USFDA INSPECTIONS: A

SYSTEMATIC APPROACH
presented by:
Daniel J. Roberts
Consumer Safety Officer,
USFDA India Office Assistant Country Director,
USFDA/OC/OIP
USFDA India Office Foreign Post: New Delhi, India
daniel.roberts@fda.hhs.gov

presented at:
American Center, New Delhi
July 15, 2016

1
 Objectives
Overview of FDA inspections
Full versus abbreviated inspection
Discussion of USFDA drug regulations
Discussion of drug compliance programs
GMP Systems-based inspections

2
 Overview of FDA Inspections
Types of Inspections
Pre-Approval Inspections (PAI)
Post-Approval Inspections
Surveillance Inspections
For-Cause Inspections
Comprehensive inspections versus
limited/abbreviated inspections

3
Pre-Approval (PAI) Program

4
Pre-Approval (PAI) Program

5
 Pre-Approval (PAI) Inspections
A pre-approval inspection (PAI) is performed to
contribute to FDAs assurance that a
manufacturing establishment named in a drug
application is capable of manufacturing a drug,
and that submitted data are accurate and
complete.

6
 PAI is Product Specific
Limited or no commercial manufacturing
More focus on development data
More emphasis on authenticity of data and application
commitments
Process validation commonly not completed
Application actions are administrative
Trend towards more multi-disciplinary team inspections

7
PAI 3 Main Objectives

8
 PAI 3 Main Objectives
Objective 1: Readiness for Commercial Manufacturing
Determine whether the establishment(s) has a quality system that is designed to achieve
sufficient control over the facility and commercial manufacturing operations.

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 of
the application for the biobatch (and other pivotal clinical batches, when applicable), the
proposed commercial scale batch, and the API(s).

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, biobatch data) were
submitted in the CMC section such that CDER product reviewers can rely on the
submitted data as complete and accurate.

9
 PAI Outcomes
The inspection is one part of the approval process.
Investigator will submit a recommendation at the conclusion of the inspection:

Recommend Approval
Indicates that the inspection found no significant issues
Response to observations is important

Recommend Withholding of Approval

Investigators observed that the site is not CGMP compliant, information in
CMC is not consistent with site records, or information submitted is not
accurate and complete.
Firms Response to observations is critical

10
 Post-Approval Inspections
The main objectives of this compliance program
are twofold:

To assure that any changes in manufacturing and process

control are in compliance with CGMP regulations;

To assure that all changes are documented in

supplemental applications or annual reports as required by
21 CFR 314.70 (Scale-up Post-Approval Changes (SUPAC
Guidance))
11
 Post-Approval Inspections

A secondary objective of this program

is to confirm that NDA/ANDA requirements

concerning Adverse Reaction Reports, NDA
Field Alerts, Annual Reports are being met.

12
 For-Cause Inspection
Assignments may be issued as a result of and/or
follow up to the following issues:
Adverse Event Reports (ADE)
Consumer product complaints
Field Alert Reports (FAR)
Product recall
Regulatory action/Warning Letter
Inspection Request for Follow-up Information
13
 Comprehensive vs Abbreviated
Comprehensive inspection will consist of an
assessment of at least four of the following
six systems:
1. Quality System*
2. Facility / Equipment (e.g., Autoclave, Lyophilizer)
3. Materials (e.g., Water System)
4. Production System (e.g., Aseptic Filling)
5. Packaging & Labeling
6. Laboratory Controls
14
*mandatory
 Comprehensive vs Abbreviated
Abbreviated Inspection includes coverage of two
(2) systems with mandatory Quality coverage.
Note: may be appropriate when the following two
are satisfied;

1. If the firm has implemented a formal risk management

program that assures effective design and control
(including maintenance). This includes a risk mitigating
design of their processing lines that incorporates a modern
separation and automation approach (e.g., isolators, closed
RABS), and upstream bioburden controls.
15
 Comprehensive vs Abbreviated
Note: Abbreviated Inspection may be appropriate when the following
two are satisfied;

2. The firm has a record of sustained acceptable compliance history

and a strong risk management program.

that provides daily assurance through the overall design and

control program;
media fills, sterility testing data, recalls, defect adverse event
complaints and reports reveals no findings of sterility failure of
a distributed batch, and
record of satisfactory CGMP compliance with no Class 1
recalls.
16
 USFDA Drug Regulations

