FDA trims reserve testing quantity requirements
Regulatory News | 18 August 2020 |
Reflecting changes in testing technology, a new and immediately effective guidance from the US Food and Drug Administration (FDA) updates the agency’s approach to retention of reserve samples for bioavailability and bioequivalence testing, generally reducing the amount of drug product that applicants must retain.
An interim rule issued in 1990 and made final in 1993 required applicants or contract research organizations (CROs) to retain an amount of test article and reference standard required for in vitro bioavailability (BA) and bioequivalence (BE) testing that is five times the amount required for release testing. “The interim rule was intended to help ensure BE between generic drugs and their reference listed drug and to help FDA investigate possible fraud in BA and BE testing,” explains the guidance document.
In practice, notes the guidance, this means that applicants might be required to remain as many as 300 tablets or capsules of the test article and reference standard. Both applicants and CROs have requested adjustment in these requirements which are currently outlines in 21 CFR 320.38(c), said FDA.
”Since the final rule was issued in 1993, technological advances in FDA’s ability to test these products have led to test methods that are less destructive and more sensitive, allowing FDA to detect the identity and composition of the test article and reference standard with smaller volumes of samples,” said the FDA.
Current testing technology generally allows FDA to achieve necessary testing with 30 units each of test article and reference standard for single-dose units and 2 articles each from each shipment for products manufactured in multi-dose units.
The compliance policy for retained samples proposed in the guidance points to an appendix that outlines minimum sample retention quantities for certain products that are considered sufficient by FDA to conduct necessary testing.
The appendix lists common routes of administration and dosage forms for drugs manufactured as single-dose units; for these drug products, FDA does not intend to enforce the requirement to retain five times the amount required for testing so long as the applicant has retained 30 units each of the test article and reference standard from each shipment.
The appendix also lists routes of administration and dosage forms for drug products commonly manufactured in multi-dose units. For these products, FDA does not intend to enforce current retention amount requirements if the applicant has retained 3 units each of the test article and reference standard from each shipment.
Applicants seeking a further reduction in the quantity of reserve samples for studies that involve multiple shipments and study sites should contact FDA for consideration on a case-by-case basis.
Applicants submitting NDAs or ANDAs for products not itemized in the appendix to the guidance should submit requests to FDA if they wish to retain a quantity less than the five-fold amount required for testing. Applicants should submit a controlled correspondence for generic-specific requests, including retention of BA/BE samples.
“This guidance does not apply to the other requirements for retention of reserve samples contained in 21 CFR 320.38, such as how testing facilities must select samples for testing, how the reserve samples must be retained, and whether reserve samples are in fact representative of the test article and reference standard used in the BA or BE study,” clarified FDA in announcing the guidance. “Additionally,” said the agency, “this guidance does not affect the requirement in 21 CFR 211.170 to retain samples under current good manufacturing practices.”
FDA
An interim rule issued in 1990 and made final in 1993 required applicants or contract research organizations (CROs) to retain an amount of test article and reference standard required for in vitro bioavailability (BA) and bioequivalence (BE) testing that is five times the amount required for release testing. “The interim rule was intended to help ensure BE between generic drugs and their reference listed drug and to help FDA investigate possible fraud in BA and BE testing,” explains the guidance document.
In practice, notes the guidance, this means that applicants might be required to remain as many as 300 tablets or capsules of the test article and reference standard. Both applicants and CROs have requested adjustment in these requirements which are currently outlines in 21 CFR 320.38(c), said FDA.
”Since the final rule was issued in 1993, technological advances in FDA’s ability to test these products have led to test methods that are less destructive and more sensitive, allowing FDA to detect the identity and composition of the test article and reference standard with smaller volumes of samples,” said the FDA.
Current testing technology generally allows FDA to achieve necessary testing with 30 units each of test article and reference standard for single-dose units and 2 articles each from each shipment for products manufactured in multi-dose units.
The compliance policy for retained samples proposed in the guidance points to an appendix that outlines minimum sample retention quantities for certain products that are considered sufficient by FDA to conduct necessary testing.
The appendix lists common routes of administration and dosage forms for drugs manufactured as single-dose units; for these drug products, FDA does not intend to enforce the requirement to retain five times the amount required for testing so long as the applicant has retained 30 units each of the test article and reference standard from each shipment.
The appendix also lists routes of administration and dosage forms for drug products commonly manufactured in multi-dose units. For these products, FDA does not intend to enforce current retention amount requirements if the applicant has retained 3 units each of the test article and reference standard from each shipment.
Applicants seeking a further reduction in the quantity of reserve samples for studies that involve multiple shipments and study sites should contact FDA for consideration on a case-by-case basis.
Applicants submitting NDAs or ANDAs for products not itemized in the appendix to the guidance should submit requests to FDA if they wish to retain a quantity less than the five-fold amount required for testing. Applicants should submit a controlled correspondence for generic-specific requests, including retention of BA/BE samples.
“This guidance does not apply to the other requirements for retention of reserve samples contained in 21 CFR 320.38, such as how testing facilities must select samples for testing, how the reserve samples must be retained, and whether reserve samples are in fact representative of the test article and reference standard used in the BA or BE study,” clarified FDA in announcing the guidance. “Additionally,” said the agency, “this guidance does not affect the requirement in 21 CFR 211.170 to retain samples under current good manufacturing practices.”
FDA
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