SEMINAR ON VALIDATION

Definition
Validation is attaining & documentation of sufficient evidence to give
reasonable assurance, stating that equipment or process does & will do
what it purports to do.
According to US FDA
validation is establishing documented evidence which provides a
higher degree of assurance that a specific process , equipment or
facility meets its pre determined specifications & quality characteristics
& will consistently produce a product of standard quality
REASONS FOR VALIDATION
Objective: to manufacture product of requisite quality with low cost
Govt regulation
Assurance of quality
Cost reduction
And to produce a zero defect product
WHEN VALIDATION BEGINS
Validation should begin in the designing stage for new facility & pre
formulation stage for a new dosage form.
WHO DOES
In order to have a valid & qualified system it must be designed by
qualified individuals only.
As it is complex process, it is performed by individuals with necessary
training & experience & who are themselves previously qualified.
VALIDATION TEAM

FUNCTIONS OF DIFFERENT DEPARTMENTS

NAGARAJA Y S , Dept. of Pharmaceutics.

NAGARAJA Y S , Dept. of Pharmaceutics.

Engineering

Install, qualify & certify plant facility, equipment &supp

systems.

R&D

Design, optimize, qualify manufacturing process with

limits & specifications.

Manufacturing

Operate & maintain plant facilities, equipments ,suppor

systems, process and strictly follow SOP.

Q.C

Follow the validation protocol develop by Q.A & validate

the incoming stock ,in process critical system &final
product.

Q.A

Establish approvable validation protocols &conduct

process validation by monitoring ,sampling ,challenging
the process & equipment.

VALIDATION PRIORITY
1. Large volume parenteral
2. Small volume parenteral.
3. Ophthalmic, other sterile products & medical devices.
Component of validation

Analytical test procedures

Instrument calibration
Critical support system
Operators
Raw materials
Packaging materials
Equipment
NAGARAJA Y S , Dept. of Pharmaceutics.

 Facilities
Manufacturing process
Product design
Utilities & services
Records & reports
Types of validation
1. Prospective validation.
2. Retrospective validation.
3. Concurrent validation.
4. Revalidation.
Prospective validation
This is validation program executed before commercialization of a new
drug/ formulation, to make sure that there are no potential hazards in full
scale manufacture of product.
Retrospective validation
It is a program chosen for established products whose manufacturing
process is considered stable (i.e. long history of state control
operation).
This method involves statistical analysis of numerical data obtained
from different batches & then justify whether the system is qualified or
not.
The data includes
a) MFR,BFR
b) Assay values.
c) End product test results
d) In process data.
Different parameters checked in parenteral.
pH value.

NAGARAJA Y S , Dept. of Pharmaceutics.

 Viscosity.
Density.
Color & clarity.
Potency.
Sterilization parameters
Concurrent validation
This method includes in process monitoring of critical process steps &
end product testing of current production along with documentation.
This shows that the manufacturing is in state of control
The same parameter of retrospective validation are evaluated with
more stress on critical parameters affecting the process

Revalidation
This method involves validation of facility which is previously validated
when
1 Change in critical component.
2 Change in critical piece of equipment.
3 Change in facility / plant (design / location).
4 Significant increased / decease in batch size.
Sequential batches fail to meet product / process specification

Validation of parenteral
Design & validation of facility
There are four basic steps in validation of facility
1. Planning
2. Documentation
3. Construction

NAGARAJA Y S , Dept. of Pharmaceutics.

4. Testing
1. Planning
Site selection
Design staff
Material flow path
Room layout

Material flow path

Typical room layout:

NAGARAJA Y S , Dept. of Pharmaceutics.

 Salient feature
Double door with interlock system
Positive pressure in sterile area.
Separate entry for material &personal.
Clean room or class-100 room in the filling area.

3. Construction
Steps involved are:
1. Ground
2. Shell
3. Rooms
4. sewers
5. Ductwork
6. Landscaping

AIR SYSTEM
HVAC system: Heating Ventilation Air Conditioning system
This system facilitates air by positive pressure to get a sterile product
In this system HEPA filters are used
The qualification include Integrity HEPA filters to get the sterile products, Air
borne particulate matter, air flow direction and humidity control

Water sampling and testing

Validation of Utilities
1. VALIDATION OF GASES: nitrogen, carbon dioxide, compressed air.
VALIDATION OF GASES INCLUDES 3 STEPS

NAGARAJA Y S , Dept. of Pharmaceutics.

