Process Validation (PV): Designing an Effective PV Program. Mike Porter Compliance Consultant Commissioning Agents Inc.

Transcription

1 Process Validation (PV): Designing an Effective PV Program Mike Porter Compliance Consultant Commissioning Agents Inc. (CAI) 24Apr2013

2 Agenda Process Validation Background Stage 1: Process Design Stage 2: Process Qualification Stage 3: Continued Process Verification

3 Requirement PV is an enforceable requirement with changing expectations Finished Dosage Form Products 21 CFR 211 Biological Products 21 CFR 610 Devices 21 CFR part 820 ISO product verification/validation

4 What PV Was Process Validation is establishing documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a product meeting its predetermined specifications and quality attributes. (CFR, ICH Q7A, EM)

5 What PV Is Guidance was revised to re-focus on Product Quality through process understanding and control: Process validation is defined as the collection and evaluation of data, from the process design stage through commercial production which establishes scientific evidence that a process is capable of consistently delivering quality product. (emphasis added) Guidelines for Industry Process Validation: General Principles and Practices FDA (January 2011) 5

6 Fundamental Change Old premise: Did we meet the design? (design is presumed to be perfect) New premise: Have we understood and met the process requirements, and have we controlled risks to quality and patient safety? (assumes we know requirements and risks)

7 Qualification vs. Validation Activities undertaken to demonstrate that utilities and pieces of equipment are suitable for their intended use and perform properly

8 Evolution of Risk and PV FDA Guide to Process Validation EU Annex 15 FDA: Pharmaceutical CGMPs For The 21st Century ICH Q9 FDA: Quality Systems Approach to Pharmaceutical cgmp ICH Q10 ISPE GPG ARM C&Q ISPE C&Q Baseline 5 Guide ISPE 21 st Century Qualification White Paper ICH Q8 ASTM E EU Annex 20 FDA Process Val. Guidance ISPE Guide FSE / ICH Q9 ASTM

9 Validation Guidance FDA Guidance for Industry Process Validation: General Principles and Practices, January 2011 EU Process Validation Guidance Effective in 2013? Elaboration of the New ICH Guidance Q8: Pharmaceutical Development Q9: Quality Risk Management Q10: Pharmaceutical Quality Systems

10 1987 vs Guideline Need for Revision Industry perceptions FDA interpretation GMP 21 st Century Initiative Encourage innovation Change from standard 3 batches to statistical analysis

11 The Challenge NEW GUIDANCE NEW IDEAS TIME TO APPROVAL

12 3 Stages of Process Validation 1. Stage 1 Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities 2. Stage 2 Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing 3. Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control

13 FDA s Guidance For Industry Guidance for Industry Process Validation: General Principles and Practices 1. The clarity of its integrated 3 stage lifecycle process DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document contact Brian Hasselbalch or Grace McNally (CDER) or , Christopher Joneckis (CBER) , or Dennis Bensley (CVM) Its emphasis on the need for effective scientific knowledge led programs U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM) November 2008 Current Good Manufacturing Practices (CGMP) 3. The elimination of the 3 Golden Batches concept.

14 Intent 1. Product and process design and development Product Lifecycle Approach 3. Maintenance of the process in a state of control during routine commercial production 2. Qualification of the commercial manufacturing equipment and Validation of the process

15 Validation Work Flow

16 On-going Continuum Validation of the process is not a one off event but represents an ongoing continuum of scientific knowledge development and ongoing assurance.

17 PV Goal Drug product or Medical Device meeting the needs of the patient, i.e., safe and effective; and has the identity, strength, purity, and quality characteristics it is represented to possess. Achieved through: proper product development proper process validation ongoing verification/ monitoring.

18 PV Lifecycle Design Confirm Assess Monitor

19 Regulatory Expectations There is an increasing expectation that manufacturing processes be well-characterized before beginning commercial manufacturing and process validation. Alignment

20 Stage 1: Process Design Product/Process Characterization Requirements Design Review Process Flow Diagram Risk Assessment

21 Product/Process Characterization Region where parameter tracking identifies drift Region where process is robust Region where process is unstable

22 Product/Process Development New Product/Process: Leverage product and process design development reports R&D integral to establishing acceptance criteria for validation Existing Product/Process: Evaluate the historical process capability to enhance understanding of acceptance criteria and risk evaluations Cpk or Ppk get a statistician to help! Can lead to: Thorough evaluation of controls needed Justification for how many lots are needed for PV

23 Considerations for PV Product key process variables (CPP, CQA, COP) Sterility Cleaning Monitoring conformance lots Clearance of contaminants Performance parameters (consistency) Analytical methods Raw Materials Product contact materials (lubricants) Product contact surfaces Shipping studies Stability studies Biocompatibility studies Manufacturing equipment capability Prior manufacturing experience

