12.
Process validation
A process is a series of interrelated functions and activities using a variety of speci-
fied actions and equipment which is designed to produce a defined result. To vali-
date the reproducibility and consistency of a process, the full defined process is car-
ried out using validated equipment, under the established procedure usually at least
3 times The process must successfully and consistently meet all acceptance criteria
each time to be considered a validated process. In many cases, "worst case" condi-
tions are used for the validation to ensure that the process is acceptable in the ex-
treme case. Sometimes worst case conditions for systems can only really be tested
over time and hence must be evaluated using a rigorous long term monitoring
programme.
Examples of processes which must be validated in pharmaceutical manufacturing
are:
Cleaning
Sanitization
Fumigation
Depyrogenation
Sterilization
Sterile filling
Fermentation
Bulk production
Purification
Filling, capping, sealing
Lyophilization
Each of these categories may apply to several distinct processes in the manufactur-
ing facility. For instance, cleaning process can be the cleaning of glassware, the
cleaning of the facility (floors and walls), equipment cleaning such as Clean-in-Place
(CIP), or Clean-out-of-Place (COP), cleaning of garments, etc. Sterilization can be
the Sterilize-in-Place (SIP) process, glassware sterilization, filter sterilization, steam
sterilization, dry heat sterilization, etc.
Each process to be validated must be a specific process clearly described in a Master
Formula or in an SOP. All the equipment, the processing parameters, and the speci-
fications at each step must be detailed. Complete descriptions of the identity, code
numbers, construction, operating capacity, and actual operating ranges must be de-
fined for the equipment. The processing parameters for all steps must be sufficiently
detailed to permit complete reproducibility of the process each time it is performed:
time periods, pH, volumes, temperatures, measurements, specifications, acceptable
WHO/VSQ/97.02 57
ranges, etc. The controls and tests and their specifications must be defined. The
purity profiles for production processes must be defined for each step. To be consid-
ered validated, the process must consistently meet all specifications at all steps
throughout the procedure at least three times consecutively.
It is very important that the specifications for a process undergoing validation be
pre-determined. It is also important that for all critical processing parameters for
which specifications have been set, there must be equipment to measure all of those
parameters during the validation study.
Process Validation studies examine a process under normal operating conditions to
prove that the process is in control. Once the process has been validated, it is ex-
pected that it remains in control, provided no changes are made. In the event that
modifications to the process are made, or problems occur, or equipment or systems
involved in the process are changed, a re-validation of the process would be re-
quired. Very often validation studies require that more measurements are made
than are required for the routine process. The validation must prove the consistency
of the process and therefore must assess the efficiency and effectiveness of each step
to produce its intended outcome.
The following format outlines the requirements for a protocol for Process Valida-
tion. (In essence, this form is an SOP titled “How to Write a Process Validation
Protocol”)
58 Good manufacturing requirements -- Part 2: Validation
13. Format for a process
validation protocol
Name of Facility:_______________________________________________ page _ of _
Validation Protocol # _________ Process Validation
Title ____________________________________________________________________
_________________________________________________________________________
Protocol written by _________________________________________________________
Departmental Approval by _____________________________ Date ________________
QA Approval by ______________________________________ Date ________________
Objective:
To determine that process consistently performs as intended by repeatedly running the system
on its intended schedules and recording all relevant information and data. Results must demon-
strate that the process meets pre-determined specifications under normal conditions, and where
appropriate worst case conditions.
Scope
To be performed with validated equipment in the specified location in validated premises. If
equipment or systems or the facility are modified or the premises where the process takes place
is changed, or the process is relocated, the process must be re-validated after the systems,
equipment and facility qualifications, as appropriate, have been performed and approved.
Responsibility
The persons responsible for the process will perform the validation and record the information.
The responsible person will supervise the study, verify the completion of the records and write the
report.
Quality Assurance will review and approve the Process Validation Protocol and Report.
WHO/VSQ/97.02 59
Validation Protocol ____________ Process validation page ___ of
___
Title ___________________________ Name of Facility
_____________________________
Materials, Equipment, Documents
Master Formula or SOPs for normal operations of the process under test. (including data record
forms, batch record forms, materials and equipment needed).
MF/SOP list:
_______________________________________________________________________
_______________________________________________________________________
_______________________________________________________________________
_______________________________________________________________________
_______________________________________________________________________
SOPs for in-process and quality control tests performed during process (validated tests) (includ-
ing data record forms, materials and equipment needed).
SOP list:
_______________________________________________________________________
_______________________________________________________________________
_______________________________________________________________________
_______________________________________________________________________
_______________________________________________________________________
SOPs for test specific to the validation study performed (validated tests) (including data record
forms, materials and equipment needed).
SOP list:
_______________________________________________________________________
_______________________________________________________________________
_______________________________________________________________________
_______________________________________________________________________
_______________________________________________________________________
60 Good manufacturing requirements -- Part 2: Validation
Validation Protocol ____________ Process validation page ___ of ___
Title ___________________________ Name of Facility
_____________________________
Procedure
Performance
Process: Run full process according to SOP three times and record all required data.
Deviations to the procedures must be recorded on the data record forms.
Analytical tests: Perform the routine tests associated with the process according to
the SOP. Test results must be approved by QC.
Evaluation
Attach all data record forms and charts.
Perform all necessary calculations and statistical analyses (pre-determined).
Compare to acceptance criteria.
Prepare Deviation Report
(including the justification of acceptance and impact on the process).
Prepare a Process Validation Report
This should include for each validation run: date study initiated; date completed; observa-
tions made; problems encountered; completeness of information collected; summary of
the deviation report; results of tests and statistical analyses; do results meet acceptance
criteria; location of original data; other information relevant to the study.
Conclusions will be made on the validity of the process in individual runs and on the three
consecutive validation runs.
Approval
Submit the Document to QA for review and approval.
The Process must meet all specifications for three consecutive runs.
WHO/VSQ/97.02 61
Validation Protocol ____________ Process validation page ___ of
___
Title ___________________________ Name of Facility
_____________________________
List of attached Data Record Forms
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
Verified by: ______________________________________________Date ___________
62 Good manufacturing requirements -- Part 2: Validation
Validation Protocol ____________ Process validation page ___ of
___
Title ___________________________ Name of Facility
_____________________________
Calculations and Statistical Analyses
Performed by: _________________________________________ Date ______________
Verified by: ___________________________________________ Date ______________
WHO/VSQ/97.02 63
Validation Protocol ____________ Process validation page ___ of ___
Title ___________________________ Name of Facility _________________________
Acceptance Criteria vs. Test Results
Criteria Results Pass/Fail
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
_________________________ ________________________________________ ______
Recorded by: ___________________________________________ Date _____________
Verified by: ____________________________________________ Date _____________
64 Good manufacturing requirements -- Part 2: Validation
Validation Protocol ____________ Process validation page ___ of ___
Title ___________________________ Name of Facility ________________________
Deviation Report
Deviation(s):
Justification for acceptance:
Impact on process:
Supervisor: _____________________________________________________ Date
_________
WHO/VSQ/97.02 65
Validation Protocol ____________ Process validation page ___ of ___
Title ___________________________ Name of Facility _________________________
Process Validation Report
Results:
Conclusions:
Written by: _____________________________________________ Date _____________
QA approved by: ________________________________________ Date ____________
66 Good manufacturing requirements -- Part 2: Validation
