https://www.fda.gov/media/81689/downloadWith pre-license and...

https://www.fda.gov/media/81689/download

With pre-license and pre-approval inspections, the firm is supposed to be ready
for an inspection at the time of their submission. So, in theory, CBER could go
out immediately after the application or the supplement is received. But, that is
not preferred, because when inspections occur, CBER wants the investigator to
see all the pertinent operations at the facility. To ensure this, the firm is contacted
so they can check their production schedule to find an appropriate time for the
inspection. Because the firm is aware of the pending inspection, it can update
CBER if there are any problems requiring a delay with the inspection.
Generally speaking, the timing of inspections is about halfway through the review
cycle. For a new BLA, that would be about 5 months after the application was
received, since there is a 10-month review time frame. For a prior approval
supplement, inspection would happen at about 2 months, because those have a
4-month review time frame.

For the pre-license or pre-approval inspections of biologic drugs and devices, the
Division of Manufacturing and Product Quality in CBER's Office of Compliance
and Biologics Quality, or OCBQ, serves as the lead on these inspections. An
investigator from the local district office at the firm's location is invited, and a
product specialist is encouraged to join and go on inspection

With respect to pre-license and pre-approval inspections, as per the CFR, CBER
will make a determination of compliance with the application and applicable
standards, including GMP standards, in order to approve the application or
supplement. The product to be introduced into interstate commerce has to be
available for inspection during all phases of manufacturing. That is why the FDA
contacts the firm and sets up the pre-license or pre-approval inspection to make
sure that they are in these stages, and in particular the manufacturing stages of
interest

B. Complete Response (CR) Letter – A letter issued when the complete review indicates that
there are deficiencies remaining that preclude the approval of the application at that time.
Note: A CR letter stops the review clock. The CR letter will summarize all of the deficiencies
remaining and describe actions necessary to place the application in a condition for approval.

Pre-license and Pre-approval Inspections
CBER acts as the "home district" for all pre-license and pre-approval inspections of
CBER-regulated products, whether foreign or domestic

https://www.fda.gov/media/73834/download

This compliance program provides inspectional guidance to investigators, inspectors, and
product specialists assigned to perform biennial, for cause, PLI, and PAI inspections of
manufacturers of CBER-regulated biological drug products, and provides
administrative/regulatory guidance for the compliance officer (CO) or investigator (hereinafter
referred to as “investigators”).

B. Strategy
This compliance program incorporates a systems-based, risk management approach to
conducting inspections, and identifies key systems and three critical elements within each system
for inspection.
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The key systems are: The three critical elements are:
1. Quality System 1. Standard Operating Procedures (SOPs)
2. Facilities and Equipment System 2. Training
3. Materials System 3. Records
4. Production System
5. Packaging and Labeling System
6. Laboratory Control System
7. Donor Eligibility System (only for certain HCT/Ps regulated as drugs (e.g., minimally
manipulated, unrelated allogeneic placental/umbilical cord blood products, also known as
hematopoietic progenitor cells, cord (HPC-C))
The inspection of biological drug manufacturers is conducted under either a Level I (Full) or
Level II (Abbreviated) inspection option. This compliance program directs an in-depth audit of
the critical elements in each key system, which may affect the safety, purity, potency, identity,
and effectiveness of the biological drug, if procedures are not performed properly or the system
controls are either inadequate or not functioning correctly.
● A Level I inspection is an in-depth audit of the three critical elements in at least four of
the key systems, one of which must be the Quality System, and provides a comprehensive
evaluation of the establishment’s compliance with CGMPs. In addition to the audit of the
Quality System:
o Level I inspections of HPC-C manufacturers should also include an audit of the
Production System and Donor Eligibility System.
o Level I inspections of all other biological drug product manufacturers should also
include an audit of the Production System
● A Level II inspection is a streamlined evaluation of an establishment’s compliance with
CGMPs. This option provides coverage of the three critical elements in one mandatory
key system (Quality System), plus at least one additional key system on a rotating basis
during successive biennial inspections.


Other inspections:
CBER is responsible for the conduct of all PLI and PAI inspections of CBER-regulated
biological drug products. These inspections are part of the review of a BLA or supplement.
CBER identifies the scope and content of the inspection and invites ORA to participate in the
inspections. CBER/OCBQ, Division of Manufacturing and Product Quality (DMPQ) will notify
the district office and the TB Supervisor of all pending pre-license or pre-approval inspections.

The Team Biologics lead investigator with the inspection team members, product specialist(s),
CBER/OCBQ/DIS and the home district, if applicable, will develop the overall inspectional
approach for individual CGMP inspections. Products needing special coverage will be addressed
as part of the specific inspectional approach. A similar approach is applied to CBER PLIs and
PAIs with CBER/OCBQ/DMPQ and the product specialist reviewer for the submission.