 Supply of gas (adequate purity & quality)

Storage conditions
Distribution network
2. Validation of steam system
Validation of steam generator
Efficiency.
Pressure.
Analysis of condensate.
Distribution network.
3. Validation of electrical system
Main objective is to meet:
Qualitative specifications. (frequency, voltage, stability ).
Quantitative specifications (load demand).
Backup system is validated.

VALIDATION OF FILLING
Parenterals are checked for
1. Fill volume
2. Syringe able volume
3. Sterile filling
Monitoring of viable &non viable particles:

Particle counter

Strip test

Reuter centrifugal sample (RCS)

Key Terms in Sterilization

NAGARAJA Y S , Dept. of Pharmaceutics.

 D-value: time required to reduce the microbial content by 90%i.e.one

logarithmic reduction
F-value: time required to destroy all spores of suspension when using
a suspension at 121c
Z-value: the no of degree required for 1 log reduction in D-value
N0 value: No of living organism / defined unit of surface
Log reduction value: ability of filter in terms of log reduction of
microbial population.

Validation of Sterilization
Biological indicator
E.g. for steam sterilization-Bacillus stearothermophillus
For dry heat sterilization- Bacillus subtilis var. niger
For ethylene oxide- Bacillus subtilis var. globigli
For ionizing radiation- bacillus pumilis
Validation of Moist Heat Sterilization
Operation condition are 121c, for 20 min
1.

Qualification & calibration:

Checking, upgrading the unit

2.

Selection & calibration of thermocouples

3.

Selection & calibration of B.I

4.

Heat distribution studies

1. Cool spot is find out
2. Temp dif should not be more than + 2.5c

5.

Heat penetration studies

By container mapping studies- in which thermocouples are introduced

at different heights in the container.

NAGARAJA Y S , Dept. of Pharmaceutics.

Validation of dry heat sterilization

Its done for

Batch oven & tunnel oven

Validation mainly includes
1. Qualification & calibration
2. Selection & calibration of thermocouples
3. Selection & calibration of B.I
4. Air balance determination
5.

Heat distribution studies

1. Cool spot is find out
2. Temp dif should not be more than + 2.5c

6. Heat penetration studies

Validation of radiation sterilization

Major source are cobalt

60

, ceasium136 .

Determine D-values using biological indicator.

The D value is defined as the dose of radiation in Mrads necessary to
produce a 90% reduction in the number of indicator microbial cells
Calibration of equipment so that same amount of radiation is released
every time.
Normal dose for over kill approach is 2.5 Mrad.
Validation of Sanitization
Sources for contamination are
Skin &hair fragments.
Droplets from mucous membrane.
Material deposition due to personal.
Fibers released from person &equipment.
NAGARAJA Y S , Dept. of Pharmaceutics.

 Packaging material.
So to maintain aseptic conditions we need something other than hepa
filters i.e. SANITIZER
Def- it is defined as a chemical agent that kills microbial contamination in the
vegetative form only.
E.g.; Hypochlorite, phenol, surfactant etc.

VALIDATION OF FILTRATION
Membrane filters are cartridges & plates
Physical integrity of filter media is checked by
1. Bubble point test.
2. Bacterial challenge test.
3. Flow rate.
4. Longevity of filter.

VALIDATION OF PACKAGING
a) INTEGRITY OF RUBBER :
1. Quality
2. Penetratability
3. Fragmentation
4. Water extractive
5. Self-seal ability
b) INTEGRITY OF GLASS :

There are mainly 4 types of glass

TYPE I (borosilicate glass). For (parenterals)
TYPE II (treated soda lime glass). (for dry powders)
TYPE III (soda lime glass).
NAGARAJA Y S , Dept. of Pharmaceutics.

 TYPE IV (non parenteral glass)

MOST COMMON TESTS PERFORMED ARE:
1. Chemical composition
2. Leaching
3. Powder glass test
4. Water attack test

C) Leaking tests:
There are mainly two types of leak test:
1. Vacuum dye leak test.
2. Autoclave dye test.

