RIPER

AUTONO
MOUS
NAAC &
NBA(UG)
SIRO -
DSIR

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
Quality is never an accident.
It is always the result of
intelligent effort.
- John Ruskin

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
Contents:

 Introduction

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
Objective:
• To prove that the equipment is consistently cleaned from
product, detergent and microbial residues to an acceptable
level.
• To prevent possible contamination and cross contamination.

Definition:

 Cleaning validation is a collection of techniques and processes

aimed at maintaining the cleanness standards for the
pharmaceutical equipment.

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 USFDA Guidelines for cleaning validation
 US FDA has required that the equipment to be clean prior to
use (GMP regulation part 133.4). This is one of the basic
GMP requirement and it is indicated in more than one section
of 21 CFR 211.
 Section 211.67 state that equipment cleaning and
maintenance.
 Section 211.180 & 211.182 relates to record that should be
kept for the maintenance, cleaning, sanitation and inspection
of equipment.

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 1 What is to be validated?

2 How it is to be validated?

3 Who is to validate it?

4 Who is to approve the validation?

5 When it must be revalidated?

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 Approach

• Equipment Cleaning Validation is typically based on:

o Product Matrix (Grouping) Approach :

 Perform validation using the most difficult to clean product(s)
produced in an Equipment Train in which all the products use
the same cleaning procedure.

o Individual Product Approach:

 Perform validation of the cleaning procedure for each product
produced in an equipment train.

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 Responsibilities
Production supervisor:
 To ensure that various pieces of equipment are cleaned
according to the relevant SOP,
 To train and monitor the operator for collecting sample by final
swab of the various parts of the equipment.

Head of Q. C department:
 Validating analytical method used to analyze traces of active
ingredients o previous product and detergents used.
 To test sample according to validated analytical method..

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
Head of the microbiology department:
 To analyze and count the microbial contamination.

Head of the Q. A department:

 For writing of the protocol and final report.
 To supervise the operation to ensure everything is done according
to the protocol.

Production manager:
 For checking of the protocol and final report.
Engineering foreman:
 For supporting production personnel during cleaning validation.

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 Complete Properly design
understanding of cleaning methods to
manufacturing ensure maximum
equipment and removal of product
process contamination
Successful
outcome

Good design and Understand the

validation of inherent errors in
analytical test testing and ensure
methods complete training

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
1 Selection of cleaning method
Selecting the scientific basis for the
2 contamination limit
Selecting the worst case related to the
3 equipment
Selecting the worst case related to the
4 product
Establishing the storage period after
5 cleaning

6 Selecting the sampling method

7 Selecting the analytical method

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 1 Selection of cleaning method

 Manual cleaning
 Semi automatic procedures
 Automatic procedures
 Clean in place
 Clean out of place

1. Clean – In – place : cleaning of equipment in place without

disassembling.
• Very consistent and reproducible method.
• Visual inspection of all components is difficult.

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
2. Clean – out – of – place :
• Cleaning of disassembled equipment is performed.
• Washed it in a central washing area using an automated
system.
• Washing area should also require validation for
temperature, detergent quantity dispensed, cleaning
operation sequence.

3. Manual cleaning method :

• Difficult to validate, most elaborate cleaning procedures.
• Training of cleaning operators.
• Risk involved process.

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
3 Selection of worst case related to the equipment

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 6 Selection of sampling method

Direct surface
sampling
Swab sampling Rinse sampling

direct Indirect
method method

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 25 sq.cm to 100
sq.cm

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 Procedure Swab
horizontally with
Pretreat the one side of the
swabs in Squeeze the swab and
sample solvent swab vertically with
other side

Use 10 ml of Cut off the

Filter the handle of swab
sample solvent to
extracted extract the drug into a
sample residue by centrifuge tube
sonication

Analyze the
sample by
HPLC

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 Swab recovery study

• It is performed to determine the ability of swab to

quantitatively remove the contaminant from the surface
sampled.
• The swab is tested as per the validated analytical procedure.

test result reported

% recovered by the swab = x 100
known amount of product spiked

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
Rinse sampling:

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 Cleaning mechanism
Some of the physical actions such as:

SLS,
Brushing Scrubbing chelating
agents

Pressurized
water to
remove Dissolution
Wetting particles
agents,
emulsifiers Oxidation,
Chemical
Detergency reactions
hydrolysis

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 residues

Active residue

Detergent residue

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
 Active residue Detergent residue

Wipe of the cleaned equipment Rinse the clean equipment with

with swab test kit, saturated with purified water.
methanol.

Collect approx. 500 ml from final

Put the cotton swab into vial and rinse into clean amber glass bottle
close with plastic pilfer proof cap. and close with lid.

Send collected sample to Q.C Send the sample to Q.C

department for analysis. department for analysis.

Raghavendra Institute of Pharmaceutical Education and Research – Autonomous

K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721
Raghavendra Institute of Pharmaceutical Education and Research – Autonomous
K.R.Palli Cross, Chiyyedu,Anantapuramu, A. P 515721