Transcript Slide 1 - Workforce Solutions

GMPs for Management:
How to Prepare for a Systems Based Inspection –
Understanding the FDA’s
Inspectional Approach and
Ensuring Compliance
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2003
1
DAY ONE

FDA’s Inspectional Initiatives & Tools for Regulating Drugs and Biotech Drugs
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FDA Structure and Organization
- Regulations and the Law
- FDA Guidelines
Administrative Enforcement Tools
- 483 Lists of Observations
- Warning Letters
Legal Enforcement Tools
FDA Inspections trends
Examine the Fundamentals of a Systems-Based Inspection

Learn the concepts of modern Quality systems including the "Six-system
Inspection Model" examined in detail and each sub-system:

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Quality System
Facilities and Equipment System
Production System
Materials System
Lab Control Systems
Packaging and labeling system
DAY ONE

Risk - base FDA Inspections
 Learn how FDA will select firms for inspections using the Risk base Approach
 Understand the FDA's intent for the systems-based inspection program
 Identify the differences between systems-based and product-based inspections
 Determine the factors that may influence which sub-systems are inspected.
 Review of additional cGMPs and the concept of Modern Quality Systems (Guidance for
Industry Quality System Approach to Pharmaceutical cGMP Regulations)
 Quality
 Quality by Design
 Quality Risk Management
 The Quality Unit
 Other critical SOPs of interest to the FDA
 Batch Control Review
 Deviation Handling
 Failure Investigations
 Change Control
 CAPA
 Training
 Validation
DAY TWO

Determine what additional the requirements under will be reviewed under the quality
systems model
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How do you comply with the additional Four Major Sections?
Examined in detail and each sub-system:
Management Responsibilities
Resources
Manufacturing Operations
Other critical SOPs of interest to the FDA
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Batch Control Review
Deviation Handling
Failure Investigations
Training
Validation
Documentation Essentials
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Controlling Documents
Document Problems
GMP Records
Compliance Within Established Standards
DAY TWO

Pharmaceutical Development Q8,Q9
 Key Development Steps

Ensuring Good Manufacturing Practices for Drug Products
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History of Regulatory Enforcement
 FDA Policy and Program Issues
 Hosting An FDA Inspection
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Preparing for a successful FDA inspection
How to develop an Inspection strategy and an inspection Tool kits (Checklist)
Learn how to save time and money by planning and focusing on the right systems
for an inspection
How to conducting Mock Inspections
Plan an effective strategy to prepare for an inspection
Maintain compliance for facilities and equipment
Questions & Wrap-Up
Module 1
 FDA’s Inspectional Initiatives & Tools for
Regulating Drugs and Biotech Drugs
 FDA Structure and Organization
- Regulations and the Law
- FDA Guidelines
 Administrative Enforcement Tools
- 483 Lists of Observations
- Warning Letters
 Legal Enforcement Tools
 FDA Inspections trends
Historical Perspective
 1938 FD&C
 1962 GMPs
 1978 cGMPs
 1997 FDAMA
 2000 (QSIT-Devices)
 2001 Pilot Program (Drugs)
 2002 System Based Inspection Program
How does FDA regulate?
 Routine inspections
 Controlling product approvals for
commercialization
 Surveillance Programs through Adverse
event reports
 Undercover surveillance (drug/device
promotion, distribution)
 Consumer complaints/former employee
complaints
 Bioresearch monitoring
Forms Commonly Used During
FDA Inspections
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FDA 482 - Notice of of Inspection
FDA 483 - List of Observations
FDA 484 - Receipt for Samples
FDA 463 - Affidavit
 Special purpose affidavits
 Various special purpose forms
 EIR - Establishment Inspection Report
Outcomes & Enforcement
 No Violation (possible Thank-you letter)
 483 Citation
 Warning Letter
 Injunction
 Consent Decree
 Legal Proceedings
Warning Letter Definition
WARNING LETTER: An informal advisory to a firm
communicating the agency's position on a matter but
does not commit FDA to taking enforcement action.
The agency's policy is that Warning Letters should be
issued for violations which are of regulatory
significance in that failure to adequately and promptly
take corrections may be expected to result in
enforcement action should the violation(s) continue
Reasons for the Letters GMP
Repetitive reasons
 Failure to follow SOPs
 Packaging and Labeling Controls
 Sampling and testing of components
 Inadequate Specifications
 Process validation
 Finished product sampling and testing
 Production and process controls
Consent Decree Definition
Consent Decree: An injunction to which
the defendant has agreed and which is
filed in court
Injunction: An order issued by the Court
requiring a defendant to do or refrain
from doing a specified act
Reasons for a Consent Decree
 Continual non-conformance in the quality management
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systems
Repeated Form 483 observations over several audits and
inspections for GMP violations
Repeated warning letters for GMP violations
Repeated unsatisfactory or no response to warning letters
and 483 observations
Failure of the company to make progress or correct
deficiencies
Why Does FDA Use
Enforcement
 To warn companies
 To stop continuing bad behavior
 To put entire industry on notice
 To control dangerous products
 To establish legal precedent
 To punish wrongdoers
Summary of Consent Decrees
 Abbott 11/99
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QSR violations
256 violations by independent consultant
100 M$ fine
 Schering Plough
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5/2002
GMP problems since 1998
Broad based observations
500 M$ fine
Impact of the Decree
 Financial Impact
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Fines
Forfeiture of profits
Injunction on sales of marketed drugs
Delays in approvals
Cost of compliance
Impact of the Decree
 Compliance Impact
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Required to hire outside consultants to
ensure compliance
Compliance plans
Expert certification
Retraining
Completion of missing or inadequate
studies
Summary of Consent Decrees
 GSK
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4/2005
Products withdrawn from market due to
consistency of dose problems
Independent party to analyze manufacturing
CAPA plan required for submission
Pay up to 10M$ per year if GSK fails in it’s
commitments
Post 650M$ bond to guarantee defective product
is disposed or reconditioned
 Pharmakon
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7/2005
Firm shut by permanent injunction order by court
Module 2
 Examine the Fundamentals of a Systems-Based Inspection

