This ppt consists of types of FDA inspection, and how to prepare for FDA inspection of pharmaceutical mfg site, and what to do before FDA inspection, During FDA inspection, and after FDA inspection.

1. Presentedby:
JINALPRAJAPATI
M.Pharm
FDA Inspections
Department of QualityAssurance TECHNIQUES
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2. What are the biggest concerns about a FDA
Inspection?
• Non compliance with cGMPs
• Won’t know the answer’s to the investigators questions
• Won’t have complete documentation
• Which investigator will conduct the inspection(i.e lack of consistency of inspectional
approach between investigator’s)
• Will not be prepared when FDA comes to inspect
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3. Types of FDA audit/inspection:
According to FDA compliance programs, FDA conducts the following inspections for drug
manufacturing:
• Pre-approval inspections.
• Post-approval audit inspections.
• Drug manufacturing inspections (routine cGMP [Surveillance] Inspection).
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4. Pre-approval inspections:
A pre-approval inspection (PAI) is performed to contribute to FDA’s assurance that a
manufacturing establishment named in a drug application is capable of manufacturing a
drug, and that submitted data are accurate and complete.
There are three primary inspectional objectives of PAI. These objectives are:
• Objective 1: Readiness for commercial manufacturing
• Objective 2: Conformance to application
• Objective 3: Data integrity audit
4Fig.no.1 Objective of pre-
approval inspection

5. Objective 1: Readiness for commercial manufacturing
The objective in this area is to demonstrate that one has a quality system in place designed
to achieve sufficient control over the facility and commercial manufacturing operations. Key
elements of control include:
• Manufacturing and laboratory changes, deviations, and trends relating to the development
of new drug substance as well as product manufacturing have been adequately evaluated.
• Appropriate program for sampling, testing, and evaluation of components, in-process
materials, finished products, and containers and closures for the purpose of releasing
materials or products has been established.
• The establishment has sufficient facility and equipment controls in place to prevent
contamination of and from the application product (or API).
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6. • Adequate procedures exist for batch release, change control, investigating failures,
deviations, complaints, and adverse events; and for reporting this information to FDA,
such as field alert reporting.
• The feasibility of the proposed commercial process and manufacturing batch record,
including instructions, processing parameters and process control measures, are
scientifically and objectively justified.
Objective 2: Conformance to application.
• Verify that the formulation, manufacturing or processing methods, and analytical or
examination methods are consistent with descriptions contained in the CMC section.
Objective 3: Data integrity audit.
Audit the raw data, hardcopy or electronic, to authenticate the data submitted in the CMC
section of the application. Verify that all relevant data (e.g., stability ) were submitted in the
CMC section such that CDER product reviewers can rely on the submitted data as complete
and accurate.
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7. Post-Approval Inspection Program
Post-approval audit inspections program is designed to audit for changes in the production
and control practices that occur after approval and to confirm that the approved applications
have been appropriately supplemented to reflect those changes.
The main objectives of this continuing compliance program are two fold:
• To assure that any changes in manufacturing and process control are in compliance with
cGMP regulations;
• To assure that all changes 21 CFR 314.70 requires are documented in supplemental
applications or annual reports. Appropriate regulatory action will be taken against those
establishments not meeting these requirements. Additionally, through the use of related
compliance programs, a secondary objective of this program is to confirm that
NDA/ANDA requirements concerning adverse reaction reports, NDA field alerts, and
annual reports are being met.
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8. Drug Manufacturing Inspections (Routine cGMP
[Surveillance] Inspection)
• The goal of this inspection’s activities is to minimize consumers’ exposure to adulterated
drug products.
• Activities in drug firms can be organized into systems that are sets of operations and
related activities
• Control of all systems helps to ensure production of drugs that meet intended safety,
identity, strength, quality and purity characteristics.
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9. Two surveillance inspectional possibilities
• This is a surveillance or compliance
inspection meant to provide a broad and
deep evaluation of the firm’s cGMP.
