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1
Protocol Development
and
Acceptance Criteria
By: Gamal Amer, Ph.D.
Principal, Premier Compliance services, Inc.
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VALIDATION
Establishing documented evidence
which provides a high degree of
assurance that a specific process will
consistently produce product
meeting its predetermined
specifications and quality attributes
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Process Validation
Process validation is establishing
documented evidence which provides a high
degree of assurance that a specific process
will consistently produce a product meeting
its pre-determined specifications and quality
characteristics.
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Process Validation: General
Principles and Practices
Guidance to industry issued by the FDA in draft
form in November 2008.
Outlines the life cycle approach to validation.
Inline with the principles advanced in ICH Q8,
ICH Q9, ICH Q10 and in ASTM E2500.
Defines PROCESS VALIDATION as the
collection and evaluation of data, from the process
design stage throughout production, which
establishes scientific evidence that a process is
capable of consistently delivering quality
products.
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FDA Proposed Guidance
November 2008
Three Stages of Process Validation
Process Design Stage (process is defined based on
development and scale-up)
Process Qualification Stage (Design is confirmed
as being capable of reproducible production)
Continued Verification and improvement
(Continuously gaining assurance the process
remains in a state of control)
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The Life Cycle Approach to Process
Validation
Planning &
Design (ICH Q8)
Implementation
& Qualification
Continuous
Verification &
Improvement
ICH Q9
ICH Q9, CAPA, PAT &
Change Control
PAT
ICH Q10
The Quality System
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Stage 1: Process Design
Understanding the science
Understanding the risk
Building Quality into the process
Establishing Control Strategy
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Stage 2: Implementation and Process
Qualification
Implement the process and Facility
Qualification of utilities and equipment
Performance qualification and PQ protocol
Protocol execution and report
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Stage 3: Continued Process
Verification
Monitoring appropriate parameters to
ensure process in a validated state of
control.
Use CAPA, PAT and Change control as
well as data collected in monitoring to
continually improve the process.
Proper maintenance of the facility, utilities,
and process equipment
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What does Process Validation Cover?
Equipment
Manufacturing
Process
Facility & Utilities
Raw Materials
Analytical/Microbial
Testing
Analytical methods
Packaging
Design/Bench work
Stability
Product Trending
Training
Cleaning
Controls
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Types of Specifications
Product
Actives
Composition
Batch size
Preservatives
Microbial effects
Raw materials
Density
Description
pH
Operating
Mixer Speed
Temperature
Mixing Times
Tensile strength
Dimensions
Capacity
Fill level
Torque
Labels
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What you need to do?
Demonstrate all equipment are installed properly.
Demonstrate equipment operate properly.
Demonstrate that systems (both manufacturing
and utility) perform correctly and are fit for the
intended use.
Finally demonstrate that the process as a whole
consistently produces product meeting
predetermined quality targets or attributes.
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Current Industry Standard
Installation Qualification (IQ)
Operation Qualification (OQ)
Performance Qualification (PQ)
Methods Validation
Process Validation (PV)
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Validation Approach
Design
Review
Protocol
Preparation
Protocol
Execution
Summary
Report
Preparation
Validation
Record
VMP
IQ, OQ, PQ
Validation
Reports
Executed
IQ,OQ, PQ
Engineering Drawings
Specifications
Manuals, P& ID,
SOPs
Weld Logs, Certifications,
Analytical and Integrity
Tests
Product Data
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The Need for Validation Protocols
Regulatory requirement.
Provide step by step instructions to perform
the validation.
Provide the repository for the data to be
collected.
Keeps it all together.
Provides documented evidence that the
work has been done.
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Protocol Preparation
Protocols provide the detailed procedure on
how to conduct the qualification and serve
as the repository for all data collected
during the execution.
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Protocol Preparation (Cont.)
Normally the protocol will have the following sections:
Purpose
Scope
Responsibilities
System description
References
Procedures
Certification records
Attachments
Approvals
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Types of Protocols
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Installation Qualification
Fabrication or construction meeting user's specifications,
applicable codes and CGMP requirements.
Existence of correct "as-built" drawings for equipment,
piping, and critical utilities.
Availability and qualification of utilities at points of use.
Presence of operation, maintenance and cleaning manuals
or substitute written procedures should manuals not be
available.
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Installation Qualification (cont.)
Defined preventive maintenance and calibration
schedules.
Completeness of the documentation of system
construction by review of the following: change
controls, submittals, punch lists, weld logs,
pressure leak tests, cleaning and passivation
records, start-up certification, instrument
inventory, calibration, loop check, manuals,
drawings, specifications, purchase orders, etc.
Equipment has been installed and connected
correctly.
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Operation Qualification
The OQ is normally designed to
confirm that the system or equipment
operates within predetermined and
approved acceptance criteria (specified
by vendor).
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Performance Qualification
The Performance Qualification Protocol is
designed to demonstrate that the
performance of a system is reproducible.
An example would be to demonstrate that a
USP water system is capable of producing
water, which meets biological and chemical
standards consistently.
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Methods Validation
Establishing through documented
evidence a high degree of assurance that
an analytical method will consistently
yield results that accurately reflect the
quality characteristics of the material
tested.
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Process Validation
The Process Validation (PV) documents
will verify that:
Process performance such as the ability of a certain
processing sequence to consistently produce a product
within predetermined and approved acceptance criteria.
This confirmation takes into account the facilitys
operation, the procedural aspects of production and the
performance of the equipment and sub-systems.
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Additional Types
Cleaning validation
Software Validation
Computer Qualification (CQ)
Transportation Validation
Others specific to your company
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Importance of IQ Confirmation
1. PO, shows that the correct equipment was
ordered.
