Regulatory Open Forum

Hi,

 As per "ANDA Submissions –Refuse to Receive for Lack of Justification of Impurity Limits- August 2016" Guidance :

 FDA will RTR an ANDA under @314.101(d)(3) if the ANDA lacks supporting data or information to justify the proposed limits for specified identified and/or specified unidentified impurities that exceed qualification thresholds and/or identification thresholds, respectively, as described below. Also, FDA will RTR an ANDA under @314.101(d)(3) with proposed limits for unspecified impurities that exceed identification thresholds.

 (1) the observed impurity levels and proposed impurity limits do not exceed the level observed in the reference listed drug (RLD) product;

(2) the impurity is a significant metabolite of the drug substance;

(3) the observed impurity levels and proposed impurity limits are adequately justified by the scientific literature;

or

(4) the observed impurity levels and proposed impurity limits do not exceed the level that has been adequately evaluated in toxicity studies.

Again, we are aware about the previous  Guidance  "Guidance for Industry ANDAs: Impurities in Drug Products- November 2010" that states :

 Setting Acceptance Criteria for Degradation Products -

"We recommend that the acceptance criterion be set no higher than the qualified level (see section IV, Qualification of Degradation Products). In establishing degradation product acceptance criteria, the first critical consideration is whether a degradation product is specified in the United States Pharmacopeia (USP). If there is a monograph in the USP that includes a limit for a specified identified degradation product, we recommend that the acceptance criterion be set no higher than the official compendia limit"

Now the question is if we set limit of specified identified impurity as per USP , exceeding the qualification thresholds (ICH Q3B) and provide a justification  (3.2.P.5.6 ) that "Specified identified impurity limit is set as per USP" will it be accepted by FDA or there is a possibility of RTR of the submitted ANDA due to not following the RTR Guidance – Aug'16 ?

Any practical experience in last 03 years, please ?

Hi,

 As per "ANDA Submissions –Refuse to Receive for Lack of Justification of Impurity Limits- August 2016" Guidance :

 FDA will RTR an ANDA under @314.101(d)(3) if the ANDA lacks supporting data or information to justify the proposed limits for specified identified and/or specified unidentified impurities that exceed qualification thresholds and/or identification thresholds, respectively, as described below. Also, FDA will RTR an ANDA under @314.101(d)(3) with proposed limits for unspecified impurities that exceed identification thresholds.

 (1) the observed impurity levels and proposed impurity limits do not exceed the level observed in the reference listed drug (RLD) product;

(2) the impurity is a significant metabolite of the drug substance;

(3) the observed impurity levels and proposed impurity limits are adequately justified by the scientific literature;

or

(4) the observed impurity levels and proposed impurity limits do not exceed the level that has been adequately evaluated in toxicity studies.

Again, we are aware about the previous  Guidance  "Guidance for Industry ANDAs: Impurities in Drug Products- November 2010" that states :

 Setting Acceptance Criteria for Degradation Products -

"We recommend that the acceptance criterion be set no higher than the qualified level (see section IV, Qualification of Degradation Products). In establishing degradation product acceptance criteria, the first critical consideration is whether a degradation product is specified in the United States Pharmacopeia (USP). If there is a monograph in the USP that includes a limit for a specified identified degradation product, we recommend that the acceptance criterion be set no higher than the official compendia limit"

Now the question is if we set limit of specified identified impurity as per USP , exceeding the qualification thresholds (ICH Q3B) and provide a justification  (3.2.P.5.6 ) that "Specified identified impurity limit is set as per USP" will it be accepted by FDA or there is a possibility of RTR of the submitted ANDA due to not following the RTR Guidance – Aug'16 ?

Any practical experience in last 03 years, please ?

Hi,

 As per "ANDA Submissions –Refuse to Receive for Lack of Justification of Impurity Limits- August 2016" Guidance :

 FDA will RTR an ANDA under @314.101(d)(3) if the ANDA lacks supporting data or information to justify the proposed limits for specified identified and/or specified unidentified impurities that exceed qualification thresholds and/or identification thresholds, respectively, as described below. Also, FDA will RTR an ANDA under @314.101(d)(3) with proposed limits for unspecified impurities that exceed identification thresholds.

 (1) the observed impurity levels and proposed impurity limits do not exceed the level observed in the reference listed drug (RLD) product;

(2) the impurity is a significant metabolite of the drug substance;

(3) the observed impurity levels and proposed impurity limits are adequately justified by the scientific literature;

or

(4) the observed impurity levels and proposed impurity limits do not exceed the level that has been adequately evaluated in toxicity studies.

Again, we are aware about the previous  Guidance  "Guidance for Industry ANDAs: Impurities in Drug Products- November 2010" that states :

 Setting Acceptance Criteria for Degradation Products -

"We recommend that the acceptance criterion be set no higher than the qualified level (see section IV, Qualification of Degradation Products). In establishing degradation product acceptance criteria, the first critical consideration is whether a degradation product is specified in the United States Pharmacopeia (USP). If there is a monograph in the USP that includes a limit for a specified identified degradation product, we recommend that the acceptance criterion be set no higher than the official compendia limit"

Now the question is if we set limit of specified identified impurity as per USP , exceeding the qualification thresholds (ICH Q3B) and provide a justification  (3.2.P.5.6 ) that "Specified identified impurity limit is set as per USP" will it be accepted by FDA or there is a possibility of RTR of the submitted ANDA due to not following the RTR Guidance – Aug'16 ?

Any practical experience in last 03 years, please ?

Hi,

 As per "ANDA Submissions –Refuse to Receive for Lack of Justification of Impurity Limits- August 2016" Guidance :

 FDA will RTR an ANDA under @314.101(d)(3) if the ANDA lacks supporting data or information to justify the proposed limits for specified identified and/or specified unidentified impurities that exceed qualification thresholds and/or identification thresholds, respectively, as described below. Also, FDA will RTR an ANDA under @314.101(d)(3) with proposed limits for unspecified impurities that exceed identification thresholds.

 (1) the observed impurity levels and proposed impurity limits do not exceed the level observed in the reference listed drug (RLD) product;

(2) the impurity is a significant metabolite of the drug substance;

(3) the observed impurity levels and proposed impurity limits are adequately justified by the scientific literature;

or

(4) the observed impurity levels and proposed impurity limits do not exceed the level that has been adequately evaluated in toxicity studies.

Again, we are aware about the previous  Guidance  "Guidance for Industry ANDAs: Impurities in Drug Products- November 2010" that states :

 Setting Acceptance Criteria for Degradation Products -

"We recommend that the acceptance criterion be set no higher than the qualified level (see section IV, Qualification of Degradation Products). In establishing degradation product acceptance criteria, the first critical consideration is whether a degradation product is specified in the United States Pharmacopeia (USP). If there is a monograph in the USP that includes a limit for a specified identified degradation product, we recommend that the acceptance criterion be set no higher than the official compendia limit"

Now the question is if we set limit of specified identified impurity as per USP , exceeding the qualification thresholds (ICH Q3B) and provide a justification  (3.2.P.5.6 ) that "Specified identified impurity limit is set as per USP" will it be accepted by FDA or there is a possibility of RTR of the submitted ANDA due to not following the RTR Guidance – Aug'16 ?

Any practical experience in last 03 years, please ?