24 Requirements Defining the requirements for the systems/ process can come in many forms: User Requirements Specification (URS) for equipment Functional Requirements Specification (FRS) for computer systems/automation Technical Specifications Define business requirements versus quality impacting requirements Align testing strategy based on outcome: Commission business requirements Qualify/validate quality impacting requirements

25 Design Review Provides opportunity to Verify that the design will meet all requirements, or Adjust requirements if proposed design is acceptable Aligns requirements with design for traceability during testing

26 Process Flow Diagram Process flow mapping a tool that shows the relationship of activities within a defined process. PFD is not Personal Flotation Device Process flow diagram (PFD) a visual map or graphical representation of a process that contains: Process steps Inputs Activities Decision points Outputs

27 Benefits Alignment between cross-functional team members on how process is intended to be run Drives a more complete understanding of the process from multiple perspectives Standard process description that can be used in: Troubleshooting problems Identifying process improvement initiatives Training personnel Identifying control points Identifying inter-departmental hand-offs that can lead to miscommunication Identifying redundancies, indirect paths, dead ends or other non-value added activities

28 Example Find appropriate level of detail Answer depends on why you are doing the mapping Can add inprocess tests or start-up verifications

29 Process Example Process Steps Process Steps out of scope Process Rooms Equipment Testing Start-up In-process Final Product Sampling Plan

30 Risk Assessment Contentious Argumentative 4 versus 5 Long Tedious Brain-numbing

31 Risk Perception Required to be done by Regulatory agency Upcoming inspection Corporate policy OR Useful tool that Provides common understanding of process Helps qualify equipment or validate process Identifies gaps in process understanding

32 What Is Risk? ICH Q9 and ISO/IEC Guide 51 Definition: The combination of the probability of occurrence of harm and the severity of that harm Note: Detection is not specifically discussed in the definition

33 Quality Risk Management (QRM) Avoidable versus Unavoidable Risk Zero risk is not scientifically achievable Although medicinal products are required to be safe, safety does not mean zero risk. A safe product is one that has reasonable risks, given the magnitude of the benefits expected and the alternatives available. As such, quantified risk must be balanced against unmet medical needs FDA Risk Management Task Force, 2009

34 QRM is Broad Company Strategic Risks Operational Risks Financial Risks Compliance Risks Competitor Advantage Company Viability Shareholder Harm Patient ICH Q9 Impact

35 QRM Program Risk Management Overall risk program Living Management accountability Processes to coordinate, facilitate and improve science-based decision making with respect to risk Risk Assessment Specific event Point in time Subject Matter Expert Deep technical knowledge Produces individual documents consisting of hazards and risk evaluations

36 Critical Aspects Process Step Mixing CQA Potency CPP Critical Aspect(s) Mixing Time, Mixing Speed Ability to control, monitor, alarm mixing time and speed

37 Critical Aspects Process Step CQA Bottle Fill Seal Integrity CPP Critical Aspect(s) Seal Dwell Time: per GMPQ-048 for each material, tooling and machine combination Sealing Power: per GMPQ-048 for each material, tooling and machine combination Induction Sealer Height: 1/8 inch per report xxx Removal Torque: 5 10 inch pounds per report xxx Material: Incoming inspection against component specification per SOP xxx Tooling: Uniquely identified per SOP xxx Machine: Uniquely identified per SOP xxx

38 Critical Aspects Process Step Bottle Fill CQA Product Contamination CPP NA Critical Aspect(s) Product Contact Surfaces per IQ xxx Product Contact Lubricants per IQ xxx Cleaning Process per Cleaning Validation Report xxx

39 Evaluate Outcome Severity x Occurrence (x Detection)

40 Key Outcomes from Stage 1 Documented rationale for process design and controls Documented requirements and a design that meets the requirements Documented process flows Documented risk assessments Documented statistical rationales to be used

41 Stage 2: Process Qualification Validation Planning Commissioning Qualification Process Validation

42 Validation Planning Site Validation Master Plan (VMP) provides all elements of validation program at the site. Project Validation Plan (VP) provides decisions on implementation for a specific project. If small or straight-forward, the VP can be addressed in a change control.

