Radiopharmaceutical Production
Process Validation
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Process Validation
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Process validation is one of the
most important aspects of the GMP
process. It is impossible to carry
out sterility testing and perhaps
some other quality control testing
on radiopharmaceuticals which
have short half-lives.
The best way to predict a safe and
effective product is to document a
history of successful production
using a set of standard operating
procedures (SOPs) and to always
use exactly those same procedures
to produce the radiopharmaceutical.
Contents
• Validation in General
• Why do we validate the
Process?
• The Scope of Process
Validation
• Validation Protocol
• Process Validation Example
• The Validation Report
• Literature
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Validation in General
Radiopharmaceutical
Production
Process Validation
Contents
Validation in General
Why do we validate the
Process?
The Scope of Process
Validation
Validation Protocol
The process of validation starts with the construction (or renovation)
of the facility to be in compliance with GMP guidelines. These
processes should be outlined in a Validation Master Plan (VMP).
The VMP should include:
• Water (generation, receipt, and distribution)
• Heating, ventilation, and air conditioning (HVAC)
• Terminal sterilization of product (either by autoclave or filter
sterilization)
• Compressed air (generation and distribution)
• Premises (to be sure they meet all GMP practices – see the
section on Facilities)
• QC laboratories (analytical and microbiological)
• Production and control operations involved in the manufacture of
radiopharmaceuticals.
Process Validation
Example
The Validation Report
Literature
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Validation continues with validation plans for individual processes and
equipment. These include:
• The development of validation SOPs
• The development of process SOPs
• Testing of the production process
• Development of analytical methods
• Validation of the process
• Revalidation of the process whenever there is a change in the
procedure or new or repaired equipment is used.
• A summary table is given on the next page
Validation in General
Radiopharmaceutical
Production
Process Validation
Contents
Validation in General
Elements
Develop a
Validation
Master Plan
Validation Protocol
Project Design
Engineering and
Construction
Operational
Readiness Review
Construction
Equipment
Choose and install
equipment
Perform validation
protocols
Start-up
Validation
Plan
Write validation
protocols
Perform the
protocols
Operation
Analytical
Methods
Write SOPs for
GMP required tests
Test product and
refine analytical
methods
Operation
Process
Test and Develop
SOPs
Optimize
parameters
Operation
Analytical
Methods
Revise SOPs for
GMP required tests
Refine analytical
methods
Revalidation
Process
Revise SOPs
Refine operational
parameters
Revalidation
The Scope of Process
Validation
Stage
Premises
Why do we validate the
Process?
Summary Table for Validation
Installation
Operation
Qualification
Qualification
Process Validation
Example
The Validation Report
Literature
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Why do we validate the Process?
Radiopharmaceutical
Production
•
Process Validation
Contents
Validation in General
•
Why do we validate the
Process?
The Scope of Process
Validation
Validation Protocol
Process Validation
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It is necessary to show that the product being delivered is safe
for human use and is identical in every way to the product we
intend to produce. This can be referred to as pharmaceutical
equivalence
Pharmaceutical equivalence – For PET products
Pharmaceutical equivalence implies the same amount of the
same active substance(s) and meeting the same or comparable
standards (ie strength, quality, purity and identity) every time the
product is produced.
Since we are taking only a sample of the batch, we must ensure
that the sample is representative of the entire batch.
Example
The Validation Report
The whole batch is released
for patient use
Literature
BATCH
But only the sample is tested
Sample
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The Scope of Process Validation
Radiopharmaceutical
Production
Process Validation
Contents
Validation in General
Why do we validate the
Process?
The Scope of Process
Validation
Validation Protocol
Process Validation
Example
The Validation Report
Literature
STOP
•
Process validation requires the identification of critical
elements of the production process. It also includes
qualification of supporting systems such as water
production, air supply systems and equipment
qualification.
Qualification and validation:
• Validation is applicable to any aspect of operation which
may affect the quality of the product - Directly or
indirectly. Qualification is a part of validation usually
applied to equipment and premises. Since validation is
applicable to all aspects of operation which may affect
the quality of the product, it includes premises
(environment conditions, space, contamination levels),
supporting utilities (e.g. water), processing equipment
performance and the actual process.
• Any significant change (e.g. adaptation of equipment or
systems, major repairs etc) may require re-qualification
or re-validation.
