GMP Inspection Process
Introduction
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Introduction
Programme Objectives
1. Familiarise with GMP
inspection
2. How to perform an inspection
3. Developing an action plan
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Inspection
Programme Overview
• Introduction
• The fundamentals of inspection
– the role of the inspector
– preparing for inspections
– the inspection process
• Types of inspection
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Inspection
• These guidelines may be useful to
inspect production and control of:
– final dosage forms
• human and veterinary use
– drug substances
• API and bulk drug substances
• Same fundamental principles:
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pharmaceutical products
including biological products
also medical devices and
diagnostic products
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Inspection
• Inspection and licensing:
– vital element of drug control
– WHO Certification Scheme on the
Quality of Pharmaceutical Products
moving in International Commerce
(see last Semester! It contains
statement on GMP inspections!)
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Inspection
• Other contexts (using the word
„inspection” in a broader meaning):
– self inspection of the company
– independent inspection by persons e.g.
from the International Organization for
Standardization (ISO)
– audit by authorized agents of a customer
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Inspectorate
• Enforcement arm of the National Drug
Regulatory Authority (DRA)
• Functions:
– Ensure adherence to licensing provisions
– Adherence to GMP
• Objectives:
– Control and enforce standards
• through sequential examination (production and
control)
– Recommend authorization of manufacture
of pharmaceutical products
• verification of performance
• verification of data
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GMP Inspection Process
The Role of the
Inspector
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The Role of the Inspector
Qualifications
• Training
• Practical experience
In pharmaceutical manufacture and/or
quality control
• Academic qualifications
– pharmacists, chemists, scientists
– pharmaceutical industry background
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The Role of the Inspector
Training
• In-post training
• Accompany experienced
inspectors
• Regular update of knowledge
• Courses and seminars
– pharmaceutical technology
– microbiology
– statistical aspects of quality control10
The Role of the Inspector
Responsibilities 1
• Detailed factual report
– manufacture and control
– specific products
• Assess GMP compliance
– faults, irregularities, discrepancies
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The Role of the Inspector
Responsibilities 2
• Advice on improving manufacture
and control
– depending on national policy
– must be consistent and available to
all
– motivate manufacturer to comply
with GMP
– correct specific deficiencies
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The Role of the Inspector
Personal Qualities
• Conform to codes of ethics and
conduct
• Independent/no conflict of
interest
• No double role as inspector and
consultant
• Resist attempts to influence
decisions
• Discrete
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The Role of the Inspector
Communication Skills
• Language
• Body language
• Company history and policy
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GMP Inspection Process
Preparation for an
Inspection
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Preparation for an
Inspection
Scope of Inspection
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Objective
Type
Depth
Timing
Inspectors:
– size of team
– make-up of team
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Preparation for an
Inspection
Notification
• The company being inspected
• Team members
– expert support
– other inspectors
• Other interested parties
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Preparation for an
Inspection
Review documentation from
Regulatory Authority
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Company file
Site Master File
Manufacturing licence
Registration dossiers
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Preparation for an
Inspection
Review documentation from
Regulatory Authority
• Reports
– Adverse Drug Reaction reports
(ADRs)
– Previous inspections
• Records
– Complaints and recalls
– Regulatory test results (surveillance)
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Preparation for an
Inspection
Review documentation from the
manufacturer
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Annual report
Complaints file
Self inspection/internal audit reports
Send a questionnaire to the manufacturer
asking to provide specific information about
the company
• Layout of site and diagrams
• Manuals
• Standard Operating Procedures
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Preparation for an
Inspection
Programme
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Checklist
Aide-mémoire for inspection
Develop inspection programme
Distribute inspection programme
– Company
– Team
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Preparation for an
Inspection
Possible Issues – I
The first inspection of a new
manufacturer
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Plant design and equipment
Processes
Documentation
Personnel
Quality control
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Preparation for an
Inspection
Possible Issues – II