21 CFR 210 and 211- Current Good

Manufacturing Practices for Pharmaceuticals
(43 FR 45077, Effective Date: Sept. 29, 1978)

21 CFR 11- Electronic records, Electronic

Signatures
(62 FR 13464, Effective Date: Mar. 20, 1997)

17
 Drug 21 CFR 211 GMP Subparts
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
18
 FDA Compliance Programs
Provide guidance and instructions for obtaining
information to help fulfill agency plans regarding
the program area

Are established procedures and policies and

should be followed

Intended for FDA personnel and are available

electronically to the public
19
 Drug Compliance Programs

CP 7356.002, Drug Manufacturing Inspections

CP 7356.002A, Sterile Drug Process Inspections

CP 7356.002F, Active Pharmaceutical Ingredients

(API) Process Inspection

CP 7346.832, Pre-Approval Inspections

CP 7346.843, Post-Approval Inspections

CP 7356.021, DQRS FARS Inspections

20
 Other Drug Compliance Programs

CP 7356.002B, Drug Re-packagers and

re-labelers
CP 7356.002C, Radioactive Drugs
CP 7356.002P, Positron Emission
Tomography (PET) Drugs
CP 7356.002E, Compressed Medical Gas
CP 7356.002M, Biotechnology Drug
Manufacturing Inspections
21
 FDA Guidance Documents
Guidance documents represent the Agency's
current thinking on a particular subject.
They do not create or confer any rights for or on
any person and do not operate to bind FDA or
the public with few exceptions.
An alternative approach may be used if such
approach satisfies the requirements of the
applicable statute, regulations, or both.

22
Relevant FDA Guidance Topics
Contract Manufacturing Quality Agreements
Investigating Out-of-Specification Results
Media Fills and Aseptic Processing
Process Analytical Technology (PAT)
Process Validation
Analytical Method Validation
Data Integrity and Compliance

23
 Guidance to Industry
Q7 Good Manufacturing Practice Guidance
for Active Pharmaceutical Ingredients-
Issued August 2001

Provides FDAs current thinking

24
 Inspectional Focus
High risk products
Potential risk of a poor quality product
Patient population
Clinical indications
Processes that are representative
Product volume
Failures/complaints/Drug Quality Reporting
System (DQRS) listing
25
 Layout of Compliance Programs and
Conducting Systems Based Inspections
Part I - Background
Part II - Implementation
Objectives
Strategy
Program management instructions
Part III - Inspectional
Part IV - Analytical
Part V - Regulatory/administrative strategy
Part VI - References and program contacts
Part VII - Center responsibilities
26
 Background Part I
The inspectional guidance in these programs is
structured to provide for efficient use of
resources devoted to routine surveillance
coverage.

Recognizes that in-depth coverage of all

systems and all processes is not feasible for all
firms on a biennial basis.

27
 Program Objectives (Part II)
Determine compliance with applicable cGMP
requirements, and if not,
Prevent adulterated products from entering
the market
Remove adulterated products from the market
Take action against persons responsible
Provide CGMP assessment of acceptability of
the firm in the pre-approval review of a facility for
new drug applications
28
 Strategy (Part II)

Activities in drug firms can be organized into six

(6) 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

29
 Strategy for Systems Inspections
(Part II)
Six systems:
Quality
Facilities and Equipment
Materials
Production
Packaging and Labeling
Laboratory Controls

30
 Inspection of Systems
Coverage of a system should be sufficiently
detailed, selecting specific examples, so the
system inspection outcome reflects the state of
control in that system for every profile class

If a particular system is adequate, it should be

adequate for all profile classes manufactured by
the firm

31
 State of Control
Operating under a State of Control
produces finished drug products for which
there is adequate level of assurance of
quality, strength, identity and purity
Any one system out of control means the
firm is out of control

32
State of Control

33
 Quality System
Review and approve all procedures related to production, QC, and QA
procedures adequate for intended use

Product reviews: at least annually; should include information from

areas listed below as appropriate; batches reviewed, for each product,
are representative of all batches manufactured; trends are identified -

Complaint reviews (quality and medical): documented; evaluated;

investigated in a timely manner; includes corrective action where
appropriate.

