Process Validation of Sterile Liquid Products_23aug06

1Process Validation of

Sterile Liquid Products

By

Weerayut Chirarutsami

23/08/2006

2Process Validation

Process validation is establishing documented evidence which demonstrate that the manufacturing process will consistently produce a product meeting its pre-determined specifications and quality Characteristics.

New Product Trial Batch, Development Batch

Transferred Product Products produced at the sending site

Revalidation Product The original product before revalidation

3Process Validation

Type of Process Validation Prospective Conducted prior to market the product

Concurrent Based on information generated during actual

implementation of the process (each batch will be released separately)

Retrospective (Not recommended for sterile product) Based on accumulated historical production, testing and

control data Generally requires data from 10-30 batches Use data only from batches made by the same process

4Validation of Sterile Product

Sterile Product :The Products which free of any viable organisms.

Sterility :Viable microorganisms are absent.

Bioburden :Total number of viable microorganisms on or in pharmaceutical product prior to sterilization.


Terminal Sterilization :Operation whereby the product is sterilized separately by autoclave after filled and packaged using sterilized containers and closures in critical processing zones.Aseptic Operation:Operation whereby the product is sterilized separately by filtering through 0.2 or less filter, then filled and packaged using sterilized containers and closures in critical processing zones.


Validation Team: Production, QC, QA, Engineer,Planner# To prepare the validation protocol

# Verify the calibration and maintenance status of equipment

# Perform qualification for equipments and system

# Verify change control

# Schedule the validation activities

# Training production operators

# Conduct validation study

# Monitor the critical steps in manufacturing process

# Assure that the approved testing standard is being used

# Evaluate all test results,

# Prepare the validation report.

7Pre-validation Requirements : Preventive Maintenance for Facilities and Utilities Calibration of Equipment Cleaning Validation Equipment & System Qualification Raw Materials/Components/Test Methods Process Justification Change Control Training operators

All must be proven suitable and reliable for the manufacturing process before the process can be validated

Validation of Sterile Product


Process Justification: To identify critical process steps & process parameter of Mixing

process

To determine the suitable Hold time Period

To confirm the analytical tests that will have to be performed

To define the optimal parameters throughout the overall ampoule filling process to consistently produce the finished products(filled ampoules) which meet the established specifications.

To assure that the product is sterile after sterilization process


Validation Protocol

A document stating how validation will be conducted,including test parameters, product characteristics, production equipment to be used and decision points on what constitutes acceptable test results

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Validation Protocol should contain : Title Page, Review/Approval Page

Purpose and Overview

Equipment List

Ingredients and Component List

Qualification List of Equipment and System

Process Flow Diagram and Description

Equipment Critical Process Parameter

Process Validation Sampling Plan/Testing Requirements

Acceptance Criteria

Stability Requirements

Process for evaluation of any deviations occurring during validation

Conclusion


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Equipment Critical Process Parameter: Mixing Speed Mixing Time Gas flushing time Type and size of filter Filtering Time and Pressure used Filling Speed Temperature and Duration for Terminal Sterilization

Critical Manufacturing Step Dissolving Step pH adjustment step Final mixing step Filtering Step Filling Step Terminal Sterilization Step Leak Test Step


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Critical Processing Parameter

Mixing Speed

Mixing Time

Flushing Time

pH


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Critical Processing Steps


Dissolved Active Ingredient

pH Adjustment

Final Mixing

Filtration

Filling

Sterilization

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Acceptance Criteria

Dissolved Active Ingredient

pH Adjustment

Final Mixing

Filtration

Clear Solution

Filter Integrity, Sterility, pH, Holdtime

pH with in specification

pH, Appearance, Assay Content,Bioburden, Holdtime


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Acceptance Criteria

Filling

Sterilization

Leak Test

Visual Inspection

Appearance, Bioburden, Holdtime, Oxygen Headspace

No. of Defected products

Sterility, Assay, pH, Endotoxin etc.

No. of Leaked products


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Product Testing Validation testing of bulk and F/G must be based on

testing standard release criteria and in-process testing criteria

Typically involves non-routine sampling/testing throughout the entire process, with special emphasis on critical process parameters.

Routine QC release testing should be performed on a routine sample. These samples should be taken separately from the validation samples.


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Validation Batch: New product and product transfer, Prospective validation is required

Manufacturing Process, Formula, Equipment and Batch Size have to be fixed during the validation trials.

Batch Size should be the same size as commercial production batch

The batch size must be fixed for production.

Different lots but same manufacturer of active ingredients should be used during validation trials.


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Validation Batch: Bulk Sampling and Testing Samples may be taken by

Collecting during Transfer

Using a sampling device

Take at least 2 samples at top, middle and bottom

Individual Testing of sample must be done and the result must meet the testing standard specification


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Qualification of Maximum Bulk Hold Time The maximum period of time which the bulk can be held prior to

filter, Fill and/or Sterilization It will be counted after finished final mixing step until transfer to

filter, finished filter until start filling and/or finished filling until start sterilization

One full scale batch should be held for most practical maximum time period prior to filter, fill and/or sterilization

If there is not enough support information / qualification done. The period of 24 hours will be used

Hold time qualification must simulate actual storage condition


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Finish Product Testing after SterilizationUniformity of filled volume

Perform testing on filled containers.Sterility

10 samples from each of the beginning and end of the filling run. Samples must represent all filling nozzles.