Learn the concepts of modern Quality systems including
the "Six-system Inspection Model" examined in detail
and each sub-system:
 Quality
System
 Facilities and Equipment System
 Production System
 Materials System
 Lab Control Systems
 Packaging and labeling system
 What is this new
 “SIX-SYSTEM INSPECTION
 APPROACH”
 CGMPS and the concepts of
modern
 Quality systems
Pharmaceutical CGMPs for
the 21st Century
 Reference:
 Pharmaceutical CGMPs for the 21st
Century – A Risk Based Approach
 Final Report – Fall 2004
 Latest release: September 2006
Six-system Inspection Model
 This diagram
shows the
relationship
among the six
systems: the
quality system
and the five
manufacturing
systems.
THE QUALITY SYSTEMS MODEL
 The quality system provides the
foundation for the manufacturing systems
that are linked and function within it.
 Much like QSIT,
 ISO9000/2000,
 ISO13485,
 “The Linked-Process Approach”
The FDA’s overhaul of the pharmaceutical
cGMPs encourages manufacturers to
modernize their methods, equipment and
facilities that will help eliminate both
production inefficiencies and undue risks
for consumers.
Lester M. Crawford, D.V.M., Ph.D., Acting Commissioner of Food and Drug
Administration -- U.S. Pharmacopeia Convention - March 11, 2005
Quality Systems Approach to
Pharmaceutical cGMPs
 Release in September 2006
 Integrate quality systems and risk
management approaches
 Harmonization of CGMPs, QSIT and
other non-US pharmaceutical regulatory
systems
 Go beyond quality control
The Guidance Document
 What is in that
guidance
document?
 Hint….
Systems!
Why Improve Systems?
 “…we are concerned of the apparent
system deficiencies that have allowed
the unacceptable practices cited herein
to occur. Such system deficiencies
appear to involve internal quality
auditing, corrective and preventive
actions, management controls relating to
quality planning and resource allocations
(staffing of appropriately qualified
individuals) and /or training of
personnel….”
Why Improve Systems?
 “…The specific violation noted in this
letter and in form FDA 483, Inspectional
Observations, issued at the conclusion
of the inspection by the FDA
investigators may be symptomatic of
serious underlying problems in your
firm’s manufacturing and quality
assurance systems.”
The quality systems
model
 Does not treat the five manufacturing systems as discrete entities, but
instead integrates them into appropriate sections of the model.
 The inter-relationship should be readily apparent.
 One of the important themes of the systems based inspection compliance
program is to be able to assess whether each of the systems is in a state of
control.
 The quality system model will also serve to help firms achieve the
desired state of control.
Six Systems Inspection
Approach
 Perform in-depth internal
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audit focusing on system
approach
Review past FDA
observations
Perform trend analysis
Continuous Improvement
Program
Review industry trends

Hot “FDA” areas
System
Covers
Quality System
(Assures overall compliance with
cGMPs and internal procedures and
specifications)
•The quality control unit and all of its review
Facilities and Equipment System
(Measures and activities which provide
appropriate physical environment and
resources used production.)
•Buildings and facilities along with
Materials System
This system includes measures and
activities to control finished products,
components, containers and closures.
•Validation of computerized inventory control
and approval duties
•All product defect evaluations and evaluation
of returned and salvaged drug products.
maintenance;
•Equipment qualifications (installation and
operation);
•Calibration and preventative maintenance;
•Cleaning and validation of cleaning processes
•Utilities
processes,
•Drug storage,
•Distribution controls and records.
21 CFR 211
Subparts B, E, F,
G, I, J, and
K.
Subparts B, C, D,
and J.
Subparts B, E, H,
and J.
System
Production System
(Measures and activities to control
the manufacture of drugs and drug
products)
Covers
Batch compounding,
Dosage form production,
In-process sampling and testing,
Process validation.
Establishing, following, and documenting
21 CFR 211
B, F, and J.
performance of approved manufacturing procedure
Packaging and Labeling System
(Includes measures and activities that
control the
packaging and labeling of drugs and
drug products.)
Written procedures, label
Examination and usage, label storage and issuance,
Packaging and labeling operations controls, and
Validation of these operations.
Subparts B, G, and
J
Laboratory Control System
(Includes measures and activities
related to laboratory)
•Laboratory procedures,
•Testing,
•Analytical methods development and validation or
Subparts B, I, J,
and K.
verification,
•Stability program.
Six-system Inspection Model
 The inspection includes coverage of 2 or
more systems, with mandatory coverage of
the Quality System.
 Inspecting the minimum number of systems, or
more systems as deemed necessary by the
District, will provide the basis for an overall
CGMP decision.
Six-system Inspection Model
 The FDA's Drug Manufacturing
Inspection Compliance Program is
based on a systems-based approach for
inspections.
 Purpose of the systems based
inspection compliance program is to
be able to assess whether each of the
company’s systems is in a state of
control.
Quality Oversight
System elements (roles & responsibilities)
Product reviews
 Complaint reviews
 Discrepancy and failure investigations
 Change control
 Product improvement projects
 Reprocess/Rework
 Rejects
 Stability failures
 Quarantine products
 Validation
 Training/Qualification of employees in quality control unit
function.
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QC Unit Under GMP
211.22 Responsibilities of quality control unit.
(a) Adequate laboratory facilities for the testing and approval (or rejection)
of components, drug product containers, closures, packaging materials, inprocess materials, and drug products shall be available to the quality
control unit.
(b) The quality control unit shall have the responsibility for approving or
rejecting all procedures or specifications impacting on the identity, strength,
quality, and purity of the drug product.
(c) The responsibilities and procedures applicable to the quality control unit
shall be in writing; such written procedures shall be followed.
Facilities And Equipment
 Cleaning and cleaning validation
 HVAC/environmental controls
 Containment
 Changes in critical areas
 Water for injection/purified water system
 Equipment maintenance and calibration
 Equipment qualification (including computer
validation and security)
Materials System
 Control of incoming materials and components
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quarantine, storage, release, and use
 Validation of computerized inventory control
processes, drug storage, distribution controls
and records
 Release procedures
 Retest procedures
 Changes in materials
Laboratory Controls
 Adequacy of equipment for intended use
 Enough space
 Calibration and maintenance
 Security of computer systems
 Change control
 Procedures, testing, analytical methodology,
development and verification/validation
 Lab documentation
 Adherence to out-of-specification procedures
Production System
 Batch record review
 Component preparation – e.g. , depyrogenation,
sterilization of container/closures
 Hold times, in-process controls, use logs
 Identification and documentation of critical process
parameters
 Contemporaneous and complete batch production
documentation
 Process validation
Packaging And Labeling
 Controls of master copies
 Issuance and restriction
 Changes in labeling
 Line clearance operations
 Reconciliation procedures, if applicable
 Vision system validation
Quality Systems Approach to Pharmaceutical
Current Good Manufacturing Practice Regulation
Draft – September 2004
 Key Concepts
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Quality
Quality by Design and Product Development
Risk Management and Risk Assessment
CAPA (Corrective and Preventive Action)
Change Control
The Quality Unit
Six-system Inspection Model
Module 3
 Risk - base FDA Inspections
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



