cleanroom classification

 room in which particles and the viable count is kept within defined ranges
 clean rooms are classified based on
1. the size of particles and
2. the number of particles per cubic meter of air. 

Classification of clean rooms

Clean rooms are classified according to following standards,
 ISO 14644-1
 Federal Standards (FS 209)
 European standards
According to ISO 14644-1
 ISO classify clean rooms into following ISO 1 to 9
 ISO 1 is cleanest from all classes of ISO and
 ISO 9 is least clean or dirtiest from all ISO classes 9 room. In
pharmaceutical Industries following ISO, classes are generally required,
 ISO 5
 1SO6
 ISO 7
 ISO 8
According to FS 209
According to the federal standard, FS 209 Clean rooms are classified as,
 Class100
 Class1000
 Class 10,000
 Class100,000

According to the EU GMP

 Grade A
 Grade B
 Grade C
 Grade D
FS 209 is replaced by ISO 14644-1 but these terms are still in use. In ISO
particle are taken as particles/m³ (cubic meter)and in FS 209 particles
were taken as particles/ft³(cubic feet)
A  simple comparison of clean rooms classification for pharmaceutical industries
is as follow
 ISO             EU GMP               FS
 ISO 5          Grade A          Class 100
 ISO 6          Grade B          Class 1000                      
 ISO 7          Grade C         Class 10,000
 ISO 8          Grade D         Class 100,000
ranges of particle size are considered for classification of clean rooms
 one is ≥0.5 micron (equal to or greater than 0.5 microns) and other is
 ≥5.0 micron (equal to or greater than 5.0-micron particles).
Types Of Particles In Cleanrooms Viable Particles Non Viable Particles
MCQ) which of the following is true about Viable Partices Counts?
a) The process of counting the number of living microorganisms in a clean
room.
b) Viable particles are generated by the personnel working in the clean rooms.
c) Viable particles are not able to move from one place to another place. So
require non viable.
d) usually measured by the settle plate method & by using an air sampler
having a media plate attached.
e) Example Of Viable Particles Bacteria
What Is Non-Viable Particle Count?
 Non-viable particles are non-living particles & do not have any living
organisms.
 Non-viable particles in cleanrooms work as a transporter or carrier  of living
organisms.
 The source of non-viable particles may be HVAC systems, processes and
materials.
 Why 0.5 & 5.0 microns?
 Bcz most of the commonly found bacteria are in the size range of 0.5
to 5.0 micron so this size range is the main source of contamination.
 why we don't measure less than 0.5 micron?
 microorganisms find it very difficult to attach particles less than 0.5
micron size.
 If the microbes attach to the particles greater than 5.0 micron then
these particles become heavy and are not transported along with air
movements but settle down on the ground.
HEPA filters
 High-efficiency particulate air filter.
 the filter which removes 99.95% or 99.97% particulate of size less than
equal to or greater than 0.3 microns.
 ialso called High-efficiency particulate absorbing filter or High-efficiency
particulate arrestance filter.
 Material of Construction a mat consisting of randomly arranged fibres of
glass or semi-synthetic material.
 HEPA filters are used in HVAC to supply clean air in clean rooms.
 HEPA filters may be installed in AHU but are more effective when used in
terminal diffusers, supplying air directly into clean rooms.
 Air from the outside environment contain contaminants like pollens, fibres,
dust, bacteria, viruses, and many other pollutants.
 So these should be filtered and removed from the air before supplying to the
clean rooms.
 Protection to HEPA is provided by using other coarse filters of low
efficiency. COURSE FILTER
 For the protection of HEPA filter following filters are used which are installed
in AHU and remove the majority of large size particulates.
 Mesh filters
 Bag Filters
Mesh filters are also called primary filters and bag filters are called secondary
filters. Mesh filters protect bag filters and in return bag filters protect HEPA filters
so the lifespan of HEPA  is increased.
Mechanism of HEPA Filter
 The HEPA filter does not work like other common filters. Because the gap
between fibres may be larger than 0.3 microns so it is a common question
that than how it filters particles of size 0.3 microns or smaller.
 The answer is that the arrangement of fibres in HEPA filters is unique and
three different mechanisms are used to remove the contaminants and
these are as follow,
 Straining/Impaction/Sieving
 Interception
 Diffusion
HEPA filter removes particulates by a combination of any of three mechanisms,
Impaction removes large particles, interception is for the filtration of medium
particles and diffusion removes smaller particulates.
Classification of HEPA Filters
HEPA filters are classified according to two standard one is European
Standards classification and other is US Standards.
European Standards 
According to European standards, the HEPA filter should be ≥99.95 % efficient.
US Standard.
According to US standards, the HEPA filter should be ≥99.97 % efficient.
European Classification 
According to European standards, HEPA filters are divided into 3 classes
 EPA Filter(Efficient Particulate Air filter)
 HEPA Filter(High-efficiency particulate Air Filter)
 ULPA Filter(Ultra Low particulate Air Filter)
EPA
Filters with efficiency 85-99.95% are called EPA filters.
Subclasses
Class           Retention
E10                >85%
 E11                >95% E12                >99.5%
EPA filters usually filter following,
 Embryo
 Smoke of tobacco
 The smoke of metal oxide
 Black carbon
 EPA is used as a pre-filter for H13 and H14 filters.

HEPA Filters

Class         Retention
H13            > 99.95%
H14            > 99.995%
HEPA filters filter,
 Microparticles aerosol
 Radioactive aerosol
 H13 is usually used as a terminal filter for ISO class 5.
 H14 is usually used as a terminal filter for ISO class 4.

ULPA Filter
 For Microparticles aerosol.
 ULPA filters are used usually for,
 ISO class 1
 ISO class 2 
  ISO class 3

            Class          Retention
U15              >99.9995%
U16             > 99.99995%
U17             > 99.999995%
Note
HEPA do not remove smell or order. for removing smell or odour Filters with
activated carbon are used.
Test for HEPA filter
if HEPA filter is damaged then air quality will be poor and it will contaminate the
cleanroom.
DOP Test (Dispersed oil particulate)
 To check, the integrity of HEPA filter DOP test is used
 in which aerosol of poly alpha-olefin is used.
 In previous practices, DOP (Dioctyl phthalate) was used
 but it was found to be carcinogenic so its use is prohibited
 in DOP test aerosol of PAO is generated and it is scanned by prob of
photometer first on upstream position and later on downstream position.
 The scanning is done by keeping a probe about 25mm away from the
HEPA filter face.
 Scanning results should not exceed 0.01%.
 If the downstream position value is above 0.01% then filter needs
inspection,
 means there may be any leakage in filter or gas kit so after rectification
again scan with scanning prob and if the value is within range filter is pass
and if again value exceeds, the filter should be replaced with a new filter.
 The leaked filter may be repaired but the repaired area should be only 0.5%
of total filter surface.
According to PIC/S HEPA filter of class A and B should be tested
for leakage after 6 months and class C and D after 1 year.

 washing of HEPA filter is not recommended because washing with water

damages the glass fibres arranged in HEPA filters.
 using Vaccume cleaner or compressed air but it is also not recommended
because there are chances of damage to the glass fibres with vacuum
cleaning or compressed air pressure. So the best practice is to replace the
HEPA filter with a new filter.
When to Change the HEPA filter No guidelines define the period after which So
HEPA life span depends upon its usage.
Pressure drop is the main indication which gives an alert to replace the
HEPA filter.
ISO 5 /Grade A

o ISO class 5 is cleanest in pharmaceutical industries

o Air changes per hour  are 240-480.
o Class A is achieved under laminar airflow hood.
o critical operations take place in this class,
 Filling
 Sealing
 Aseptic manufacturing(If sterile filtration is not done)
 Handling of sterile starting materials.
 Manufacturing and filling of sterile creams, ointments
o 3520 particles/m³ for particle size  ≥0.5 micron, ≥5.0 micron is 29
particles/m³.