• This occur when little or no information
is known about a firm’s cGMP
compliance;
• or for firms where there is doubt about
the cGMP compliance in the firm; or
follow up to previous regulatory actions.
• This is a surveillance or compliance
inspection that is meant to provide an
efficient updated evaluation of a firm’s
cGMP.
• The abbreviated inspection will provide
documentation for a firm continuing in a
satisfactory cGMP compliance status.
• Generally this will be done when a firm
has a record of satisfactory cGMP
compliance, with no significant recall, or
product defect or alert incidents, or with
little shift in the manufacturing profiles
of the firm within the previous two years
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FULL INSPECTION ABBREVIATED INSPECTION

10. FDA Systems inspection:
• Quality
• Production
• Laboratory
• Materials
• Facilities & Equipment
• Packaging & Labeling
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Fig.no.2 Quality system

11. • Quality
• Facilities and Equipment
• Materials
• Production
• Packaging and Labeling
• Laboratory Controls
• Subpart A- General provisions
• Subpart B -Organization and Personnel
• Subpart C -Buildings and Facilities
• Subpart D -Equipment
• Subpart E -Components and
Container/Closures
• Subpart F – Production and Process Controls
• Subpart G -Packaging and Labeling
• Subpart H- Holding and distribution
• Subpart I -Laboratory
• Subpart J- Records and Reports
• Subpart k- Returned and salvaged drug
product
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Six systems: 21 CFR 211:

12. Quality System
• The system includes the quality control unit and all of its review and approval duties (e.g.,
change control, reprocessing, batch release, annual record review, validation protocols,
and reports, etc.).
• It includes all product defect evaluations and evaluation of returned and salvaged drug
products
Facilities and
Equipment
System
• This system includes the measures and activities that provide an appropriate physical
environment and resources used in the production of the drugs or drug products.
Materials
System
• This system includes measures and activities to control finished products, components,
including water or gases, which are incorporated into the product, and containers and
closures.
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13. Production
System
• This system includes measures and activities to control the manufacture of drugs and drug
products including batch compounding, dosage form production, in-process sampling and
testing, and process validation.
Packaging and
Labeling
System
• This system includes measures and activities that control the packaging and labeling of
drugs and drug products.
Laboratory
Control System
• This system includes measures and activities related to laboratory procedures, testing,
analytical methods development and validation or verification, and the stability program
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14. Initiatives to prepare for an FDA inspection:
Commission a Quality System Self-Study
Invest in a comprehensive, self-assessment of one’s system by third-party experts who can
identify cGMP compliance gaps in one’s established procedures and practices.
Design Quality Systems to Measure Performance
Each system should be designed to provide performance metrics that explain how well the
system is being managed, as well as what quality issues and trends the system reveals.
Train Employees to Manage FDA Inspections
Each and every employee does not need to know the details of the execution and goings on
within the audit, but they do have to be prepared and know the role they play within the
audit. Employees should be prepared to answer key questions such as:
“What is the quality policy?”
• Ensure each employee understands and can speak to what the policy means to them
• Use the quality policy training
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15. “How do you know what’s required of you in your job?”
Employees must know what is defined by their job description
>Make sure employees know to follow approved procedures and work instructions
>Make sure employees know how to access procedures and work instructions
>Have employees bring up errors in procedures and instructions now
“Is your training current?”
>Ensure the training is current
>If there are gaps, complete the training now and maintain it!
What if one doesn’t know the answer?
The correct answer for employees is
“I am not sure but I will get the information for you.”
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16. Conduct Mock Inspections to Rehearse Systems and Assess Employee Readiness
• These exercises can be very useful both to identify compliance issues that need to be
addressed before an inspection takes place as well as familiarize employees with the
process and how best to respond to questions that may be addressed to them.
• It should be noted that FDA inspections differ from internal audits performed by company
personnel in several important ways.
