1. Validation
SAPRAA March 2013

2. Presentation What will be covered in this presentation…..
Why do we validate?
What do we validate?
Approach to validation
Qualification
Process validation – a look at the FDA guidelines

3. Purpose of Validation OR Factors affecting quality
GMP Guide Chapter 5, Annex 11, Annex 15
In compliance
Dossier submission
Ever look at those files…..
Raw Materials
Personnel
Procedures
Validated processes
Equipment
Premises
Environment
Packing Materials OR
Validation
Change Control

4. FDA Warning Letters

5. Why do we validate
Manufacturers must assume responsibility for the quality of products & ensure they are:
fit for use
comply with registered requirements
do not place patients at risk

6. Why do we validate
Validation establishes & provides documented evidence that premises, utilities and equipment:
are designed in accordance with GMP
are installed in compliance with design criteria
operate in accordance with design criteria
Validation establishes that a specific process will consistently produce a product meeting its pre-determined specification

7. Validation Validation a requirement not an option
Is validation a ‘tick box’?
Validation documentation always checked in GMP inspection (the ‘action of proving..’)
MCC and PIC/S….. design, installation, operational and performance…. qualification
MCC and PIC/s…. validation of processes, cleaning and analytical methods…. validation
A system or equipment must be qualified in order to operate in a validated process
Process validation protocols required for dossier submission

8. Validation / Qualification
Proving procedures, processes, equipment, materials, activities, systems lead to the expected results
Qualification:
Proving and documenting premises, systems, equipment properly installed and/or work correctly & lead to the expected results
Qualification often initial stage of validation, individual steps alone do not constitute process validation

9. What gets validated Facilities Utilities / Services / Systems
Equipment
Computer systems
Analytical methods
Cleaning methods
Processes
Facilities, systems and equipment qualified prior to process validation being completed

10. What gets validated Utilities / Services / Systems
Critical systems with direct impact e.g.
Purified Water
HVAC
Compressed air (in contact with product or primary containers)
Steam (if used for cleaning product contact surfaces)

11. What gets validated Processes Non-sterile manufacturing
Sterile manufacturing – media fills
Sterilizing loads
Waste

12. Sequencing of Validation Stages
Validation Master Plan
Site Master File
Overall Validation Master Plan
User Requirement Specification
Validation SOP
Design Qualification
Process Validation
Documents that are required to be in place and are routinely updated
Installation Qualification
Operational Qualification
Performance Qualification

13. Approach to Validation
Validation requires:
Collaboration between the all relevant parties (validation, QA, production, engineering, consultants, contractors)
Resources – time, budget, people
Planning (including defining scope of work) and control

14. Approach to Validation Planning
Risk-based approach to validation; not all components need to be validated
Avoids making validation unnecessarily complex
A Risk Assessment or Impact Assessment determines which components are critical and non-critical, or have a direct impact or indirect impact on product quality
Critical Process Parameters & Critical Quality Attributes
These decisions have implications on the extent, cost and time of the qualification process

15. ISPE Commissioning and Qualification
Fig. 1.1
ISPE Pharmaceutical Engineering Baseline Guide: Commissioning and Qualification
Vol. 5 March 2001

16. Impact Spectrum
Fig. 2.1
ISPE Pharmaceutical Engineering Baseline Guide: Commissioning and Qualification
Vol. 5 March 2001

17. Qualification Requirements
Direct Impact Systems
Indirect Impact Systems
Direct impact on product quality
Designed & commissioned in line with GEP
Also subject to qualification
No direct impact on product quality
Designed & commissioned in line with GEP
No qualification required

18. Impact Assessment Indicators
Direct Impact Systems
Direct Impact Components
Direct contact with product (e.g. air)
Produces an excipient / ingredient (e.g. WFI)
Used in cleaning / sterilizing - malfunction could result in failure which poses risk
Controls a risk to the product (e.g. Nitrogen blanket)
Produces data used to accept / reject product
Produces identification information (e.g. expiry date)
Used to demonstrate compliance with registered process (e.g. hardness tester)
Has a direct effect on product quality (e.g. blister embossing)
Failure or alarm of component having a direct effect on product quality (e.g. in-line TOC)
Information from component recorded as part of batch record (e.g. drying temperature)
Has direct contact with product

19. Approach to Validation Verification and GEP
Verification and GEP – processes that function within the engineering environment
Support the validation effort
Operate continually, not only at one point in time
Based on quality management principles e.g. documentation control, change management, authorization processes, deviations / discrepancies

20. Approach to Validation Engineering Risk-based Verification
Risk Management applied - identifies critical aspects for product quality & patient safety
List of critical aspects approved by QA
Acceptance criteria specified for the critical aspects
Non-critical aspects may be included (do not require same level of involvement by QA)
Acceptance and release must provide documented confirmation of fitness for intended use

