Peer-Reviewed: Medical Devices

Examples of PQ elements are as follows:

Verification of released process documentation (e.g., manufacturing procedures, inspection
procedures, product specifications, engineering
drawings, tool drawings, material specifications,
related forms)
Dimensional verification (e.g., first article, layout
inspection)
Process stability (x-bar & R charts)
Process capability (Cp, Cpk)
Fault seeding
Product performance evaluation (i.e., impact of the
process on follow-on operations, product functionality, material and physical properties)
Cleanliness tests (e.g., extraction tests, ESCA)
Biological tests (e.g., bioburden, cytotoxicity,
hemolysis)
Product sterility
Manned and unmanned testing of controlled environments (3).

PROCESS CONTROL AND MONITORING

After the process is validated, it is important to control the validated state of the process. GHTF states,
Trends in the process should be monitored to ensure
the process remains within the established parameters.
When monitoring data on quality characteristics demonstrates a negative trend, the cause should be investigated, corrective action may be taken and revalidation
considered (4).
Process monitoring and control should not be limited to the review of quality charts and data. Possible
process variations may be caused by personnel deviations from work instructions; changes in environmental
conditions, or equipment failure. GHTF states, Various
changes may occur in raw materials and/or processes
which are undetected, or considered at the time to
be inconsequential. (An example of this type of process is sterilization.) These changes may cumulatively
affect the validation status of the process. Periodic
revalidation should be considered for these types of
processes (4).
The process map (Figure 1) can be used to evaluate the
changes, which can impact the process.

REVALIDATION
According to the FDA medical device manual, the process revalidation is necessary in the following cases:
When process changed
When process deviations occur
On a periodic basis.
88 Journal of Validation Technology [SPRING 2012]

In all cases, the process must be reviewed and

evaluated; and activities for review, evaluation, and
revalidation must be documented (5). To document
that the process is not changed and operating in a
state of control, day-to-day in process control data and
finished product testing data should be analyzed for
conformance with specifications and for variability.

WARNING LETTERS
FDA Warning Letters are published on the FDA website
(www.fda.gov). These letters contain valuable information
about issues related to process validation. Table I contains
examples of Warning Letters related to observations pertaining to process validation activities.

STATISTICAL TECHNIQUES
AND SAMPLE SIZE
The QSR doesnt provide specific requirements for statistical
techniques and sampling plans. However, FDA requires that
the rationale for the statistical techniques and sampling
plans should be documented, as follows:
Sec. 820.250 Statistical techniques][1]
(a) Where appropriate, each manufacturer shall establish and maintain procedures for identifying valid statistical techniques required for establishing, controlling, and
verifyingtheacceptabilityofprocesscapabilityandproduct
characteristics.
(b) Sampling plans, when used, shall be written and
based on a valid statistical rationale. Each manufacturer
shall establish and maintain procedures to ensure that sampling methods are adequate for their intended use and to
ensure that when changes occur the sampling plans are
reviewed. These activities shall be documented (1).
Standards for acceptance sampling (14, 15, 16) and
publication (17) refer to acceptance sampling for lots.
The GHTF guidance provides an explanation of how
these techniques can be used for process validation:
Acceptance sampling plans are commonly used in
manufacturing to decide whether to accept (release)
or to reject (hold) lots of product. However, they can
also be used during validation to accept (pass) or to
reject (fail) the process. Following the acceptance by a
sampling plan, one can make a confidence statement
such as: With 95% confidence, the defect rate is below
1% defective (4).
The final decision on how many samples to test cannot
be made until process test results are available. The following approach can be used:
1. Using preliminary assumptions about the process,
define the number of samples
2. Execute the sample plan
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