Discrepancy and failure investigations related to manufacturing and

testing: documented; evaluated; investigated in a timely manner;
includes corrective action where appropriate. 34
 Quality System
Change control: documented; evaluated; approved; need
for revalidation assessed.
Product Improvement Projects: for marketed products
Reprocess/rework: evaluation, review and approval;
impaction validation and stability
Returns/salvages: assessment; investigation expanded
where warranted; disposition.
Rejects: investigation expanded where warranted;
corrective action where appropriate.
Stability failures: investigation expanded where
warranted; need for field alerts evaluated; disposition.
Quarantine products and segregation. 35
 Quality System
Validation: status of required validation/revalidation (e.g.
computer, manufacturing process, laboratory methods).
Training/qualification of employees in quality control unit
function.
SOP of QCU Responsibilities
Training/job description/SOP Quality unit and covered
under other system
GMP training
Review gowning certification SOP and compare to actual
records.
36
 Facilities and Equipment System
Evaluate if floors, walls, & ceilings have smooth, hard
surfaces that are easily cleanable.
Evaluate equipment for adequate control over air
pressure, microorganisms, dust, humidity, & temperature
Evaluate if the flow of components, drug product
containers, closures, in-process materials, & drug
products through the facilities is designed to prevent
contamination.
Cleaning and maintenance
Facility layout and air handling systems for prevention of
cross-contamination
37
 Facilities and Equipment System
Specifically designated areas for the manufacturing
operations to prevent contamination or mix-ups
General air handling systems
Control system for implementing changes in the building
Lighting, potable water, washing and toilet facilities,
sewage and refuse disposal
Sanitation of the building, use of rodenticides, fungicides,
insecticides, cleaning and sanitizing agents.

38
 Facilities and Equipment System
What is critical on the piece of equipment?
Example: If temperature is critical, how is
monitored/controlled?
What needs to be calibrated on the piece
of equipment?
Where are samples collected/how/with
what?

39
 Facilities and Equipment System
Tank farm
How are deliveries handled?
Does the truck have dedicated hoses?
Are covers placed on hoses, use ports?
Recovered solvent? Need SOP, adequate test to
ensure recovered materials are suitable.
Mother liquors may be reused provided quality
of the API is not adversely effected

40
 Facilities and Equipment System
Equipment installation and operational qualification
where appropriate
Adequacy of equipment design, size, and location
Equipment surfaces should not be reactive, additive, or
absorptive
Appropriate use of equipment operations substances,
(lubricants, coolants refrigerants, etc.) contacting
products/containers/etc.
Controls to prevent contamination, particularly with any
pesticides or any other toxic materials, or other drug or
non-drug chemicals
41
 Facilities and Equipment System
Qualification, calibration and maintenance of storage
equipment, such as refrigerators and freezers for
ensuring the standards, raw materials, reagents, etc. are
stored at the proper temperatures
Equipment qualification, calibration and maintenance,
including computer qualification/validation and security
Control system for implementing changes in the
equipment
Equipment identification practices (where appropriate)
Documented investigation into any unexpected
discrepancy
42
 Facilities and Equipment System
Production train description
Cleaning procedure (CIP, manual, combination)
Cleaning documentation
Cleaning Validation
Max. allowable residue
Swab/rinse water analysis
Test method and LOQ
Data review
Report and conclusion

43
 Materials System (Warehouse)
Training/qualification of personnel
Identification of components, containers, closures
Inventory of components, containers, closures
Storage conditions
Storage under quarantine until tested or examined and
released
Representative samples collected, tested or examined
using appropriate means
At least one specific identity test is conducted one
each lot of each component
44
 Materials System (Warehouse)
A visual identification is conducted on each lot of
containers and closures
Testing or validation of suppliers test results for
components, containers and closure
Rejection of any component, container, closure not
meeting acceptance requirements. Investigate fully the
firms procedures for verification of the source of
components.
Appropriate retesting/reexamination of components,
containers, closures
First in-first out use of components, containers, closures
45
 Materials System (Warehouse)
Quarantine of rejected materials
Containers and closures should not be additive, reactive,
or absorptive to the drug product
Control system for implementing changes in the
materials handling operations
Qualification/validation and security of computerized or
automated processes (ERP Systems)
Finished product distribution records by lot
Documented investigation into any unexpected
discrepancy
46
 Materials System (Water)
What type of process water is used?
Where is the water collected for use in production?
How are water samples collected should be the same? And
frequency?
Water also used for cleaning?
Water used in production for a sterile products? Water used in the
final isolation & purification steps should be monitored and
controlled for total microbial counter, objectionable organisms &
endotoxins.
Walk thru look for slope in water line and areas for stagnation
Water System last validated
Any changes to the water system
Any water system excursions? 47
 Materials System (Water)
Investigations specs for WFI