Learn how FDA will select firms for inspections using the
Risk base Approach
Understand the FDA's intent for the systems-based
inspection program
Identify the differences between systems-based and productbased inspections
Define the difference between a full inspection, an
abbreviated inspection, and determine how previous
inspection results may influence the current inspection
Determine the factors that may influence which sub-systems
are inspected.
FDA’s Risk-Based Approach
to GMPs Inspections
 Routine Inspection: FDA tries to audit
Manufacturers at least every two years.
 Non compliant history
 New product, i.e., PMA
 Consumer complaints
 Competitor complaints
FDA Risk-Based Inspections
 General Statutory Inspections
 Submission Related
Inspections
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NDA / IND / BLA / IDE / PMA
 Problem Related Inspections
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Complaints
Adverse Reports
 Recalls
Pilot Risk-Ranking
Model to Prioritize
Manufacturing Sites for
GMP Inspections
GMP Initiative Announcement:
August 21, 2002
 Evaluate the currency of our drug quality
programs so that FDA resources are used most
effectively and efficiently to address the most
significant public health risks.
 In order to provide the most effective public
health protection, FDA must match its level of
effort against the magnitude of the risk.
 Resource limitations prevent uniformly intensive
coverage of all pharmaceutical products and
production. Although the agency has been
implementing risk-based programs, a more
systematic and rigorous risk based approach
will be developed.
ICH Q9: Defining Risk
 Preliminary working definitions (March 2004)
from ICH EWG on Quality Risk Management
(Q9):
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Risk: Combination of the probability of occurrence
of harm and the severity of that harm. ISO 14971
Harm: Damage to health, including the damage
that can occur from loss of product efficacy, safety,
quality or availability
 Focus on quality for our purposes
ICH Q9: Defining Risk (cont’d)
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Quality: Degree to which a set of inherent
characteristics of a product, system or
process fulfils requirements
Requirements: Needs or expectations
that are stated, generally implied or
obligatory by the patients or their
surrogates (e.g. health care professionals,
regulators and legislators)
Combining key terms: Risk to quality is the
probability/severity that drug will fail to
meet the needs/expectations of the
patients and their surrogates
Risk to Quality
Probability
Failure to meet
Needs/Expectations
of Patients/Surrogates
Severity
HARM
Quality Attributes
Probability/Severity
of Adverse Impact on
Quality Attributes
Loss of Quality
Identifying Risk Factors
 What hazards can adversely impact drug
quality attributes/surrogates?
 What processes and parameters are critical for
quality attributes/surrogates?
 What factors may affect the identified hazards
and critical parameters/processes?
 Other variables predictive of drug products with
or without identified quality attributes?
A RISK-BASED FRAMEWORK FOR PRIORITIZING SITES FOR
cGMP INSPECTION
SITE RISK
POTENTIAL
PRODUCT
PROCESS
FACILITY
Site risk potential (SRP):
A function of the risk potentials for the PRODUCT, PROCESS and
FACILITY component risk factors.
The SRP is a weighted combination of the PRODUCT, PROCESS
and FACILITY risk potentials
Semi-quantitative risk potentials represented as “high,” “medium,” or
“low,” and are numerically discrete variables in calculations.
Risk Ranking Model:
Facility Factors
 Are some manufacturing facilities (or
manufacturers) more likely to produce a product
with quality problems?
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Effectiveness of quality systems
Inspectional record and compliance history
Exposure: volume produced at facility
Other characteristics?

Macher and Nickerson study
Risk Ranking Model:
Process Factors
 Are some manufacturing processes, for
particular product classes, more likely to go
wrong than others?
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Use expert elicitation to identify risk factors and
weightings
 Risk of contamination or mix-ups
 Maintaining state of control of the process
 Potential for process capability metrics?
Selecting Systems for Coverage
 System(s) for coverage will be made by the
District Office based on:
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Specific operation,
History of previous coverage,
History of compliance, or
Other priorities determined by the District Office.
Pilot Risk Ranking Model: Risk-Based Method
for Prioritizing cGMP Inspections-Pharma
Sites
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Top-Level Components for the Site Selection Model : Factor
Category and Description Example(s)
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Product: Factors pertaining to the intrinsic properties of drug
products such that quality deficiencies could potentially and
adversely impact public health - examples: Dosage form; intrinsic
chemical properties
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Facility: Factors relating to characteristics of a manufacturing site
believed to be predictive of potential quality risks, such as the lack
of effective quality systems - examples: Poor cGMP compliance
history

Process: Factors pertaining to aspects of drug manufacturing
operations that may predict potential difficulties with process
control and/or vulnerability to various forms of contamination examples: Measuring; mixing; compression; filling
Pilot Risk Ranking Model: Risk-Based Method for Prioritizing
cGMP Inspections-Pharma Sites
Pilot Risk Ranking Model: Risk-Based Method for Prioritizing
cGMP Inspections-Pharma Sites
Pilot Risk Ranking Model: Risk-Based Method
for Prioritizing cGMP Inspections-Pharma
Sites
 The facility component of the risk ranking model includes 4
factors:
 History of violation (e.g., CGMP deficiencies have higher
weights)
 History of inspection (e.g., no prior inspection, newly
registered/licensed or no CGMP inspection in the past 2
years have higher weights than those with recent CGMP
inspection)
 Estimated volume of production output (surrogate for
exposure, e.g., higher volume and production output, higher
weights)
 Type of establishment (e.g., manufacturer, repacker, contract lab)
Drug Pilot Inspection Program:
Implemented 2/1/02
 This program applies to all drug manufacturing
operations.
 Currently there are not enough FDA resources to
audit every aspect of cGMP in every
manufacturing facility during every inspection
visit.
Drug Pilot Inspection Program:
Implemented 2/1/02
 The Full Inspection Option
 The Full Inspection Option is a surveillance or
compliance inspection which is meant to provide a
broad and deep evaluation of the firm's CGMP.
 This will be done when little or no information is
known about a firm's CGMP compliance (e.g., for
new firms); or for firms where there is doubt about the
CGMP compliance in the firm (e.g., a firm whose
history has documented short-lived compliance and
recidivism); or follow up to previous regulatory
actions.
Drug Pilot Inspection Program:
Implemented 2/1/02
 The Abbreviated Inspection Option
 The Abbreviated Inspection Option is a surveillance or compliance
inspection which is meant to provide an efficient update evaluation of a
firm's CGMP.
 The abbreviated inspection will provide documentation for continuing a
firm in a satisfactory CGMP compliance status.
 Generally: 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.
Drug Pilot Inspection Program:
Implemented 2/1/02
 Selecting Systems for Coverage
 The selection of the system(s) for coverage will
be made by the District Office based on such factors
as a given firm's specific operation, history of
previous coverage, history of compliance, or
other priorities determined by the District Office.
Drug Pilot Inspection Program:
Implemented 2/1/02
 Goal is to minimize consumers’ exposure to
adulterated drug products. Program applies to all
drug manufacturing operations.
 Recent observations/findings:
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inadequate documentation,
no procedures, not following procedures,
did not establish/follow a control system for
changes,
did not review/approved procedures, and
failed to qualify computers.
Drug Pilot Inspection Program:
System-Wide Implementation as of 2/1/02
 Importance of Operating Under a State of Control
 Produces finished drug products for which there is an
adequate level of assurance of quality, strength, identity,
and purity.
 If any one system is out of control, this means the firm
is out of control!
If Out of Control – What Does this Mean?
 Will result in regulatory action and follow up.
 Action may include the full inspection option for the next visit, a
warning letter, seizure or injunction.
 The follow up will be enacted once the compliance division concurs
that the company has an OAI (Official Action Indicated) situation.
 The OAI situation results in an unacceptable profile of all drug profile
classes for a company.
Module 4

Review of additional cGMPs and the concept of Modern Quality Systems (Guidance for
Industry Quality System Approach to Pharmaceutical cGMP Regulations)

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
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
Quality
Quality by Design
Quality Risk Management
CAPA
The Quality Unit
Other critical SOPs of interest to the FDA

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Deviation Handling
Failure Investigations
Change Control
Training
Validation
Quality System
 Quality unit’s responsibilities


responsibility to review all procedures
under its control
although not explicitly noted in the
program, the practice of FDA is to
identify the most responsible company
individuals who have the responsibility,
duty and power (authority) to detect,
prevent and correct any manufacturing
and quality problems that may exist in
their facility
Quality System
(cont’d)
 Quality unit’s duties
 annual product review
 discrepancy reports
 corrective and preventive actions
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
change control
product improvement projects
reprocess/reworking/rejects
stability failures
status of required validations
training in quality unit functions
Quality Markers
 Annual Product Review
 Stability Trends
 QC Profiles (raw materials, in-process and




finished product test results, etc.)
Supplier Qualification Program
Number of Recalls / Complaints
Manufacturing Deviations
Laboratory OOS/OOT
Quality Unit
 Starts at the top: Management
 Define organizational structure
 Build to meet requirements
 Define vision: establish policies,
objectives and plans
 Review and tweak
 Resource planning
Quality by Design
 Facilities and Equipment
 Design / Develop Product
and Process
 Monitor Processes and
Operations