21. Approach to Validation Verification Execution
Verification confirms critical aspects meet acceptance criteria
Extent of verification commensurate to risk to product quality
Execution:
Design review
Factory Acceptance Test (FAT)
Site Acceptance Test (SAT)
Installation testing
Functional testing
Performance testing
Handling of discrepancies, change management
Acceptance and release

22. Good Engineering Practice
Focus on practices that add value - providing evidence of fitness for use & proper performance
GEP is expected in pharmaceutical enterprises; it is not required by GxP regulations
However value of effective GEP is supported by regulatory and engineering guidance / standards

23. Qualification Approaches
International regulations: facilities, equipment & systems qualified and automation systems validated
ISPE Guide: ensures facilities, equipment, systems, and associated automation are ‘fit for intended use’
ISPE Guide: states critical aspects, and the installation & operational acceptance criteria documented in the final risk assessment / design review could be labeled as the IQ / OQ
Emphasis on ensuring fitness for use through verification activities during the life cycle rather than ‘incidents’ that represent qualification

24. Life Cycle
Fig. 2.2
ISPE Guide: Science and Risk-Based Approach for the Delivery of Facilities, Systems and Equipment (2011)

25. Sequencing of Validation Stages
Validation Master Plan
Site Master File
Overall Validation Master Plan
User Requirement Specification
Validation SOP
Design Qualification
Process Validation
Documents that are required to be in place and are routinely updated
Installation Qualification
Operational Qualification
Performance Qualification

26. User Requirement Specification (URS)
Details of requirements from an operational and GMP perspective
One of the most important documents but usually drafted as an after thought!
Examples:
Speed e.g. 200 bottles per minute
Temperature e.g. drying temperature range 50 to 80ºC
Finishes e.g. SS304
Safety features e.g. guards
Documentation required e.g. manuals

27. Design Qualification(DQ)
Verification that what is to be supplied is in line with the requirements specified in the URS and will meet GMP requirements
Does the design incorporate sufficient provisions to control all risks to the end user?
Examples:
Speed e.g. 50 to 200 bottles per minute
Temperature e.g. drying temperature range 35 to 90ºC
Finishes e.g. mild steel (does not meet requirements)
Safety features e.g. guards present
Documentation required e.g. manuals available

28. Installation Qualification (IQ)
Installation complies with design specification and manufacturer’s recommendations
Examples:
Correct make / model installed
All components present
Connections made
Instruments calibrated
As-built drawings available and correct
Materials of construction correct

29. Installation Qualification (IQ)
A thoroughly executed IQ process ensures:
A fully verified installation that complies with the documented design
All deviations and changes recorded, assessed and approved
Accurate ‘as built’ drawings available and verified
Calibration of measuring instruments completed
Materials of construction verified

30. Operational Qualification (OQ)
Installation performs as intended throughout the anticipated operating ranges
Examples:
Test, for example, speeds / temperatures / fill volumes through full operating range & comparable load (inert material used if required)
Test alarms
Test safety mechanisms
Test interventions, stoppages, start-up etc.
Operational and maintenance procedures available
PPM and calibration schedules are drafted
SOPs are compiled & authorized
Training performed & documented

31. Operational Qualification (OQ)
A thoroughly executed OQ process ensures:
Formal commissioning reports available
Ability of systems to maintain set points in all operational modes demonstrated
Correct functioning of the control system demonstrated
All alarms verified as functioning correctly
Operational ranges, specific alert and action limits identified
Operational and Maintenance manuals available
PPM and calibration schedules available
SOPs available and authorized
Personnel training successfully completed

32. Performance Qualification (PQ)
Effective and reproducible performance, based on the approved process method and product specification
Does the qualification provide assurance that the system / equipment is fit for use and any deviations from specification have been identified and evaluated?
Examples:
Performance of filling equipment:
Consistent fill volume within registered specification using placebo product
Performance of Purified Water system:
Microbial contamination within specification
Performance of HVAC:
Non-viable particle count within specification

33. Performance Qualification (PQ)
A thoroughly executed PQ process ensures:
Demonstration of consistent delivery of process / product specification
Demonstration that the systems have been successfully validated and will not contribute any risk to the quality of products routinely produced
Re-validation criteria, where required, have been formalized

34. Process Validation: General Principles and Practices
FDA
Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
‘…aligns process validation activities with a product lifecycle concept…’
ICH Q8 Pharmaceutical Development
ICH Q9 Quality Risk Management
ICH Q10 Pharmaceutical Quality System

35. Process Validation FDA Process Validation: General Principles and Practices
‘The lifecycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production.’
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1

36. Process Validation FDA Process Validation: General Principles and Practices
Guidance covers:
Human drugs
Veterinary drugs
Biological and biotechnology products
Finished products and APIs/drug substances
The drug constituent of a combination (drug & medical device) product
Medical devices, dietary supplements, human tissues, medicates feeds excluded
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1

37. Process Validation FDA Process Validation: General Principles and Practices
Products should be produced that are fit for their intended use
Quality, safety and efficacy are built into the product
Quality cannot be adequately assured through in-process and final product inspection and testing
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1

