protocol development and acceptance criteria

5/21/2018 Protocol Development and Acceptance Criteria

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Protocol Developmentand

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 processwill 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 processdesign stage throughout production, whichestablishes scientific evidence that a process iscapable 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 processremains in a state of control)


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The Life Cycle Approach to Process

ValidationPlanning &

Design (ICH Q8)

Implementation

& QualificationContinuous

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 ofcontrol.

Use CAPA, PAT and Change control aswell 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/MicrobialTesting

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 manufacturingand utility) perform correctly and are fit for the

intended use.

Finally demonstrate that the process as a wholeconsistently 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

ProtocolPreparation

Protocol

Execution

SummaryReport

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 serveas 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 manualsor substitute written procedures should manuals not be

available.


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Installation Qualification (cont.)

Defined preventive maintenance and calibrationschedules.

Completeness of the documentation of system

construction by review of the following: changecontrols, submittals, punch lists, weld logs,

pressure leak tests, cleaning and passivationrecords, start-up certification, instrumentinventory, calibration, loop check, manuals,drawings, specifications, purchase orders, etc.

Equipment has been installed and connectedcorrectly.


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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 isdesigned to demonstrate that the

performance of a system is reproducible.

An example would be to demonstrate that aUSP water system is capable of producingwater, which meets biological and chemicalstandards consistently.


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Methods Validation

Establishing through documented

evidence a high degree of assurance that

an analytical method will consistentlyyield 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 theperformance 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 wasordered.

2. Confirming equipment model and serialnumbers indicates the right equipment was

delivered.3. Weld certificate shows welds were tested.

4. Existence of SOP show equipment can beoperated, maintained and cleaned consistently

5. Passivation certificates ensure theequipment/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 accurateand 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. operationalSampling-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 CompendialRequirements

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 controlreproducible

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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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 thespecified acceptance criteria.


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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 theproduct 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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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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OVEN (PQ) Temperature distribution within the chamber reach the minimum

design temperature and does not vary by more than 5 F from therequired temperature for the required period of time. (vendorspecs/design)

The oven is capable of reaching the required temperature (ramp-up)within the time specified in the design documents or specified by theequipment vendor. (vendor spec/design)

The oven can cool down (ramp-down) within the time specified in thedesign documents or specified by the equipment vendor. (vendor

spec/design) Repeat testing with all tests meeting the specified acceptance criteriafor 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 profilearound each door between the spaces.When performing the smoke test, verify

that all other doors adjacent to thespaces 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-LockCorridor

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 technicalaspect prepare the protocol

People reviewing and commenting shouldbe the people approving the protocol

Minimize the number of people who shouldreview 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 bystep 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.

protocol development and acceptance criteria

Documents

process iscapable

pq protocol protocol

processdesign stage

life cycle approach

change control aswell

risk building quality

specific processwill

highdegree of assurance