VALIDATION OF SOLID DOSAGE FORM

Validation is a systematic approach to identifying, measuring,
evaluating ,documenting,& reevaluating a series of critical steps in
manufacturing process that require control to ensure are producible
final product.

VALIDATION OF RAW MATERIAL

It includes validation of both active ingredients& excipients.
Characteristics
Particle size, surface area, color, density.
Chemical characteristics- water content residue on ignition & heavy
metals.
Variables:
Flow, blend uniformity, granulation solution/binder uptake compressibility,
lubricant efficiency

NAGARAJA Y S , Dept. of Pharmaceutics.

Eg; 1) Mg sterate (lubricant). Its action depends on particle size.

2) Dyes (color)
Variation in material occurs depending up on .
a) Method of transportation chosen,
b) Exposure of material to undesirable conditions (heat and humidity)

Steps involved in validation of raw materials

Each raw material should be validated by performing checks on several
batches, preferably 3,from the primary supplier as well as the alternate
supplier .the batches chosen should be selected to represent the range
of acceptable specifications both high and low
Depending on susceptibility of the raw material to ageing, physical,
chemical or microbial stability assessed.
Once the samples of raw materials have been selected it should be
used to manufacture a batch of final dosage form it may be
appropriate to manufacture to several lots of final product with raw
material at the low &high ends of the specifications limit.
The final step of raw material should involve an on site inspection of
the supplier to review the vendors manufacturing operations and
control procedures

ANALYTICAL METHODS OF VALIDATION

Analytical criteria must be assessed .
1. Accuracy of method
2. Precision of method
3. In day /out of-day variation
4. Operator variation.
5. Instrument variation
6. Laboratory variation

NAGARAJA Y S , Dept. of Pharmaceutics.

DEFINATION &CONTROL OF PROCESS VARIABLES

Process validation can be defined as means of challenging a process
during development to determine which variables must be controlled
to ensure consistent production of a product or intermediate.
Steps in development of validation program :
1. Obtaining test data to determine the numerical range of each
parameter
E.g.: assess the tablet hardness over a series of
batches.
2. Establishing specification limits from the test data derived for a given
parameter.
3. Determining how well the specification limit indicates that the process
is under control
4. Certify the equipment operating conditions
Eg: rpm, temp, are within specification limits.

General tests in process validation are

1. Moisture content
2. Content uniformity
3. Hardness
4. Disintegration & dissolution
5. Friability
6. Weight variation

NAGARAJA Y S , Dept. of Pharmaceutics.

7. Granulation particle size distribution

Guidelines for process validation
A. Tablet composition:
Normal properties
Density
Particle size distribution
Surface area
Flow properties
Moisture content
solubility
B. Process evaluation & selection:
Blending operation
Determine time of un mixing
Characteristics of blend

bulk density

Particle size distribution

Color uniformity

C. Wet granulation
1. Evaluation of binder
Binder concentration
Solubility in granulating solution
2. Evalution of mixed granulation
3. Evalution of drying
4. Tablet compression
Appearance
NAGARAJA Y S , Dept. of Pharmaceutics.

 Color quality
Powder flow
Speed of tablet machine
5. Tablet coating
Evaluate coating procedure in different size pans
Coating speed
Amount of material required / application

D. Equipment evaluation
Blending equipment
Granulating equipment
Tablet equipment
Tablet coating.

Good Manufacturing Practices

"GMP" - A set of principles and procedures which, when followed by

manufacturers of therapeutic goods, helps ensure that the products
manufactured will have the required quality.

Usually see cGMP where c = current, to emphasize that the

expectations are dynamic

A basic tenet of GMP is that quality cannot be tested into a batch of

product but must be built into each batch of product during all stages
of the manufacturing process.

It is designed to minimize the risks involved in any pharmaceutical

production that cannot be eliminated through testing the final product.

Some of the main risks are

NAGARAJA Y S , Dept. of Pharmaceutics.

Unexpected contamination of products, causing damage to

health or even death.

Incorrect labels on containers, which could mean that patients

receive the wrong medicine.

Insufficient or too much active ingredient, resulting in ineffective

treatment or adverse effects.

Why GMP is important?

A poor quality medicine may contain toxic substances that have

been unintentionally added.

A medicine that contains little or none of the claimed ingredient

will not have the intended therapeutic effect.