2. Confirming equipment model and serial
numbers indicates the right equipment was
delivered.
3. Weld certificate shows welds were tested.
4. Existence of SOP show equipment can be
operated, maintained and cleaned consistently
5. Passivation certificates ensure the
equipment/pipes have been properly
passivated.
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Importance of Instrument
Calibration
In process instruments used to measure
and indicate processing variables
Instruments are part of the control loop
Instruments are the basis for operator
interference
Instrument readings should be accurate
and representative of the variable
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Importance of Methods
Validation
Only required for non-compendial methods
Ensures that the analytical methods used are
reflective of the actual quality attributes of the
material being analyzed
Ensure accurate measurement of quality
attributes during the validation
Used for operator intervention if necessary
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Acceptance Criteria
Issues to consider:
Types of Acceptance criteria-Product
specifications vs. operational
Sampling-What, where, and how (equipment
sample ports, end product, incoming, etc.)
destructive and non-destructive
Defending your acceptance criteria-How?
Fit for Intended Use as the end result
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Defining Acceptance Criteria
How to Define Acceptance Criteria
Manufacturer/Vendor Specifications
Engineering Design Specifications
Specific Requirements of System (e.g Homogeneity in mixing)
Regulatory Application Requirements (NDA)
GMP and/or other Regulatory or Compendial
Requirements
Product/Intermediate Characteristics Requirements
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Types of Acceptance Criteria
Within specification range
Demonstrate equipment is working properly
Demonstrate process produces consistent
product
Statistically in control reproducible
process
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Acceptance Criteria for HVAC
Maintain temperature at 72 F 5 (design).
Maintain Relative Humidity at 50% 15% (design).
Provide 12 (or 20) air changes per hour (design standard).
Maintain a positive air pressure in the room with respect to
the hallway (GMP-prevent cross contamination).
Maintain class 100,000 (GMP requirement, Compendial
requirement).
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Acceptance Criteria for
Deionized Water System
Maintain Flow Rate at 7 GMP within the loop. (design).
Confirm water resistivity at use point is 10 million ohms.
(design/Compendial).
Maintain minimum requirements of USP for water quality
(Compendial).
Repeated testing over 7 days with all tests meeting the
specified acceptance criteria.
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Acceptance Criteria for
Nitrogen Gas Distribution System
Maintain pressure and flow rate at specified criteria at all
use points. (design).
Ensure gas quality at use point meets NF criteria
(Compendial).
99 % Nitrogen
Not More Than 1 %Oxygen
Not More Than 0.001 % Carbon Monoxide .
Repeated testing over 7 days with all tests meeting the
specified acceptance criteria.
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Acceptance Criteria for
Equipment Cleaning (PV?)
The cleaning procedure used for the processing equipment
will consistently clean the product contact surface so that
they will meet the following criteria:
The surfaces will have less than 1/1000 of the daily dosage of the
product being cleaned, left on it. (Industry Standard).
The surface will meet product microbial limits established for the
product to be produced next. (Regulatory applications)
Repeated testing on separate days during normal operation until a
minimum of three consecutive tests meet the requirements.
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Acceptance Criteria for
Isolator
Vacuum/pressure is maintained within the box in
accordance to design requirements. (design)
No detectable leaking into or out of isolator should occur.
(safety/design)
No leaking of material through the gloves should be noted.
(safety/design)
Repeat testing over a period of three days of operation with
all tests meeting the specified acceptance criteria.
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Acceptance Criteria for
OVEN (PQ)
Temperature distribution within the chamber reach the minimum
design temperature and does not vary by more than 5 F from the
required temperature for the required period of time. (vendor
specs/design)
The oven is capable of reaching the required temperature (ramp-up)
within the time specified in the design documents or specified by the
equipment vendor. (vendor spec/design)
The oven can cool down (ramp-down) within the time specified in the
design documents or specified by the equipment vendor. (vendor
spec/design)
Repeat testing with all tests meeting the specified acceptance criteria
for three consecutive runs.
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Responsibilities
Who will prepare the protocol?
Who will review the protocol?
Who will execute the protocol?
Who will review the data collected?
Who will prepare the final report?
Who will review and approve the executed
protocol?
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Example Procedure and Acceptance
Criteria
Verify the directional airflow between
the production rooms and adjacent
areas by performing a smoke profile
around each door between the spaces.
When performing the smoke test, verify
that all other doors adjacent to the
spaces are closed.
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Example Data Sheet Attachment
Expected Airflow
Direction
Actual Airflow Direction Pass (P)
/Fail (F)
Verified
By / Date
Room 101 Air-Lock
Corridor
Room 102 Air-Lock
Corridor
Room 101 Air-Lock
Room 101
Room 102 Air-Lock
Room 102
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Preparing an Effective Protocol
Make certain you have the correct criteria identified
Avoid un-necessary restriction
Develop the right experiments and identify the step by step
procedure to conduct
Develop the appropriate tables to collect the information
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Getting the Protocol Approved
Have people familiar with the technical
aspect prepare the protocol
People reviewing and commenting should
be the people approving the protocol
Minimize the number of people who should
review and approve. (IQ & OQ: Validation,
Engineering & QA; PQ: Validation,
Operation, & QA)
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In Summary
Protocols should by simple and easy to follow
All tests should be fully described with step by
step procedure outlined
Protocols should have appropriate space pre-
prepared to enter data and comments
Carefully select the acceptance criteria, do not
invent them or unduly restrict yourself
Carefully involve the right people in preparation,
execution and approval.

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