ISO 6  /Grade B
o Microbial count in Grade B according to EU is 10 cfu/m³.
o Air changes per hour  are 150-240.
o Grade B is the background area of Grade A mean area in which
laminar airflow hood is placed.
o ≥0.5micron  is 35200 particles/m³ and particle count for particles ≥5.0
micron is 293 particles/m³.

ISO 7 /Grade C
o ≥0.5 micron is 352000 particles/m³ ≥5.0 micron is 2930 particles/m³.
o Air changes per hour  are 60-90.
o Microbial count in Grade C according to EU is 100 cfu/m³.
o Grade C is for following operations,
 Solution preparation( if sterile filtration is to be done
later on)
  Manufacturing and filling of creams, ointments,
 emulsions and suspension before terminal steralization.
 Liquid manufacturing area at rest is Grade C.

ISO 8/Grade D 
o ≥0.5 micron is 3520,000 particles/m³ ≥5.0 micron is 29300 particles/m³.
o Air changes per hour  are 05-48.
o Microbial count in Grade D according to EU is 200 cfu/m³.
 Handling of components after washing
 washing of components.
 Tablet,Capsule section(OSD) is Grade D at rest.
 Liquid manufacturing area in operation is Grade D.
 All clean rooms are separated from each other
through the Airlock system.
At Rest
 At rest mean all the equipment are installed in a clean room &
 HVAC system is operational but manufacturing activity is stopped.
 It means the area is cleaned and no operator is performing manufacturing
activity.
At rest particle count in clean rooms is as follow,
Grade A
≥0.5 micron=3520 particles/Cubic meter
≥5.0 micron=29 particles/Cubic meter
Grade B
≥0.5 microns=35200 particles/Cubic meter
≥5.0 micron=293 particles/Cubic meter
Grade C
≥0.5 microns=352000 particles/Cubic meter
≥5.0 micron=2930 particles/Cubic meter
Grade D
≥0.5 micron=3520000 particles/Cubic meter
≥5.0 micron=29300 particles/Cubic meter
In Operation
In operation means all the equipment are installed in a cleanroom and HVAC
system is operational and manufacturing activity is going on in the cleanroom.

Door Interlocking In Pharmaceutical Industries

 clean rooms are the areas where viable and non-viable particles are kept
under control
 to protect the higher cleanroom class from less clean room class,
airlock systems are built.

MCQ) which of the following is true about AIR LOCK SYSTEM?

a) a lock created by the air pressure between various clean rooms

b) to prevent cross-contamination.
c) The airlock is the room which has two or more doors which open into
various areas.
d) Airlock protect clean rooms from contaminants and to prevent cross-
contamination.
e) An airlock is produced by creating differential pressure between two areas
and
f) differential pressure is produced by HVAC.
g) According to WHO a differential pressure of 10-15 pascals should be
maintained.
h) Personnel Airlock (PAL) Material Airlock(MAL)
i) Purpose of Airlock
 To prevent the entry of contaminants ,microbs,less clean air from less 
 In oral solid dosage forms, manufacturing areas prevent the outflow of
powders.
j) The airlock is a closed room between two cleanrooms of different classes
k) Air lock is usually with two doors one door open in one clean room like in
class C and other door opens in another class area like in class  D.
 l) Both doors of airlock should not be opened simultaneously.
m) Interlocking system should be installed in airlocks to prevent the
opening of both door at the same time.
n) An alarm system should be installed which give an alert if both doors are
opened at the same time.
o) The doors of air look should be opened towards higher pressure side so that
it can easily be closed by air pressure.
p) The airlock should always be free from any furniture, chairs, table, shoe
covers etc.
Principle of Air Lock
As it is a general role that air moves from an area of higher pressure
towards the area of lower pressure.
So all airlocks work on the same principle just we have to change the pressure in
airlocks or in adjacent areas to change the type of airlock either it is a bubble,
sink or cascade. 
Types Of Air Locks
There are three types of an airlock system
 Bubble Airlock
 Sink Air Lock
 Cascade Air Lock
Bubble Air Lock  
 pressure inside the airlock is high or positive and in adjacent sides, the
pressure is less or negative.
 Mean air moves from the airlock to the primary manufacturing area and in
the same way from the airlock to the corridor.
 Higher air changes are produced in the airlock.
 It is called bubble because it pushes air outside from the airlock.

 Suppose we want to prevent cross-contamination by Bubble airlock for
granulation area,
 we will build an airlock room between granulation area and corridor and
 create positive pressure in airlock by supplying more air through HVAC say
it is 20 Pa.
  In granulation room produce 10 Pa so when we will open the door, clean air
will move from airlock to granulation area and
 powders from granulation will not enter to airlock because of differential
pressure.
 In the same way in corridor create 10 Pa so when we will enter from corridor
the clean air from air look will move into the corridor.
Sink Air Lock
 the pressure inside airlock is negative and in adjacent areas pressure is
positive
 so air moves from higher pressure area to lower pressure area mean from
adjacent rooms to the airlock.
 from the primary manufacturing area to airlock and in the same way from
the corridor the airlock. It is called sink because the air from both sides
come into the airlock.
Cascade Airlock
 In cascade airlock system pressure increases or decreases in ascending or
descending order
 for example from 30 Pa to 20 Pa to 10 Pa or 10 Pa to 20 Pa to 30 Pa.
 So air moves from higher pressure to lower pressure side and prevent
cross-contamination.
i. For cascade airlock inside of granulation area is maintained negative for
example at 10 Pa and airlock is maintained at more positive e.g 20 Pa and
corridor is maintained at 30 Pa mean highly positive.
ii. According to principle air will move from higher pressure to lower pressure 
so air will move from corridor to airlock and from airlock to manufacturing area.
III. In this case, the corridor will be cleaned corridor having high air changes.

What Is Interlocking?
1. Interlocking is the concept which was make for strong controls over cross-
contamination
2. by controlling the opening & closing of doors of airlocks, pass boxes and
transfer hatches.
 3. Interlocking is the locking system which is applied to the doors of airlocks to
ensure that both doors are not opened at the same time.

Why Interlocking?
the strict SOPs of airlock passage which are as follows ::: During man or material
flow through the airlocks, always enter from one door and then close it tightly and
when it is assured that the door is closed they open the next door.This procedure
helps to prevent cross contamination due to differential pressure built inside the
airlock & adjacent areas 

Wrong Practice
Apart from adopting the above-mentioned practice most of the personnel in
pharmaceutical industries open both doors simultaneously which may result in
following,

 Movement of air from less clean areas to high clean areas.

 Cross-contamination
 Movement of  microorganisms from one clean room to another.

Working Principle Of Interlocks : mutual locking system meaning if one door

is open, the other will not be opened.