For e.g.

USA - 1937 Sulphanilamide Elixir, Diethylene Glycol to suspend drug,

this lead to107 deaths due to renal failure mostly children

Manufacturer fined $26 000

Led to Food, Drug and Cosmetic Act 1938

Ten Basic Rules of GMP

Be sure that the written instructions before any job are started.

Always guard against labeling errors.

Always follows those instructions EXACTLY

Ensure that the correct material being used.

Ensure that the correct equipment being used & that is CLEAN.

Prevent contamination & mix up.

Always work accurately & precisely.

Keep thing (including personnel) clean & tidy.

NAGARAJA Y S , Dept. of Pharmaceutics.

Always be on the lookout for mistakes errors and bad practices &
report them immediately.

Make clear, accurate records of what has been done & the checks
carried out.

cGMP divided into two parts :

Part 1 : Deals relating to factory premises

Part 2: Deals with the plant and equipment for manufacture of drugs.

Part 1 : Factory premises :

General
Requirements

Location and
Surroundings

Buildings

Water supply

Disposal of
Waste

2. Requirements for sterile products manufacturing area

3. Working space and storage area
4. Health, clothing and sanitation of workers
5. Medical services
6. Sanitation in the manufacturing premises

7. Requirements for sterile products manufacturing area

8. Working space and storage area

NAGARAJA Y S , Dept. of Pharmaceutics.

9. Health, clothing and sanitation of workers

10. Medical services
11. Sanitation in the manufacturing premises

12. Reprocessing and recovery

13. Product containers and closures
14. Labels and other printed materials
15. Distribution of records
16. Records of complaints and adverse reactions
17. Quality control department

Personnel

Personnel Qualification:
Persons should be qualified with appropriate education.
Responsibilities must be specified in writing.
Training should be conducted by qualified person.

Personnel Hygiene.
Should practice good sanitation and health habits.
Should wear clean clothing suitable for manufacturing activity.
Must avoid direct contact with intermediates or active ingredients.
Smoking, eating, drinking, chewing and storage of food must be
restricted.
Personnel suffering from infections or any disease should not engaged
in activities.

Building and Facilities

Design and Construction

Must be located, design and constructed to facilitate cleaning,
maintenance and operations as appropriate to the type & stage of
manufacture.

NAGARAJA Y S , Dept. of Pharmaceutics.

Adequate space for equipment & materials.

Premises must be well drained.
Flow of materials & personnel should be such that it avoids
contamination.
Adequate cleaning, washing & toilet facilities.
Laboratory areas or operation areas must be separate from production
areas.
Adequate lighting must be provided in all areas.
The fitting of lighting should be done inside the walls to avoid the
corner and crevices for microbial contamination
Raw Materials

Responsible person should keep an inventory of raw materials &

maintain records as per schedule-U

Schedule-U:

Records of each raw materials shall be maintained indicating

the date of receipt, number, name and address of manufacture/supplier,
batch no. quantity received, pack size, date of manufacturing & expiry, if any
Master Formula Records

It is defined as written procedures that give the complete description

of all aspects of its manufacture, packing and control with an intension
to ensure the purity, identity, quality & strength of each dosage unit
throughout the entire shelf life.

Master formula includes

1. Specifying a fixed formulation

2. Identifying consistent quality criteria for components
3. Providing an explicit set of manufacturing instructions along with
parameters for critical steps such as mixing, drying, blending, sieving,
sterilizing the product
4. Describing systematic sampling procedure
5. Listing precise assays & tests

NAGARAJA Y S , Dept. of Pharmaceutics.

6. Establishing methods for ensuring complete accountability for all

material including packing and labeling

Batch Manufacturing Records

The license shall maintain batch manufacturing records as per

schedule U for the each batch of drug produced.

Manufacturing records are required to provide a complete account of

the manufacturing history of each batch of a drug showing that it has
been manufactured, tested and analyzed in accordance with the
manufacturing procedures and written instructions as per the master
formula.

Reprocessing and Recoveries

If the product batch has to be reprocessed, the procedure shall be

authorized and recorded. An investigation shall be carried out into the
causes necessitating re-processing and appropriate corrective
measures shall be taken for prevention of recurrence. Re-processed
batch shall be subjected to stability evaluation.

