1. 1 GMP Inspection Process Introduction

2. 2 Programme Objectives 1.Familiarise with GMP inspection 2.How to perform an inspection 3.Developing an action plan

3. 3 Inspection Programme Overview Introduction The fundamentals of inspection –the role of the inspector –preparing for inspections –the inspection process Types of inspection

4. 4 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

5. 5 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!)

6. 6 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

7. 7 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

8. 8 GMP Inspection Process The Role of the Inspector

9. 9 Qualifications Training Practical experience In pharmaceutical manufacture and/or quality control Academic qualifications –pharmacists, chemists, scientists –pharmaceutical industry background

10. 10 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 control

11. 11 The Role of the Inspector Responsibilities 1 Detailed factual report –manufacture and control –specific products Assess GMP compliance –faults, irregularities, discrepancies

12. 12 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

13. 13 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

14. 14 The Role of the Inspector Communication Skills Language Body language Company history and policy

15. 15 GMP Inspection Process Preparation for an Inspection

16. 16 Preparation for an Inspection Scope of Inspection Objective Type Depth Timing Inspectors: –size of team –make-up of team

17. 17 Preparation for an Inspection Notification The company being inspected Team members –expert support –other inspectors Other interested parties

18. 18 Preparation for an Inspection Review documentation from Regulatory Authority Company file Site Master File Manufacturing licence Registration dossiers

19. 19 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)

20. 20 Preparation for an Inspection 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

21. 21 Preparation for an Inspection Programme Checklist Aide-mémoire for inspection Develop inspection programme Distribute inspection programme –Company –Team

22. 22 Preparation for an Inspection Possible Issues – I The first inspection of a new manufacturer Plant design and equipment Processes Documentation Personnel Quality control

23. 23 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

24. 24 Preparation for an Inspection Possible Issues – III Inspection because of complaints about a product The product in question Manufacturing process Premises Systems for handling complaints and recalls Quality control records

25. 25 GMP Inspection Process Types of GMP Inspection

26. 26 Types of GMP Inspection Objective of the inspection Routine inspection Concise (abbreviated) inspection Follow-up inspection Special inspection Quality systems review

27. 27 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

28. 28 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

29. 29 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

30. 30 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

31. 31 Types of GMP Inspection 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

32. 32 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

33. 33 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

34. 34 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

35. 35 Types of GMP Inspection Regulatory Actions Based on national regulations Correction of unsatisfactory situations Closing down of a factory Withholding of authorizations Product recall

36. 36 GMP Inspection Process The Inspection

37. 37 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

38. 38 Getting Started Location Contact Time Introductions Walk-round Company escort The Inspection

39. 39 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

40. 40 The Inspection Methods of Fact-Finding Trace forward Trace backward Random

41. 41 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

42. 42 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

43. 43 The Inspection Good Listening – II Be patient Hold your temper Try not to criticize Ask questions Stop, look and listen

44. 44 The Inspection How to Take Notes Detail and facts — trust, but verify Specifics not generalizations Record detail as seen Ensure accuracy Be open

45. 45 The Inspection What to Record – I Persons interviewed Document numbers Equipment numbers Item identification

46. 46 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

47. 47 The Inspection How to Record – I Checklists Flow-charts/process charts Symbols such as a star (*) or a tick Checks and follow-up

48. 48 The Inspection How to Record – II Highlights Short notes for the report (reminders) Tape recorder Video camera Camera

49. 49 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

50. 50 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

51. 51 The Inspection Aide-Mémoire Simple, short list of actions and aspects to be checked Tailored for the inspection Checklist and/or an aide-memoire

52. 52 The Inspection Taking Samples Finished-released products Raw materials In-process materials Inspector or sampler Number of samples and sample size Authorization

53. 53 The Inspection Objectives of Exit Meeting Communicate observations Inform management of findings No surprises in report

54. 54 The Inspection Preparing for Exit Meeting – I Group non-compliances Categorise non-compliances –Critical, major and minor

55. 55 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

56. 56 The Inspection Exit Meeting Attendees The inspectors Senior management representative Inspected managers and supervisors Other interested parties

57. 57 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

58. 58 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

59. 59 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

60. 60 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

61. 61 The Inspection Do Not Include Subjective opinions Irrelevant information Ambiguous statements Antagonistic statements

62. 62 The Inspection Style of Report Use past tense Keep it simple and based on fact Include a summary

63. 63 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

64. 64 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

65. 65 The Inspection Company Strategies – I TricksRemedies Time-wastingThreaten to extend inspection Side-tracking Stick to programme ProvocationRemain calm Samples providedSelect your own sample Special case Take notes and keep „never happened before” looking is there a trend? Circular argumentRecognize and stop

66. 66 The Inspection Company Strategies – II TricksRemedies Trial of strengthBe firm; know your facts InsincerityIgnore it PitySympathize; carry on AbsenteesCall for deputy AmnesiaGo back and get it yourself

67. 67 Exam topic

68. 68 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