Inputs / Outputs
 Address variables
Risk Assessment /
Management
 Identify quality issues
 Determine impact
 Define CAPA
 Promote Continuous
Improvement
CGMP regulations correlation to specific
elements in the quality systems model
21 CFR CGMP Regulations Related to Manufacturing Operations
Quality System Element
Regulatory Citation
1. Design and Develop Product and Processes
Production: § 211.100(a)
2. Examine Inputs
Materials: §§ 210.3(b), 211.80 – 211.94, 211.101, 211.122, 211.125
3. Perform and Monitor Operations
Production: §§ 211.100, 211.103, 211.110, 211.111, 211.113
QC criteria: §§ 211.22(a-c), 211.115(b), 211.160(a), 211.165(d)
QC checkpoints: §§ 211.22 (a), 211.84(a), 211.87, 211.110(c)
4. Address Nonconformities
Discrepancy investigation: §§ 211.22(a), 211.115, 211.192, 211.198
Recalls: 21 CFR Part 7
Evaluation Activities


Analyze Data for Trends:
Quality systems call for continually monitoring trends and improving systems. This
can be achieved by monitoring data and information, identifying and resolving
problems, and anticipating and preventing problems.

Quality systems procedures involve collecting data from monitoring, measurement,
complaint handling, or other activities, and tracking this data over time, as
appropriate.

Analysis of data can provide indications that controls are losing effectiveness. The
information generated will be essential to achieving problem resolution or problem
prevention (see IV.D.3.).

Although the annual review required in the CGMP regulations (§ 211.180(e)) call for
review of representative batches on an annual basis; quality systems calls for
trending on a regular basis.

Trending enables the detection of potential problems as early as possible to plan
corrective and preventive actions. Another important concept of modern quality systems
is the use of trending to examine processes as a whole; this is consistent with the annual
review approach. These trending analyses can help focus internal audits.
Conduct Internal Audit
 A quality systems approach calls for audits to be conducted at
planned intervals to evaluate effective implementation and
maintenance of the quality system and to determine if
processes and products meet established parameters and
specifications.
 Quality systems recommend that procedures takes into
account the relative risks of the various quality system
activities, the results of previous audits and corrective actions,
and the need to audit the entire system at least annually
 Also describe how auditors are trained in objective evidence
gathering, their responsibilities, and auditing procedures.
CAPA
 Investigate the right way!
 Monitor for effectiveness
 Evaluate across the board
 Understand the process /
operation before initiating
CAPA
Corrective Action

Corrective action is a reactive tool for system
improvement to ensure that significant problems do not recur.

Both quality systems and the CGMP regulations
emphasize corrective actions.

Quality systems approaches call for procedures to be
developed and documented to ensure that the need for action
is evaluated relevant to the possible consequences, the root
cause of the problem is investigated, possible actions are
determined, a selected action is taken within a defined
timeframe, and the effectiveness of the action taken is
evaluated.

It is essential to maintain records of corrective actions
taken (CGMP also requires this; see § 211.192).
CAPA (Corrective and
Preventive Action)
 CAPA focuses on investigating and correcting discrepancies
and attempting to prevent recurrence.
 Quality system models discuss CAPA as three concepts, all of
which are used in this guidance.
 Remedial corrections
 Root cause analysis with corrective action to prevent
recurrence
 Preventive action to prevent initial occurrence
Why are Investigations Critical: Regulatory Need
 CFR 21 Part 211
 References Investigations a number of times
 211.22 Responsibilities of the Quality Control Unit (a) ……, if
errors have occurred, they have been fully investigated.

211.192 Production Record Review …..Any unexplained
discrepancy (including a percentage of theoretical yield
exceeding maximum or minimum percentages established in the
master production and control records) or the failure of a batch
or any of its components to meet specifications shall be
thoroughly investigated, whether or not the batch has already
been distributed. The investigation shall extend to other
batches of the same drug product and other drug products that
may have been associated with the specific failure or
discrepancy. A written record of the investigation shall be made
and shall include conclusions and follow-up.
What is an Investigation?
A written record of the facts surrounding
(an) unexpected circumstance(s) and the
actions undertaken to correct the
situation both immediately and in the
future.
Deviation Definition and
Acronyms
Deviation – Deviation is a departure from an
approved instruction or established
standard. Deviations are also known as:
 Non Conformances
 Incidents
 Test Incidents
 Discrepancies
Deviation Clarity
The intent of deviations is to document issues with
the system/piece of equipment and to gain a
satisfactory resolution to meet the owner’s
needs.
The expectation of a completed deviation is to
clearly define the deviation and the steps taken
to resolve the deviation. The deviation should
be clear so that it can be understood on a stand
alone basis.
Change Control
 Have a management system for
handling change
 Understand the impact of the
change
 Evaluate the change
Quality and Change Control
 Quality reviews proposed changes for adequacy of rationale for the
decision to make the change, compliance to the change control
procedure, assurance that adequate documentation of the change is
present, impact on internal and external customers or cGMP, required
changes to other procedures, specifications, batch records, etc.
 Although Quality manages change control, other departments
coordinate change control
 Quality must have a system for tracking and monitoring changes
 Quality is the last department to review and approve change control -
responsible for ensuring everything has been completed as
required/agreed to.
Change Control
 Change control and periodic reviews are critical to
ensuring deviations are minimized and that systems and
processes are maintained in a “state of control”.
 Purpose of change control is to ensure that all changes
(planned and emergency) are documented, evaluated,
approved, and implemented in a timely manner.
 There should be a time period in which changes are
considered “void” if not implemented within a specified
time period.
 Changes can apply to equipment, utilities, processes, and
documents.
CGMP regulations correlation to specific
elements in the quality systems model
21 CFR CGMP Regulations Related to Management Responsibilities
Quality System Element
Regulatory Citations
1. Leadership
—
2. Structure
Establish quality function: § 211.22 (a) (see definition
§ 210.3(b)(15))
Notification: § 211.180(f)
3. Build QS
QU procedures: § 211.22(d)
QU procedures, specifications: § 211.22(c), with reinforcement in: §§ 211.100(a), 211.160(a)
QU control steps: § 211.22(a), with reinforcement in §§: 211.42(c), 211.84(a), 211.87, 211.101(c)(1),
211.110(c), 211.115(b), 211.142, 211.165(d), 211.192
QU quality assurance; review/investigate: § 211.22(a), 211.100(a-b) 211.180(f), 211.192, 211.198(a)
Record control: § 211.180(a-d), 211.180(c), 211.180(d), 211.180(e), 211.186, 211.192, 211.194,
211.198(b)
4. Establish Policies, Objectives and Plans
Procedures: § 211.22(c-d), 211.100(a)
5. System Review
Record review: § 211.180(e), 211.192, 211.198(b)(2)
A documented quality system
 For example, according to the model, when
 documenting a quality system, the following should
 be included:
 The scope of the quality system, including any
outsourcing
 The manufacturer’s policies to implement the quality
systems criteria, and the supporting objectives
 The procedures needed to establish and maintain
the quality system
CGMP regulations correlation to specific
elements in the quality systems model
21 CFR CGMP Regulations Related to Resources
Quality System Element
Regulatory Citation
1. General Arrangements
—
2. Develop Personnel
Qualifications: § 211.25(a)
Staff number: § 211.25(c)
Staff training: § 211.25(a-b)
3. Facilities and Equipment
Buildings and facilities: §§ 211.22(b), 211.28(c), 211.42 – 211.58,
211.173
Equipment: § 211.63 – 211.72, 211.105, 211.160(b)(4), 211.182
Lab facilities: § 211.22(b)
4. Control Outsourced Operations
Consultants: § 211.34
Outsourcing: § 211.22(a)
Resources
 Under a robust quality system, sufficient allocation of resources
for quality system and operational activities is critical.
 Senior management, is responsible for providing adequate