• The mock FDA investigator should know how to “play the role” effectively in order for
the preparation to be fully useful.
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17. Establish Systems to Manage the FDA’s Presence On-Site
Key things to address in the system include:
• Where to take the FDA employee upon arrival.
• Who will accept the Notice of Inspection on behalf of the company?
• Who will be in charge of the inspection for the company?
• Who will escort the FDA personnel while they are on-site?
• Where will the FDA personnel be housed (conference room, etc.) while on-site.
• How will the company assure prompt access to needed people and documents?
• Who will discuss daily audit summaries?
• Who will participate in the exit discussion, what the strategy for that discussion will be, and who
will speak for the company.
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18. Commonly Requested Information
• Organizational charts with full name and title of corporate officers, plant officers and
managers, and key plant personnel to the supervisory level
• Name and title of key officials on-site and description of responsibilities
• Name and address of the individual to whom regulatory correspondence should be
addressed
• Regulatory agent (US Agent): name, address, phone, fax, and e-mail
• List of US product with (drug master file [DMF] number, NDA/ANDA number and
status)
• List of post-approval supplement (NDA/ANDA number and status) since the last
inspection
• List of customers for US product (name, address, contact name)
• List of all lots shipped to US (product, lot number, quantity, customer)
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19. • Manufacturing flow chart for each product manufactured at the site
• Floor diagrams of facilities with details on production and filling areas
• Production and laboratory work schedule
• Diagram of water purification systems and changes implemented since the previous
inspection
• List of process and critical equipment and it’s changes since the last inspection
• Annual reports and product reviews for all products since the last inspection
• Lots rejected, reworked, or reprocessed including the reason and disposition
• Procedure for reprocessing and reworking
• Procedure and list of the following (include the open date, closed date, description of
event, lot number and outcome):
– Deviation reports
– Change controls
– CAPA
– Complaints
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20. – Laboratory out-of-specification reports (including finished products, in-process
products, raw materials, stability tests, bio burden, and sterility tests)
– Summarized environmental monitoring data for all controlled (aseptic) areas since the
previous inspection
– Summarized water systems monitoring data since the previous inspection
– Stability data for all products (include list of all lots currently on stability and a
summary)
– Recalls
– Filed alerts
• Validation master plan and timetable
• Labels, inserts and marketing materials
• Current year facility drug registration
• Copy of FDA assigned labeler code
• Site master file
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21. During the site FDA inspection:
Arrival of FDA inspector
The FDA coordinator, FDA escort, vice president (VP)/quality assurance (QA) director/regulatory
affairs (RA) director/production director should be available when the inspector first arrives.
Receptionist/FDA coordinator must notify each of company department managers that FDA
inspector/investigator is on-site/company premises. This will ensure that all appropriate personnel are
available for consultation during the inspection.
Initial Meeting with FDA Inspector
• The names of the investigators
• The credentials of the investigators
• The purpose of the visit
• If the purpose of the visit is for facility inspection, the investigators should issue a Notice of
Inspection (FDA Form 482)
Chief executive officer or director of regulatory affairs and director of quality assurance make a short
presentation regarding the nature of the company business. Provide a brief tour of the company
facility to the FDA investigators. 21

22. FDA Coordinator, FDA Escort(s)
The principal responsibility of the FDA coordinator and the FDA escorts is to create and
maintain an atmosphere of professional and congenial cooperation.
The FDA coordinator should attempt to directly answer the FDA investigators questions.
The FDA coordinator may allow department managers or other personnel to answer
questions but only upon a determination that a particular employee is appropriate to
respond.
The FDA investigators may be left alone to review documents that they have collected,
although the FDA coordinator should remain conveniently available to the FDA
investigators during the review in order to answer any questions that may arise.
The FDA investigators may physically observe any area, equipment, or process related to
manufacture.