Where monitored? Return loop back into tank should be

tested

Temperature maintained

Most recent annual water system report and trending

data

48
 Production System
Training/qualification of personnel
Control system for implementing changes in processes
Formulation/manufacturing at not less than 100%
Identification of equipment with contents, and where
appropriate phase of manufacturing and/or status
Validation and verification of
cleaning/sterilization/depyrogenation of container and
closures
Calculation and documentation of actual yields and
percentage of theoretical yields
49
 Production System
Contemporaneous and complete batch production
documentation
Established time limits for completion of phases of
production
Implementation and documentation of in-process
controls, tests, and examination (eg, pH, adequacy of
mix, weight variation, clarity)
Justification and consistency of in-process specifications
and drug product final specifications
Preventation of objectionable microorganisms in non-
sterile drug products
50
 Production System
Adherence to preprocessing procedures (eg set-up, line
clearance, etc.)
Equipment cleaning and use logs
Master production and control records
Batch production and control records
Process validation, including validation and security of
computerized or automated processes
Change control; the need for revalidation evaluated
Documented investigation into any unexpected
discrepancy
51
 Packaging and Labeling System
Training/qualification of personnel
Acceptance operations for packaging and labeling
materials
Control system for implementing changes in packaging
and labeling operations
Adequate storage for labels and labeling, both approved
and returned after issued
Control of labels which are similar in size, shape, and
color for different products

52
 Packaging and Labeling System
Finished product cut labels for immediate containers
which are similar in appearance without some type of
100 percent electronic or visual verification system or the
use of dedicated lines
Gang printing of labels is not done, unless they are
differentiated by size, shape, or color
Control of filled unlabeled containers that are later
labeled under multiple private labels
Examination of the labeled finished product
Adequate inspection (proofing) of incoming labeling
Documentation of unexplained discrepancy 53
 Packaging and Labeling System
Use of lot numbers, destruction of excess labeling
bearing lot/control numbers
Physical/spatial separation between different labeling
and packaging lines
Monitoring of printing devices associated with
manufacturing lines
Line clearance, inspection and documentation
Adequate expiration dates on the label
Conformance to tamper-evident packaging requirements
Validation of packaging and labeling operations including
validation and security of computerized processes 54
 Laboratory System
Training/qualification of personnel
Adequacy of staffing for laboratory operations
Adequacy of equipment and facility for intended use
Calibration and maintenance programs for analytical instruments
and equipment
Validation and security of computerized or automated data handling
system
Reference standards; source, purity and assay, and tests to
establish equivalency to current official reference standards as
appropriate
System suitability checks on chromatographic systems (e.g., GC or
HPLC)
55
 Laboratory System
Specifications, standards, and representative sampling
plans
Adherence to the written methods of analysis
Validation/verification of analytical methods
Control system for implementing changes in laboratory
operations
Required testing is performed on the correct samples
Documented investigation into any unexpected
discrepancy
Complete analytical records from all tests and
summaries of results
56
 Laboratory System
Quality and retention of raw data (e.g.,
chromatograms and spectra)
Correlation of result summaries to raw data; presence of
unused data
Adherence to an adequate Out-of-Specification (OOS)
procedure which includes timely completion of the
investigation
Adequate reserve samples; documentation of reserve
sample examination
Stability testing program, including demonstration of
stability indicating capability of the test methods
57
 Resources and Acknowledgements
Resources
21 CFR 211 USFDA Drug GMP Regulations
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=211

21 CFR 11 USFDA Electronic Records Regulations

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm

Guidance for Industry Part 11, Electronic Records; Electronic Signatures -

Scope and Application- August 2003
http://www.fda.gov/RegulatoryInformation/Guidances/ucm125067.htm

ICH Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical

Ingredients- Issued August 2001
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073497.pdf

USFDA Pharmaceutical cGMP Compliance Programs

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm252671.htm

USFDA Pharmaceutical cGMP Guidance Documents

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064971.htm

Acknowledgements
Thomas Arista, USFDA Consumer Safety Officer, (Assistance w/ slide content)
James Dunnie, USFDA Consumer Safety Officer, Assistance w/ slide content)
(

Denise DiGiulio, USFDA Consumer Safety Officer, Assistance w/ slide content)

(
58
THANK YOU

59