Radiopharmaceutical Production

Process Validation

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 Process Validation
• Process validation is one of the Contents
most important aspects of the GMP
• Validation in General
process. It is impossible to carry
out sterility testing and perhaps • Why do we validate the
some other quality control testing Process?
on radiopharmaceuticals which • The Scope of Process
have short half-lives. Validation
• The best way to predict a safe and
• Validation Protocol
effective product is to document a
history of successful production • Process Validation Example
using a set of standard operating • The Validation Report
procedures (SOPs) and to always
• Literature
use exactly those same procedures
to produce the radiopharmaceutical.

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 Validation in General
The process of validation starts with the construction (or renovation)
Radiopharmaceutical of the facility to be in compliance with GMP guidelines. These
Production processes should be outlined in a Validation Master Plan (VMP).
The VMP should include:
Process Validation • Water (generation, receipt, and distribution)
• Heating, ventilation, and air conditioning (HVAC)
Contents • Terminal sterilization of product (either by autoclave or filter
Validation in General sterilization)
Why do we validate the • Compressed air (generation and distribution)
Process? • Premises (to be sure they meet all GMP practices – see the
The Scope of Process
section on Facilities)
• QC laboratories (analytical and microbiological)
Validation
• Production and control operations involved in the manufacture of
Validation Protocol
radiopharmaceuticals.
Process Validation
Example Validation continues with validation plans for individual processes and
The Validation Report equipment. These include:
Literature • 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.
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• A summary table is given on the next page
 Validation in General
Summary Table for Validation
Radiopharmaceutical
Production Elements Installation Operation Stage
Qualification Qualification
Process Validation Develop a Project Design
Validation
Contents Master Plan
Validation in General
Premises Engineering and Operational Construction
Why do we validate the Construction Readiness Review
Process?
Equipment Choose and install Perform validation Start-up
The Scope of Process
equipment protocols
Validation
Validation Write validation Perform the Operation
Validation Protocol
Plan protocols protocols
Process Validation
Example Analytical Write SOPs for Test product and Operation
The Validation Report
Methods GMP required tests refine analytical
methods
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Process Test and Develop Optimize Operation
SOPs parameters
Analytical Revise SOPs for Refine analytical Revalidation
Methods GMP required tests methods
Process Revise SOPs Refine operational Revalidation
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 Why do we validate the Process?
Radiopharmaceutical
Production
• 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
Process Validation
intend to produce. This can be referred to as pharmaceutical
Contents equivalence
Validation in General • Pharmaceutical equivalence – For PET products
Why do we validate the Pharmaceutical equivalence implies the same amount of the
Process? same active substance(s) and meeting the same or comparable
The Scope of Process standards (ie strength, quality, purity and identity) every time the
Validation product is produced.
Validation Protocol
• Since we are taking only a sample of the batch, we must ensure
Process Validation
that the sample is representative of the entire batch.
Example
The Validation Report
Literature The whole batch is released
for patient use
BATCH
But only the sample is tested
Sample
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 The Scope of Process Validation
Radiopharmaceutical • Process validation requires the identification of critical
Production elements of the production process. It also includes
qualification of supporting systems such as water
production, air supply systems and equipment
Process Validation qualification.

Contents
Qualification and validation:
Validation in General
• Validation is applicable to any aspect of operation which
Why do we validate the may affect the quality of the product - Directly or
Process? indirectly. Qualification is a part of validation usually
The Scope of Process
applied to equipment and premises. Since validation is
applicable to all aspects of operation which may affect
Validation
the quality of the product, it includes premises
Validation Protocol (environment conditions, space, contamination levels),
Process Validation supporting utilities (e.g. water), processing equipment
Example
performance and the actual process.
The Validation Report
• Any significant change (e.g. adaptation of equipment or
systems, major repairs etc) may require re-qualification
Literature
or re-validation.