resources for the following:
To supply and maintain the appropriate facilities and equipment
to consistently manufacture a quality product
To acquire and receive materials that are suitable for their
intended purpose
For processing the materials to produce the finished drug
product
For laboratory analysis of the finished drug product, including
collection, storage, and examination of in-process, stability,
and reserve samples
Training
 Continued training is critical to ensure that the employees
remain proficient in their operational functions and in their
understanding of CGMP regulations.
 Under a quality system (and the CGMP regulations), training is
expected to focus on both the employees’ specific job functions
and the related CGMP regulatory requirements.
 Managers are expected to establish training programs that
include the following:




Evaluation of training needs
Provision of training to satisfy these needs
Evaluation of effectiveness of training
Documentation of training and/or re-training
211.25 Personnel
Qualifications.
(a) Each person engaged in the manufacture, processing, packing, or
holding of a drug product shall have education, training, and experience,
or any combination thereof, to enable that person to perform the
assigned functions.
(b)
Training shall be in the particular operations that the employee
performs and in current good manufacturing practice (including the
current good manufacturing practice regulations in this chapter and
written procedures required by these regulations) as they relate to the
employee's functions.
(c)
Training in current good manufacturing practice shall be conducted
by qualified individuals on a continuing basis and with sufficient
frequency to assure that employees remain familiar with CGMP
requirements applicable to them.
Things to consider….

What are the education, training, skills and
experience required by this job/task?

How does this person meet those
qualifications?

Do you Train the entire organization?

Starting from the top?
Determine needs…..
 How do you determine the necessary education,
training, skills and experience for people
performing work affecting product quality?
 What training or other actions do you provide to
satisfy the needs of personnel?
Facilities and Equipment
 Under a quality system, the technical experts (e.g., engineers,
development scientists), who have an understanding of
pharmaceutical science, risk factors, and manufacturing processes
related to the product, are responsible for specific facility and
equipment requirements.
 According to the CGMP regulations, equipment must be qualified,
calibrated, cleaned, and maintained to prevent contamination and
mix-ups (§§ 211.63, 211.67, 211.68).
 The CGMP regulations place as much emphasis on process
equipment as on testing equipment (§ 211.42(b)), while most quality
systems focus only on testing equipment.
Manufacturing
Operations

There is significant overlap between the elements of a quality system and the CGMP
regulation requirements for manufacturing operations.

It is important to emphasize again that FDA’s enforcement programs and inspectional
coverage remain based on the CGMP regulations.

Design and Develop Product and Processes:
 In a modern quality systems manufacturing environment, the significant characteristics
of the product being manufactured should be defined, from design to delivery, and
control should be exercised over all changes.

Quality and manufacturing processes and procedures — and changes to them — should
be defined, approved, and controlled (CGMP also requires this; see § 211.100).
Process Validation
 The design concept established during product
development typically matures into a commercial
design after process experimentation and progressive
modification.
 Areas of process weakness should be identified, and factors
that are influential on critical quality attributes should receive
increased scrutiny.
 Process validation provides initial proof that the design
of the process produces the intended product quality.
Definition of Process
Validation
‘87 Process Validation Guidance:

establishing documented evidence which
provides a high degree of assurance that a
specific process will consistently produce a
product meeting its predetermined
specifications and quality attributes.
Process Validation
 Although initial commercial batches can provide
evidence to support the validity and consistency of
the process, the entire life-cycle should be
addressed by the establishment of continuous
improvement mechanisms in the quality system.
 Process validation is not a one time event, but an
on-going activity.
Process Development and
Optimization (or Process R&D)
 Build Quality into a product & Build
Robustness into the process
 Robustness- ability to produce the same
result under the reasonably expected and
inherent variation in materials, environment,
personnel, equipment, etc.
 To make a process robust, you must
know what variation may be
encountered and how that variation
affects the process.
Production System
Production & Process Controls
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.
 It
also includes establishing, following, and documenting
performance of approved manufacturing procedures.
See the CGMP regulation, 21 CFR 211 Subparts B, F,
and J.
Production and Process
Controls
 Production and process changes
 Environmental control
 Personnel
 Contamination control
 Buildings
 Equipment (PM, cleaning)
 Manufacturing material
 Automated processes
 Inspection, measuring, and test equipment; calibration
 Process validation
Production & Process Controls
 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
Process Monitoring
 FDA expects the manufacturer to develop procedures for
monitoring, measuring, and analyzing operations
 When implementing data collection procedures, consider the
following:
 Are collection methods documented?
 When in the product life-cycle will the data be collected?
 How and to whom will measurement and monitoring
activities be assigned?
 When should analysis and evaluation (e.g. trending) of
laboratory data be performed (see V.E.1.)?
 What records are needed?
Must apply appropriate analytical methods
and/or statistical techniques
Lab Control System
 Laboratory Control System:


Resources, measures and activities related to
laboratory procedures, testing, analytical methods
development and validation or verification, and the
stability program.
….Provide “Test Data”
QUALITY SYSTEMS
Interrelations
Systems
CGMP Quality
System Element
Quality
System
(Address Nonconformities)
CAPA &
Investigations
Lab
Control
System
Lab Investigations
Stability
Program
Lab Control System
CGMP vs. Quality System element(s)
 CGMP system elements













Training/qualification
Staffing
Facility and Equipment
Instrument calibration
Reference Standards
System Suitability
Validation/verification
Change Control
Investigations
Record keeping
Testing and Release
Testing and Release
Stability Testing
 Modern “Quality System” Elements













Develop Personnel
Develop Personnel
Facilities and Equipment
Facilities and Equipment
Perform & Monitor Operations
Perform & Monitor Operations
Perform & Monitor Operations
Build Quality System
Address Nonconformities
Build Quality System
Perform & Monitor Operations
Examine all inputs
Perform & Monitor Operations
Module 5
 Documentation Essentials
 Controlling
Documents
 Document Problems
 Batch Records & Review
 GMP Records
 Compliance Within Established
Standards
What does this mean?
 There must be adequate written procedures
 Procedures must be approved by appropriate
persons
 Procedures must be followed
Concept of cGMP
General Rules of
Documentation
 Procedures are designed so that, if followed
the drug products will comply with:


Specifications
Assure compliance with regulations
General Rules of
Documentation
 Verify that dates reflect correct
manufacturing sequence
 Actual conditions comply with
manufacturing parameters



Processing temperature
Mixing time/speed
Filter integrity test pressure
Regulatory Requirements for
Documentation
 “Each manufacturer shall establish and maintain
procedures to control all documents that are
required by this part. The procedures shall provide
for the following:”
(a) Document approval and distribution.