Components Of Interlocking System

A good interlocking system has the following main components,

 Electric Lock
 Green Light
 Red Light
 Alarm
 Control Panel
Electric Lock 
The main component attached to the upper portion of the door to perform its
functions.
Green Light When the green light is on it means that the door is properly closed.
Red Light it means the door is open.Red light is not only an indicator of the
opening of the door, but it also gives alertness if the door is not properly closed
due to any fault or reason
An important note
Interlocking systems should be designed in such a way that during any
emergency like a fire accident or electrical failure both locks should be in a
neutral state to prevent any mishap & to allow easy escape of working staff

Why is a Separate Manufacturing Facility Required For

Penicillin And Non Penicillin Products
MCQ) which of the following is true about Penicillin?

a) Penicillins are a group of natural or semisynthetic antibiotics

b) containing beta-lactam rings with 6 aminopenicillanic acid and are effective
against bacteria.
c) Beta-lactam is a 4 membered ring & lactam is an amide in the form of cyclic
amide.

d) This lactam is called beta-lactam because nitrogen is attached to the beta

carbon.
e) Beta-lactam is part of many important antibiotics and these antibiotics work
by inhibiting the synthesis of the cell wall of bacteria.
f) Name of Antibiotics Containing Beta-Lactam Ring
 Penicillin
 Cephalosporin
 Penams
 Carbapenem
 Monobactams
What Is Common In All Beta Lactam?
The similarity between all the above-mentioned classes of beta-lactam
antibiotic is  that all contain 4 membered  lactam ring having 3 carbon & 1
nitrogen cyclic amide.

How Does the Beta-lactam Antibiotic Class Differe?

o The difference between activity or reactivity of different classes of beta-
lactam antibiotics
o is due to the  difference in the attachment of the side chains or different
groups attachment by a peptide bond.

Explanation
The difference is explained as,

Penicillins
 Penicillins have 6 APA or 6 aminopenicillanic acids.

Cephalosporins
 Cephalosporins have 7 aminocephalosporanic acids.

Penams
 In penams, the beta-lactam ring is fused to a saturated 5 membered ring
which has 1 sulfur atom.

Carbapenem
 Here carbon is substituted by sulfur.

Monobactams
 Alone beta-lactam ring,not fused to another ring.

The hypersensitivity reactions of penicillin may include the following,

 Skin Rashes
 Hay Fever
 Asthma
 Hives
 Itching Eyes
 Swelling Of Tongue
 Swelling of face
 Difficulty in breathing
 Runny nose
 Fever
 Anaphylaxis
Anaphylaxis is a life-threatening effect and it may contain many symptoms which
are as follows,

 Tightening of airways resulting in difficulty of breathing,

 Nausea
 Vomiting
 Abdominal Cramps
 Fainting
 Fast or slow pulse rate
 Reduction in B.P

Penicillin allergy is observed in patients sensitive to penicillin because the

immune system recognizes the penicillin drug as a bacteria or virus and
starts fighting against the drug.

Differences in 6 aminopenicillanic acid side chains may cause allergic reactions.

Skin Test
If the amount of IgE is increased after the skin test it indicates that the individual
is sensitive to penicillin.

Why Does Penicillin Manufacturing Require a Separate Facility?

As we discussed in the above portion, penicillins are sensitizing agents
and may trigger hypersensitivity reactions, although the ratio is very low as
10% but US-FDA and other regulatory bodies demand to manufacture these
antibiotics in separate facilities to prevent cross-contamination.

So a common question is 

"What does a separate manufacturing facility mean?

The answer  is very simple:

A separate manufacturing facility is a design that has, 

 Separate manufacturing area from the main plant for manufacturing of other
products.
 Separate HVAC System
 Separate Equipment
 Separate WorkForce
 Separate Laundry
 Separate Canteen
 Separate Washrooms

A rough estimation is that a distance of 75 meters or more than 75 meters should

be maintained between plant to plant.
Good Manufacturing Practice|GMP|Difference between GMP & cGMP

MCQ) which of following is true about GMP?

a) set of guidelines introduced by the US-FDA(Food and Drug Administration).

b) Set of documentation consists of all the good practices
c) which are required for the manufacturing, packaging, testing and
distribution of pharmaceutical produc
d) the guidelines which ensure that
 o high-quality standards are maintained in all batches
of the product and
o the product is safe for use, no risks are associated
with the use of this product and it is free from
contamination.Why GMP?

GMP gives assurance to the consumers that products manufactured here are
of high quality and fit for use without any harmful effect.

Chapters of GMP
GMP has the following 7 chapters
1. Pharmaceutical Quality system
2. Personnel
3. Premise and Equipment
4. Documentation
5. Production
6. Quality Control
7. Complaints and product recall

Pharmaceutical Quality system

It has many guidelines some are as follow,
 Products are manufactured according to GMP.
 Production and control operations are defined.
 Managerial responsibilities are defined.
 Procedure for self-inspection is available.
Personnel
 GMP is implemented by the people working in pharmaceutical industries so
they should be properly trained.
 A training calendar should be available for all the staff.
 Training providers should also be qualified.
Premice & Equipment
 The building should be situated in an area suitable for manufacturing
activities and should not affect the surroundings.
 Guidelines are given for building layout, size and design for all areas like for
production area, Quality Control area, storage area etc.
 Proper Environmental Conditions like temperature and humidity should be
maintained.
 Systems and  Procedures should be available to prevent cross-
contamination.
Equipment
 Guidelines for Equipment size, designing, handling and Preventive
maintenance are defined.
Documentation
 Guidelines for good documentation practice are defined.
 All processes should be written.
 Manufacturing record is stored properly.
Production
 Guidelines for production activities are defined.
Quality Control
 Guidelines for the quality control department are defined.
Complaints and Recalls.
 Procedure and guidelines for handling of complaints and product recall are
defined.
What is cGMP?
 cGMP is currently Good Manufacturing Practice.
 c is always written in small letters and represents a continuous
improvement.
 Current means use of most latest or recent techniques.

 GMP defines the guidelines to get the required results.

 cGMP defines the use of the currently available or recent techniques to get
the required results.
 The basic concept of GMP remains constant like Documentation is the
requirement of GMP and we have to prepare and maintain a proper document
record.
  cGMP is continuously changing with the development of new techniques
like documentation changes from papers to electronic systems.
We can further understand the difference between GMP and cGMP on the
following basis.
1. Based on Technology
a. Weighing Balance
The example to understand the difference between GMP and cGMP is that in
old-time the physical balance was used to weigh the ingredients.
It is the GMP requirement to weigh all ingredients during dispensing,
manufacturing and other critical operations in pharmaceutical industries.
At that time the use of physical weighing balance was cGMP meaning the latest
method available to weigh the ingredients.
When electronic analytical balances were introduced to weigh the ingredients it
became cGMP and the use of physical balance became GMP.

