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VALIDATION
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PR
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ID  Introduction
AT  Various regulatory requirements of validation
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N  When should a process be validated
 Types of process validation
 Priority for Process Validation
 Types of documentation.
 Process validation of some Pharmaceutical
Processes

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PR
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V Why Is Validation Required?
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ID
AT Ø It would not be feasible to use the equipments without
IO knowing whether it will produce the product we wanted
N or not.

ØEfficient use of resources is necessary for the continued

success of the industry.

The pharmaceutical industries are concerned about

validation because of the following reasons.
Ø Assurance of quality
Ø Cost reduction
Ø Government regulation
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PR
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V Department /Designation Responsibility
AL Responsible for manufacturing of batches and
ID Manager Production
review of protocol and report.
AT
Responsible for analysis of samples
IO Manager QC
N collected
Responsible for samples collection and
Executive QC
submission to QC
Providing utilities and engineering
Manager Maintenance
support
Responsible for preparation of protocol and
Executive Production
manufacturing of validation batches
Responsible for protocol authorization and
Manager QA
preparation of summary report.

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SS Process Validation

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ID Process validation is defined as the collection and evaluation
AT of data, from the process design stage throughout
IO production, which establishes scientific evidence that a
N process is capable of consistently delivering quality products.

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 consistently produces a product meeting its
predetermined specifications and quality attributes”
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SS Qualification

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Design Qualification (DQ)
ID
AT Defines the functional and operational specification of
IO the instrument, program, or equipment and details the
N rationale for choosing the supplier.

Installation Qualification (IQ)

Demonstrates that the process or equipment meets all
specifications, is installed correctly, and all required
components and documentation needed for continued
operation are installed and in place.

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Operational Qualification
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to provide a high degree of assurance that the equipment

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functions as intended.
AL Component Operational Qualification
ID
of which calibration can be considered a large part.
AT System Operational Qualification
IO
to determine if the entire system operates as an integrated
N
whole.
Process Performance Qualification:
This verifies that the system is repeatable and is consistently
producing a quality product.

Performance Qualification (PQ)

Demonstrates that the process or equipment performs as
intended in a consistent manner over time.
Test with materials like placebo

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SS When To Validate

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ID
AT • After finalizing formula, process, and specifications
IO
N • Either before or after new drug application (NDA)
Approval

• Prefer to start during process development phase

• More frequently being done before NDA

approval/filing

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AL SECTION Deal with
ID
AT 21 CFR Parts 210 and 211. Current Good Manufacturing Practice
Regulations for Finished
IO Pharmaceuticals,
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Section 211.110 Sampling and testing of in-process

materials and drug products.

21 CFR Part 820. Current Good Manufacturing Practice

Regulations for medical device

Section 211.113 Control of Microbiological

Contamination.

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SS Types Of Process Validation

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AL Process
ID Validation
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N Experimental Analysis of Revalidation
Approach Historical data

Prospe Concur Periodi Revalid

ctive rent c ation
Retrospective
Validat Validation Revalid After
ion Validat ation Change
ion

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CE A) Prospective validation TE
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SS Also called as premarket validation

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V Carried out prior to distribution of new product or existing product
AL made under a revised manufacturing processes where such revision
ID may affect product specification or quality characteristic
AT
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N B) Concurrent validation
 Study is carried out under a protocol during a course of normal
production.
It gives assurance of present batch being studied and offer limited
assurance regarding consistency of quality from batch to batch.
This may be practical approach under certain circumstances….
 When previously validated process is being transferred to a third party
contract manufacturer or to another manufacturing site.
 Where the product is a different strength of a previously validated
product with the same ratio of active / inactive ingredients.

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V Conducted for a product already being marketed, and is based
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on extensive Historical data accumulated over several lots and
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over time.
IO Some essential elements of retrospective validation:-
N • Batches manufactured for a defined period
• Batch size/ strength/ manufacturer/ year
• Master manufacturing/ packaging documents
• Current specifications for active materials/ finished products
• List of process deviations, corrective actions and change to
mfg documents
• Data for stability testing for several batches
• Trend analysis including those for quality related complaints

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D) Revalidation
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 All or a portion of validation that is required to be

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AL repeated when changes that affect original
ID validation are made.
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Examples of changes requiring revalidation
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N – Changes to product specifications
– Process parameters
– Equipment (type, function, location, control
system, major repairs)
– Raw materials
– Manufacturing materials
– Packaging material

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SS Change Control

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AL Written procedures should be in place to describe
ID
actions to be taken if a change is proposed to a product
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IO component, process equipment, process environment,
N processing site, method of production or testing or any
other change that may affect product quality or support
system operations.

All changes must be formally requested, documented

and accepted by the validation team. The likely impact /
risk of the change on the product must be assessed and
the need for the extent of re-validation should be
determined.

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SS

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V Commitment of the company to control all changes to
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ID premises, supporting utilities, systems, materials,
AT equipment and processes used in the fabrication/
IO packaging of pharmaceutical dosage forms is essential to
N ensure a continued validation status of the systems
concerned.
.

