Facility Evaluation by FDA
Before
approval, FDA evaluates the firm or facility by on-site inspections and/or by
establishment file review when the firm is called within the Chemistry, Manufacturing,
and Controls (CMC) section of a New Drug Application (NDA), Abbreviated New
Drug Application (ANDA) or Biologic License Application (BLA)
Facility
evaluations are conducted for:
–
Finished dosage manufacturers
–
API manufacturers
–
Finished dosage and API testing sites
–
Primary packaging and labeling sites
–
For animal-derived APIs, the power that performs the crude extraction
FDA
generally doesn't evaluate the subsequent sites for a pre-approval inspection:
Intermediate
manufacturers
•
On a case-by-case basis; evaluated on condition that the intermediate is taken
into account critical to the standard of the drug product.
Exhibit
batch manufacturers (if not proposed commercial site)
•
Note: the positioning may be added on a for-cause basis if the review
identifies concerns
Component
manufacturers
•
Includes syringes, glass vials, or rubber-stoppers manufacturers and
component-only sterilization sites
•
OPF/DIA generally doesn't evaluate these sites unless the for-cause basis
Excipient
manufacturers
•
OPF/DIA generally doesn't evaluate these sites, unless it's a completely unique
excipient and/or the excipient
the
manufacturing process is taken into account a critical step within the overall
drug manufacturing process.
Secondary
packager/labeller
•
OPF/DIA generally doesn't evaluate these sites
*note
all the above sites are required to fulfil the statutory CGMPs per FD&C Act
and should be routinely inspected if registered as a drug manufacturer.
When
does FDA perform PAIs?
Use
risk-based Priority Inspection Criteria to create the choice supported the
subsequent risks:
•Facility
Risk
•Product
Risk
•Process
Risk
Facility
Risk
•
CGMP issues relevant to application product
•
Recent FARs relevant to application product
•
Recent recalls relevant to application product
•
Numerous applications filed without delay
Product
Risk
•
New molecular entity
•
First application filed by the applicant
•
First ANDA filed for an approved drug
•
RLD has complaints, ADEs, stability issues
•
Patient population or for a heavy condition
•
Breakthrough therapy, shortage situation
Process
Risk
•
Narrow therapeutic range (95%-105%)
•
Derived API is high risk (derived from animal tissues)
•
PAT, NIR, QbD
•
Development data is incomplete
•
Batch records non-specific
•
Complicated process
•
Substantially different process than previously covered at the power.
The
Pre-Approval Inspection team
If
an inspection is confirmed to be conducted, FDA will send a team of people to
conduct the pre-approval inspection. The team may include:
•
Investigators
•
Other Specialists
–
Chemistry Expert
–
Microbiology Expert
–
Process/Facility Expert
–
Formulation Expert
Scope
of PAI
A
pre-approval inspection (PAI) is performed to contribute to FDA’s assurance
that a producing establishment named during a drug application is capable of
producing a drug, which submitted data are accurate and complete.
PAI
is product specific
•
Limited or no commercial manufacturing
•
More specialise in development data
•
More emphasis on the authenticity of information and application commitments.
•
Process validation commonly not completed
•
Trend toward more experts involved.
PAI
Coverage: Objectives
Objective
1: Readiness for Commercial Manufacturing
Determine
whether the establishment(s) includes a quality system that's designed to
attain sufficient control over the power and commercial manufacturing
operations.
Objective
2: Conformance to Application
Verify
that the formulation of product, processing methods and analytical (or
examination) methods are according to descriptions contained within the CMC
section of the application for the bio-batch (and other pivotal clinical
batches, when applicable), the proposed commercial-scale batch, and also the
API(s).
Objective
3: Data Integrity Audit
Audit
the information, hardcopy or electronic, to authenticate the data submitted
within the CMC section of the application. Verify that each one relevant data
(e.g., stability, bio-batch data) were submitted within the CMC section that product
reviewers can depend on the submitted data as complete and accurate.
PAI
Outcomes
The
lead investigator will make a recommendation at the conclusion of the
inspection:
Recommend
Approval
•
Depicts that the inspection has no significant issues
•
Response to observations is vital
Recommend
Withholding of Approval
•
Investigators observed that the positioning isn't GMP compliant, the data in
CMC isn't according to site records, or information submitted isn't accurate
and complete.
•
Response to observations is critical
*CDER’s Office of
latest Drugs or Office of Generic Drugs makes the final word decision on whether
to approve or withhold approval of the applying or licensure
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