1. Qualification And Validation In Pharmaceutical Manufacturing
KHADIJAH ADE-ABOLADE MPH. FPCPharm.
Chief Regulatory Officer/Lead Inspector
Drug Evaluation & Research
NAFDAC

2. OBJECTIVES
Discuss the requirements for Qualification and Validation in Pharmaceutical Manufacturing
Appreciate the need for Validation

3. OUTLINE Definitions Validation documentation Qualification
Types of validation
Approaches
Life cycle concept of validation
Conclusion

4. INTRODUCTION
Safety, quality and efficacy are built into the product – cannot be "inspected or tested into a product"
Need for confidence that the product will consistently meet predetermined specifications and attributes
Every manufacturer should be in business to produce safe, efficacious & good quality products. All these are built in with all that goes into the process but there is need to be confident that the products will consistently have these attributes

5. WHAT IS VALIDATION?
“Validation is defined as the collection & 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.”
Documenting that a process or system meets its pre-determined specifications and quality attributes

6. WHAT IS VALIDATION?
EU GMP - it is “Action of proving, in accordance with the principles of Good Manufacturing Practice (GMP), that any procedure, process, equipment, material, activity or system actually leads to expected results.”
The US FDA defines “Validation as establishing documented evidence which provides high degree of assurance that a specific process will constantly produce a product meeting its pre-determined specification and quality attributes.”

7. WHAT IS QUALIFICATION
Performed to establish confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances.
Provides documented evidence that the subject equipment has been installed as per specification (manufacturer’s recommendation) and will attain and maintain critical process parameters repeatedly and reliably.
A subset of validation, typically done as part of a larger validation effort.

8. Comparison between Qualification and Validation
Validation and Qualification are essentially components of the same concept.
Qualification is normally used for equipment, utilities and systems
Validation is normally used for processes and methods
In this sense, qualification is often a part (the initial stage) of validation but the individual qualification steps alone do not constitute process validation.
Process validation cannot take place without first carrying out qualification

9. WHY VALIDATION?
Assures Quality
Regulatory Requirement
Reduces Cost
It’s the LAW !

10. Consequences of NOT Validating Systems and Processes
Poor Product Quality
Bad Publicity
Death
Financial losses

11. What to Qualify/Validate
Facility
equipment
Premises
Test Methods
Processes
Systems
What to Qualify/Validate

12. Pharm.(Mrs) Edosa Ogbeide
Responsibility
Responsibility for qualification and validation is a multi-disciplinary one which includes:
Heads of Production and QC
Heads of Engineering and Contractors/suppliers
Respective responsibilities clearly defined in the VMP.
Pharm.(Mrs) Edosa Ogbeide

13. Validation Life Cycle Process
Validation should not be viewed as a one-off event.
Validation must follow a structured documented process applying a lifecycle approach having the following key elements:
Initial Validation
Validation Review and
Change Management
Change Management
Initial Validation
Structured
Documented
Lifecycle
Approach
Validation Review
Validation encompasses the entire life of the system from the initial requirements definition through to maintenance and eventual decommissioning of the system
Pharm.(Mrs) Edosa Ogbeide

14. Validation Documentation
Validation Master Plan (VMP)
Validation Protocols (VP)
Validation Reports (VR)
Standard Operating Procedures (SOPs)

15. Validation Documentation
Validation Master Plan
Contains key elements of the validation program.
Concise, clear, contains at least:
a validation policy
organizational structure of validation activities
summary of facilities, systems, equipment and processes validated (and to be validated)
documentation format (e.g. protocol and report)
planning and scheduling
change control and references to existing documents

16. Validation Documentation
Validation Protocol
A validation protocol is a detailed document relating to a specific part of the validation process.
Outlines tests to be carried out, the acceptance criteria and the information that must be recorded.
Defines the approval process for the validation.
Describes the procedure to be followed for performing validation.
Objectives of the validation/qualification study, the site of the study, the responsible personnel

17. Validation Documentation
Validation Protocol
Description of the equipment to be used (including calibration before and after validation)
SOPs to be followed (e.g. the operation and cleaning of the equipment) and the standards and criteria for the relevant products and processes.
Type of validation and time/frequency should also be stipulated.
Processes and/or parameters to be validated (e.g. mixing times, drying temperatures, drying times, physical characteristics, content uniformity, etc.)