Visual Evaluation Appearance, Color of solution

Other Testing Assay, pH, Density, Pyrogen or Endotoxin etc.

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Validation Report Validation Team must prepare the report

Report must be reviewed and approved by QA.

Written Notification or either successful completion or failure of the process validation must be issued to top management.

In case of failure, an investigation must be completed and documented

prior to repeat the validation study.

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Changes and Revalidation Change of any of the following may need revalidation Formula Composition

Raw Material Source

Manufacturing Process

Manufacturing Location

Equipments

Batch Size

Testing Specification


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Changes

Minor: It seems to have no impact on formulation It is not necessary to validate

Intermediate : It could have significant impact on formulation Depend on case-by-case (A minimum of 1 trial)

Major : It is likely to have significant impact on formulation Revalidation is required (A minimum of 3 trials)


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Minor Change

Qualitative inactive excipient change deemed minor by change control review

Process change deemed minor by change control review

Manufacturing location change with in same building, same equipment, personnel, procedure and utilities are used

Equipment change but same design, configuration


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Intermediate Change Active ingredient source or synthesis change deemed

intermediate by change control review

Qualitative inactive excipient change deemed intermediate by change control review

Manufacturing location change to a different building on the same site and same utilities, same equipment, personnel, and procedure are used


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Intermediate Change Process changes, such as mixing times or operating speeds

for solutions.

Change in release specification to a tighter limit caused original validation results to be out of specification

Extension of the qualified in process hold time for intermediateor finished product prior to packaging

Equipment change deemed intermediate by change control review


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Major Changes Quantitative or qualitative formulation change deemed major by

change control review

Inactive excipient or active ingredient source change deemed major by change control review

Transfer product from on site to another

Significant change in process

Equipment change to a different design, configuration or operating principle.


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Major Changes New Dosage

Rework Procedure

Process changes deemed major by change control review such as mixing times or operating speeds for suspensions.

Change in release specification to a tighter limit caused original validation results and routine production results to be out of specification


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Conclusion Validation Protocol identifies critical process parameters to be

evaluated and predetermined acceptance criteria

Process must be continually monitored and change control used toidentify need for process revalidation

Production and QA have to review and approve the validation result

Product must be held until the validation get approval


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Re-validation

Regular performance of process simulation studies Monitoring of environment, disinfection procedures,

equipment cleaning and sterilisation (including containers and closures)

Routine maintenance and re-qualification of equipment, e.g. autoclaves, ovens, HVAC (heating, ventilation and air conditioning) systems, water systems, etc.

Regular integrity testing of product filters, containers, closures and vent filters

Re-validation after changes

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Process simulation studies (media fills)

Process simulation studies (media fills) are simulating the whole process in order to evaluate the sterility confidence of the process. Process simulation studies include formulation (compounding), filtration and filling with suitable media. Simulations are made to ensure that the regular process for commercial batches repeatedly and reliably produces the finished product of the required quality. However, each process simulation trial is unique and so it is not possible to extrapolate these results directly to actual production contamination rates.

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Where filling takes place over extended periods, i.e. longer than 24 hours, the process simulation test should extend over the whole of the standard filling period. In order to prevent excessively high numbers of units being filled it is usually acceptable to just run the machine for a reasonable time, if the validity of the simulation is not diminished by this procedure.The fill volume of the containers should be sufficient to

enable contact of all the container-closure seal surfaces when the container is inverted and also sufficient to allow the detection of microbial growth.

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Where filling takes place over extended periods, i.e. longer than 24 hours, the process simulation test should extend over the whole of the standard filling period. In order to prevent excessively high numbers of units being filled it is usually acceptable to just run the machine for a reasonable time, if the validity of the simulation is not diminished by this procedure.The fill volume of the containers should be sufficient to

enable contact of all the container-closure seal surfaces when the container is inverted and also sufficient to allow the detection of microbial growth.

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Incubation Temperature It is generally accepted to incubate at 20-25C for a

minimum of 14 days without having collected data to support this incubation schedule. It is similarly acceptable for firms who prefer a two

temperature incubation schedule to incubate at 20-25C for a minimum of 7 days followed immediately by incubation at a higher temperature range not to exceed 35C for a total minimum incubation time of 14 days.

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Process simulation studies (media fills)Acceptance Criteria Ideally the contamination rate should be zero. However currently the

accepted contamination rate should be less than 0.1 % with a 95 % confidence level according to the Annex I to the EU/PIC/S Guide to GMP.

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FILL MUST MEET THE ACCEPTANCE LIMITS FROM THE FOLLOWING TABLE:MAXIMUM ACCEPTABLECONTAMINATED UNITS NUMBER OF GOODOBSERVED IN THE LOT VIALS INCUBATED

0 30001 47502 63003 77604 91605 105206 118507 131508 144409 1571010 1697011 1821012 19440

Acceptance Criteria

Documents

Process Validation of Sterile Liquid Products_23aug06