Review and approve prior to issuance; signature and
date
Document availability for use
Obsolete documents not available for use
- 21 CFR 820.40, Document Controls, Quality System Regulations
GMP Procedures
 Create a documentation strategy
 Write clear, concise, logical procedures
 Associate procedures with applicable
records
 Evaluate sample procedures
Create a documentation
strategy
Policies
Standard
Operating
Procedures
Standard
Test Methods
Master
Batch Records
SOP Forms
Forms
Production
Batch Records
Write clear, concise,
logical procedures
 Put steps in the procedure in the order in which they occur.
If this principle is followed, there’s no need to refer to the
next step (go to step 10.4) if it immediately follows the
previous step.
 Balance the following two principles:
 Don’t make the procedure too long to be understood by a
trainee, but
 Don’t make too many short procedures that have to be
followed – too many documents to train on and follow.

GMP Records
 Design records to match the process
 Ensure records include required data
 Use good documentation practices
 Complete records neatly and legibly
 Evaluate sample records
Design records to match the
process
Start with a flowchart of the process, then
write the SOP.
Attach the flowchart to the SOP
Use the flowchart as a training tool (many
people learn best visually)
Flowcharts from SOPs are useful to
summarize how a procedure works in an
audit or inspection
Design records to match the process
Responsible Party
Dir. Quality
and QA Lead
Auditor
Internal
audit
schedule
Production,
QC, QA, etc.
For cause
audit
Assemble audit
team: lead +
supporting
auditors + SMEs
QA Lead
Auditor
QA Lead
Auditor
Need
for
internal
audit
Gather
backgroun
d info and
prepare
audit plan
Schedule
opening
meeting &
audit
dates
Ensure records include
required data
2. Check regulatory requirements for
records:

Master Batch Records:



Name of product and reference code
List of raw materials and intermediates
with quantity to be used, including unit of
measure
Production location and major production
equipment to be used…
- Q7A, 6.41
Ensure records include
required data
2. Check regulatory requirements for records:
Production Batch Records





Actual results recorded for critical process
parameters
Any sampling performed
Signatures of persons performing…and checking
critical operation steps
Actual yield at appropriate phases
Representative label
- Q7A, 6.52
Use good documentation
practices
 Regulatory requirements:
 Entries in records are:










Legible
Indelible
Made in designated spaces
Identify person responsible
Include dates of tasks performed
Made directly after performing task (real-time)
Detailed enough for clear understanding
Laid out in orderly fashion
Easy to check
Reproduction process of master should not
introduce errors
Use good documentation
practices
 Regulatory requirements:
 Corrections to entries in records are:




Dated
Signed
Leave original entry legible
Reason for correction is indicated
Use good documentation
practices
 When an error is made on a record, DO NOT:
 Obscure the data by:
scribbling over it,
 trying to change the written data,
 erasing it,
 using correction fluid
 Copy it to a new record and discard the
original data,
 Backdate (fill in an earlier date on a later date
with no explanation that it was added later)

Regulatory Inspection of Documents
 Follow written procedures and complete
records as required
 Ensure quick and accurate retrieval of
requested documentation
 Review documentation before
presentation to regulatory body
Adequacy of SOPs
 SOPs are the first thing asked for during audits and provide an
inspector with the following information:
 Are the SOPs current, accurate, and is there a procedure
for writing SOPs?
 Do


operators follow both the steps and order of steps
as detailed?
Do procedures exist not only for operation, but also for
maintenance, change control, and cleaning?
Is there a routine review of procedures?
SOP Content
 SOPs should be concise, easy to manage and updated
as necessary.
 SOPs should provide sufficient detail to allow an
operator the ability to run the unit if doing it the first
time with training.
 SOPs should reference operating limits determined
during validation studies, applicable diagrams for the
placement of equipment components or sampling
locations used for environmental sampling.
 SOPs should be kept to a minimum number of pages
since the greater the number of pages, the less an
operator reads it.
Records and Reports
 Batch / Production Records






Relates to In-Process / Finished Product
Production History for Each Lot
Critical to Decision Analysis – Accept / Reject
Availability for Review, Analysis, Copying
Retained in Hard Copy, Electronic, Microfilm,
Microfiche
Retention – 1 Year post expiration date
 OTC
3 Years after last distribution of lot
Master Production and Control
Records
 Written Procedures
 Master Production Record Contents





Product Name / Dosage Form /
Strength
Detailed Formula
Theoretical Weight / Yield
Packaging / Labeling
Manufacturing / Processing Instructions
Batch Production and Control
Records
 Reproduction of Master Production Record
 Process Documentation
Formulation – Identity, Weights, Measures
 Equipment
 Packaging / Labeling Operation (Labeling Control)
 Sampling
 Responsible Personnel / Supervision
 Examination / Test Results
 Production / Batch Record Review - QC

Records and Reports
 Complaint

Investigations
 Recalls
 Returned Goods
 Salvage Operations
 Corrective Actions
 Management Reporting
 Reports to FDA
Module 7
 Pharmaceutical Development Q8,Q9
 Key Development Steps
 Ensuring
Good Manufacturing Practices
for Drug Products
 History of Regulatory Enforcement
 FDA Policy and Program Issues
CGMPS AND THE CONCEPTS OF
MODERN QUALITY SYSTEMS
 Key concepts which are critical for any
discussion of modern quality systems.
 The following concepts are used
throughout this guidance as they relate to
the manufacture of pharmaceutical
products.
Quality

Every pharmaceutical product has
established identity, strength, purity, and other
quality characteristics designed to ensure the
required levels of safety and effectiveness.

For the purposes of the draft guidance
document, the phrase achieving quality means
achieving these characteristics for the product.
Quality by Design and
Product Development

Quality by design means designing and developing
manufacturing processes during the product development
stage to consistently ensure predefined quality at the end of the
manufacturing process.


A quality system provides a sound framework for the
transfer of process knowledge from development to the
commercial manufacturing processes and for postdevelopment changes and optimization
What is “Quality by Design”?
 Quality

“Good pharmaceutical quality represents
an acceptably low risk of failing to achieve
the desired clinical attributes.”
 Quality by Design (QbD)

“Means that product and process
performance characteristics are
scientifically designed to meet specific
objectives, not merely empirically derived
from performance of test batches.”
Quality by Design
 Design features and decisions that deliver a high degree of
confidence that manufactured lots will have the intended
product quality and performance
 Design to specifications (not setting specifications after the
fact)
 Redundant (i.e., an additional layer of security –risk based)
end product testing (not testing to document quality)
ICH – Q8
 An ability to describe and justify why proposed design
features deliver with confidence the intended quality (not
awaiting test results to be submitted in a post approval
supplement)
 More fully defined, developed pharmaceutical development
 Directed at product rationale instead of simple data reporting
 Better understanding of critical aspect effects on quality
attributes
Adoption of Q8 delivers a new
state:
 Product quality and performance achieved and assured by
design of effective and efficient manufacturing processes
 Product specifications based on mechanistic
understanding of how formulation and process factors
impact product performance
 An ability to effect Continuous Improvement and
Continuous "real time" assurance of quality
Q8 applicable to all products
-but at the applicant’s discretion
 Not all information “mandatory”
 Guideline constructed to avoid potential
misunderstanding that may evolve from this
 Guideline describes one system with different
levels of design focus

we use the “process understanding – predictive
ability” principles as a means to create a
continuous framework and avoid “two different
systems”
Q8 & Pharmaceutical
Q8
 Fully characterised
product
 Well defined process
 Assessed (& mitigated)
risk
 Process monitoring plan
Framework for
continuous
improvement
Regulatory
Flexibility
Product & Process Knowledge + Risk Management
= Manufacturing Sciences
Risk Management and Risk
Assessment
 The concept risk management is a major focus of the
Pharmaceutical CGMPs for the 21st Century
Initiative.
 Risk management can guide the setting of
specifications and process parameters.
 Risk assessment is also used in determining the
need for discrepancy investigations and corrective
action and how to prioritize them.
 As risk assessment is used more formally by
manufacturers, it can be implemented within the
quality system framework.
ICH Q9: Defining Risk
 Preliminary working definitions
(March 2004) from ICH EWG on Quality
Risk Management (Q9):