Recovery of the product residue may be carried out, if permitted, in the

master production and control records by incorporating it in subsequent
batches of the product
For product containers and closures

All containers and closures intended for use shall comply with the
pharmacopoeial requirements. Suitable validated test methods, sample
sizes, specifications, cleaning procedure and sterilization procedure,
wherever indicated, shall be strictly followed to ensure that these are
not reactive, additive, absorptive, or leach to an extent that
significantly affects the quality or purity of the drug. No second hand or
used containers and closures shall be used.

Whenever bottles are being used, the written schedule of cleaning

shall be laid down and followed. Where bottles are not dried after
washing, they should be rinsed with de-ionized water or distilled water,
as the case may be.

Distribution records:

NAGARAJA Y S , Dept. of Pharmaceutics.

Records for distribution shall be maintained in a manner such that

finished batch of a drug can be traced to the retain level to facilitate
prompt and complete recall of the batch, if and when necessary.
Complaints and Adverse Reactions

Reports of serious adverse drug reactions resulting from the use of a

drug along with comments and documents shall be forthwith reported
to the concerned licensing authority.

There shall be written procedure describing the action

recall to be made of the defective product

to be taken,

Storage

To insure stability of a pharmaceutical preparation for a period of its

intended shelf life, the label should contain desired conditions of
storage.
Storage Specifications

Temperature

Cold

Not to exceed 80c

Freezer

-100C to 200C

Cool

80C to 150C

Room temp.

150c to 300c

Warm

300c to 400c

Excessive heat

Above 400c

Ware Housing Procedure:

Records of store items should contain following data.

NAGARAJA Y S , Dept. of Pharmaceutics.

Name of the material and manufacturer.

Quantity and strength of material.
Batch number and control number.
Date of manufacture and expiry.
Method of dispense and
Special precautions as per necessary.

Quality Control System

Quality control shall be concerned with sampling, specifications,

testing, documentation, release procedures which ensure that the
necessary and relevant tests are actually carried and that the
materials are not released for use, nor products released for sale or
supply until their quality has been judged to be satisfactory.

It is not confined to laboratory operations but shall be involved n all

decisions concerning the quality of the product. It shall be ensured that
all quality control arrangements are

effectively and reliably carried out the department as a whole shall

have other duties such

as to establish evaluate, validate and implement all Quality Control

Procedures and methods.

Type of manufacturing Area

or category

NAGARAJA Y S , Dept. of Pharmaceutics.

Equipments

A. Semisolids
preparations

30 M2

Mixing tank
Kettle

Ointments

Power driven mixer

Emulsions

Storage tanks

Lotions

Colloid mill

Suspensions

Triple roller mill

Liquid filling equipment
Jar/tube filling equipment

B. Oral liquids

30 M2

Mixing and storage tanks

Syrups

Portable mixer

Elixirs

Filter press

Solutions

Vacuum/gravity filter

NAGARAJA Y S , Dept. of Pharmaceutics.

 Granulating section
m2

30

a) Disintegrator
Powder mixer
Mass mixer
Granulator
Ovens

Compression section
(table ting ) 30 m2

b) Tablet machine
Pill machine
Punch/dies storage cabinet
Tablet counter
Tablet inspection belt
Hardness tester
Weighing balance
D.T. Apparatus

Capsules

(For the manufacture of capsules, separate enclosed area suitably airconditioned and dehumidified with an airlock arrangement shall be
provided. The following

equipment is recommended for filling Hard Gelatin Capsules, namely: -

(1) Mixing and blending equipment (electrically or power driven).

(2) Capsules filling units (preferably semi automatic or automatic filling

machines).

(3) Capsules counters (wherever applicable)

(4) Weighing balance.

(5) Disintegration test apparatus.

NAGARAJA Y S , Dept. of Pharmaceutics.

(6) Capsule polishing equipment.

Ophthalmic Preparations

1) Thermostatically controlled hot air ovens (preferably double ended).

(2) Jacketed kettle/stainless steel tanks (steam, gas or electrically

heated).

(3) Mixing and storage tanks of stainless steel/Planetary mixer.

(4) Colloid mill or ointment mill.

(5) Tube filling and crimping equipment (semi-automatic or automatic

filling

machines).