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SS Priority for Process Validation

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ID A. Sterile Products and Their Processes
AT 1. Large-volume parenterals (LVPs)
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N 2. Small-volume parenterals (SVPs)
3. Ophthalmics, other sterile products, and medical
devices
B. Nonsterile Products and Their Processes
1. Low-dose/high-potency tablets and
capsules/transdermal delivery systems
(TDDs)
2. Drugs with stability problems
3. Other tablets and capsules
4. Oral liquids, topicals, and diagnostic aids
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SS Types of Documentation L

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ID  Validation Master Plan (VMP)
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IO  Validation protocols (VP)
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 Validation reports(VR)
 Standard Operating Procedures (SOPs)

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Validation Master Plan
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AL The format and content should include:
ID
AT Introduction: validation policy, scope, location and schedule
IO Organizational structure: personnel responsibilities
N Plant/ process /product description: rational for inclusions or
exclusions and extent of validation
Specific process considerations that are critical and those requiring
extra attention
List of products/ processes/ systems to be validated, summarized
in a matrix format, validation approach
Re-validation activities, actual status and future planning
Key acceptance criteria
Documentation format
Reference to the required SOP’s
Time plans of each validation project and sub-project.
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Validation Protocol
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V 1. General information & Objective
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ID 2. Responsibility
AT 3. Protocol Approval
IO 4. Validation Team
N 5. Process Flow Chart
6. Manufacturing Process
7. Review of Equipments/ Utilities, Raw Materials and
Packing Materials,
8. Validation Procedure
9. Sampling Location
10. Documentation
11. Acceptance Criteria
12. Summary & Conclusion
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O Some Common Variables In The Manufacture K
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AL • Particle size of drug substance
ID • Bulk density of drug substance/excipients
AT • Powder load in granulator
IO • Amount and concentration of binder
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• Mixer speed and mixing times
• Granulation moisture content
• Milling conditions
• Lubricant blending times
• Tablet hardness
• Coating solution spray rate

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V Parameters Response (Test)
AL Variable (Monitor) •Drug distribution
ID •Mixing speeds •Water/solvent
Fixed
AT •Amount of •content
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•Granulation
•Equipment granulation fluid •Appearance (size)
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•Batch size •Feed rate •Power consumption
•Granulation time (amp/torque)
•Load

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V Control parameters Response (Test)
AL Variable (Monitor) •Particle size
ID Fixed •Inlet/exhaust air distribution
AT •Bowl charge temperature •Densities
IO •Porosity of •Product temperature •Loss on drying
N •Drying time •Assay (for heat
filter bags
•Bowl sieve •Air volume sensitive
•Humidity of incoming materials)
air (dew point)
•Humidity of exhaust
air

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Milling
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V Control parameters
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ID
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Variable Response
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N Screen size Particle size
Milling speed distribution/shape
Feed rate Loose/tapped densities

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Powder Blending
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Variable Response
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IO Blending time Content uniformity
N Blender speed Assay
Intensifier bar Particle size distribution
Powder flow
Densification/Aeration

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Lubrication
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AL Variable Response
ID
AT Blender speed Particle size distribution
IO Blending time Loose/tapped densities
N Method of addition Flow properties
Tabletting characteristics
(friability, hardness)

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Compression
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AL Variable Response
ID
AT Speed of press Appearance
IO Pre-compression Weight variation
N Compression force Hardness/friability
Feed frame Thickness
(open/forced) Moisture content
Feeder speed Disintegration/dissolution
Assay/dose uniformity

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Pan Coating
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AL Variable Response
ID
AT Pan load Percent weight gain
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Inlet/exhaust temperatures Thickness
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Inlet/exhaust humidities Elegance
Pan speed Dissolution
Spray nozzle size Assay
Atomizing pressure Degradation level
Spray rate Residual solvent
Spray angle
Gun to bed distance
Tablet core characteristics

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Approaches to Improve Process Validation #1
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V Focus on “newness”
AL anything new like components or raw materials, equipment,
ID process or package steps, dosage form
AT • Adequate trials at full-size for new item
IO • Assure raw material/component is from vendor’s
N routine production

Complete review of pre-validation documentation

Adequately identify cause and correct problems

Data used in establishing operating ranges and specifications

Data submitted to regulatory agencies

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Approaches to Improve Process Validation #2
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V Handling out-of specification (OOS) results
AL Identify if caused by equipment, product, normal process
ID variation, or error or combination
AT May require additional experimentation
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Pursue conservative approach, if unsure of cause
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Mechanism to bring development/validation issues to team
management for resolution
Review meetings
Team approach
Open, honest interactions

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Liquid dosage form

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ID
Solution Suspension Emulsion
 Studies of Milling Homogenization /
AT
IO Ingredients  Mixing Emulsification
N  Fill Uniformity  Viscosity Viscosity
 Re suspendability Creaming

 Filter
Re emulsify
Compatibility  Agglomeration
Coalesce
 Product Tubing  Caking Globule Growth
Interaction
 Flush Volumes
Cleaning /
Sanitization
Inert Gas
Effectiveness
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Semi solid dosage form

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AL Ointments / Creams
ID
AT Active Distribution
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 Particle Size
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 Mixing

 Emulsification

 Viscosity

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Study Question
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1. Short note on Process validation
ID
AT 2. What do you mean validation and explain process
IO validation in detail with special reference to Solid
N dosage form?
3. Focus out the regulatory requirement of Process
validation?
4. Discuss type of process validation and types of
documentation for process validation

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Referances
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AT I. R. Berry, R. A. Nash ,Pharmaceutical Process Validation,Eastern
IO Hemisphere Distribution, 3rd edition 2003
N
Elsie J, Augustine O Review article:An Overview of Pharmaceutical
Validation and Process Controls in Drug Development Tropical
Journal of Pharmaceutical Research, December 2002; 1 (2): 115-122
Guideline on General Principles of Process Validation
([Link]/cder/guidance/[Link]), May 1987)
Quality System Regulation, Title 21 Part 820 of the Code of
Federal Regulations ([Link]/scripts/cdrh/ cfdocs/
cfcfr/[Link]? CFRPart=820 (Apr 2003)

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