Code oF Federal Regulations (21CFR)

1. it is a combination of many guidelines published by the US federal
department and is published in the official federal register.
Structure Of CFR
 CFR consists of 50 titles.
 Each Title deals with different fields like 
o Title 1 =General provisions
o Title 4 =Account
o Title 10= Energy
o Title  12 =Banks and banking
o Title 21 =Food and drug(For Pharmaceuticals)
 What is 21 CFR?
1. The 21st title of CFR deals with food and drugs so in pharma it is commonly
known as 21 CFR.
2. 21 CFR is cGMP guidelines for all the departments and sections of
pharmaceutical industries.
3. Any pharmaceutical industry or plant which wants FDA approval or
wants to export drugs to the USA must follow guidelines of 21 CFR.
 4. Title 21 of CFR is divided into the following 3 chapters
    Chapter 1 
Food and Drug Administration.
    Chapter 2 
Drug Enforcement Administration.
    Chapter 3 
Office of National Drug Control Policy.
Subchapters
Chapter 2 is divided into 12 subchapters from A to subchapter L.
    Parts 
 Subchapters are divided into parts.
 Three important  parts of Subchapter C are as follow,
 Part 201 
 Part 210 
  Part 211
Part 201
 Part 201 deals with labelling guidelines.
Part 210
 Part 210 deals with guidelines for manufacturing unit activities like raw
material dispensing, manufacturing, packaging till finish products.
Part 211
 Part 211 deals with guidelines for the finished products.
 It gives guidelines for testing of finished products.

Glass Packaging In Pharmaceutical Industries

 Glass is prefered pharmaceutical packaging material because of its high
level of barrier property for moisture and gases.

 Manufacturing & Composition Of Glass 

 The main component of glass is silicon dioxide or sand or silica and it also
contains soda ash,limestone and cullet.
 Glass  is prepared by heating the sand or silicon dioxide,limestone (as
calcium carbonate),soda ash (as Sodium carbonate) and cullet.OTHER INGRI
Selenium or Cobalt Oxide
Selenium or cobalt oxide give better clarity to the glass.
Lead Oxide 
Lead Oxide gives clarity to glass but it also makes the glass soft.
Alumina
It Increases glass hardness,gives clarity and durability.
Boron 
Boron results in low thermal expansion of glass.It also gives high heat resistance
to the glass.
Arsenic Trioxide and Sodium Sulphate
These are used to reduce blistering of glass.
Colourants.
amber color glass is used for pharmaceutical packaging of those products which
are degraded by the light.
Amber Color Glass
For amber color it contains carbon and sulphur or iron and manganese.

Advantages of Glass

Compatible
 Glass is compatible for most of the pharmaceutical products  .
Impermeable
 Glass provides strong barriers for gases and moisture penetration so keep
inside products stable.
Heat Stable
 Stable for holding hot products.
Visibility
 Clear Glass containers allow visual inspection because the product is
visible.
Light Protection
 Amber color glass is used to protect the light sensitive products.
Sterilization
 Product packed in glass packaging material can easily be sterilized.
Dis-Advantages Of Glass Packaging
Cost.
Weight
Brittle
Product Loss
.Ion Leaching
Types Of Pharmaceutical  Glass
Following are types of glass 
 Type I Glass
 Type II Glass
 Type III Glass Type IV Glass/Type NP
MCQ) which of the following is true about Type I Glass ?

a) contains a high level of boric oxide so it is also known as borosilicate glass.

b) Highest grade Of Pharmaceutical glass.
c) Type I glass consists of Boric Oxide Aluminium Oxide Alkaline earth oxide
d) the most inert type of pharma glass
e) having highest hydrolytic resistance and
f) the lowest leaching effect.
g) It is highly resistant to heat.
h) Its Cost of manufacturing is very high.
i) It can easily be sterilized.
Uses of Type I Glass for packaging of Parenteral Products.non- parenteral
Products.
MCQ) which of the following is true about Type I Glass ?
a) made of soda lime alkali glass.
b) Type II Glass contains Sodium Oxide and Calcium Oxide.
c) has average hydrolytic resistance.
d) Hydrolytic resistance of Type II Glass is increased by treating the inner
surface of type II glass containers with sulphur dioxide.
 Due to sulphur dioxide treatment the oxides on the surface react with
sulphur dioxide e.g sodium oxide on the surface is converted into sodium
sulphate and sodium sulphate can easily be removed from the surface by
washing the glass containers.
 This treatment with sulphur dioxide reduces the chances of ions leaching
and  increases the hydrolytic resistance of Type II glass.
 Type II glass is also known as treated soda lime glass or De-alkalized glass.

Uses of Type II Glass

Type II  glass are used for following
 Acidic Aqueous Preparations
 Neutral Aqueous Preparations
 Parenteral Preparations
 Non parenteral Preparations
Note:Type II glass are not suitable for packaging of basic preparations.

Type III Glass

o Type III glass is simple soda lime silica glass.
o Type III Glass has moderate hydrolytic activity.
o When type III is treated with sulphur dioxide it becomes type II glass.
Uses of Type III Glass
 Type III Glass is used for non parenteral products.
 Type III glass is not suitable for aqueous parenteral products.
 Type III glass can be used for non aqueous parenteral products like
sterile powders.

Type IV Glass Containers/Type NP

 Type IV glass is also known as NP Non Parenteral general purpose soda
lime glass.
 Type IV glass has low hydrolytic resistance.
 It is not suitable for autoclave.
Uses of Type IV Glass
 It is not used for Sterile products.
 It is used for topical products.
 It is used for Oral Dosage forms.
Test For Glass Containers
Following test are used for glass containers
 Crushed Glass Test
 Whole Container Test
 Water Attack Test
 Chemical Resistance Test

Validation|Process validation

Validation is one of the most important and common terms used in

pharmaceutical industries and its simple meaning is to provide a high degree of
assurance or confirmation regarding  product quality and system reliability

The concept of validation gives a high level of assurance that products

manufactured in pharmaceutical industries are fit for use and the same quality is
maintained in all batches of the product.
In this article,we will learn about,

 History
 What is Validation?
 Importance of Validation
 Process Validation
 Guidelines & Definitions
 Types Of Process Validation
 What is Prospective Validation?
 When To Perform Prospective Validation?
  What to Do in Prospective Validation?
 What is Concurrent Validation?
 When To Perform Concurrent  Validation?
 What to Do in Concurrent Validation?
 What is Retrospective Validation
 When To Perform Retrospective  Validation?
 What to Do in Retrospective Validation?
 What is Re-Validation
 When To Perform Re-Validation?
 What to Do in Re-Validation?
 Cleaning Validation
 Method Validation
 Computer Validation
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History 
  The concept of Validation in pharmaceutical industries was introduced by FDA
due to the problems in the sterility of parenteral products.
 It was first adopted for the processes but later on,it spread to the following,

 Equipment 
 Media fill
 Purified water production
 Environment control etc.

Pharmaceutical Validation
 In pharmaceutical industries,Validation is a documented evidence to
demonstrate that all the processes, system,utility or facility are designed in such
a way that they produce the same results on repeated usage.
To understand the pharmaceutical validation simply and easily we can say that
validation means to get the same output results  for all pharmaceutical  products
and systems at different time intervals provided that the input should remain the
same.

Explanation
Suppose we manufacture a tablet product by wet granulation method using a
specific procedure,formulation,area and equipment
etc.
During first manufacturing we will check and perform analysis of all critical steps
during granulation to observe the results of the product and when we complete
our three batches with the same quality using same input we declare that our
product is now validated and we can get same quality of product using same
input unless and until we do not change any input value.

