Top Annual 483 Observations: The Cycle of Quality June 2017 Presented by: Susan Schniepp

Transcription

1 Top Annual 483 Observations: The Cycle of Quality June 2017 Presented by: Susan Schniepp 2016 Regulatory Compliance Associates Inc.

2 Top Observation for 5 years Year Drugs #1 citation Device #1 citation Biologics #1 citation (d) (a) (b) (d) (a) (b) (d) (a) (b) (d) (a) (b) (d) (a) (b) 21 CFR (d) states The responsibilities and procedures applicable to the quality control unit shall be in writing. Such written procedures shall be followed. 21 CFR (a) states Each manufacturer shall establish and maintain procedures for implementing corrective and preventive action. 21 CFR (b) states Establishments must establish, maintain, and follow written standard operating procedures 2

3 Other Observations #2 Inadequate lab controls Inadequate lab controls Inadequate lab controls Investigations #3 Investigations Investigations Investigations Absence of written procedures #4 Absence of written procedures #5 EM procedures inadequate No procedures to prevent microbial contamination Absence of written procedures Absence of written procedures Written procedure not followed/establi shed Inadequate lab controls Written procedure not followed/establis hed 3

4 Discussion Topics What s Going on with SOPs? What s Going on with Investigations? 2016 Regulatory Compliance Associates Inc. 4

5 Definition of an SOP 2015 Regulatory Compliance Associates Inc. 5

6 Definition standard operating procedure, n. 1. Established procedure to be followed in carrying out a given operation or in a given situation. 2. A specific procedure or set of procedures so established. American Heritage Dictionary of the English Language, Fifth Edition. 3. A set of fixed instructions or steps for carrying out routine operations. Abbr.: SOP Random House Kernerman Webster's College Dictionary, A set of instructions covering those features of operations which lend themselves to a definite or standardized procedure without loss of effectiveness. The procedure is applicable unless ordered otherwise. Also called SOP. Dictionary of Military and Associated Terms. US Department of Defense Regulatory Compliance Associates Inc. 6

7 Why do we write SOPs 2015 Regulatory Compliance Associates Inc. 7

8 Why Do We Write SOPs? Because: Personnel can conduct operations with Consistency Assures Quality Consistency Assures Regulatory Compliance Makes Good Business Sense 2015 Regulatory Compliance Associates Inc. 8

9 Do NOT Write SOPs For Regulators, OR Because you think they are required by the regulations SOPs written for these reasons are not based on your operations and often lead to compliance troubles Regulatory Compliance Associates Inc. 9

10 SOP Characteristics 2015 Regulatory Compliance Associates Inc. 10

11 Characteristics of a Good SOP Tailored to your organizational design and needs. Provides sufficient detail to allow your personnel to conduct operations as management wants. If you have a very experienced work force you may need less detail. Takes into account who has the authority to make decisions. Clearly defines accountability (i.e. who performs what actions). Provides guidance on what to do when things don t go right. Defines decision points and actions to take for each decision Regulatory Compliance Associates Inc. 11

12 Characteristics of a Good SOP(Cont.) Defines/Specifies Outputs From Each Process (documentation, work product, etc.) Process Owners Assures process is working Can initiate change Process Stakeholders Run the process Trainees 2015 Regulatory Compliance Associates Inc. 12

13 How Do We Get There? Regulatory Compliance Associates Inc.

14 How Do We Accomplish This? SOPs should have: Clear Instructions Instructions may be in one or various styles Playscript (operator does a now and b next) General description paragraph form Flow chart Pictorial OR ANY COMBINATION as long as personnel can follow 2015 Regulatory Compliance Associates Inc. 14

15 How Do We Accomplish This? (Cont.) Type of style and level of detail depends on what would be most effective for your personnel Experienced vs. Inexperienced Employee Predominate primary language may not be English May Need Dual Language SOPs 2015 Regulatory Compliance Associates Inc. 15

16 Essential SOP Elements 2015 Regulatory Compliance Associates Inc. 16

17 Seven Basic Format Requirements 1. Unique Identifying Number & Title 2. Effective Date 3. Purpose and Scope 4. Roles and Responsibilities 5. Change History 6. Official Signatures 7. Step-by-Step Instructions 2015 Regulatory Compliance Associates Inc. 17

