V l a d i m i r V e s e l o v, H e l e n Ro y tm a n , a n d Lo r i A l q u i e r

Otherwise, the process must be redesigned or validated (4).

The Medical Device Quality Systems Manual provides a more
detailed explanation for the processes that are required to
be validated:
Routine end-product tests have insufficient sensitivity
to verify the desired safety and efficacy of the finished
devices
Clinical or destructive testing would be required to
show that the manufacturing process has produced
the desired result or product
Routine end-product tests do not reveal all variations
in safety and efficacy that may occur in the finished
devices
The process capability is unknown, or it is suspected
thattheprocessisbarelycapableofmeetingthedevice
specifications (5).
Examples of the processes are as follows:
Processes that should be validated
Sterilization processes
Cleanroom ambient conditions
Aseptic-filling processes
Sterile packaging sealing processes
Lyophilization process
Heat treating processes
Plating processes
Plastic injection molding processes
Processes that may be satisfactorily covered by
verification
Manual cutting processes
Testing for color, turbidity, total pH for solutions
Visual inspection of printed circuit boards
Manufacturing and testing of wiring harnesses (4).

When to Validate
There are two types of validation depending on when
the process is validated in relation to product design,
transfer to production, and release for distribution:
prospective validation and retrospective validation
(5). Prospective validation is conducted before a new
product is released for distribution or when the process
is modified. Retrospective validation is based on historical information that is accumulated during product
production, testing, control, and review of customer
complaints, and can typically be retrieved from batch
records, production log books, lot records, control
charts, test and inspection results, customer feedback,
field failure reports, service reports, and audit reports.
Statistical process control is a valuable tool for generating the type of data needed for retrospective analysis
to revalidate a process and show that it continues to
operate in a state of control.
g x p a n d j v t . co m

PRINCIPLES FOR PROCESS VALIDATION

The basic principles for validation are stated as follows in
the GHTF guidance:
Establishthattheprocessequipmenthasthecapability
of operating within required parameters
Demonstrate that controlling, monitoring, or measuring equipment and instrumentation are capable
of operating within the parameters prescribed for this
process equipment
Perform replicate cycles (runs) representing the
required operational range of the equipment to demonstratethattheprocesseshavebeenoperatedwithin
theprescribedparametersfortheprocessandthatthe
output or product consistently meets predetermined
specifications for quality and function
Monitorthevalidatedprocessduringroutineoperation.
As needed, requalify and recertify the equipment (4).

GUIDANCES AND STANDARDS

The GHTF guidance provides harmonized requirements for process validation, which conforms to the
FDA quality system regulation (QSR), and ISO 13485
(4, 1, 2). Despite the fact that FDA has issued a guidance document for process validation (6), the agency
refers to the GHTF guidance in Warning Letters that
contain observations for inappropriate process validation. An additional reference is the Medical Device
Quality Systems Manual, which provides useful information for understanding the GHTF guidance recommendations (5).
Most modern processes are automated and may use
electronic records with electronic signatures, which
are regulated by 21 CFR Part 11 (7). The current Part
11 guidance refers to General Principals of Software Validation (8) and GAMP 4, which has been revised to
GAMP 5 (9).
FDAs Guide to Inspections of Medical Device Manufacturers provides a practical roadmap for internal audits and
also helps identify some specific requirements for process
validation (10).
ICH Q8 and ASTM E2500 standards should be taken
into consideration for combination product manufacturing (11, 12).
Process development and validation should take into
account the ISO 14001 for waste management systems
requirements (13).
ANSI/ASQ Z1.9, ANSI/ASQ Z1.4, and ANSI/ASQ S2
provide instructions, examples, and tables for sampling plans to assist in defining appropriate sample
quantities that should be tested for a typical process
validation (14-16).
Journal of Validation Technology [SPRING 2012] 83