Regular inspection of an
established manufacturer
• Actions arising from the previous
inspection
• Areas not previously inspected
• New areas, processes and
products
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Preparation for an
Inspection
Possible Issues – III
Inspection because of
complaints about a product
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The product in question
Manufacturing process
Premises
Systems for handling complaints
and recalls
• Quality control records
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GMP Inspection Process
Types of GMP
Inspection
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Types of GMP Inspection
Objective of the
inspection
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Routine inspection
Concise (abbreviated) inspection
Follow-up inspection
Special inspection
Quality systems review
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Types of GMP Inspection
Routine Inspection
• Full inspection of all components of
GMP
• Newly established manufacturer
• Renewal of a license
• Changes:
– new product or product lines
– modifications to manufacturing methods
– key personnel, premises or equipment
• History of non-compliance with GMP
• Not inspected in the last 3 -5 years
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Types of GMP Inspection
Concise Inspection
• Consistent record of compliance with
GMP
• Focus on limited number of GMP
requirements
– selected as indicators
• Identify significant changes
• Indicate attitude towards GMP
• Non-compliance:
– should trigger comprehensive inspection
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Types of GMP Inspection
Follow-up Inspection
• Reassessment or re-inspection
• Monitor result of corrective actions
• 6 weeks to 6 months after initial
inspection
– nature of defects
– work undertaken
• Specific GMP requirements
– not observed
• not adequately implemented
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Types of GMP Inspection
Special Inspection
• Spot check focusing on:
– one product, a group of related products
– specific operations e.g. mixing, labeling
• Complaints or recalls
• Adverse Drug Reactions
• Marketing approval or export
certificate
• Information or investigation:
– specific information
– advise on regulatory requirements
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Types of GMP Inspection
Quality Systems Review
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Assess the quality assurance (QA) system
Description of the QA system (e.g. manual)
Policy and standards to be observed
Management structure
– implementation
• Procedures
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quality standards set for products
correctly defined manufacturing processes
records kept
QC and QA functions are performed
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Types of GMP Inspection
Frequency of Inspections
• Depends on type of inspection
• Inspectorate resources (e.g. workload,
number of inspectors)
• New facilities - before licensed
• All companies - regular schedule
– ideally annual
• Large companies
– several visits over a period e.g. 5 years
– validity of manufacturing license or GMP
certificate
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Types of GMP Inspection
Duration of Inspections
• Depends on type of inspection
• Inspectorate resources (e.g.
workload, number of inspectors)
• Size of the company
• Purpose of the visit
• Days to weeks
• Number of inspectors
– including specialist support
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Types of GMP Inspection
Announced and
unannounced inspections
• Depends on type of inspection
• Announced:
– comprehensive inspection
• Unannounced:
– routine inspection (depending on country
policy)
– concise inspection
– follow-up inspection
– special inspection
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Types of GMP Inspection
Regulatory Actions
• Based on national regulations
• Correction of unsatisfactory
situations
• Closing down of a factory
• Withholding of authorizations
• Product recall
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GMP Inspection Process
The Inspection
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The Inspection
Timetable
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Entry briefing/opening meeting
Orientation tour
Fact finding and assessment
Review progress against audit plan
Revised activity
Final review/recommendations
Exit review with management/closing
meeting
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Report with time frame
The Inspection
Getting Started
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Location
Contact
Time
Introductions
Walk-round
Company escort
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The Inspection
Remember that an Inspection….
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Is a systematic approach
Involves interpersonal skills
Identifies deficiencies
Looks at what went wrong
Requires participation from both
parties
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The Inspection
Methods of Fact-Finding
• Trace forward
• Trace backward
• Random
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The Inspection
Asking Questions…..
Open questions (that can not be answered by
„yes” or „no”) starting with:
• What
• Why
• When
• How
• Where
• Who
Silence can be very powerful – people find it
uncomfortable and try to say something
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The Inspection
Good Listening – I
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Stop talking!