18 1. Unique Identifier = Unique Title Document Identifier: Assigned by Document Control Is often combination of Alpha/Numeric Characters Unique Title: Assigned by Applicable Area Should Reflect the Operation Should be Specific Enough to Avoid Confusion 2015 Regulatory Compliance Associates Inc. 18

19 Examples QC QC Laboratory OOS Procedure QC is Department Owner 001 is the Document Sequence Number.01 is the Revision Number QC Laboratory OOS Procedure is the Title 2015 Regulatory Compliance Associates Inc. 19

20 2. Effective Date The Date the Document Instructions are Official Assigned after completion of training Assigned after official signatures are obtained Represents the most current version of SOP Should be traceable to Unique Identifier and Title 2015 Regulatory Compliance Associates Inc. 20

21 Examples Some Date Formats /30/15 30 Aug Aug 2015 Dates Should be Legible and Readable Format of Date is Not Important 2015 Regulatory Compliance Associates Inc. 21

22 3. Purpose and Scope Purpose Describes the Reason for the SOP Scope Describes the boundaries of the SOP 2015 Regulatory Compliance Associates Inc. 22

23 Examples Purpose: The purpose of this SOP is to describe the procedure for establishing raw material specifications. Scope: This procedures applies to components and materials used in the manufacturing of drug products Regulatory Compliance Associates Inc. 23

24 4. Roles and Responsibilities Defines Who Can Initiate Changes to SOP Content Defines Who does What at a High Level Defines Who should be Trained 2015 Regulatory Compliance Associates Inc. 24

25 Examples Quality Control is responsible for testing the components and materials. Quality Assurance is responsible for reviewing and approving the results of the QC tests Regulatory Compliance Associates Inc. 25

26 5. Change History Describes what has changed between versions Describes the Reasons for Changing the SOP 2015 Regulatory Compliance Associates Inc. 26

27 Examples Reason for Change: This SOP was established to define the process for review and approval of QC laboratory test results. Reason for Change: Step 5 of the SOP was changed to clarify that Quality Assurance has the final approval of QC test results Regulatory Compliance Associates Inc. 27

28 6. Official Signatures Management Acknowledgement Changes are consistent with policy/procedure Changes are necessary Changes do not impact Quality of Product Validation Status of Product 2015 Regulatory Compliance Associates Inc. 28

29 7. Step-by-Step Instructions Defines the steps in the operation being performed from initiation to completion of the task Written Language should be Clear and Concise Consider flow diagrams Consider pictures Consider Combinations Detail Depends on Company Philosophy Should be 10 pages If 10 pages consider smaller sections 2015 Regulatory Compliance Associates Inc. 29

30 Additional Considerations Reference to Related SOPs Useful in identifying documents also requiring revision References to Regulatory Requirements Helps identify the origin of the requirement May help identify documents needing changes based on regulation changes Attachments Helps ensure changes in the SOP are carried through to related documents Definitions Defines terms specific to the SOP Deviation / Failure Response (What to do/where to go/who to involve) Identify steps necessary to involve QA and initiate a formal investigation (OOT, OOS, Deviation, CAPA, etc ) 2015 Regulatory Compliance Associates Inc. 30

31 Avoiding Pitfalls 2015 Regulatory Compliance Associates Inc. 31

32 Common SOP Pitfalls 1. Providing too much information Requirement: Use a Pentel R.S.V.P. Ballpoint Stick Pen with Grip; Fine Point, Black Part #BK90-A Why is this a pitfall: Using a different pen is a deviation from your SOP 2. Providing too little information No requirement specified regarding the use of writing tool. Why is this a pitfall: It allows for the use of any writing implement including Pencil. Acceptable Statement: Using a blue or black indelible pen 2015 Regulatory Compliance Associates Inc. 32

33 Other Pitfalls 3. Using the manufacturer s supplied SOP verbatim if equipped with optional ABC-123 printer You either have the printer or not 4. Leaving things for individual interpretation causing lack of consistency between operators Pitfall: Inspect a sufficient number of units Acceptable: For a batch size between units, inspect 12 units 5. Not having SOP available in the area at the time of use Can t follow it from memory if it is a detailed stepwise instruction Operators will do what they were shown to do and not what their procedure instructs them to do 2015 Regulatory Compliance Associates Inc. 33