18. Validation Documentation
Validation Report
Record of results obtained during the performance of the validation.
Reflects the final test results and other documents such as instrument calibration certificates.
Basis on which the decision is taken on whether a particular process is judged to be validated.
Includes evaluation, analysis and comparison of results with acceptance criteria by the responsible personnel.
Results should meet acceptance criteria and satisfy the stated objective.

19. Validation Documentation
Validation Report
Refer to the protocol, state details of material, equipment, programs and cycles used, together with details of procedures and test methods.
Include recommendations on the limits and criteria to be applied to all future production batches.
Protocol and the report may be combined into a single set of documents.
The protocol is approved as a form on which the test results are recorded as they become available.

20. Types (Stages) of Qualification
Design qualification (DQ)
Installation qualification (IQ)
Operational qualification (OQ)
Performance qualification (PQ)

21. QUALIFICATION

22. Pharm.(Mrs) Edosa Ogbeide

23. Commissioning
Include equipment start-up, adjustments, fine-tuning, cycle development, testing and documentation flexibility.
Leaves the equipment in a “State of Control”, which ensures the equipment is ready for formal qualification, testing, and approval.
Supplements validity and regulatory compliance
checks to verify the system or equipment is built to design specifications
No safety issues
Takes place at the manufacturer’s premise (FAT) or User/Client’s Premise (SAT)

24. Design qualification (DQ)
Process of completing and documenting design reviews to illustrate that all quality aspects have been fully considered at the design stage.
To ensure that all the requirements for the final systems have been clearly defined at the start.
In other words, has it been designed and selected correctly?

25. Design qualification (DQ)
Before purchasing, a manufacturing equipment
Collection of data about similar equipment available in the market
Assessing your needs
Resources to buy, operate, space and maintenance they would need, etc.
Making the decision

26. Installation Qualification (IQ)
Process of checking the installation, to ensure that the components meet the approved specification and are installed correctly, and to see how that information is recorded.
To ensure that all aspects (static attributes) of the facility or equipment are installed correctly and comply with the original design.

27. Installation Qualification (IQ)
Considerations include:
Equipment design features (i.e. materials of construction cleanability, etc.)
Installation conditions (functionality, utilities, wiring, etc.)
Calibration, preventative maintenance, cleaning schedules; safety features
Supplier documentation, prints, drawings and manuals, software documentation
Environmental conditions (such as clean room requirements, temperature, humidity)
Spare parts list

28. Installation Qualification (IQ)
E.g., a manufacturing equipment
After purchasing (or critical repair)
Place it on its intended place
Connect with other equipment, electric power, material flow devices.
Collect its documents including Operation Manual, etc.
Its formally “released”: it is ready for working with

29. Operational Qualification
Process of testing to ensure that the individual and combined systems function to meet agreed performance criteria and to check how the result of testing is recorded.
To ensure that all the dynamic attributes comply with the original design.
Does it work correctly?

30. Operational Qualification
Assuring that the critical components and systems are capable of operating within established limits and tolerances
“Worst case” (Proven Acceptable Range) demonstration that the equipment will perform as expected while operating at the extremes of the proposed range of operation.

31. Operational Qualification
Considerations include:
Process control limits (e.g. time, temperature, pressure, line speed, setup conditions)
Software parameters; starting material specifications
Process operating procedures; material handling requirements
Process change control; training; short term stability and capability of the process, (latitude studies or control charts)
Risk analysis and potential failure modes, action levels and worst-case conditions (Failure Mode and Effects Analysis, Fault Tree Analysis

32. Operational Qualification
E.g., a manufacturing equipment
”Model manufacturing” experiments with model materials, similar to those to be used in the real manufacture
E.g. qualifying an autoclave, we use culture-media
Permit the acceptable fluctuations of parameters, even set the ”worst conditions”

33. Operational Qualification
Worst Conditions
For example, if an equipment is to be operated within the limits of:
Temperature: 20 and 35 oC
Pressure: 0.9 and 1.2 atm
The worst cases are when it operates at
20 oC and 0.9 atm
35 oC and 1.2 atm
20 oC 0.9 and 1.2 atm
35 oC and 0.9 atm

34. Performance Qualification
Also called process qualification
Process of testing to ensure that the individual and combined systems function to meet agreed performance criteria on a consistent basis and to check how the result of testing is recorded.
To ensure that the criteria specified can be achieved on a reliable basis over a period of time.
Does it produce the product correctly.