1. Quality System
Assessment of the Quality System is two-phased. The first phase is to evaluate whether the QC
unit has fulfilled its responsibility to review and approve all procedures related to production,
quality control and quality assurance, and to ensure the procedures are adequate for their
intended use. This also includes the associated record keeping systems.
Review records related to product recall, product deviations, complaints, out of specification
results, rejects, and failure investigations. Verify the firm routinely reviews its records pertinent
to the manufacture of lots or units prior to their release or distribution. Examine, report, and
track counterfeit imported products, returned and rejected imported products, and complaint files
concerning imported products. The second phase is to assess the data collected in order to
identify quality problems that may be linked to other systems.

2. Facilities and Equipment System
This system includes the measures and activities that provide an appropriate physical
environment, along with the equipment and resources that are used in the production of the
biological drug product.
Coverage of this system should include verifying the appropriateness of buildings and facilities,
including maintenance; equipment qualifications (installation and operation); equipment
calibration and preventative maintenance; cleaning and validation of cleaning processes as
appropriate; prevention of contamination and cross contamination; extractable and leachable or
other contaminants on product contact equipment causing deterioration or rendering product less
suitable for intended use; and utilities that are not intended to be incorporated into the product;
such as HVAC, compressed gases, and steam and water systems. Process performance should be
evaluated as part of the inspection of the overall process, which is done within the system where
the process is employed.

3. Materials System
This system includes the measures and activities to control finished products, such as
components, source materials, water or gases that are incorporated into the product, and
containers and closures. The audit of this system should include examining the validation of
computerized inventory control processes, product storage, distribution controls, records, and
detection and prevention of counterfeiting, including counterfeit imported materials. Facilities
used in support of this system must be maintained in a clean and orderly manner, and must be of
suitable size, construction and location to facilitate adequate cleaning, maintenance and proper
operation. The audit of this system should include a determination of significant physical
changes, and an evaluation of routine monitoring of the utility systems. Equipment used in
support of this system must be maintained in a clean and orderly manner, and located so as to
facilitate proper cleaning and maintenance. The audit of this system should include review of
procedures and records of calibration and maintenance, verification that the firm is following
procedures and that the procedures conform to the manufacturer’s recommendations and/or user
manuals. In addition, the audit should verify whether equipment has been adequately qualified
for its intended use, if necessary, and if any new equipment was added or any modifications to
existing equipment were made since the last inspection

4. Production System
This system includes the measures and activities to control the manufacture of biological drug
products, including following and documenting performance of approved manufacturing
procedures. Inspection of this system should include, among other things, batch formulation;
dosage form production; sterile filtration; aseptic filling; in-process testing; lot release, and
process validation.
Review a sampling of records for operations performed. Verify that records are complete and
maintained as required, and are related to the history and disposition of all products produced
and distributed. All records must be legible and indelible, and must identify the person
performing the work, including dates of the various entries; show test results as well as the
interpretation of results; show the expiration date assigned to specific products; and be as
detailed as necessary to provide a complete history of the work performed.
Facilities used in support of this system must be maintained in a clean and orderly manner, and
must be of suitable size, construction and location to facilitate adequate cleaning, maintenance
and proper operation. The audit of this system should include a determination of significant
physical and/or manufacturing changes, and an evaluation of routine monitoring of the utility
systems. Equipment used in support of this system must be maintained in a clean and orderly
manner, and located so as to facilitate proper cleaning and maintenance. The audit of this system
should include review of procedures and records of calibration and maintenance, verification that
the firm is following procedures and that the procedures conform to the manufacturer’s
recommendations and/or user manuals. In addition, the audit should verify whether equipment
has been adequately qualified for its intended use, if necessary, and if any new equipment was
added or any modifications to existing equipment were made since the last inspection.

5. Packaging and Labeling System

6. Laboratory Control System
An in-depth audit of this system should include review of the firm’s SOPs for control
of microbiological contamination and environmental monitoring; review of records for source
materials, in-process and finished product testing; evaluation of the firm’s methods for sampling
and testing products for identity, potency, safety, sterility and conformance with final
specifications; and review of the firm’s test methods to ensure that they have been appropriately
validated

7. Donor Eligibility System
Inspectional coverage should include review of the firm’s written procedures for all
steps performed in screening, testing, and determining donor eligibility.

C. INSPECTION COVERAGE
For each of the systems defined above, the inspection must include, coverage of the following
three critical elements: (1) procedures, (2) training/personnel, and (3) records. Actual
observations of the processes applicable to each system should be performed whenever possible.

State of Control
A firm is considered to be operating in a state-of-control when it employs conditions and
practices that ensure compliance with the intent of Section 501(a)(2)(B) of the Act, and the
portions of the CGMP regulations that pertain to their systems. A firm in a state of control
produces finished biological drug products for which there is an adequate level of assurance of
quality, strength, identity, purity, and potency.

When inspectional findings indicate the potential for fraud, e.g., falsification, counterfeiting,
illegal importation, and/or drug diversion, the investigator should notify the Team Biologics
Compliance Officer lol- just seeing if Whytee uses this

Reg