1 gmp inspection process introduction. 2 programme objectives 1.familiarise with gmp inspection...

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GMP Inspection Process

Introduction

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Introduction

Programme Objectives

1. Familiarise with GMP inspection 2. How to perform an inspection3. 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:– 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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The Role of the Inspector

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Qualifications• Training• Practical experienceIn pharmaceutical manufacture and/or

quality control

• Academic qualifications– pharmacists, chemists, scientists– pharmaceutical industry background

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Training• In-post training• Accompany experienced inspectors• Regular update of knowledge • Courses and seminars

– pharmaceutical technology– microbiology– statistical aspects of quality control

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Responsibilities 1• Detailed factual report

– manufacture and control– specific products

• Assess GMP compliance– faults, irregularities, discrepancies

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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 InspectorPersonal 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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Communication Skills• Language• Body language• Company history and policy

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Preparation for an Inspection

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Scope of Inspection• Objective• Type • Depth• Timing• Inspectors:

– size of team– make-up of team

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Preparation for an InspectionNotification

• The company being inspected• Team members

– expert support– other inspectors

• Other interested parties

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Review documentation from Regulatory Authority

• Company file• Site Master File• Manufacturing licence• Registration dossiers

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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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Review documentation from the manufacturer

• 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 InspectionProgramme

• Checklist• Aide-mémoire for inspection• Develop inspection programme• Distribute inspection programme

– Company– Team

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Possible Issues – IThe first inspection of a new

manufacturer• Plant design and equipment• Processes• Documentation• Personnel• Quality control

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Possible Issues – IIRegular inspection of an established manufacturer

• Actions arising from the previous inspection

• Areas not previously inspected• New areas, processes and products

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Possible Issues – IIIInspection because of complaints

about a product• The product in question• Manufacturing process• Premises• Systems for handling complaints and

recalls• Quality control records

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Types of GMP Inspection

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Objective of the inspection

• Routine inspection• Concise (abbreviated) inspection• Follow-up inspection• Special inspection• Quality systems review

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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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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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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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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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Quality Systems Review• Assess the quality assurance (QA) system• Description of the QA system (e.g. manual)• Policy and standards to be observed• Management structure

– implementation

• Procedures– quality standards set for products– correctly defined manufacturing processes– records kept– QC and QA functions are performed

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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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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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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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Regulatory Actions• Based on national regulations• Correction of unsatisfactory

situations• Closing down of a factory• Withholding of authorizations• Product recall

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The Inspection

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Timetable• 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• Report with time frame

The Inspection

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Getting Started• Location• Contact• Time• Introductions• Walk-round• Company escort

The Inspection

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Remember that an Inspection….

• Is a systematic approach• Involves interpersonal skills• Identifies deficiencies• Looks at what went wrong• Requires participation from both

parties

The Inspection

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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• WhoSilence can be very powerful – people find it

uncomfortable and try to say something

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The Inspection

Good Listening – I• 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• 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• 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• 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• 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• 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• 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• 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• 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

implemented

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The InspectionRegulatory 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 InspectionCompany Strategies – I

Tricks RemediesTime-wasting Threaten to extend inspectionSide-tracking Stick to programmeProvocation Remain calmSamples provided Select your own sampleSpecial case Take notes and keep „never happened before” looking is there a trend?

Circular argument Recognize and stop

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The InspectionCompany Strategies – II

Tricks RemediesTrial of strength Be firm; know your factsInsincerity Ignore itPity Sympathize; carry onAbsentees Call for deputyAmnesia Go back and get it

yourself

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Exam topic

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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

1 gmp inspection process introduction. 2 programme objectives 1.familiarise with gmp inspection...

Documents

inspection inspection

self inspection

fundamentals of inspection

word inspection

inspection notification

policy slide

customer slide

company independent