35. Performance Qualification
PQ includes:
Actual product and process parameters and procedures established in OQ
Assurance of process capability as established in OQ
Acceptability of the product
Process repeatability, long term process stability

36. Performance Qualification
Similar to the Operational Qualification, but the real manufacture is running
Permits accepted fluctuations up to their limits (incl. worse conditions, if occur)
Integrates procedure, personnel, systems, and materials to verify that the pharmaceutical grade utility, environment, equipment, or support system produces the required output
Production is done under conditions that simulate those planned to be used during actual manufacturing

37. Change Control Policy and procedure Risk assessment Authorization
Failure to properly document changes to the system means invalidation of the process

38. Changes that require revalidation
Change Control
Changes that require revalidation
Software changes; Controllers
Site changes; Operational changes
Change of source of material
Change in the process
Significant equipment change
Production area changes
Support system changes

39. Validation Types Process Validation Analytical Method Validation
Cleaning Validation
Water Systems Validation
Computerized System Validation

40. Process Validation
Means of ensuring, and providing documentary evidence that processes (within their specified design parameters) are capable of repeatedly and reliably producing a finished product of the required quality.
PV should be completed prior to commercial manufacturing
Where this is not possible, it may be necessary to validate processes during routine production

41. Approaches to Validation
Prospective Validation
Prospective validation is carried out during the development stage.
Includes division of the production process into separate steps
Analysis of potentially critical points in the manufacturing process e.g. mixing times, or temperature.
Trials are carried out in which these steps and critical points are simulated and the effect on the process is assessed.

42. Approaches to Validation
Prospective Validation
Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical factors/parameters that may affect the quality of the finished product.
Representatives from Production, QC/QA, Engineering, and in some cases Research and Development (if available) will normally be involved in this process.
May incorporate a challenge element to determine the robustness of the process.
Such a challenge is generally referred to as a "worst case" exercise.
Pharm.(Mrs) Edosa Ogbeide

43. Approaches to Validation
Concurrent Validation
Carried out during normal production.
Requires full understanding of the process based on prospective work.
Involves very close and intensified monitoring of the steps and critical points in at least the first three production-scale batches

44. Approaches to Validation
Documentation requirements are the same as specified for Prospective Validation and the testing to be carried out in-process and on the finished product will be as specified in approved protocols.
The completed protocols and reports should be reviewed and approved before product is released for sale or supply.
Concurrent Validation
In certain circumstances it may not be possible to complete a validation programme before routine production starts. In these cases it will be known in advance that the finished product will be for sale or supply.
It is important however, that the premises and equipment to be used have been qualified previously and that the decision to carry out Concurrent Validation is made by appropriately authorised people.
Pharm.(Mrs) Edosa Ogbeide

45. Approaches to Validation
Retrospective Validation
The analysis of accumulated results from past production to assess the consistency of a process.
Includes trend analysis on test results and a close examination of all recorded process deviations.
It is important to analyze 10 to 25 batches manufactured over a period of 12 months to provide a statistically significant picture.
It is not the preferred method of validation and should be used in exceptional cases only and never for sterile products

46. Approaches to Validation
Retrospective Validation
There are many processes in routine use in many companies that have not undergone a formally documented validation process.
Validation of these processes is possible, using historical data to provide the necessary documentary evidence that the process is doing what it is believed to do.
Data
This type of validation exercise is only acceptable for well established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment.
The steps involved in this type of validation still require the preparation of a protocol, the reporting of the results of the data review, leading to a conclusion and recommendation.
Pharm.(Mrs) Edosa Ogbeide

47. REQUIREMENTS FOR PROCESS VALIDATION
Pre-approved validation protocol
Analytical methods must be fit for the purpose
Materials (APIs and Excipients) must meet Raw Material specifications
Standard Operating Procedures followed
Calibration and maintenance schedule developed
Operatives taking part in the validation work should have been appropriately trained
Fully qualify all equipment, the production environment and analytical testing methods 1 2 3 4 5 6 7
REQUIREMENTS FOR PROCESS VALIDATION
Pharm.(Mrs) Edosa Ogbeide

48. The Lifecycle concept of Process Validation
Stage 1: Process Design
Define Process Knowledge Space
Identify Critical Process Parameters
Determine Control Strategy
Stage 2: Process Qualification
Equipment/Utility/Facility Qualification
Process Performance Qualification
Stage 3: Process Maintenance
Monitoring of Critical Process Parameters
Process Validation Lifecycle
Pharm.(Mrs) Edosa Ogbeide

49. The Lifecycle concept of Process Validation
The Lifecycle concept links product and process design, qualification of the commercial manufacturing process and maintenance of the process in a state of control during routine production
A science- and risk-based approach to verify and demonstrate that a process operating within predefined specified parameters consistently produces material that meets all its critical quality attributes.