Importance Of validation
 Validation ensures the product quality.
 Validation reduces the chances of non compliance.
 Validation reduces the chances of product recall.
 Data of validation acts as proof in making decisions.
 During inspection validation data gives assurance to the inspecting bodies
that the procedures are reliable.
 Meet regulatory requirements.
 Cost of manufacturing is reduced due to less testing because once the
product is validated we do not require intensive testing on all the stages.
 The pharmaceutical industries which do not have a validation system for
manufacturing perform testing on all the stages,means after granulation they
have to perform the analysis of blend to ensure that the assay of the product is
in the range.
 After analysis of blend they compress the tablets and after compression
again testing is performed for content uniformity,assay,dissolution and
disintegration etc.
 In the same manner again testing is required after coating.
  The product is then packed and testing is done for the finish product before
its dispatch to the finish good store.
 We repeat testing on all stages because our process is not validated and it
makes our process costly.
 Once we validate our process then intensive testing is not required. We
build quality in our product by using validated procedures and testing is done
only at critical steps which reduces the cost.

Types of Validation
There are following types of validation
 Process Validation
 Cleaning Validation
 Method Validation
 Computer validation
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Process Validation
It is an establishment of documented evidence which gives assurance that a
process will continuously produce a product having predetermined specifications
and quality attributes.
  Validating each individual step of a process is known as process validation
in the pharmaceutical industry.

Guidelines for Process Validation

 The concept of process validation was first introduced by the US FDA in
1978.
  (cGMP) of finished products give details of validation.

US FDA Definition
US FDA defines the process validation as follow,
 It is establishing documented evidence(prove)which provides a degree of
assurance that a specific process will consistently produce a product meeting
its predetermined specifications and Quality characteristics.

ICH Definition
 According to ICH It is the process of ensuring and providing documentary
evidence that processes within their design parameters are capable of
repeatedly and reliably producing a finished product of the required quality.

WHO Definition
 The documented action of proving that any
procedure,process ,equipment,material,activity or system actually leads to the
expected result.

Explanation
 Process validation in pharmaceutical industries starts from the initial
developmental stage in research and development and continues till its shelf
life in the market to provide assurance of a finished product even after its
dispatch to the market.
 When a pharmaceutical company is going to manufacture a new product it
has no documents for its manufacturing and testing.
 The development of all the procedures for testing and manufacturing which
ensures product quality is known as process validation and method
development.
 When the product is manufactured using the developed  procedure and its
quality and efficacy is tested by using the analytical method which was
developed,we claim that our process for manufacturing and testing is validated.

Also Read
Qualification|FAT|SAT|DQ|IQ|OQ|PQ

When to perform Process Validation?

Process validation is performed in case of following,

 For manufacturing new products.

 In case of any change in the manufacturing process which has a major
effect on product quality.
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Types Of Process Validation

Process validation in pharmaceutical industries are of following types

1. Prospective Validation
2. Concurrent Validation
3. Retrospective Validation 
4. Revalidation

1.Prospective Validation
 Prospective validation is establishing documented evidence that a system
performs as it is intended based on pre-planned protocol.(Before process
implementation).
 Prospective validation is performed in a research and development lab on a
small scale.

When To Perform
 Prospective validation is performed for developing new products.
 Prospective validation is performed if we make any change in the
manufacturing process which has a major effect on the product quality.
 This type of validation is performed before starting the routine batches of
production.
 Prospective validation is performed at the stage of product development.
  In this type of validation all the process is divided into different steps and
each step is monitored critically.
 The impact of different parameters is observed.
 
What to Do in Prospective Validation?
 As we know, prospective validation is carried out in the research and
development stage so its start from developing formulation.
 Formulation of a new product is developed at this stage.
 Specification of raw materials are defined.
 Procedure for manufacturing is developed in the form of validation protocol.
 Procedure for cleaning validation is defined.
 All the critical points are observed on risk based analysis.
 Process parameters like mixing time,drying time etc are defined and
adjusted to get desired results.
  Batch Manufacturing Record  is prepared.
 Testing method for analysing the product is developed.
 Sampling plan is prepared.
 Technology transfer documents are  prepared.
 Environmental factors like temperature and humidity and storage conditions
are defined.

Results 
 Usually three batches are manufactured at this stage and all should produce
desired results using the same parameters.
 If we have to make changes in parameters of the first batch to adjust the
results,these changes are made through proper change control procedure.
 The batch in which we make changes will not be considered the validation
batch.
 We will have to take the next three batches with the same parameters to
build confidence that our procedures and methods are reliable.
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2.Concurrent Validation
 The word concurrent can be remembered by a simple word current,which
means this type of validation is performed on current production batches.
 Concurrent validation is performed in the production area after getting
satisfying results of prospective validation.
 In concurrent validation the product is manufactured in the production  area
using the production facility and equipment.

When to Perform Concurrent?

Concurrent validation is performed in following,

 Product which has completed its prospective stage,is validated in the

production area during concurrent validation.
 When there is a change in process which has no significant effect on
product quality.
 Change in a raw material source.
 When a validated batch is required to be manufactured in other
facilities(Plant) then no need to perform prospective validation only to do is to
perform concurrent validation.
 When there is change in equipment used.
 When there is only change in tablet strength and previous strength was
validated by the prospective validation and change strength has the same ratio
of API and Excipients.

What to Do?
 Before starting the concurrent validation it is ensured that the operators
involved in the manufacturing process are trained.
 All the equipment,utility and systems are qualified.
 Three batches are manufactured  to ensure the same product quality.
 In concurrent validation all the critical parameters of batches which are
under manufacturing are observed.
  All the parameters are adjusted according to prospective validation.
 Sampling plan is followed as provided by the product development
department.

Summery
In concurrent validation we manufacture the large scale batches using the same
parameters as manufactured in small scale during prospective validation to
ensure that our process developed is capable of producing the quality results.
 Samples are checked at specified time intervals.
 Prospective validation is done for three batches.
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Also Read
100 MCQs to revise your pharmaceutical knowledge.

3.Retrospective Validation
Retrospective validation is documented evidence that products manufactured in
the pharmaceutical industry using validated procedure maintain its quality and
purity in the market during the period of its shelf life.
Retrospective validation is performed after the dispatch of product in the market.
What to Do?
 In the pharmaceutical industries the reference samples are withdrawn from
the finish product batches before its dispatch to the market.
 After the specified time period the sample is taken from the reference
samples and is tested.
 It is done to ensure that our product in the market is still meeting a quality
attribute during its shelf life.
Following type of data is also collected during Retrospective validation,
 Number of  batches manufactured for a defined period of time.
  Batch size
 Strength of the product.
 Manufacturing and expiry date of the product.
 Master documentation.
 List of deviations and corrective actions.
 Stability testing data for different batches.
It is used for audits of validated processes.

4.Re-Validation
Validation is done once in the product life cycle until there is no change in the
product manufacturing parameters.
In some specific circumstances we have to revalidate our products.

When To Re-validate
The revalidation of process is required in following cases,

 When there is a change in critical parameters.

 When there is a change in product formulation.
 When there is a change in the product process.
 When there is a change in equipment.
 When there is a change in the facility.
 When there is a change in primary packaging.
 When there is a change in raw material density,particle size etc.
 Source change of API.
 Change in any process parameter like mixing time,drying temp,etc
 When there is a change in batch size.
 When there is a change in the plant.(Shifting from one plant to other)
 Periodically checking the validation results.
 When the product fails to meet the specification.

Also Read
Pharmaceutical Questions and Answers.
Cleaning Validation
 Cleaning validation is documented evidence that method developed for
cleaning is capable of removing the chemical,biological residues and all traces
of excipients, API and detergent are properly removed.