(6) Tube cleaning equipment (air jet type),

(7) Tube washing and drying equipment, if required

(8) Automatic vial washing machine.

(9) Vial drying oven.

(10) Rubber bung washing machine.

(11) Sintered glass funnel, Seitz filter and filter candle (preferably
cartridge and

Membrane filters).

(12) Liquid filling equipment (semi-automatic or automatic filling

machines).

(13) Autoclave (preferably ventilator autoclave).

(14) Air conditioning and dehumidification arrangement (preferably

centrally air-conditioned and dehumidification system).

(15) Laminar airflow units.

Powders

The following equipment is recommended for the manufacture of

powders,

NAGARAJA Y S , Dept. of Pharmaceutics.

namely:-

(1) Disintegrator

(2) Mixer (electrically operated)

(3) Sifter.

(4) Stainless steel vessels and scoops of suitable sizes.

(5) Filling equipment (electrically operated).

(6) Weighing balance.

Pessaries and Suppositories

The following equipment is recommended for manufacture of
Pessaries and

Suppositories, namely: -

(1) Mixing and pouring equipment

(2) Moulding equipment.

(3) Weighing devices.

Parenteral preparations in glass containers,

(1) Water management area: this includes water treatment and

storage

(2) Containers and closures preparation area: This includes washing

and drying of

Ampoules, vials, bottles and closures.

(3) Solution preparation area: This includes preparation and filtration of

solution.

(4) Filling, capping and sealing area: This includes filling and sealing of
ampoules and/or filling, capping and sealing of vials and bottles.

(5) Sterilization area

(6) Quarantine area

(7) Visual inspection area

(8) Packaging area

NAGARAJA Y S , Dept. of Pharmaceutics.

Repacking of Drugs and Pharmaceutical Chemicals

The following equipment is recommended for repacking of drugs and

pharmaceuticals chemicals, namely:-

(1) Powder disintegrator

(2) Powder sifter (electrically operated)

(3) Stainless steel scoops and vessels of suitable sizes

(4) Weighing and measuring equipment.

(5) Filling equipment (semi-automatic / automatic machines).

(6) Electric sealing machine

GMP helps boost pharmaceutical export opportunities

Most countries will only accept import and sale of medicines that have
been manufactured to internationally recognized GMP.

Governments seeking to promote their countries export of

pharmaceuticals can do so by making GMP mandatory for all
pharmaceutical production and by training their inspectors in GMP
requirements.

GMP Covers

ALL aspects of production; from the starting materials, premises and

equipment to the training and personal hygiene of staff.

Detailed, written procedures are essential for each process that could
affect the quality of the finished product.

There must be systems to provide documented proof that correct

procedures are consistently followed at each step in the manufacturing
process - every time a product is made.

How Do GMPs Change?

GMPs change formally and informally.

NAGARAJA Y S , Dept. of Pharmaceutics.

GMPs are currently undergoing significant changes.

Example of formal change:
The U.S. medical device GMPs have been completely rewritten, making
them more compatible with the ISO-9001 quality document. In fact device
GMPs were renamed - FDA now calls them the Quality System Regulation
(QSR).
Example of informal change:
Expectations that inspectors have evolved over time.
In the U.S., these changes are communicated by seminars and papers
presented by FDA personnel and through agency Guides and Guidelines.
One other way industry personnel can keep track of changes in expectations
is by watching the FDA-483s (inspectional observations) and Warning Letters
issued to firms by the agency.
How do GMPs of different countries compare?
At a high level, GMPs of various nations are very similar; most require things
like:

Equipment and facilities being properly designed, maintained,

and cleaned

Standard Operating Procedures (SOPs) be written and approved

An independent Quality unit (like Quality Control and/or Quality

Assurance)

Well trained personnel and management

References
Theory And Practice Of Industrial Pharmacy By Leon Lachman, H.A.
Liberman, Verghese Publication House, 3rd Edition, Dader, Bombay
Good Manufacturing Practices for Pharmaceuticals, A Plan for Total
Quality Control, 3rd edition, west publishing company.
Good Manufacturing Practices for Pharmaceuticals, schedule M.by S
Iyer.
www.google.com

NAGARAJA Y S , Dept. of Pharmaceutics.

NAGARAJA Y S , Dept. of Pharmaceutics.