During the course of an inspection, the FDA investigators may identify a condition that
merits correction. If proper correction can be promptly made, then remedial action should be
taken immediately during the inspection. Even so, this remedial action may not prevent the
mention of the condition on the FDA’s list of inspectional observations (FDA Form 483).
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23. Note-Taking
FDA coordinator, escorts, department managers, must take detailed notes during the FDA
visit. All notes shall be recorded on form, and shall be factual, accurate, and without
opinion.
FDA coordinator, escorts, must record all documents and files that are reviewed by the FDA
investigators.
The FDA investigators should be given adequate time to review these documents and files.
Identify all items that require follow-up during the investigation.
Keep Documents Flowing Expeditiously
Only documents specifically requested by the inspector should be provided for review.
Release only single copies of documents to the FDA investigators. A copy of each document
released to the FDA investigators should be made prior to release (it is very important to
keep a copy of every record/document that is provided to the inspector during the
inspection). A file shall be maintained that contains a complete copy of all documents
released.
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24. Communicate Effectively
• Develop effective means of communication during the inspection between company
personnel involved in the inspection and the FDA investigators, as well as communication
within the company.
• FDA investigators are open to a debriefing session at the end of the day, particularly after
the first few days of an inspection. Take the opportunity to ask if they have identified any
issues.
Inspection Conclusion
The exit discussion shall be scheduled such that the following relevant management
personnel are in attendance:
• Chief executive officer
• Director of regulatory affairs and director of quality assurance
• Head/managers from all inspected departments
During this meeting, if serious deficiencies have been found during the inspection,
an Inspectional Observations Form FDA 483 will be issued, which lists the deficiencies.
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25. Do not argue with the FDA investigators. If there is a misunderstanding, or if the
investigator is in factual error, an explanation shall be made as to why he/she/they is/are in
error.
The FDA investigators is unlikely to delete an item from the FDA Form 483, but may cross
out and initial an item.
The FDA investigators may discuss in more detail some observations on the FDA Form 483
than actually appears on the form, and will often suggest what should be done to make
corrections, but will usually avoid specifying how to make corrections.
If FDA Form 483 is not presented, it is appropriate to request a copy of the Establishment
Inspection Report (EIR).
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26. Actions to be taken after an FDA inspection:
The FDA coordinator shall prepare an executive summary of the FDA inspection to
company senior and executive management. The report should be kept with documents and
include:
• A summary of questions and discussions between inspector and each employee
• List of all product or facilities/departments viewed
• List of all records reviewed
• Copies of all documents duplicated for the inspector
• Note of all samples taken, and receipt for samples (FDA Form 484)
• Note of all commitments made (include completion dates if set with FDA)
• Inspector comments
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27. Write a Cooperative Response to Form FDA 483
The written response, directed to the FDA district office, should be submitted within 15 days
of receipt of the FDA Form 483.
The response should address the following:
• An explanation of any matters the FDA investigators included on the FDA Form 483, but
which the company does not intend to change
• A description of changes that have been implemented
• A description of changes currently being implemented, with an estimated date of
completion
• An identification of any unclear or incorrect observations
• A request for a copy of the EIR
The written response shall be a point-by-point response to the items identified on the FDA
Form 483.
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28. REFERENCES:
• FDA, Facts About Current Good Manufacturing Practices (cGMPs), available at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing
/ucm169105.htm
• FDA, “Sec. 501, Chapter V: Drugs and Devices,” Federal Food, Drug, and Cosmetic Act,
available at:
http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticAct
FDCAct/FDCActChapterVDrugsandDevices/default.htm
• FDA, “Pre-Approval Inspections, Program 73456.832, Chapter 46, New Drug
Evaluations,” FDA Compliance Program Guidance Manual, 2010.
• FDA, “Drug Manufacturing Inspections, Program 7356.002,” FDA Compliance Program
Guidance Manual, 2002.
• How to Prepare for an FDA Inspection, PathWise, available at:
http://www.pathwise.com/audit_consulting.php
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29. THANK YOU
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