While the passage of the long awaited GDUFA legislation brings the ultimate promise of shorter ANDA review times, the GDUFA-prescribed timing goals will not go into effect until cohort year 3 (2015).  Consequently, ANDA sponsors will need to weather the impact of extensively long ANDA review times in the interim period.  With the median ANDA review time approaching 34 months, an ANDA sponsor runs the risk that one or more of the facilities referenced in its application will need to be re-inspected as a prerequisite to the approval of the ANDA, even if the facility had achieved satisfactory cGMP status, at some previous point during the pendency of the ANDA.  The effective “expiry” of a satisfactory inspection and the need to re-inspect a facility before granting of ANDA approval has become a practical problem for the generic industry, which carries the risk of potentially significant consequences including marketing delays, loss of projected revenues and forfeiture of exclusivity entitlement in a worse-case scenario.

In light of this continuing challenge, and in light of some existing ambiguities regarding FDA inspection policy, Lachman contacted CDER’s Office of Compliance to determine its current policy regarding conduct of inspections required in support of approval of ANDAs.  Our goal was to determine the following:

1)  How much time may elapse from the date of the last acceptable
inspection of a dosage form manufacturing facility, before the Agency deems the inspection not sufficiently “current” for purposes of supposing an ANDA approval?

2)  Is the time period different for API manufacturing facilities versus facilities that produce the finished dosage form?

3)  Are there any exceptions to general rules/approaches that apply?


We received the following response to a written inquiry on this subject matter:

“CDER ensures that each facility identified in a pending application has received a timely and appropriate GMP inspection as a prerequisite to application approval.  For many applications, CDER does not perform an application-specific pre-approval inspection and instead relies on a recent GMP surveillance inspection.  Generally, among other considerations, an application-specific facility inspection is waived for a finished dosage facility inspected within 2 years of application review, an API facility inspected within 3 years, and certain ancillary sites (e.g., a control-testing laboratory or packaging-only facility) for an even longer period since last GMP surveillance inspection.  There are exceptions to this general rule.  For example, CDER will inspect during application review a new facility and a facility that is making a significant change from previously approved drugs (e.g., using a new or novel unit operations and/or control test).  FDA intends to continue the practice of using a risk-based assessment in determining the length of time since the last inspection.  Under GDUFA, FDA has committed to assure comparably robust inspections and parity in the risk-adjusted inspection frequency between all facilities, regardless of location.”


Application sponsors should be aware of this policy and should assess the state of cGMP compliance (as determined by FDA inspection) for each of the facilities referenced in an ANDA initially and throughout the duration of the review period, with the above in mind.  Sponsors must be keenly aware of situations where an acceptable inspection is at risk of expiring while an application in under review, and should bring this situation to the attention of OGD Regulatory Project Management, especially in cases where an exclusivity entitlement may be at risk of forfeiture.

The above pertains to facilities that perform manufacturing and testing operations relative to APIs and finished dosage forms.  However, ANDA sponsors must also be aware that a CRO that performs clinical and/or bioanalytical work in support of bioequivalence studies contained in an ANDA must also have satisfactory inspection status at the time of ANDA approval.  Once a CRO has completed a satisfactory inspection, the satisfactory status will generally hold for a period of 3 years. (see MAPP 5210.7) (This may not apply if the CRO is performing a nonconventional study and/or if there is a question regarding the integrity of data submitted in the ANDA.  In these cases, a specific inspection would likely be requested even if the 3 year period has not elapsed).   There is some additional positive news on the horizon in regard to these types of inspections.  Specifically, FDA and the European Medicines Agency (EMA) have agreed to expand an ongoing good clinical practice inspection and information sharing program to bioequivalence/bioanalytical inspections.  Speaking at a Drug Information Association Annual Meeting Compliance Session on June 26 in Boston, CDER Office of Scientific Investigations Senior Medical Officer Cynthia Kleppinger stated that the Agencies have agreed to share inspection reports with negative outcomes and to participate in joint inspections at this time.  This might be an important step towards eventual full mutual recognition, which would mean that the Agencies could use each other’s inspection reports to support approval of an application in their respective regions.


For further assistance on this or other regulatory matters please contact Joan Janulis, Vice President, Regulatory at J.Janulis@LachmanConsultants.com.