Read More
Cleaning Validation In Pharmaceutical Industry

Method Validation
Method validation is documented evidence that the method developed for
analysis of pharmaceutical products is suitable for producing the desired results.

Computer Validation
Computer validation is documented evidence that all the computer-based
operations will produce the desired results.

Cleaning Validation In Pharmaceutical Industry

Cleaning validation  is a process that is gaining more & more attention day by
day in the pharmaceutical industries. The reason behind its highest demand is
that most of the regulatory bodies are now strict on the process of cleaning
validation.
Cleaning validation is the process of validating the cleaning method or process
so first have a look at what is cleaning?

What Is Cleaning?
The process of removal of residues of previous products from any equipment
used for manufacturing/packaging or area is known as cleaning.

The pharmaceutical products or area can be contaminated by one of the

following,
 API Of Previous Product
 Excipients Of Previous Product
 Microbes
 Airborne Particles
 Residues Of Detergents

If all the steps and processes involved in cleaning are written and documented, it
is known as cleaning method validation.

What Is Cleaning Validation?

 Cleaning validation is a process that ensures that the method or process
used for cleaning is so accurate that it removes not only residues of previous
product, APIs & excipients but also removes microbes, chemicals & residues of
the detergent up to defined limits.

 Cleaning Validation is documented evidence that gives us a strong

assurance that the process which we are using to clean equipment, parts,
utensils or an area will produce a predetermined level of cleanliness by removing
the residues of previous product, microbes and detergents.

 The process of cleaning is documented and validated to prevent cross-

contamination of manufactured products from carryover of the previous product, 
microbes, chemicals or detergents.

Theme / Principle Of Cleaning Validation

The theme or basic principle of cleaning validation is as follows,

 To give assurance that the performed cleaning activity is done in such a

way that it removes all carryover or residues of previous product,  microbes or
detergents or all above mentioned are removed up to the acceptance criteria.
Cleaning Validation Explanation By Simple Example
 Cleaning validation is used to ensure that the cleaning procedure used is
accurate to remove the contaminants.

 It can easily be explained by the example of Building Construction & its

inspection process to award the clearance certificate.

 For large buildings when the construction is completed it is inspected by the

inspection bodies to ensure that the contractor built it by following all the required
measures and it is completely suitable to use or live in.

 The inspectors may take some samples of concrete and marbles to ensure
that the high-quality material is used during building construction.

 On surety of all the required parameters, the building is awarded the license
or certificate to use and live.

 In the same way,any equipment in the pharmaceutical industry cleaned by

the designated staff is then inspected by the inspection body to cross-check that
the cleaning procedure used is adequate to fulfill the regulatory requirement.

 The inspectors collect the samples from the surface of cleaned equipment
and test it in  the Quality Control Department to ensure that the required level of
cleanliness is achieved.

 If the results of samples meet the requirements then it is said that the
method used for cleaning is validated and it can be used with confidence.
Also Read
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Importance Of Cleaning Validation

Cleaning validation importance in pharmaceutical industries can be described by
some following key points,

 Cleaning validation protocols fulfill the regulatory requirements.

 Cleaning validation provides a high level of assurance that by using the
written procedure we can achieve the same level of cleanliness all the time.
 The cleaning validation method assures that there are no chances of cross-
contamination.
 Cleaning Validation gives surety that microbial growth is prevented.
 With proper cleaning, equipment life is increased & downtimes are reduced.
 Product quality is improved.
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Cleaning Validation Requirements

A common question is how a cleaning validation is started? or what are the
requirements for cleaning validation in pharmaceutical industries?
Following are the main requirements,

1. Cleaning Validation Protocol

2. Validation Team 
3. Equipment Selection
4. Cleaning Method 
5. Sampling Plan
6. Acceptance Plan

1. Cleaning Validation Protocol

 For any cleaning validation process,  first of all, a protocol is prepared.
 Cleaning validation protocol is a basic document like BMR or Batch
Manufacturing Record.
 As we know that in BMR every step is mentioned which guides us on how a
batch is manufactured.
 In the same way, the cleaning validation protocol includes all the details
regarding how the cleaning validation will be performed.

Cleaning validation protocol also includes information regarding the following,

 Cleaning Method Used

 Amount Of water/solvent Used
 Type Of detergent
 Cleaning Type
 Sampling Type
 Sample Size
 Analytical Method Used
 Acceptance criteria 

2. Validation Team
 For performing cleaning validation a team is established & the roles of each
individual or department are defined.

Team Structure
The structure of the validation team may vary pharma to pharma but a basic
team may consists the of following,

 Validation Officer
 Production Officer
 Quality Assurance Officer
 Quality Control Department
 Product Development Department
 Maintenance Department

The personnel or team involved in cleaning process validation should be trained

regarding all the cleaning steps and must be aware of the cleaning protocols.

3. Equipment Selection
 The equipment for which cleaning validation is to be performed is checked
critically to establish how to clean.

 The parts of equipment which are in direct contact with the product are
selected for cleaning validation.

 The parts or locations of the equipment which are difficult to clean are
highlighted to ensure proper cleaning & sampling.

4. Type Of detergent
 The detergent used for cleaning validation should be selected carefully and
those which are easily removed by rinsing are encouraged.

 Before using any detergent its composition should be known and

acceptance criteria should be given to calculate the results.

5. Sampling Plan
 Sampling plays an important role during cleaning validation and the
sampling plan should carefully be defined, meaning how to take samples i.e
direct sampling or indirect sampling.

6. Acceptance Criteria
 Before starting the cleaning validation the acceptance criteria or acceptance
limit should be defined based on the product properties and size of equipment
used.
 Here swab limits and rinse samples limits are defined and our cleaning
results should comply with the defined limits.

When Should Cleaning Validation be Performed?

Cleaning validation is generally performed in the following circumstances,

 Cleaning Validation is performed first time during qualification or validation

of the manufacturing process.
 When we make any critical change in the cleaning process.
 When there is a critical change in formulation.
 Cleaning validation is also performed when there is a change in Equipment.
 When there is any modification or change of cleaning agent.

FDA Guidelines For Cleaning Validation

US-FDA or U.S Food and Drug Administration describes guidelines for cleaning
validation in 21 CFR section 211.67.(21 CFR cleaning validation)

Section 211.67 (A) states that,

Equipment & utensils should be cleaned, maintained as recommended for the
nature of the drug, sanitized / sterilized at suitable intervals to prevent
contamination which would alter the safety, identity, strength, quality  of the drug 
beyond the official or other established requirements.
Section 211.67 (B) states that 
 Written methods should be developed and followed for cleaning &
maintenance of equipment and utensils used in manufacturing,processing,
packaging and holding of drug products.

The above mentioned written procedures shall include following,

1.
 Assignment of responsibility of cleaning & maintaining the equipment.

2.
 Cleaning & maintenance schedule.

3.
 Description of details of the method,equipment & materials used in cleaning
and maintenance also include disassembling & reassembling of equipment
necessary to assure proper cleaning & maintenance.

4.
 Removal of previous product or batch.

5.
 Protection of cleaned equipment before use.

6.
 Equipment inspection for cleanliness just prior to use.

Section 211.67 (C) states that,

 Record of cleaning & maintenance shall be maintained.