50. Validation Maintenance2 3
Change Management Program
Periodic re-qualification 1
Periodic Validation Review
Pharm.(Mrs) Edosa Ogbeide

51. Validation Maintenance
Change Management is the primary mechanism by which validation is maintained
Effective change control system must be in place to control changes to validated systems
Changes should be formally documented and approved before implementation and records maintained
Commitment of the company to control is essential to ensure a continued validation status of the systems concerned.

52. Validation Maintenance
Revalidation
change in operating parameters
component specifications have changed
new accessories or components are added to previously qualified equipment
process changes that potentially impact product effectiveness or quality

53. Decommissioning
Documented demonstration that at the time of removal from routine operational use, system was operating in compliance with specific requirements and fit for purpose
Should be planned
Requirements depends on system complexity
Outcome should be reported and provide conclusion

54. Continuous Process Verification
Introduced to cover an alternative approach to process validation based on a continuous monitoring of manufacturing performance
Based on the knowledge from product and process development studies and / or previous manufacturing experience.
Can be introduced at any time in the lifecycle of the product. It can be used for the initial commercial production, to re-validate commercialized products as part of process changes or to support continual improvement

55. Continuous Process Verification
Involves extensive in-line, on-line or at-line controls and monitoring process performance and product quality on each batch.
Relevant data on quality attributes of incoming materials or components, in-process material and finished products should be collected.
Verification of attributes, parameters and end points, and assessment of CQA and critical process parameter (CPP) trends
At-line: Measurement where the sample is removed, isolated from, and analysed in close proximity to the process stream
In-line: Measurement where the sample is analysed within the process stream and not removed from it.
On-line: Measurement where the sample is diverted from the manufacturing process and not returned to the process stream

56. Cleaning Validation
Establishing documented evidence that the equipment is consistently cleaned of product, microbial and cleaning agent residues to predetermined acceptable levels
Provides a high degree of assurance that the Cleaning procedure can effectively remove residues of a product and a cleaning agent from the manufacturing equipment, to a level that does not raise patient safety concerns

57. Cleaning Validation Basic Considerations
Cleaning mechanisms: Mech. action, dissolution, chem. reaction, detergency
Cleaning Procedure: SOPs, tools & materials
Cleaning method: CIP, COP, manual cleaning
Determination of contamination limits: TD, blanket spec.
Worst case selection
Clean Hold times
Sampling: swab, rinse, location, surface area, swab recovery, analytical method

58. Analytical Method Validation
ICH Q2 (R1)
Specificity
Linearity
Accuracy
Precision
Robustness
LOD
LOQ

59. Water Systems Validation
Conducted in 3 phases:
Phase 1: 2-4 weeks - intensive system monitoring, develop operating ranges, implement & refine SOPs
Phase 2: 2-4 weeks – deploy refined SOPs, demonstrate operation within established ranges, demonstrate production of required quality & quantity
Phase 3: 1 year – verify long-term control, demonstrate consistent production of required quality & quantity
Ongoing system monitoring

60. Computerized Systems Validation
Basic Considerations
System specification – hardware, software, user training
Functional specification – testing, operating & maintaining the system
Security – controls against unauthorized data manipulation, audit trail
Back-ups – secure data storage

61. Conclusion Validation is an essential component of GMP
Helps to achieve goal of is assuring product quality, safety and efficacy
Offers huge business benefits
Lifecycle approach covers entire systems and processes and must be structured, planned and documented
Validation maintenance is essential element of validation lifecycle

62. Benefits of Validation and Qualification
Facilities
Eqmt
Utilities
Processes
VALIDATION
****Note: Eqmt= equipment
Design
Maintenance
Qualification
Benefits
Pharm.(Mrs) Edosa Ogbeide

63. References NAFDAC cGMP for Medicinal Products Regulations 2009
WHO Supplementary Training Modules on GMP. WHO TRS No. 937, Annex 4
ICH Tripartite Guidelines: Validation of Analytical Procedures: Text and Methodology Q2(R1)
WHO TRS 986 Annex 2; Good manufacturing practices for pharmaceutical products: Main principles
NAFDAC Good manufacturing Practice for Pharmaceutical Products Guidelines 2016
Chukwumerije O. (2016). Presentation on Pharmaceutical Qualification & Validation
Ogbeide E. (2013). Presentation on Equipment Qualification & Process Validation

64. THANK YOU

65. QUESTIONS?