Of critical importance, with particular attention, is the
validation of:
• Analytical test methods
• Automated systems and
• Cleaning procedures
The Scope of Process Validation
Process validation is a
stepwise path that leads
to a product that is safe
and effective. It starts
with validation of
equipment and premises
Once any problems have been corrected, a
new protocol is written and approved
Revise
Protocol
Validation and
Qualification of
Premises, Equipment
And Utilities
Process
Validation
A protocol is generated and
and a pre-validation approved and the validation
process begins
review
STOP
Determine
Causes
If there are
problems,
these must
be
Non-conforming investigated
Results
and resolved
And the process
begins again
Approved
Protocol
Pre-Validation
Review
Adjust
Process
Prepared
Validation
Package
Start
Production
A validation
package is
prepared
containing all
the results of
the validation.
If there are no
problems, production
can begin
The Validation Protocol
Radiopharmaceutical
Production
Process Validation
•
•
Contents
Validation in General
Why do we validate the
Process?
The Scope of Process
Validation
Validation Protocol
Process Validation
Example
The Validation Report
Literature
STOP
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A validation protocol is a detailed document relating to a specific
part of the validation process. It outlines the tests that are to be
carried out, the acceptance criteria and the information that
must be recorded. It also defines the approval process for the
validation.
The protocol should clearly describe the procedure to be
followed for performing validation. It should include at least the
objectives of the validation and qualification study, the site of
the study, the responsible personnel, a 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.
The type of validation and time/frequency should also be
stipulated. The processes and/or parameters to be validated
should be clearly identified.
The Questions to be answered include:
• What will be validated?
• Who is responsible for the validation tasks?
• How will the equipment be qualified and the processes
validated?
• How will the validation be documented?
• What are the criteria by which a successful validation will be
judged?
Validation Example – Aseptic
Processing
Radiopharmaceutical
Production
Process Validation
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Contents
Validation in General
Why do we validate the
Process?
The Scope of Process
•
Validation
Validation Protocol
Process Validation
Example
The Validation Report
Literature
STOP
Media Fill test
– simulation of the process replacing reagents and solvents
by growth media
– gives the support for eventual bacteria
– tests the process without inhibiting bacteria growth by
reagents
– every operator, at least 3 times
BioBurden test
– real test production without sterile filtration at the end
– gives the idea of how aseptic is the process
• test for sterility
• detect type of bacteria present
• count the microbial contamination
The Validation Report
Part 1
Radiopharmaceutical
Production
Process Validation
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Contents
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Validation in General
Why do we validate the
Process?
The Scope of Process
Validation
Validation Protocol
Process Validation
Example
The Validation Report
Literature
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A qualification or validation report should reflect the elements of
the protocol, and should contain elements such as:
- Title
- Objective of the study
- Reference to the protocol
- Details of materials, equipment, instruments, personnel
- Program and cycles used
- Details of procedure and test methods
... etc.
The results obtained during the performance of the validation,
must be recorded.
The Validation Report
Part 2
Radiopharmaceutical
Production
•
Process Validation
Contents
Validation in General
Why do we validate the
Process?
The Scope of Process
•
Validation
Validation Protocol
Process Validation
•
Example
The Validation Report
Literature
STOP
The validation report reflects the final test results and other
documents such as instrument calibration certificates. It is on
the basis of this report that the decision is taken on whether a
particular process is judged to be validated. All results should
meet the criteria of acceptance and satisfy the stated objective.
If necessary, further studies should be performed. If the results
are found to be acceptable, the report should been approved
and authorized (signed and dated).
The report should include the title and objective of the study,
and refer to the protocol, details of material, equipment,
programs and cycles used, together with details of procedures
and test methods. It should provide a comparison of the results
with the acceptance criteria.
In addition, it should include recommendations on the limits and
criteria to be applied to all future production batches. It is
common practice in many companies for the protocol and the
report to 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. This reduces the amount of
paperwork that needs to be stored and makes an overall
assessment of the validation results easier to carry out.
Literature
Radiopharmaceutical
Production
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Literature on Validation Master plans and the Validation Process
can be found in the references to GMP
Process Validation
Contents
More
Validation Master Plan
More
PICS Validation Master Plan
Validation in General
Why do we validate the
Process?
The Scope of Process
Validation
•
The major references and some presentations on GMP are
available by following the MORE arrow.
Validation Protocol
Process Validation
Example
The Validation Report
Literature
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More
GMP Regulations
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