Risk: Combination of the probability of
occurrence of harm and the severity of
that harm. ISO 14971
Harm: Damage to health, including the
damage that can occur from loss of
product efficacy, safety, quality or
availability
 Focus
on quality for our purposes
ICH Q9: Defining Risk (cont’d)

Quality: Degree to which a set of inherent
characteristics of a product, system or process
fulfils requirements

Requirements: Needs or expectations that are
stated, generally implied or obligatory by the
patients or their surrogates (e.g. health care
professionals, regulators and legislators)

Combining key terms: Risk to quality is the
probability/severity that drug will fail to meet the
needs/expectations of the patients and their
surrogates
Identify Predicted/Known Hazards
to Quality Attributes: Risk Factors
 Risks to pharmaceutical quality can be
identified based on the probability and
severity of adverse impact on these quality
attributes

Explicitly include factors that mitigate
probability/severity of adverse effects or factors
that have a positive impact
Risk Management
Risk Management Includes:
 Risk Assessment

Risk Control
 Option analysis
 Implementation
 Residual

risk Analysis
 Over-all risk acceptance
Option:
 Additional Risk Analysis
 Design Mitigations
 Verification and Validation Testing
Risk Management
Risk Management Planning
Identify risk management process
Assign responsibilities
Define Risk acceptability criteria
Hazard Analysis
Risk Estimation
Risk Evaluation
Risk Control
Risk Analysis
Define intended use
Describe device
Identify hazards
Estimate risks
Risk
Assessment
Risk Evaluation
Determine/decide risk acceptability
Re-assess
residual risks,
design changes
or new hazards
Risk Control
Analyze options
Implement measures
Evaluate residual risk
Decide overall risk acceptability
Post Production Control
Evaluate production results
Review risk management results
Control design changes
Risk
Management
Module 8
 Hosting An FDA Inspection
Preparing for a successful FDA inspection
 How to develop an Inspection strategy and an inspection
Tool kits (Checklist)
 Learn how to save time and money by planning and
focusing on the right systems for an inspection
 How to conducting Mock Inspections
 Plan an effective strategy to prepare for an inspection
 Maintain compliance for facilities and equipment
 Questions & Wrap-Up
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They’re Here
 After verification of credentials and
issuance of FD482, the FDA investigator
is immediately escorted to a conference
room that will be set aside for exclusive
use during the inspection
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Post a notice on the door that an
inspection is in progress
QA Management
Verify
Credential
Accept Notice of
Inspection
(FDA Form 482)
Escort to
Conferenc
e Room
Review
Company
Policies
Mock Systems based inspection agenda!
QUALITY SYSTEM
Evaluate Quality Control Unit. (This also includes the associated recordkeeping systems)
Preparedness for “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; refer to 21 CFR 211.180(e).
- 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. S0P.
- Change Control: documented; evaluated; approved; need for revalidation assessed.
- Product Improvement Projects: for marketed products
- Reprocess/Rework: evaluation, review and approval; impact on 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.
- Validation: status of required validation/revalidation (e.g., computer, manufacturing process, laboratory methods).
- Training/qualification of employees in quality control unit functions.
Mock Systems based inspection agenda!
FACILITIES AND EQUIPMENT SYSTEM
1. Facilities
- cleaning and maintenance
- facility layout and air handling systems for prevention of cross-contamination (e.g. penicillin, beta-lactams, steroids, hormones, cytotoxics, etc.)
- specifically designed areas for the manufacturing operations performed by the firm 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
2. Equipment
- 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.
- cleaning procedures and cleaning validation
- controls to prevent contamination, particularly with any pesticides or any other toxic materials, or other drug or non-drug chemicals
- qualification, calibration and maintenance of storage equipment, such as refrigerators and freezers for ensuring that 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
Mock Systems based inspection agenda!
MATERIALS SYSTEM
- 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 on each lot of each component
- a visual identification is conducted on each lot of containers and closures
- testing or validation of supplier's test results for components, containers and closures
- rejection of any component, container, closure not meeting acceptance requirements. Investigate fully the firm's procedures for
verification of the source of components.
- appropriate retesting/reexamination of components, containers, closures
- first in-first out use of components, containers, closures
- quarantine of rejected materials
- water and process gas supply, design, maintenance, validation and operation
- 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
- finished product distribution records by lot
- documented investigation into any unexpected discrepancy
Mock Systems based inspection agenda!
PRODUCTION SYSTEM
- training/qualification of personnel
- control system for implementing changes in processes
- adequate procedure and practice for charge-in of components
- 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 containers and closures
- calculation and documentation of actual yields and percentage of theoretical yields
- contemporaneous and complete batch production documentation
- established time limits for completion of phases of production
- implementation and documentation of in-process controls, tests, and examinations (e.g., pH, adequacy of mix, weight variation, clarity)
- justification and consistency of in-process specifications and drug product final specifications
- prevention of objectionable microorganisms in non-sterile drug products
- adherence to preprocessing procedures (e.g., 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
Mock Systems based inspection agenda!
PACKAGING AND LABE LING 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
- 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
- adequate packaging records that will include specimens of all labels used
- control of issuance of labeling, examination of issued labels and reconciliation of used labels
- examination of the labeled finished product
- adequate inspection (proofing) of incoming labeling
- 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 (TEP) packaging requirements (see 21CFR 211.132 and Compliance Policy Guide, 7132a.17)
- validation of packaging and labeling operations including validation and security of computerized processes
- documented investigation into any unexpected discrepancy
LABORATORY CONTROL 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 processes
- 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)
- 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
- 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
D. Sampling
Samples of defective product constitute persuasive evidence that significant CGMP problems exist.
F. Reporting
The Summary of Findings will identify and explain in the body of the report the rationale for inspecting the profile classes covered. Report and
Developing an Effective SOP for
FDA Inspections
 Inspection preparedness is essential for
a successful outcome
 A well-written Standard Operating
Procedure
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Defines the roles
Describes the process
Who is Involved?
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Establish the roles and responsibilities
Senior management
Audit host
Department representatives
Legal department
Documents
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Anticipate what will be needed
Regulatory documents
Organizational charts
Floor plans
Company documents
Standard Operating Procedures
Logistics
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Prepare in advance of an audit
Locate a suitable room
Personal comfort matters
Stage documents
Anticipate audit topics
Training the Staff
 Who has authority?
 Who provides answers?
 How to get information?
 Who approves information?
Training the Staff
 Providing documents
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Give what is asked for, and no more
Be sure that it is OK to provide it
Have someone review it first
Provide documents promptly
Providing Documents
 Have someone review these first
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Right documents?
Complete?
Post-it notes removed?
Organized?
What was asked for?
Providing Documents
 Make a list of requested items
 Check them off when presented
 Log them back when returned
 Complete review and return
 Avoid leaving a lot of documents
Copying Documents
 Limit what is copied if possible
 Make duplicate copies
 Keep one set for your files
 Verify that copies match original