Also Read
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Steps Of Cleaning Validation In Pharmaceutical Industries

For basic and easy understanding the cleaning validation after the above-
mentioned requirements  is divided into the following steps

 Step 1
               Cleaning

 Step 2
              Sampling

 Step 3 
             Testing/Analysis

 Step 4
            Acceptance Criteria

Step 1
                      Cleaning
The first step in cleaning validation is the type of cleaning to be used.

 An important point to be remembered is that Cleaning is the main activity

that is to be validated in the cleaning validation process.

 So the method used for cleaning should be acceptable and accurate.

Types Of Cleaning.
Following are main types of cleaning which are used in pharmaceutical industries
for the cleaning of equipment,

1. Manual Cleaning
2. Cleaning In Place (CIP)
3. Cleaning Out Of place
4. Immersion cleaning Method
5. Ultrasonic Cleaning

1. Manual Cleaning
As the name indicates it is the most traditional type of cleaning performed by
hands.
It is usually the most difficult method to validate due to person to person
variation.
This cleaning method consists of the following main steps,

 Wiping with water/solvent

 Brushing or scrubbing
 Thorough Cleaning With Detergent
 Rinsing with water/solvent
 Disinfection

2. Cleaning In Place (CIP)

Cleaning in place is also known as CIP and it is the automated type of cleaning.
In the CIP method following are commonly used,

 Fixed or Rotating Spray Balls

 Washing Tank
 Recirculating Pump
 Detergent Tank
 Pipings

In this type of cleaning the inputs are given and all the parameters like water
quantity, water pressure, amount of detergent and drying time remain constant or
fixed during all the cleaning process of a specific equipment.

3. Cleaning Out Of place

As the name indicates this cleaning is not done at the equipment place, here
parts removed are washed and dried outside the area in a specific place using
cabinets or tunnels.

4. Immersion Cleaning Method

In the immersion cleaning method,the equipment to be cleaned is dipped in the
cleaning agent to achieve the required level of cleaning.

5. Ultrasonic Washing
This type of cleaning is done using ultrasonic waves to ensure proper cleaning.

Bracketing Method In Cleaning Validation

To perform Cleaning validation for all the products is not possible because it will
require a lot of time and money for testing so we decide the cleaning validation
for a product based on bracketing or matrix approach.

Bracketing Approach
In the bracketing approach, we select only one drug from many which are
manufactured using the same equipment,procedures and may have the same
class of excipients.

Worst Case Scenario In Cleaning Validation

We select the one product based on the Worst Case Scenario.Worst worst-case
is also known as 'difficult to clean' and product for the worst case is selected on
the following basis.

 The least soluble drug product manufactured on the equipment.

 Most toxic drug product
 A product having a low therapeutic daily dose
 Higher concentration of API
 Color Product

Step 2
                    Sampling
Sampling means to take samples after cleaning of equipment which is used for
manufacturing or packaging.

 The samples are collected from the cleaned equipment and then these
samples are analyzed for acceptance criteria.

Types Of Sampling Method

The sampling method used for cleaning validation in pharma may be of two
types,

 Direct Sampling Method

 Indirect Sampling Method

Direct Sampling Method / Swab Sampling Procedure

 In the direct sampling method, the surface Swab sampling procedure is
used.

 The swab is usually a sterile cotton bud-like structure that is physically

rubbed over the hotspots or defined places of the equipment.
Swab Recovery Method
The swab recovery method is the procedure that is used to recover the residues
or carryovers from the swab bud into the solvent and then it is analyzed to
calculate whether it is within limits or not.

Validated Swab Recovery 

The swab recovery method used for a specific worse case drug product is
validated to ensure that the residues are dissolved or recovered from the solvent
or not.

During establishing a validated swab recovery method we check the following,

 Is the solvent used, properly recover the residues or not?

 The swabbing procedure used is accurate or not.
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Procedure
 Take swab needles or swab sticks (usually 2) according to the requirements
(surface area) and dip them into a flask containing the solvent.

 The solvent is selected according to the solubility of the worst-case drug.

 The swab needles are pressed along the walls of the flask to remove
excess solvent.

 The swab needles are then placed in covers or vials and are closed.
 The swab needles are then delivered to the production or packaging area
where the equipment or part is to be sampled.

 As we are validating the method, the worst-case selected drug samples are
randomly applied at the surface of equipment above & below the acceptance
criteria to calculate acceptance limits for swab samples.

 The constant surface area is required for calculations so a constant area is

sampled with a swab.

 To ensure the constant area for swab the plates of SS 316L are used.

 Usually, a 10cm×10cm plate is used so the total surface area is 100cm².

 Place a 10cm×10cm plate on the equipment surface containing applied

residues.

 The swab stick is removed from the cover & and is rubbed inside the area of
the plate from right to left or left to right.

 Rotate the swab stick face and rub it from up to down side within the same
surface area.

 One or two swab sticks can be used depending upon the validated method
 All the swab sticks are placed in covers & are delivered to the Validation
department for testing.

 The swabs are removed from the cover and heads or buds of the swab
sticks are cut with a sterile cutter and are dipped inside the same solvent vessel
which was previously used.

 These swab bulbs or buds are stirred in the extraction solvent for some time
and later are removed.

 The solvent is then analyzed by using specified testing methods to calculate

the acceptance criteria.

 If analysis gives required results then it indicates that the method is

validated and if not then the solvent used or swab procedure can be changed &
again validation is done to establish a proper acceptance criteria.

Also Read
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Actual Swab Sampling during Cleaning Validation / Swab Sample

Collection
 For most cases the surface of the equipment may not be smooth and it may
be difficult to take swab samples in pharma from 100cm².

  It may be the case where surfaces are difficult to reach so here the area
taken is calculated and adjustments are made for acceptance criteria according
to the validated sampled area.
Cautions
 During Swab sampling,rub swab stick only  in one direction and don't rub
the swab stick back and forth.

 Immediately after taking swab samples, place the swab stick in the cover
and close it.

Advantages Of direct Sampling

Following are some main advantages of swab or direct method of sampling,

 Samples can easily be taken from places that are difficult to clean and are
accessible.
 If the residue is insoluble in the cleaning solvent then it can be physically
removed by swab and then tested.
 This method is also suitable for taking samples of the material which is dried
out on the equipment surface.

Indirect Sampling Method / Rinse Sampling Technique

The indirect method of sampling in cleaning validation is also known as the rinse
sampling technique or rinse sampling method in pharma.

In this method the equipment is rinsed with water or solvent and then this sample
is tested for acceptance criteria.

During the rinse sampling technique used in pharmaceutical industries, the

samples of water or solvent are taken after final cleaning and are analyzed by the
method specified in the validation protocol.

In the rinse sampling technique, the amount of water used for rinsing samples
and the time of rinsing is also measured.

Advantages
The advantage of this indirect method of sampling in cleaning validation is that a
large surface area can be analyzed.

This method is also used for the places to take samples that are not accessible
for swab samples.

Note
 One important point to remember before sampling either by the swab or
rinse method is that,first of all, organoleptic senses are used.

 It Means visual inspection & checking the equipment  for smell or odor.