38. Process Validation FDA Process Validation: General Principles and Practices
‘… 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…’
Stage 1- Process Design: Commercial manufacturing process defined through development & scale up activities
Stage 2 – Process Qualification: Process design evaluated to verify capability of reproducible commercial manufacturing
Stage 3 – Continued Process Verification: On going assurance during routine production that process remains in state of control
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1

39. Process Validation FDA Process Validation: General Principles and Practices
Gain high degree of assurance in performance of manufacturing process before any commercial batch is distributed for use
Attributes consistent
Identity
Strength
Quality
Purity
Potency
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1

40. Process Validation FDA Process Validation: General Principles and Practices
Successful validation depends on information / knowledge from product & process development
Understand sources of variation
Detect presence & degree of variation
Understand impact of variation
Control variation (commensurate with risk to process & product)
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1

41. Process Validation FDA Process Validation: General Principles and Practices
Focus on qualification without understanding the process and variation may not lead to quality assurance
Continue to maintain state of control during lifecycle regardless of changes (materials / equipment / facilities / personnel)
On-going programs collect and analyze data to evaluate state of control
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1

42. Process Validation FDA Process Validation: General Principles and Practices
Stage 1 – Process Design
Do not need cGMP conditions
Sound scientific methods & principles, good documentation practices (ICH Q10)
Decisions & justification of controls documented and reviewed – value for use and later adaptation
Product development provides key inputs to quality attributes and manufacturing process
Functionality & limitations of commercial manufacturing equipment considered
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1

43. Process Validation FDA Process Validation: General Principles and Practices
Stage 1 – Process Design
Predicted variability considered
Strategies for process control:
Reduce input variation
Adjust for input variation (to reduce impact on output)
Both
Process controls address variability → assures quality
Controls:
Examination of material quality
Equipment monitoring
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1

44. Process Validation FDA Process Validation: General Principles and Practices
Stage 2 – Process Qualification
Determine capability for reproducible commercial manufacture
Two elements:
Facility design & equipment / utilities qualification
Process Performance Qualification
Successful completion before distribution of product (FDA expects concurrent release to be rarely used)
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1

45. Process Validation FDA Process Validation: General Principles and Practices
Stage 2 – Process Qualification
Qualification: Demonstrate utilities and equipment are suitable for intended use and perform properly
Qualification must precede Process Performance Qualification (PPQ)
PPQ combines facility, utilities, equipment, trained personnel, commercial manufacturing process, control procedures and materials / components
Successful PPQ required before distributing product
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1

46. Process Validation FDA Process Validation: General Principles and Practices
Stage 2 – Process Qualification
PPQ has:
Higher level of sampling
Additional testing
Greater scrutiny of process performance
Above could be extended in certain cases e.g. complexity of process, production volume
Manufacture under normal conditions using routine personnel
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1

47. Process Validation FDA Process Validation: General Principles and Practices
Stage 2 – Process Qualification
PPQ protocol:
Manufacturing conditions (including operating parameters, processing limits, materials)
Data to be collected (when, how, evaluation)
Tests to be performed and acceptance criteria
Sampling plan (sampling points, number of samples, frequency of sampling)
Process performance indicators (statistically based)
Status of qualification & analytical method validation
Process for addressing deviations
Review & approval
FDA Guidance for Industry, Process Validation: General Principles and Practices
January 2011 Revision 1

48. Process Validation FDA Process Validation: General Principles and Practices
Stage 3 – Continued Process Verification
Objective: Continual assurance that process remains in a state of control / validated state
Managing change
Routine monitoring systems, maintenance, calibration
Data collection & review (product reviews)
Evaluation of process – identify problems, corrective / preventative actions
Statistical process control techniques
FDA Guidance for Industry, Process Validation: General Principles and Practices
January 2011 Revision 1

49. Process Validation FDA Process Validation: General Principles and Practices
Stage 3 – Continued Process Verification
Changes include:
API supplier
Excipient physical properties
Primary packaging material
Equipment
Process
Facility / plant
Changes require documented description, well-justified rationale, implementation plan, QA approval

50. Concurrent & Retrospective Validation
Concurrent: Validation carried out during routine production of products intended for sale
Exceptional cases
Justified, documented, approved
Retrospective: Validation based on historical / collected data (manufacturing, testing, control data)
Only for well established processes
Inappropriate where changes to composition, equipment & processes made
Suggested source data

51. Challenges / Issues Timing
Generating the protocol for submission
Technology transfer from design to commercial
PPQ batches manufactured but cannot be released
Time for regulatory approval
Launch
New sites for existing products - protocol and results
Prospective vs. concurrent
Availability of design data and initial validation data
Risk

52. Challenges / Issues Multi-disciplinary teams
PPQ performed when equipment / utilities have not
Robust Change Control process
Data collection and review

53. Thank you