Help the speaker to feel free to talk
Be approachable
Show the speaker that you are
interested
• Remove distractions
• Try to understand the speaker’s point
of view
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The Inspection
Good Listening – II
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Be patient
Hold your temper
Try not to criticize
Ask questions
Stop, look and listen
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The Inspection
How to Take Notes
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Detail and facts — trust, but verify
Specifics not generalizations
Record detail as seen
Ensure accuracy
Be open
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The Inspection
What to Record – I
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Persons interviewed
Document numbers
Equipment numbers
Item identification
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The Inspection
What to Record – II
• Selection of document recipients
• Condition of environment
• Changes to facilities, equipment
etc
• Layout of area
• Any obvious non-conformities
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The Inspection
How to Record – I
• Checklists
• Flow-charts/process charts
• Symbols such as a star (*) or a
tick
• Checks and follow-up
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The Inspection
How to Record – II
• Highlights
• Short notes for the report
(reminders)
• Tape recorder
• Video camera
• Camera
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The Inspection
Checklists
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Are structured
Detailed
Standard for all full inspections
Advantages
– Useful as reference
– Good for training inspectors
• Disadvantages
– Can lead to overlooking vulnerable areas of
QA
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The Inspection
Checklists –How to Use Them
• Follow, but be prepared to be
flexible
• Use in preparation stage
• Use to collect information and
chart progress
• Preparation for the exit meeting
• Preparation of the report
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The Inspection
Aide-Mémoire
• Simple, short list of actions and
aspects to be checked
• Tailored for the inspection
• Checklist and/or an aide-memoire
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The Inspection
Taking Samples
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Finished-released products
Raw materials
In-process materials
Inspector or sampler
Number of samples and sample
size
• Authorization
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The Inspection
Objectives of Exit Meeting
• Communicate observations
• Inform management of findings
• No surprises in report
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The Inspection
Preparing for Exit Meeting – I
• Group non-compliances
• Categorise non-compliances
– Critical, major and minor
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The Inspection
Preparing for Exit Meeting – II
• Anticipate questions and
discussion or debate
• In the case of a team of
inspectors:
– Agree on a spokesperson
– Agree on a note-taker
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The Inspection
Exit Meeting Attendees
• The inspectors
• Senior management
representative
• Inspected managers and
supervisors
• Other interested parties
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The Inspection
Running the Meeting – I
• Inspectors must lead
• Concise presentation
• Discussion
– When to invite discussion and when
to limit the discussion
• Mention good points before
deficiencies
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The Inspection
Running the Meeting – II
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Treat challenges politely
Discuss and resolve conflicts
Admit if wrong
Don’t back down if convinced you
are right
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The Inspection
Writing the Inspection Report
• Each team member writes own
part
• Team leader has overall
responsibility
• Signed by all team members
• Approval from supervisor
• To company within 4 weeks or
less
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The Inspection
Report Content
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Part 1. General information on
company
Part 2. Description of the
inspection
Part 3. Observations
Part 4. Conclusion and
recommendation
Annexes
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The Inspection
Do Not Include
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Subjective opinions
Irrelevant information
Ambiguous statements
Antagonistic statements
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The Inspection
Style of Report
• Use past tense
• Keep it simple and based on fact
• Include a summary
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The Inspection
Report with Covering Letter to
Company
• Any corrective actions to be
taken
• Time limits for implementing them
• Confidential information
• Exchange of reports
• Regulatory measures if not
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implemented
The Inspection
Regulatory Measures
Depend on national legislation. Examples:
For new plants
– No manufacturing licence/GMP certificate
until compliance
For licence/certificate holders
– Warnings
– Fines
– Suspension/withdrawal of marketing
authorization for product(s)
– Suspension/withdrawal of manufacturing
licence/GMP certificate
– Access to appeal
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The Inspection
Company Strategies – I
Tricks
Remedies
Time-wasting
Side-tracking
Provocation
Samples provided
Special case
„never happened before”
Circular argument
Threaten to extend
inspection
Stick to programme
Remain calm
Select your own
sample
Take notes and keep
looking is there a trend?
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Recognize and stop
The Inspection
Company Strategies – II
Tricks
Remedies
Trial of strength
Insincerity
Pity
Absentees
Amnesia
Be firm; know
your facts
Ignore it
Sympathize; carry on
Call for deputy
Go back and get it
yourself
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Exam topic
67
GMP inspections
• The role of the Inspectorate and
the inspectors
• Inspectors’ training and education
• Personal qualities
• Preparation for an inspection
• Types of a GMP inspection (5)
• Conduct a GMP inspection
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