Of critical importance, with particular attention, is the

validation of:
• Analytical test methods
• Automated systems and
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• Cleaning procedures
 The Scope of Process Validation
Process validation is a Once any problems have been corrected, a
stepwise path that leads new protocol is written and approved
to a product that is safe
and effective. It starts Revise Adjust Determine If there are
with validation of Protocol Process Causes
problems,
equipment and premises these must
be
Non-conforming investigated
Validation and Results and resolved
Qualification of And the process
Premises, Equipment
begins again A validation
And Utilities
Prepared package is
Approved Process Validation
Protocol Validation Package
prepared
containing all
Pre-Validation
Review the results of
A protocol is generated and Start the validation.
and a pre-validation approved and the validation Production
review process begins If there are no
problems, production
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 The Validation Protocol
Radiopharmaceutical • A validation protocol is a detailed document relating to a specific
Production 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
Process Validation validation.
• The protocol should clearly describe the procedure to be
Contents followed for performing validation. It should include at least the
Validation in General objectives of the validation and qualification study, the site of
Why do we validate the
the study, the responsible personnel, a description of the
equipment to be used (including calibration before and after
Process?
validation), SOPs to be followed (e.g. the operation and
The Scope of Process cleaning of the equipment) and the standards and criteria for
Validation the relevant products and processes.
Validation Protocol • The type of validation and time/frequency should also be
Process Validation
stipulated. The processes and/or parameters to be validated
should be clearly identified.
Example
The Validation Report
The Questions to be answered include:
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• 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
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judged?
 Validation Example – Aseptic
Radiopharmaceutical
Production
Processing
Process Validation • Media Fill test
Contents
– simulation of the process replacing reagents and solvents
by growth media
Validation in General
– gives the support for eventual bacteria
Why do we validate the
– tests the process without inhibiting bacteria growth by
Process?
reagents
The Scope of Process
– every operator, at least 3 times
Validation
• BioBurden test
Validation Protocol
– real test production without sterile filtration at the end
Process Validation
– gives the idea of how aseptic is the process
Example
• test for sterility
The Validation Report
• detect type of bacteria present
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• count the microbial contamination

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 The Validation Report
Radiopharmaceutical
Production
Part 1
Process Validation • A qualification or validation report should reflect the elements of
the protocol, and should contain elements such as:
Contents
• - Title
Validation in General
• - Objective of the study
Why do we validate the
• - Reference to the protocol
Process?
• - Details of materials, equipment, instruments, personnel
The Scope of Process
• - Program and cycles used
Validation
• - Details of procedure and test methods
Validation Protocol
• ... etc.
Process Validation
• The results obtained during the performance of the validation,
Example
must be recorded.
The Validation Report
Literature

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 The Validation Report
Radiopharmaceutical
Production
Part 2
• The validation report reflects the final test results and other
Process Validation
documents such as instrument calibration certificates. It is on
the basis of this report that the decision is taken on whether a
Contents
particular process is judged to be validated. All results should
meet the criteria of acceptance and satisfy the stated objective.
Validation in General
If necessary, further studies should be performed. If the results
Why do we validate the are found to be acceptable, the report should been approved
Process? and authorized (signed and dated).
The Scope of Process • The report should include the title and objective of the study,
Validation
and refer to the protocol, details of material, equipment,
programs and cycles used, together with details of procedures
Validation Protocol
and test methods. It should provide a comparison of the results
Process Validation with the acceptance criteria.
Example • In addition, it should include recommendations on the limits and
The Validation Report criteria to be applied to all future production batches. It is
Literature
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.

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 Literature
Radiopharmaceutical
Production
• Literature on Validation Master plans and the Validation Process
can be found in the references to GMP
Process Validation
More Validation Master Plan
Contents
Validation in General
Why do we validate the More PICS Validation Master Plan
Process?
The Scope of Process
• The major references and some presentations on GMP are
Validation available by following the MORE arrow.
Validation Protocol
Process Validation
Example
The Validation Report More GMP Regulations
Literature

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