Pharmaceutical Process

Validation
Dr Hasan Imam
FDA GUIDELINES
The U.S. Food and Drug Administration (FDA)
has proposed guidelines with the following
definition for process validation:
• Process validation is establishing documented
evidence which provides a high degree of
assurance that a specific process (such as the
manufacture of pharmaceutical dosage forms)
will consistently produce a product meeting its
predetermined specifications and quality
characteristics.
According to the FDA, assurance of product quality is
derived from careful and systemic attention to a
number of important factors, including:
1. Selection of quality components and raw materials,
2. adequate product and process design, and
3. (statistical) control of the process through in-process
and end-product testing: such as
(a) Tablet or capsule weight variation
(b) Disintegration time.
(c) Adequacy of mixing to assure uniformity and
homogeneity
(d) Dissolution time and rate
(e) Clarity, completeness, or pH of solutions
The ideal number of batches required to study a
product is based on variables of the process. By
process variables, we mean
• Formulation changes involving one or more of
the active ingredients or key excipients
• raw materials from different but approved
vendors,
• introduction of similar but different pieces of
equipment, personnel and
• Changes to the manufacturing facility
• seasonal changes, and the like.
Example of a process validation report
A. The Protocol
Table of Contents
• The table of contents is nothing more than a map
of the document listing every major section of
the protocol and detailing page numbers.

Section I: Background/Methodology. This section is

the communication part of the document. It is
strictly instructional, providing history, how the
validation will be accomplished, and so on. There
is no requirement for data entries in this first
section.
• Objective. The objective states what the intent of
the activity is.
• Scope. The scope section establishes the
boundaries or limits of the validation event. It
identifies every major thing to be included by
identification and therefore excludes everything
that is not a part of the event.
• Responsibilities. This section captures the
responsibilities of the approving departments
prior to document approval. This way there will
be no confusion when a responsibility arises
during or after the document execution.
• Background. The background provides the
reader with a bit of history regarding not only
what is being validated, but also why and how
it is being validated. Typically very little detail
is provided in this section.
• Process Descriptions. The process
descriptions break down and define every
major process step. It should also discuss the
processing sequence. Forexample, “the
process entails dispensing, milling, blending,
and tableting.
Critical Process Control Parameters. The critical
process control parameters, for e.g. in-process
quality control parameters test.
Validation Procedure. This section is devoted to
telling the audience
• how this particular validation will be achieved to
meet the FDA’s expectations of process validation.
• How many successful runs will be required? Three?
Seven?
• What if a failure is encountered?
Validation Methodology. The methodology
section speaks to the areas of documentation,
protocol execution, and postexecution.
Documentation. Documentation addresses
• how the entries should be made, the
timeliness of those entries, and how to correct
an incorrect entry.
• Results generated in or related to this activity
should be properly documented and/or
attached to this protocol.
Execution. The execution section addresses courses
of action during actual execution, and the
items(s) to undergo validation.
Postexecution. The postexecution subsection deals
with the document flow upon completion of the
activity. An example is upon completion of the
execution of this protocol, this document and all
related third party testing reports attached are to
be submitted to the validation project manager.
• A validation report summarizing the results and
including an explanation of all deviations from
the procedures, specifications, or acceptance
criteria will be prepared.
• Acceptance Criteria/Rationale. The acceptance
criteria for each measurable attribute and a
rationale be provided for each criteria. For
example, why must the final product moisture
content be 70–80%? What if it is 83%?
• Labeling. The labeling section simply discusses
how labels will be prepared and with what
information. Typically the batch number, the
validation document number, the validation
sequence or event number (run x of y),
• the sample number (or other descriptive
information; e.g., sample type and/or time),
• and of course the date that sampling occurred
are recorded on a validation label.
Method of Analysis. In this particular section,
some time is devoted to addressing the
methods to be employed in analyzing the
samples collected.
• For example, if chemical residue analysis will
be performed using HPLC during validation, it
should be identified by method name and
number (e.g., HPLC method xyz).
Section II:
• Data Documentation. Section II deals with the
data documentationaspect of the protocol. It
requires entries on the part of the executor(s),
such as lot numbers of raw materials used,
equipment used, and batches produced.
• Safety Awareness. This subsection addresses
this issue, forcing the executors to
acknowledge via signature and by date with all
of the safety aspects of the validation activity.
Training. To comply with CGMP guidelines, all persons
involved with the execution of an activity covered by
the protocol must have been trained on general CGMP
and applicable internal procedures.
Availability of standard operating procedures. This
section requires the executors to verify and list
applicable operational, preventative maintenance,
calibration, and equipment cleaning procedures that are
available.
Materials. This section documents each component (raw
materials, laminates, pouch stock, applicable
lot/identifying numbers, etc.) used and the identifying
numbers for each batch manufactured.
• Sample Execution. This interactive section
documents activity sampling, and therefore
provides proof that sampling did occur.
• Results. The results section is where findings
are documented for each analysis.
• Conclusions. The conclusions section simply
captures the overall results of the activity.
B. The Validation Summary
1. Summary. This section summarizes the
validation activity, citing the fact that
validation occurred and for what purpose.
2. Discussion of Results and Deviations
3. Conclusions
4. Future Activities This section makes a
statement about the revalidation activities for
the process and also states that any changes
will be captured under the existing (validation)
change control system.