34 Other Pitfalls (con t) Allowing access to SOPs that are out of date We removed that equipment 2 years ago Common to find tables from previous SOP version in Lab Notebooks still being used Why is this a pitfall? People may not be performing the appropriate steps The information being generated may not be correct It calls into question your quality system and your document control processes Regulatory Compliance Associates Inc. 34

35 Summary Don t Write for Regulators - Write for Your Processes SOPs should be clear and concise and understood by the intended user There is a fine line between being too specific vs. being too general. Know your company s philosophy on the level of detail to be included Regulatory Compliance Associates Inc. 35

36 2015 Regulatory Compliance Associates Inc. 36

37 Investigations 2016 Regulatory Compliance Associates Inc. 37

38 Regulations Required by law Food, Drug and Cosmetic Act 21 CFR CFR 820 EudraLex ISO ICH GHTF 2016 Regulatory Compliance Associates Inc. 38

39 Food, Drug and Cosmetic Act SEC [21 USC 351] (a)(2)(b) a drug shall be deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess Regulatory Compliance Associates Inc. 39

40 21 CFR (a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company Regulatory Compliance Associates Inc. 40

41 21 CFR : Investigating the cause of nonconformities relating to product, processes, and the quality system : Any complaint involving the possible failure of a device, labeling, or packaging to meet any of its specifications shall be reviewed, evaluated, and investigated : The evaluation and any investigation shall be documented : Corrective and preventive action. (a)each manufacturer shall establish and maintain procedures for implementing corrective and preventive action 2016 Regulatory Compliance Associates Inc. 41

42 EudraLex Volume 4 A Pharmaceutical Quality System appropriate for the manufacture of medicinal products should ensure that: The results of product and processes monitoring are taken into account in batch release, in the investigation of deviations, and, with a view to taking preventive action to avoid potential deviations occurring in the future. An appropriate level of root cause analysis should be applied during the investigation of deviations, suspected product defects and other problems. Appropriate corrective actions and/or preventative actions (CAPAs) should be identified and taken in response to investigations. A review of all batches that failed to meet established specification(s) and their investigation. A review of all quality-related returns, complaints and recalls and the investigations performed at the time Regulatory Compliance Associates Inc. 42

43 Other International Organization for Standardization (ISO) ISO 13485: Quality Management for Medical Devices International Conference on Harmonization (ICH) Q10: Pharmaceutical Quality System Global Harmonization Task Force* (GHTF) Quality management system Medical Devices Guidance on corrective action and preventive action and related QMS processes *The International Medical Device Regulators Forum (IMDRF) is continuing the work of the Global Harmonization Task Force (GHTF) Regulatory Compliance Associates Inc. 43

44 What is CAPA? 2016 Regulatory Compliance Associates Inc. 44

45 The CAPA Process 2016 Regulatory Compliance Associates Inc. 45

46 Key Point to Remember CAPA System Identifying Issues Production and Process nonconformances Complaints Audit Observations Performing Risk Assessment Investigating to root cause Resolving the Issues Corrections Interim Controls Corrective Action Verifying the Resolution Effectiveness Checks Trends Preventive Action 2016 Regulatory Compliance Associates Inc. 46

47 Risk Assessment What is the impact of the issue to the health and safety of the patient and/or user. What is the scope of the issue: Product in the field Multiple lots Multiple locations Frequency of occurrence Identified in Hazard Analysis Use your Risk Management Tools Regulatory Compliance Associates Inc. 47

48 Investigations If an initial evaluation and risk assessment indicates, a documented investigation consistent with the significance of the quality issue, is performed to determine Root or Probable Cause Regulatory Compliance Associates Inc. 48

49 Investigations continued Initial Risk Assessment will determine the: Depth of investigation: Simple issues = simple investigations Complex/safety critical issues = detailed investigations Urgency of the investigation. Obtain Quality Management support 49

50 Investigations continued Write an Investigation Plan. Identify an Owner (process or event). Engage a team if applicable. Determine tools to be used. Determine areas to be investigated. Determine how to investigate. Establish a timeline Regulatory Compliance Associates Inc. 50

51 Investigations continued Investigate the following areas: Personnel, Materials, Equipment, Process/Methods, Suppliers, Validation, Storage conditions, Think big, think creatively Regulatory Compliance Associates Inc. 51

