QUALIFICATION-VALIDATION-_-Khadijah-Ade-Abolade.ppt

FDA and GAMP approaches for qualification and validation

1. Qualification And Validation In
Pharmaceutical Manufacturing
KHADIJAH ADE-ABOLADEMPH. 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

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
Financial losses
Death Bad Publicity

11. •What to
Qualify/Validate
equipment
Systems

12. 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.
Responsibility
12Pharm.(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
Pharm.(Mrs) Edosa Ogbeide 13
Validation Review
Structured
Documented
Lifecycle
Approach
Validation encompasses the entire life of the system from the
initial requirements definition through to maintenance and
eventual decommissioning of the system

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

21. QUALIFICATIONDQ IQOQPQ
Certification
GMP Process
under control
Review
periodically
Training
Calibration
Change
control

22. Pharm.(Mrs) Edosa Ogbeide 22

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
•Assessingyourneeds
•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 setthe ”worst
conditions”

33. Operational Qualification
Worst Conditions
•For example, if an equipment is to be operated
within the limits of:
–Temperature: 20 and 35
o
C
–Pressure: 0.9 and 1.2 atm
•The worst cases are when it operates at
–20
o
C and 0.9 atm
–35
o
C and 1.2 atm
–20
o
C 0.9 and 1.2 atm
–35
o
C 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
•Permitsaccepted 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
•Policyandprocedure
•Riskassessment
•Authorization
•Failuretoproperlydocumentchangesto
thesystemmeansinvalidationofthe
process

38. 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.
42Pharm.(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
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.
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.
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.
44Pharm.(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.
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.
Data
46Pharm.(Mrs) Edosa Ogbeide

47. 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
47
Pharm.(Mrs) EdosaOgbeide

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
•Identify Critical Process Parameters
•Process Performance Qualification
Stage 3: Process Maintenance
•Monitoring of Critical Process
Parameters
Process
Validati
on
Lifecycl
e
48
Pharm.(Mrs) EdosaOgbeide

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. V
A
L
I
D
A
T
I
O
N
Periodic Validation Review
2
3
Change Management Program
Periodic re-qualification
1
Pharm.(Mrs) EdosaOgbeide 50
M
A
I
N
T
E
N
A
N
C
E
Validation Maintenance

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

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. Eqmt
UtilitiesProcesses
Benefits of
Validation and
Qualification
Facilities
62
VALIDATION
****Note: Eqmt= equipment
Pharm.(Mrs) EdosaOgbeide

63. References
•NAFDAC cGMP for Medicinal Products Regulations 2009
•WHO Supplementary Training Modules on GMP. WHO TRS No.
937, 2006. 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?