Pre-approval inspection

Introduction
A Pre-approval inspection is carried out by FDA to check whether a drug can be effectively
manufactured, processed, packed, tested by using the methods proposed in application complying to
CGMP standards and the data submitted are accurate and complete.

 Preapproval facility evaluation: Centre for drug evaluation and research (CDER), with
office of regulatory affairs (ORA) checks whether a preapproval inspection (PAI) is needed
for the facility proposed in the application.
 Preapproval inspection: ORA, with CDER evaluates the compliance to CGMP of the
facility and processes proposed with added consideration on adequacy and control strategies
whether to approve a drug application.

Strategy
1. Risk based determination of PAI
When a marketing application is submitted, CDER initiates the preapproval facility
evaluation by assembling an integrated quality assessment (IQA) team to perform the quality
assessment. The IQA team provides patient-focused and risk-based quality recommendations
relating to the drug product, including recommendations for facilities that manufacture,
process, package, or hold and test the drug product or drug substance. The team, led by an
application technical lead and managed by a regulatory business project manager, consists of
a drug substance assessor, drug product assessor, OPMA manufacturing assessor, and ORA
representative.

The IQA team determines the need for PAIs of facilities listed in the application by
assessing:
 Product risk and manufacturing (process and facility) risks.
 The accuracy and reliability of the information provided in the application.

If all the information provided in the application are complete and satisfactory then the IQA team
has the authority to rule of out PAI.

2. Inspection by objective
The three primary objectives of a PAI are
● readiness for commercial manufacturing
● conformance to application
● data integrity

The objective readiness for commercial marketing emphasises on the CMC data which should be
compliant to the pharmaceutical CGMP, this encourages a risk based and science based approach that
focuses on critical areas for better and more consistent solutions to existing issues and control measures.
Conformance to application focuses on the whether the provided data in the application is true and
feasible. Data integrity explores on the authenticity and accuracy of the data provided.

The Process
1. For NDA and ANDA
 Within 60 calendar days of receiving an NDA or ANDA, the pharmaceutical
manufacturing assessment (OPMA) sends a PAI or district file review (DFR) request to
ORA with specific information on inspectional strategy.
 ORA evaluates the request, schedules the inspection and intimates OPMA. If ORA feels
that an inspection is not needed, then within 10 calendar days ORA can justify the reason
for not initiating a PAI to OPMA.
 ORA leads the investigation and CDER participates in it.
 The inspection team reports its findings and recommendations to OPMA through pre-
approval program manager (PAM).
 OPMA evaluates the inspection reports with the application and communicates the
relevant observations and concerns to IQA team.
 For PAI withhold recommendations from ORA or significant deficiencies noted by
OPMA, OPMA evaluates the inspection team’s findings and the firm’s response and
makes the final recommendation to ORA.

Establishments named in the application all electronically processed and tracked in the
establishment evaluation system (EES). Each establishment is assigned an Establishment
Evaluation Request (EER).

Assignment of inspection

There are two types of pre approval inspection performed

● Priority
● Discretionary

An inspection falls under priority if it meets one or more of the following criteria
1. A new establishment
2. First application filed by applicant
3. First ANDA for an approved drug
4. Finished product contains a new molecular entity
5. Finished product content assay has a narrow range or the drug is expexted to be given in titrated
doses
6. Finished product and API is manufactured by a different process
7. API derivation is high risk or intended use has significantly changed
8. Numerous application submission or changes filed that are expected to pose significant challenge
to the state of control or process of the facility
9. Profile class status of application product or API is “unacceptable” or not updated via a site
inspection within the past 2 years (3 years for control laboratories and 4 years for packaging and
labeling), for original applications or significant pre-approval CMC supplements.