52 Investigations continued Document all investigation activities. At a minimum, include the following elements: Description of Nonconformity Event Root or Probable Cause Outcomes of all tools used Objective evidence supporting conclusions Description of statistical methods used Final risk assessment 2016 Regulatory Compliance Associates Inc. 52

53 Investigative Tools Brainstorming Fishbone 5 Whys Design of Experiments Contradiction Analysis News and Views, News 2016 Regulatory Compliance Associates Inc. 53

54 Correction Correction: Action taken to fix a detected nonconformity. Typically one time fixes. Immediate solution such as training, repair or rework. Also known as remedial or containment action. Corrections require verification. Thorough documentation required 2016 Regulatory Compliance Associates Inc. 54

55 Correction, continued Interim controls Type of correction that remains in place until a corrective action is deemed effective Examples 100% inspection Third party oversight and review 55

56 Corrective Action Corrective action (CA): action to eliminate the cause(s) of a detected nonconformity or other undesirable situation and the recurrence of the issue Regulatory Compliance Associates Inc. 56

57 Corrective Action continued Write a Corrective Action Plan. Identify the CA strategy. Describe all the corrective actions that will be performed and associated action items. How will the corrective action be tested Identify who is responsible for each action item. Set a timeline with completion dates Regulatory Compliance Associates Inc. 57

58 Corrective Action continued Implement the Corrective Action(s). Implementation requires monitoring and oversight. Structured monitoring of progress against actions, monitoring of the impact of actions, engagement of management, and governance. Documents any changes, and reflects any revisions or changes to timelines in the documentation. Formal tracking of the overall progress of the CA, tracking of the individual actions, and review of milestones on a defined frequency Regulatory Compliance Associates Inc. 58

59 Preventive Action Preventive Action (PA): action to eliminate the cause of a potential nonconformity or other undesirable potential situation. Should prevent the occurrence of the potential issue. Not dependent on the occurrence of a nonconformity Example: Results of a Finished Product QC check are within specification limits yet over the past 10 batches are trending upward Regulatory Compliance Associates Inc. 59

60 Preventive Action continued Preventive action require a plan with same elements as a corrective action: Write a plan. Implement the preventive actions. Monitor preventive action activities Regulatory Compliance Associates Inc. 60

61 Effectiveness Check Effectiveness Check (EC): Monitoring activity over a defined duration for ensuring that CA/PA s have been identified, implemented, and sustained the problem has been solved, and no new quality problems have been created Regulatory Compliance Associates Inc. 61

62 Effectiveness Check continued Key Components of Effectiveness Checks: Methods for determining success of the Corrective Action or Preventive Action must be defined. Effectiveness criteria or key performance indicators must be measurable. Duration for conducting effectiveness checks must determined. Data, graphs, charts, metrics as applicable for evidence of effectiveness of the Corrective or Preventive Action 2016 Regulatory Compliance Associates Inc. 62

63 Effectiveness Check continued Effectiveness Check Plan: Addresses the key elements. Describes statistical techniques to be used. Lists responsibilities and includes due dates Regulatory Compliance Associates Inc. 63

64 CAPA Closure All actions must be completed and assessed for effectiveness prior to CAPA closure. (Note: In rare occasions CAPA may be closed prior to effectiveness check however solid justification is required.) Use common sense 2016 Regulatory Compliance Associates Inc. 64

65 Corrective Action/Preventive Action Not all nonconformities require Corrective or Preventive Action. If Corrective or Preventive Action are not necessary, as determined by Quality, then appropriate justifications should be documented and approved Regulatory Compliance Associates Inc. 65

66 Corrective Action/Preventive Action continued Low Level Investigations may not routinely require CAPAs. However, these investigations should be tracked and trended. If a recurring trend is found, Corrective Actions should be required Regulatory Compliance Associates Inc. 66

67 Corrective Action/Preventive Action continued CAPA Leader Excellent communication/presentation skills. Strong analytical problem solving skills. Influence management skills; ability to work constructively across all functions of the organization. Experience in all areas of the CAPA process. Experience with quality tools and process improvement techniques. Project management experience Regulatory Compliance Associates Inc. 67

68 When to Create a CAPA Not all nonconformance needs to become a CAPA. Use a method to determine if a CAPA is needed. Use a combination impact and frequency Regulatory Compliance Associates Inc. 68

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