Ann: FDA Schedules GvHD Pre-License Manufacturing Inspection, page-174

A more succinct reference for our Pre License Inspection (PLI)

ATTACHMENT 6
PRE-LICENSE AND PRE-APPROVAL INSPECTIONS
BACKGROUND
Section 351 of the Public Health Service Act and section 704 of the Federal Food, Drug and
Cosmetic Act provide the regulatory authority to conduct inspections at any establishment where
biological products are manufactured. Under 21 CFR 601.20, a biologics license shall not be
issued except upon a determination that the product and establishment comply with the
applicable regulations. Under the reauthorization of Prescription Drug User Fees in the Food and
Drug Administration Modernization Act of 1997, an inspection, if needed, is considered to be
part of the complete review of an application.
A pre-license inspection (PLI) or pre-approval inspection (PAI) is performed at establishments
named in a biologics license application or supplement to ensure compliance with applicable
requirements and to ensure that the data submitted are accurate and complete. This program
directs CBER in the evaluation of biological drug establishments by on-site inspections when the
firm submits a BLA or a prior approval supplement. This may include original submissions,
Chemistry, Manufacturing, and Controls (CMC) amendments to pending original submissions,
and CMC supplements to approved BLAs. Domestic and international PLIs and PAIs may cover
all establishments associated with the submission, including the drug substance, finished dosage
product manufacturing, and control testing laboratories.
The CMC section of an application or supplement includes the analytical test methods and
specifications for drug intermediates, drug substances, and drug product, and general description
of the product’s manufacturing and control procedures as well as facility controls for traditional
BLAs. Sections in the BLA including facility and equipment information, batch records, and
other information can be verified on inspection. The assessment of CMC and other sections
always includes a review of information submitted in the application or supplement and
generally includes an inspection of manufacturing operations by the Division of Manufacturing
and Product Quality in CBER’s Office of Compliance and Biologics Quality and a product
specialist. Team Biologics investigators are also invited to participate in the inspection.
CBER's policy is to ensure that manufacturing establishments and processes meet the appropriate
requirements and comply with the regulations through inspections and review. CBER will
determine if a PLI or PAI is necessary based on CBER SOPP 8410 “Determining When PreLicense or Pre-Approval Inspections Are Necessary.” The scope of the inspections will be based
on the systems approach described in this Compliance Program in addition to specific areas
described in this Attachment.
INSPECTION SCHEDULING AND PREPARATION
A PLI or PAI should be performed based on when the establishment is in operation, inspection
team availability, and to meet PDUFA timeframes. It may be combined with other inspection
programs.
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The preparation before a PLI or PAI should involve the following:
 Review the CMC section or other sections of the application or supplement and any
related DMFs for the establishments to be inspected.
 Identify any issue/deviation that needs to be evaluated in more detail while on-site.
 Develop, with the other team members, an inspection plan and strategy specific to the
establishment and product being inspected that is consistent with this program’s
objectives.
INSPECTION TEAM
PLIs and PAIs should be, whenever possible, a team approach with a DMPQ inspector as the
team lead and a product specialist (for all inspections, except for final biological drug product
facilities). CBER requests ORA participation in CBER PLIs and PAIs. Staff conducting these
inspections will be qualified by appropriate training and experience.
CONDUCTING THE INSPECTION
The PLIs and PAIs should be performed using the systems-based approach, covering all systems
(if applicable) and the three critical elements for each system, the equivalent of a Level I
inspection. In addition, and as part of the systems-based approach to these types of inspections,
the following objectives should also be assessed based on the inspection plan:
 Verify that all relevant data were submitted to the BLA or supplement, and data are
accurate and complete.
 Verify that the manufacturing history is accurate and complete when compared to the
submission.
 Observe the processes, manufacturing and testing, and compare with the description
and/or batch record submitted in the CMC section and other sections of the
submission.
 Review product process, process controls, analytical testing, and process validation
for the drug substance and drug product.
 Review facility and process changes not covered in the submission that could affect
the product or manufacturing.
 Review product development data if submitted in the application.
 Review batches or lots that did not meet and met specifications and verify out of
specification investigations are completed.
 Review stability data and verify it meets specifications.
 Review data as needed, determined by submission review for qualification of new
manufacturing areas, equipment, and utilities.
 Verify raw materials and components testing have been performed.
 Verify the new product has been incorporated into all aspects of the quality system.
 Review shipping validation for drug substance and drug product.
 Verify procedures have been established for reporting of Biological Product
Deviation Reports and Adverse Experience Reports (21 CFR 600.14 and 600.80,
respectively).
INSPECTION REPORTING
Any reportable inspectional observations will be issued to the establishment on a Form FDA-483
consistent with instructions in the IOM. Use the CBER/OCBQ/DMPQ address and phone
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number as the district office address on the Form FDA-483. The address is:
FDA/CBER/OCBQ/DMPQ HFM-670, 1401 Rockville Pike, Rockville, MD 20852-1448, phone
301-827-3031.
After the inspection is conducted, communications with the applicant's authorized official or
other authorized personnel should be documented. These communications, including telecons,
are entered into RMS-BLA and uploaded to the EDR as part of the application or supplement
under review. Official correspondence regarding the inspection and Form FDA-483 responses
submitted by the applicant are added as amendments to the application or supplement under
review.
The inspection team lead will coordinate with the team concerning the specific establishment
inspection report (EIR) sections that each is responsible for writing. The EIR should be written
shortly upon return from the inspection, as the application and/or supplement is under a
predetermined review time clock that FDA is required to meet. All inspectional findings
reported on the Form FDA-483 should be resolved prior to the approval of the application or
supplement.