GMP, Life Sciences, Regulatory Focus News Letter, Rules

FDA Finalizes Rule to Go From Paper to Electronic Devices Submissions

Hi, Welcome to FWQRC Regulatory Focus News Letter.

Here we are going to discuss about the finalised rule for the submission process.

As part of an effort to improve the US Food and Drug Administration’s (FDA) medical device submission process, the agency on Friday issued a final rule to remove the requirements for multiple paper copy submissions and replace them with a single electronic submission.

The agency said the rule, proposed in September 2018 and will take effect in 30 days, is in response to an executive order from the Trump Administration in 2017 made famous as the “one-in, two-out” order. FDA’s rule is meant to improve the device premarket submission program and create a more efficient submission system.

“The requirement for a single submission in electronic format applies to all submission types that fall within the provisions listed in section 745A(b) of the FD&C Act; under this final rule, FDA is only amending those regulations that specifically mention paper and/or multiple copies of such regulatory submissions and are not consistent with this final rule,” FDA said.

The agency responded to four comments on the proposal but did not update the rulemaking. The agency noted that the final rule will produce cost savings for firms without imposing any additional regulatory burdens for submissions or affect the agency’s ability to review submissions.

“Firms will incur minimal administrative costs to read and understand the rule. We expect the economic impact of this regulation to be a total net costs savings yielding positive net benefits,” FDA said.

The agency also noted that submissions in electronic format can include those created and submitted on CD, DVD or flash drive and mailed to FDA.

For premarket approval applications (PMAs), the final rule changes one section to take out a section requiring an applicant to submit three copies of any updated safety and effectiveness report for pending applications.

FDA also previously required that PMAs be submitted in six copies, each bound in one or more numbered volumes, but that language has been removed with this final rule.

In another section, FDA removes the requirement that a PMA applicant has to provide copies of information that it believes to be trade secret or confidential commercial or financial information in the PMA.

FDA in September also published a draft guidance with “both binding and nonbinding provisions”

Please contact FWQRC for electronic submissions. (+91 8072483812)

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

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