M4 - Lesson 1 - Introduction To Process Validation

INTRODUCTION

Process Validation is a means of ensuring that manufacturing processes are capable of consistently
producing a finished product of the required quality. It involves providing documentary evidence that
key steps in the manufacturing process are consistent and reproducible. A validated  manufacturing
process is one that has been proven to do what it purports or is presented to do.

As a general rule, anything that can affect patient safety or product quality should be validated including
the following:

     1. Processes - such as manufacturing processes that produce a product

     2. Manufacturing Steps - each step may be validated separately for long processes

     3. Analytical Test methods - applicable for raw materials, intermediates, active pharmaceutical
ingredients, finished pharmaceutical products, method used for stability studies and those methods
used in quality control.

     4. Systems and Programs -  including those that support Good Manufacturing Processes (GMP) such
as facility (building specifications), utilities, programs like pest control, software, hardware (enterprise
Resource Platform) and laboratory information management systems and water for injection.

     5. Facilities - including rooms and equipment used for processing products that are sterile must
adhere to strict criteria and be validated before use.

     6. Cleaning processes - including sterilize in place and clean in place

The term `validation’ is intended to apply to final verification at the production scale. Typically a
minimum of three consecutive production batches should be successfully validated prior to the
marketing of the product.

Types of Validation

1. Analytical Method Validation - these are used to test and ensure the Quality of Drug substances /
Drug products. These are processes of determining the suitability of a given methodology for providing
useful analytical data.

2. Raw Material Validation - evaluating and testing materials like active ingredients, excipients,
processing aids, chemicals, official standards and laboratory material.  Evaluating and properly selecting
supplier. Then a written standard operating procedures and establish proper raw material storage
conditions and distribution.
3. Cleaning Validation - is documented evidence that an approved cleaning procedure will reproducibly
remove the previous product or cleaning agents used in the equipment below the scientifically set
maximum allowable carryover level.

4. Calibration - is the activity of checking, by comparison with a standard, the accuracy of a measuring
instrument of any type. It may also include adjustment of the instrument to bring it into alignment with
the standard

5. Process Validation - involves a series of activities taking place over the lifecycle of the product and
process.

    I. Experimental approach

        a. Prospective Validation -means validation done during the development stage. During this step
the input resources are selected and clearly specified. Each step in the development of new
manufacturing process is required to be established to give a desired result. The approach in this
validation often leads to transfer of the manufacturing process from the development function to
production.  Examples are clearly defined material specification; defined equipment and process
parameter; specified operating condition, if there is any; and defined level of training of people 

        b. Concurrent Validation - is carried out during production. It is more appropriate to validate
process during routine production due to well understanding of the process. Extensive testing &
monitoring ensure the desired quality characteristics of product with high degree of confidence. In this
type, verification of process still goes on after three initial commercial batches are taken and process is
handled over to manufacturing personnel. So, batch after batch, the process parameter is evaluated for
manufacturing facilities and studied if there is any change or deviation is observed.

II. Analysis of Historical data

        a. Retrospective Validation - is used for facilities, processes and process control parameters used in
operation that have not undergone in documented validation process but it is possible using historical
data (QA/QC records) to provide the necessary documented evidence that the process is doing what is
believed to do. Therefore this type of validation is only acceptable for well established processes.

III. Revalidation - is a repetition of the validation process and it is required under the  following
circumstances: major changes in critical process parameters of formula, equipment, procedures, or
quality of raw material or even in physical variation of raw material like particle size, changes in facilities
and installation which influence process.

        a. Periodic Revalidation - is done to identify the change in process that may happen during a period
of time. There may be any change in standard operating procedure, master formula, specification,
calibration, analytical method etc during the period.

        b. Revalidation After Change - revalidation that can affect the quality of the product. The following
includes any change in raw material including the physical properties as changing the bulk density,
viscosity and the particle size of the material because these can alter the dissolution and the
disintegration of the product manufactured. another is if the source of the raw material is changed as
the manufacturer of the material is changed because the quality of the material may change due to the
change in the manufacturer which may also affect the quality of the product. And if the type of the
packaging material is change like glass bottle to plastic bottle and polyvinylidene dichloride (PVDC) to
alu-alu for blister packaging.