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Complete
Legible
Nothing cut off
If You Cannot Find a
Document
 Be open and honest
 Limit the scope of what’s missing
 Don’t be evasive
 It is not the end of the world
 Do not stall or delay the audit
Daily Summaries
 Ask how things are going
 Identify what was reviewed
 Record the observations
 Plan for the following day
 Request and prepare documents
Close Out Meeting
 Who should attend?
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Management
Department heads
Quality assurance
Regulatory affairs
Legal
Close Out Meeting
 What to say/ what not to say
 Listen carefully, it is OK to clarify
 You are listening, not agreeing
 Do not become defensive
 Be respectful during the meeting
 Plan to respond in writing
Unwritten Observations
 Suggestions may be offered
 These are good advice
 Record these items for review
 Implement suggestions if appropriate
 Share this information with others
Preparing a Response
 Respond in writing
 Address each item
 List corrective actions taken
 Describe changes to systems
 Commit to times and dates
 Be positive in your response
FDA Readiness Kit
Anticipate Having Available
 Floor Plan
 Organizational Chart (Current)
 Company History
 Master Schedule
 SOP Table of Contents
 CV’s
 Training Records
FDA Inspection Follow up
Activities
 Retrieve copy of final issued FD481 or
Establishment Inspection Report (EIR), which is
the audit “narrative” the FDA investigator writes
and states what records and reports were
reviewed, questions asked, responses received,
tours of the facility.
 The EIR is a very useful document to review to
understand the inspectional approach scheme for
future inspection planning.
FDA Inspection Follow up
Activities
 The Establishment Inspection Report (EIR), a diary of the
inspection, is subject to the Freedom of Information Act
(FOIA) disclosure, except during an ongoing investigation
 Try to get the EIR
 If FDA doesn’t give it to you, this could be a bad
sign
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Might also serve as a useful road map of other FDA
concerns not cited in a 483
Staff Readiness for
Inspections
FDA Inspection procedure in place.
- Plan on a recording secretary.
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Meeting place.
Work out rough schedule with investigator.
Disclosable/nondisclosable information.
Photographs/recording devices and
affidavits.
Readiness for Inspections
 Documentation review and discussion
area.
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Set up a room where documentation can
be reviewed prior to presenting to the FDA.
Need to be sure it is the right document,
pages are not missing, post it notes are not
attached etc.
Room is a place where discussions can be
held for response to complex questions.
Facility Appearance
 Facility should always appear neat and orderly.
Areas that appear out of control usually are!
 Materials labeled and in the proper locations
 Large quarantine areas are a target for inspection.
 Housekeeping creates first impression of anyone
touring facility.
GMP Training
 Not enough to have policies and
procedures, staff must understand and
follow.
 Train on the FDA inspection procedure.
 Train on the GMP’s.
 Train on Defect Awareness.
Preparation
1.
2.
3.
4.
Tour of the process flow
Preparatory audits of
impacted areas
Retrieval and staging of any
pre-requested documentation
Familiarization of audit
responsibilities given to the
selected personnel for the
various audit roles
Training on General Interview
Guidelines:
1. Don’t Panic!
2. Be Honest and Direct
3. Be Polite
4. Control Emotions
5. Do NOT volunteer
information; answer questions
to the best of your ability
Remember first impressions are
lasting impressions
• You represent the company
• Ultimate goal – leave the inspector with a
positive mental picture of yourself
• Confidence and attitude are key
• There are NO second chances in making
first impression
Preparation –
Training the Participants
Know company policies and procedures
Are SOPs in your area:
1.
2.
3.
4.
Current?
In Compliance?
Followed?
Defined clearly?
Preparation –
Training the Participants
Know how to answer the question
1. Listen Carefully
2. Ask for clarification if needed
3. Provide only what is asked for
4. Be honest and direct. If you don’t know – say so!
5. Be confident in your answers
6. Back up verbal info. with documentation
7. STOP when the question is fully answered
Preparation –
Training the Participants
Understand the various
interview techniques
• Direct Questions – “Do you have”
• Open ended questions – “Tell me about”
• The “Silence” Technique
• The “Buddy” Technique
Answering Questions:
The Basic Rules
 Tell the TRUTH
 Know your rights (and FDA’s)
 Listen to the question
 Answer the question that is asked
 Refer to others what you do not know
 STOP when the question is fully answered
 Always tell the truth
Do’s During Inspections
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Listen carefully and repeat the question or ask it to be
repeated, if necessary
Answer completely, directly and honestly
Speak slowly and clearly
Speak only for your area of expertise
Know your procedures
Be able to verify everything you say
Expect what you say to be documented in FDA field
notebook
Dont’s During Inspections
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Do not make casual conversation
Do not assume the investigator is your “buddy”
Do not guess or make up an answer
Do not lie
Do not volunteer more information than
necessary to completely answer the question
Never say “That’s not how we do things
around here” or “We’ve always done it
that way”.
Dont’s During Inspections
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Do not speculate. Don’t be afraid to find information and
give it to the investigator later
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Do not assume to know what the investigator means
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If not certain how to answer, ask to confer with the
escort privately
Ask for clarification, examples or specifies
Do not conduct the inspection for the investigator
Never question the investigator’s authority
Never argue or raise your voice
Preparation –
Training the Participants
Do NOT :
 Volunteer information
 Provide inaccurate information
 Provide “hearsay” answers
 React negatively to a question/comment
Preparation –
Training the Participants
Do NOT :
 Make the auditor’s wait for information
 Override a Liaison’s decision in front of the
auditors
 Have a BAD attitude
FDA Investigators ...
 Are aware that interviewees may be
nervous
 Understand that firms prepare their
employees for inspections
 Know that firms do not want to
divulge adverse information
 Are trained to detect deception
 Know that true deception is rare
FDA Investigators ...
 Want the inspection to go smoothly
 Do not seek to “trap” anyone
 Expect most people to be fully
honest and forthcoming
 Want to “get it right the first time”
Conduct during the audit
 Hold debriefing sessions at the end of
each day.
 Discuss any observations or concerns
expressed by the investigator.
 Obtain clarification of outstanding issues.
 Discuss conversations that occurred.
The closing meeting
 Closing meeting, there should be no surprises.
 Assemble those that were key during the inspection and key
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members of top management.
A FDA form 483 may have been prepared – A Notice of
Objectionable Conditions.
If the observation is unclear, ask for clarification.
Discuss the findings, tactfully debate misinterpretations.
Usually not a good time to make any major commitments.
Conclusion
 Implementation of a comprehensive quality systems model for
pharmaceutical products, including biological products, will
facilitate compliance with 21 CFR parts 210 and 211.
 The central goal of a quality system is to ensure consistent
production of safe and

effective products and that these activities are
sustainable.
 A robust quality system will promote process consistency by
integrating effective knowledge-building mechanisms into daily
operational decisions.
Successful quality systems
share the following:
 Science-based approaches
 Decisions are based on an understanding of the intended use
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of a product
Proper identification and control of areas of potential process
weakness
Responsive deviation and investigation systems that lead to
timely remediation
Sound methods for assessing risk
Well-defined processes and products, starting from
development and extending throughout the product life cycle
Systems for careful analyses of product quality
Supportive management (philosophically and financially)
Good Business Sense!
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Both good manufacturing practice
and good business practice require a
robust quality system.
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When fully developed and effectively
managed, a quality system will lead to
consistent, predictable processes that
ensure that pharmaceuticals are safe,
effective.