 If the equipment is visually not cleaned or there is some type of smell or

odor it means the method used for cleaning was not accurate so first ensure
accurate cleaning.
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Stage 3
                            Testing
For testing or  analysis, two types of methods are used,

 Specific Method 
 Non-Specific Method

Specific Method
For accurate testing of toxic contaminants, the specified method is used and it
involves following,
 HPLC
 Flame Photometry
 Titration
 Ion Selective Electrode
 UV spectrometry
 Enzyme Detection

Non-Specific
It involves following,
 pH
 Conductivity
 Total Organic Carbon (TOC)

Stage 4
              Acceptance Criteria
Acceptance criteria are calculations that we have done and established during
method validation and then during cleaning validation, the results are compared.
Acceptance criteria can be established by following three methods,

 Visual Inspection
 Dose Percent
 Parts Per Million

Visual Inspection
 Acceptance criteria for cleaning validation by visual inspection is that there
should be no visible contamination on the equipment or area.

Dose Percent
 Not more than 0.1% of the normal therapeutic dose of one product should
appear in the maximum daily dose of subsequent products.
Parts Per Million
Not more than 10 parts per million (ppm) of one product will appear or occur in
another product.

Acceptance criteria should have the following properties,

 Achievable
 Practical
 Verifiable
 Scientifically Sound

Calculations Of Acceptance Criteria

Main important point to keep in mind is that acceptance criteria calculations are
made before starting the cleaning validation as we discussed earlier & actual
results are compared with these values.

Based On Therapeutic Daily Dose

 This method of calculation is used when we have the value of TDD or
therapeutic daily dose.

 It is commonly used during final product changeover or cleaning.

Principle
 The basic principle of this calculation is that the standard therapeutic daily
dose of the contaminated product(next,) may be contaminated by not more than
a specific proportion, usually 1/1000 of the therapeutic daily dose of the drug
substance which is under investigation(previous) in cleaning validation.
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MACO Method In Cleaning Validation

To establish a method for allowable carryover also known as Maximum Allowable

carryover (MACO) use the following formula,

MACO =    TDD(previous) × MBS

                    SF    × TDD(next)

MACO = Maximum Allowable carryover (It is the acceptable transferred amount

from the previous product)

TDD(previous) = Standard therapeutic daily dose of the investigated product in

the same dosage form.

MBS = Minimum  size of Batch (Of the Next product)

TDD(next) = Standard therapeutic daily dose of the next product.

SF = Safety Factor (Usually 1000 is used)

Example
In the pharmaceutical industry,  Product A was manufactured having TDD of 15
mg with a batch size of 150 kilograms.

Cleaning was done for product B having TDD of 300 mg with a batch size of 60
kilograms.

Both are tablet products and the safety factor is 1000. 

Calculate Maximum Allowable carryover (MACO) for Product A In Product B

Use above mentioned formula as

MACO =    TDD(previous) × MBS
                    SF    × TDD(next)

Now put values according to the statement

MACO =    15(mg) × 60,000,000(mg)

                    1000   × 300 (mg)

After calculation, the answer is 3000 mg or 3 grams.

Based On Toxicological Data

During the situation where the therapeutic daily dose is not given then in those
circumstances, the toxicity data are used to calculate the MACO.

This method is used for following,

 Detergents
 Intermediates

The calculation method used is known as NOEL

No Observable Effect Level (NOEL)

No Observable Effect Level or NOEL method is also used to calculate the MACO
but first, we have to calculate the NOEL by using lethal dose as follows,

NOEL = LD⁵⁰(g/kg) 70(kG person)

                              2000

Using the NOEL value the MACO can be calculated from the following equation

MACO = NOEL × MBS

                SF × TDD(next)
MACO= This term represents Maximum Allowable Carryover.

NOEL= No Observed Effect Level

LD⁵⁰ = Lethal dose 50 g/kg

70kg = Weight Of An Average Adult

2000 = Empirical Constant

TDD(next) = Largest Normal daily dose for Next Product

MBS = Minimum  size of Batch (Of the Next product)

SF= Safety Factor

Safety factor 200 is used when API is taken Orally & it varies depending on the
dosage form.

 Safety Factor for Topical = 10-100

 Safety Factor for Oral Products = 100-1000
 Safety Factor for Parenterals = 1000-10,000
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Limits For Swab

If we assume a homogeneous distribution then a general recommended value
can be set for swabs content.

It is used for the preparation of method of analysis & limit of detection.

For whole equipment, the target value can be set using the following equation,

Target Value(ug/dm²) = MACO(ug)

                       Total Surface Area(dm²) 

Example
If MACO is 600 mg and total surface area is 1600 dm² calculate the swab value.

Solution
Put values in above 
600×1000/1600 = 375ug/dm²

Rinse Limits
The amount of residue on the equipment is assumed to be equal to the amount
of residue in the rinse volume.

The rinse limit can be calculated by following

Target Value(mg/l) = MACO(mg)

                       Total Rinse Volume

Why Do We Use Three Batches For Validation?

In this article we will discuss the answer of a very common question which arises
in the minds of all professionals dealing with the processes which require
validation.

 The question is,

"Why do we use 3 batches for validation?
Before the answer of the above question first we should be aware of validation.
What is Validation?
 Validation is documented evidence that ensures that a process or procedure
consistently produces a product with the same quality standards.

Validation has a great importance in pharmaceutical industries because for every

product  manufacturing we conduct a validation activity.

This process validation gives us assurity that by using the defined process we
can consistently get the same quality product.
Read more
Validation and types of validation

Basic Concept
 The conventional practice or basic concept regarding validation is that we
should always take 3 batches for validation and if all the 3 batches meet the
requirements then we can start commercial scale production.

Now the question is that is there any regulatory requirements for 3 batches?
Or
Why do we take only 3 batches, not 1,2 or 4? 
 The answer to the first question is that there are no guidelines for the 3
batches concept,even FDA,ISO have not specified the 3 batches concept.

"FDA guidelines for industry on process validation general principles and

practices" does not talk about the 3 batches concept and it also does not specify
the number of batches.

 Actually the number of batches for validation depends on the risk involved.
 The pharmaceutical industries have to decide the number of batches
required for manufacturing.
 The main purpose for selecting the number of batches is to support the
statistical data.
 The product for which we have less data we will have to perform validation
on more batches.

Justification for 3 Batches.

 The traditional justification behind the selection of 3 batches is that during
manufacturing of 1st batch quality may be built in the product accidently.
 During manufacturing of 2nd batch quality may be regular.
  If the same quality is achieved in the 3rd batch it means that our results are
consistent and are reproducible so it ensures  validation or quality of the 3rd
batch gives us assurance that our process is validated.
 If we get desired quality standards in the first batch it may be incident and if
we get the same quality in the second batch it may be coincident and if we get
the same quality in the third batch it is called consistent.

Why not less than 3?

 For confirmation of reproducibility  we should have sufficient numbers of
batches  to compare batch to batch variations.
 If we select 2 batches for validation then we can not compare the data of
two batches because comparison between two points always gives a linear line
so to show a difference we need three points.
 So generally we take 3 or more than 3 batches for validation.
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Why not More than 3?

 As we know currently there are no guidelines available for selecting the
minimum or maximum  number of batches so we can also take 4 or 5 batches.
 As the number of batches is increased the cost of the process and time
required is increased so all pharmaceutical companies usually select 3 batches
for validation.
Conclusion
There are no guidelines for selecting 3 batches for validation; we only use 3
batches to show better statistical data for reproducibility.

GMP.
Later on, it became the latest practice to attach a printer with the analytical
balance to get results of all to weigh in print form so it became cGMP and use of
simple analytical balance became GMP.
Compression
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