authorities place a high value on RCA and CAPA. Indeed, a large number of FDA observations cite inadequate RCA, ineffective investigation and inappropriate CAPA.

When a deviation occurs, whether in the pharmaceutical or any other industry, the responsible firm must undertake an investigation to determine what went wrong and what damage, if any, the product might have suffered. The investigation process should include some specific steps. These include:

  • Notification of the appropriate stakeholders;
  • Containment action;
  • Classification of the event;
  • Decision to investigate;
  • Determination of the root cause or RCA; and
  • Review and approval process.

The effectiveness of the CAPA taken by an organisation marks another key step in the overall RCA. By monitoring the CAPA, an investigative team can determine whether it truly identified an incident’s root cause and then applied the “appropriate fix.”