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Đề cương thẩm định quy trình sản xuất thuốc tiêm của FDA

Process Validation
of
Sterile Liquid Products
By
Weerayut Chirarutsami
23/08/2006

1


Process Validation

‰

Process validation is establishing documented evidence
which demonstrate that the manufacturing process will
consistently produce a product meeting its predetermined 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


2


Process Validation
Type of Process Validation
‰

Prospective
„

‰

Concurrent
„

‰

Conducted prior to market the product
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
3


Validation 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.

4


Validation of Sterile Product

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 µ or less filter, then filled and packaged using
sterilized containers and closures in critical processing zones.

5


Validation of Sterile Product
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.
6


Validation of Sterile Product
Pre-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

7


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

8


Validation of Sterile Product
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

9


Validation of Sterile Product
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

10


Validation of Sterile Product
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

11


Validation of Sterile Product
Critical Processing Parameter
•Mixing Speed
•Mixing Time
•Flushing Time
•pH

12


Validation of Sterile Product

Critical Processing Steps

Dissolved Active Ingredient
pH Adjustment
Final Mixing
Filtration
Filling
Sterilization
13


Validation of Sterile Product
Acceptance Criteria
Dissolved Active Ingredient
pH Adjustment

Clear Solution

pH with in specification

Final Mixing

pH, Appearance, Assay Content,
Bioburden, Holdtime

Filtration

Filter Integrity, Sterility, pH,
Holdtime
14


Validation of Sterile Product
Acceptance Criteria
Filling
Sterilization
Leak Test
Visual Inspection

Appearance, Bioburden,
Holdtime, Oxygen Headspace
Sterility, Assay, pH, Endotoxin etc.

No. of Leaked products

No. of Defected products

15


Validation of Sterile Product
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.

16


Validation of Sterile Product
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.

17


Validation of Sterile Product
Validation Batch: Bulk Sampling and Testing
Š

Samples may be taken by
Š

Collecting during Transfer

Š

Using a sampling device

Š

Take at least 2 samples at top, middle and bottom

Š

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

18


Validation of Sterile Product
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

19


Validation of Sterile Product

Finish Product Testing after Sterilization
‰

Uniformity of filled volume
„

‰

Sterility
„

‰

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

Visual Evaluation
„

‰

Perform testing on filled containers.

Appearance, Color of solution

Other Testing
„

Assay, pH, Density, Pyrogen or Endotoxin etc.

20


Validation of Sterile Product

„

Validation Report
¾

Validation Team must prepare the report

¾

Report must be reviewed and approved by QA.

¾

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

¾

In case of failure, an investigation must be completed and documented
prior to repeat the validation study.

21


Validation of Sterile Product

„

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
22


Validation of Sterile Product

„

Changes
‰

Minor: It seems to have no impact on formulation
„

‰

Intermediate : It could have significant impact on formulation
„

‰

It is not necessary to validate

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)

23


Validation of Sterile Product

„

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
24


Validation of Sterile Product

„

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

25


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