43 VMP Strategic approach to: Facility, Utility, Equipment Computer, Laboratory, Packaging PV, Cleaning Define where automation fits: Equipment vs. Computer Define Roles and Responsibilities Can point to other documents or procedures for specifics Provide list of validated systems, site layout and room classification, material and people flows Provide list of proposed validations Update annually

44 VP Specific project Roles and Responsibilities Address commissioning plan (FAT/SAT). Address leveraging strategy so that commissioning is handled appropriately. Address qualification strategy: IOQ combined or separate PQ versus PV

45 Qualification A Broken Process? IQ/OQ had become more intensive than PQ Organizations refused to leverage commissioning Automated systems and the controlled equipment were qualified separately and inefficiently Deviations for trivial items diluted Q-unit attention Change-is-bad attitudes driven by cost/time

46 QRM in Qualification ASTM E : A consensus standard based on sound scientific, engineering and quality principles that separates business risk from patient safety risk Focus on product and process design through detailed requirements and mitigating risks in the design phase

47 Science and Risk Based Approach The identification and control of risks to product quality Formality and documentation commensurate with risk The use of (GEP) to verify installation and operation Verification that system performance meets product and process user requirements Think about it: If everything is critical, then nothing is.

48 Models Traditional V Model or Risk Based Verification User Requirements Specification Functional Specification Design Specification related to related to related to Performance Qualification Operational Qualification Installation Qualification Product Knowledge Process Knowledge Regulatory Requirements Company Quality Reqs. Requirements Good Engineering Practice Specification and Design Risk Management Design Review Verification Acceptance and Release Operation & Continuous Improvement System Build Change Management Figure 1: The Specification, Design and Verification Process Emphasis on Documents Not System Performance Emphasis on Meeting Process Requirements

49 Risk Based Verification Product Knowledge Good Engineering Practice Process Knowledge Regulatory Requirements Requirements Specification and Design Verification Acceptance and Release Operation & Continuous Improvement Company Quality Reqs. Risk Management Design Review Change Management Figure 1: The Specification, Design and Verification Process

50 Validation Lifecycle Design Development Enhanced Design Review Commissioning PQ Process Validation IQ & OQ CONSTRUCTION Strongest Point Of Interest to the Regulators

51 PV Protocol Process Validation must be performed using an approved protocol containing predetermined acceptance criteria The number of runs must be justified Acceptance is based on consecutive runs meeting all pre-defined acceptance criteria In most cases, the protocol will contain a higher level of sampling than a routine commercial production run

52 Contents Purpose describe the objective of the validation activity Scope define the boundary for the validation References list supporting site documents that are referenced in the protocol Responsibilities Validation overview, including: Description of the process being validated: Operating parameters, Processing limits, Raw material inputs Process flow diagram Justification for the number of validation runs: It is no longer automatically 3 runs Tests to be performed and acceptance criteria: Start-up, In-process, Finished product Batch size Sampling plan

53 Contents Protocol Execution Pre-requisites General procedures Data shall be collected and recorded on the appropriate data sheets contained in the protocol Must follow Good Documentation Practices Each item must be initialled and dated as the activity is completed At completion of protocol, a review will be performed and documented by a second person All personnel executing the protocol will provide signatures and initials in a Log contained in the protocol Deviation Management Data Collection and Analysis Report Are the executed protocol, charts, printouts, etc. attached to the report? The decision to release the system will be documented in the report Criteria for Product Disposition

54 Content Test Cases Acceptance Criteria Appendices Protocol Deviation Form if not in a separate procedure Signature Log Approvers Originator Research & Development Engineering Manufacturing Quality Assurance Regulatory Affairs

55 Protocol Format Examples PROCESS STEP 1: XXX Instructions: Perform the Actions in the table below and verify the Actual Results meet the Expected Results. Process Step 1: XXX Step Action Expected Result Actual Results Pass/Fail Initial / Date 1. Document the work order number uniquely identifying the batch record being executed. 2. Verify the process step is executed per batch record XXX, TITLE. 3. Record the results for the required sampling in the Sampling Plan table below. 4. Record the equipment operational parameters at the beginning and end of the run in the Equipment Parameters table below. 5. Record the room temperature and humidity at the beginning and end of the run in the Room Conditions table below A unique work order number is recorded on the batch record. The process was executed per the current revision of batch record XXX, TITLE. All results meet the required specifications: Criteria 1: X ± 10% Criteria 2: Y Criteria 3: Z The equipment setpoints are maintained throughout the run. Tension at end of run will be recorded for information only. The room temperature and humidity are maintained throughout the run. The unique work order number is recorded on the batch record. The process executed per the current revision of batch record XXX, TITLE. All results the required specification. The equipment setpoints are/are not maintained throughout the run. The room temperature and humidity maintained throughout the run REVIEWED BY: DATE:

56 Protocol Format Examples Process Step 1: Sampling Plan Sample Number Sampling Time Sample Size 1 Start-up of Run: 3 samples First Spool per spool Test Method Acceptance Criteria Method XXX, TITLE Criteria 1: X ± 10% Criteria 2: Y Criteria 3: Z Actual Results Criteria 1: Criteria 2: Criteria 3: Time Sample Taken: 2 Middle of Run: After spool samples per spool Method XXX, TITLE Criteria 1: X ± 10% Criteria 2: Y Criteria 3: Z Criteria 1: Criteria 2: Criteria 3: 3 End of Run: Last Spool 3 samples per spool Method XXX, TITLE Criteria 1: X ± 10% Criteria 2: Y Criteria 3: Z Time Sample Taken: _ Criteria 1: Criteria 2: Criteria 3: Time Sample Taken: Process Run 1: Critical Operating Parameters Critical Operating Parameter Sampling Time Acceptance Criteria Actual Results Temperature Record the value at the start of the run and monitor during the entire run and then evaluate the min / max data for the entire run F Start Time: End Time : Start-up temperature: MIN temperature: MAX temperature: Humidity Record the value at the start of the run and monitor during the entire run and then evaluate the min / max data for the entire run % RH Start Time: End Time : Start-up humidity: MIN humidity: MAX humidity: REVIEWED BY: DATE:

57 Execution Trained operations personnel under normal operating conditions Following approved procedures Using released materials Completing an approved batch record and validation protocol Using qualified equipment, utilities, facilities and lab instruments And using validated test methods

58 Report Discuss and cross-reference all aspects of the protocol Summarize the data collected and analyze the data specified in the protocol Evaluate any unexpected observations and additional data collected not specified in the protocol Summarize and discuss all non-conformances (Protocol deviations, Aberrant test results, Other information having a bearing on the validity of the process) Describe in sufficient detail any corrective actions or changes that should be made to procedures and controls State a clear conclusion as to whether the data indicates the process met the conditions of the protocol and is considered to be in a state of control. If not, what needs to be done to reach this conclusion Approvals

59 Example 1 Meet Specification? Good Process Capability? Finished Product Testing Batch Number Min Max Avg Cpk All Batches

60 Example 2 Meet Specification? Good Process Capability? Finished Product Testing Batch Number Min Max Avg Cpk All Batches

61 Key Outcomes from Stage 2 Documented plan for validation Approved protocols with pre-defined acceptance criteria Executed protocols demonstrating Fit For Intended Use Approved Reports discussing protocol deviations Statistical analysis for process robustness

62 Stage 3: Continued Process Verification Continual assurance that the process remains in a state of control Control strategy is implemented Knowledge is gained and added through deviations, changes, complaints, adverse events, aberrant test data, yield variations or other process events Detect and improve undesired process variability Drives continuous improvement

63 Maintenance of the Validated State Standard Operating Procedures Operation Calibration Maintenance Cleaning Training Link to Batch Records Document Control Calibration Preventive Maintenance Change Control Periodic Review and Requalification Change controls Performance Trends CAPAs Deviations Complaints Maintenance trends

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66 Back-up Slides Risk Management

67 Define the System Boundary From incoming material to secondary packaging for process xxx

68 Identify the Process Areas Docking Manual Cleaning VHP Cycle Environmental Monitoring Vial In Tray Handling Vial Loading Filling Stopper Handling Stoppering Cap Handling Capping Crimping Vial Unloading Vial Out Tray Handling Undocking Maintain a focus on the process steps within the defined boundary: Assume everything coming in across the boundary is good Address materials, lab, other supporting processes in separate risk assessments Address pulling samples as it can impact process being run

69 Identify Hazards 1. Identify the harms related to patient safety and product quality 2. Document the hazards that relate to each category 3. Identify the causes for each hazard Hazard 1 Hazard Category 1 Hazard 2 Brainstorm to catch hidden hazards or causes Representation from multiple groups with different knowledge of the process Capture risk, but avoid controls or severity until later Cause 1 Cause 2 Cause 3 Cause 1 Cause 2

70 Hazard Example

71 Evaluate Risk and Controls Identify design control(s) What was built into the design of the equipment or system? Identify other/process control(s) What is defined in the SOP, training, monitoring, or other systems? Identify the detection mechanism(s) List all alarms, indicators, gauges, visual inspection, or lab results used to detect and out of limit condition. List specifications/acceptance criteria and supporting rationale Provide the agreed upon reference now so it can be found later. Hazard Category Hazard Process Area(s) Affected Cause Controls from Process / Equipment Design Specification / Acceptance Criteria Rationale for Other Control Specification M echanisms Specification / Acceptance Criteria Rationale for Specification Detection M echanism for Hazard Notes 1 2 3