6. Equipment Validation - comprises a series of qualifications, such as Design, Installation, Operational,

     a. Design Qualification - means showing that a piece of technology – a device, apparatus, machine or
system – has a GMP-compliant design. It is the generally made inquiry while examining qualification of
any instrument or gear. It is the reported gathering of exercises which characterize the utilitarian and in
addition operational determinations of any instrument and the criteria for choice of the seller in view of
the planned reason for the instrument.

     b. Installation Qualification - means showing it is set up, connected and installed as planned. It is a
documented process that verifies that all aspects of facility, utilities and equipment that affect product
quality adhere to the approved design specifications, and that the piece of equipment or instrument has
been properly delivered. 

     c. Operational Qualification - means showing it works as intended in all respects. It is an essential
process during the development of equipment often used by pharmaceutical companies. OQ can simply
be defined as a series of tests which ensure that equipment and its sub-systems will operate within their
specified limits consistently and dependably.

     d. Performance Qualification - means showing it delivers the overall desired performance. These are
collection of test cases used to verify that a system performs as expected under simulated real-world
conditions.

The guidance for Industry outlines the general principles and approaches that the Food and Drug
Administration (FDA) considers appropriate elements of process validation for the manufacture of
human and animal drug and biological products, including active pharmaceutical ingredients (APIs ),
collectively referred as drugs or products.

Process Validation (PV) is defined as the collection and evaluation of data, from the process design
stage throughout production, which establishes scientific evidence that a process is capable of
consistently delivering quality products. In January 2011, the Food and Drug administration (FDA) issued
the guidance for industry on “process validation: general principles and practices” to replace the
process validation guide from 1987. This revised guidance conveys FDA’s current thinking on process
validation and is consistent with basic principles first introduced in the 1987 guidance. The revised
guidance also provides recommendations that reflect some of the goals of FDA’s initiative entitled
“Pharmaceutical CGMPs for the 21st Century ― A Risk-Based Approach,” particularly with regard to
the use of technological advances in pharmaceutical manufacturing, as well as implementation of
modern risk management and quality system tools and concepts. This revised guidance replaces the
1987 guidance.

FDA has the authority and responsibility to inspect and evaluate process validation performed by
manufacturers. The Current Good Manufacturing Practices (CGMP) regulations for validating
pharmaceutical (drug) manufacturing require that drug products be produced with a high degree of
assurance of meeting all the attributes they are intended to possess

The New guidance promotes the following: 1) modern manufacturing principles, 2) process
improvement, 3) innovation, 4) sound science, and 5) risk assessment and mitigation.

Effective process validation contributes significantly to assuring drug quality, identity, strength, and
purity. Validation is a key process for effective quality assurance.  Quality Assurance (QA) is the heart
and soul of Quality Control (QC). Quality control is incomplete without coordination with production.

 QA = QC + GMP

The FDA Principle of Quality Assurance incorporates the understanding that the following conditions
exist: 1) Quality cannot be adequately assured merely by in-process and finished-product inspection or
testing.  2) Quality, safety, and efficacy are designed or built into the product. 3) Each step of a
manufacturing process is controlled to assure that the finished product meets all design characteristics
and quality attributes including specifications.

Product quality in the context of process validation means that product performance is consistent from
batch-to-batch and unit-to-unit.

Process Validation During the Product Life

Process validation involves a series of activities taking place over the lifecycle of the product and
process. This guidance describes process validation activities or lifecycle approach in three stages.1)
Process design   2) Process Qualification    3) Continued Process Verification

Many products are single-source or involve complicated manufacturing processes. Homogeneity within
a batch and consistency between batches are goals of process validation activities. Validation offers
assurance that a process is reasonably protected against sources of variability that could affect
production output, cause supply problems, and negatively affect public health.