Preparing For Cleaning Validation

FITHRUL FARMASIINDUSTRI.
COM
PREPARING FOR CLEANING

VALIDATION
CLEANING VALIDATION SEMINAR

Surabaya , 20 August 2015
Sayekti Sayekti Sulisdiarto

1
ISPE Indonesia Affiliate
FITHRUL FARMASIINDUSTRI.COM
OUTLINE
• Why cleaning validation
• Cleaning validation
• Definition
• Objectives
• Cleaning procedure
• General requirements
• Preparation for Cleaning Validation
• Master Planning for Cleaning Validation
2
References
• Pedoman CPOB 2012
• PIC/S Guide to Good Manufacturing Practice, (PE-009-11
especially Annex 15 - 2014)
• ISPE Risk – Based Manufacture of Pharmaceutical Products
Volume 7 – A Guide to managing Risks Associated with Cross-
Contamination (September 2010)
• PIC/S Recommendations on Validation Master Plan, Installation
and Operational Qualification, Non Sterile Process Validation and
Cleaning Validation (PI-006-3, 2007)
• FDA Validation of Cleaning Processes, Guide to inspections
validation of cleaning processes ( 7/93)
3
Why Cleaning Validation

PRODUCT CONTAMINATION
Other
medicinal
products
Other Material Medicinal

eg.
dust,lubricants
products can be Cleaning
, air-borne contaminated by agents
particles etc.
:
Micro-
organism
4

PREMISES AND EQUIPMENT
Any building , facilities or equipment used in the manufacture,
processing, packing, or holding of a drug product shall be of:
Suitable
Suitable size : construction:
All surfaces can be Coved corners, free-
readily contacted by draining, non-reactive,
cleaning process; non-additive, non-
accessed for absorptive materials of
inspection
Design and construction
construction Suitable location :

Location appropriate to
cleaning utilities /
supplies; away from
walls or other
interfering surfaces
to facilitate cleaning, maintenance, and proper operations.

5
Why of Cleaning Validation

BACKGROUND
• When two or more products are to be manufactured in ,
• one facility
• one room within facility , or
• using common equipment
the potential for cross-contamination becomes a significant
issue
• Residues from a compound which remain after equipment
cleaning or other product contact surfaces may pose a risk to
patient safety
• Cleaning procedures should be developed to minimize the risk from
residues .
• The cleaning procedure should be capable of reducing residues to or
below
predetermined safe level base on the risk assessment of a compound
6
Why of Cleaning Validation

CROSS-CONTAMINATION CASE
Recall of a finished product Cholestyramine Resin USP
Case Root cause
Pesticide contamination -On the API manufacturer :
-Pesticide contamination of API due to
in adequate control over solvent drums
-No validated cleaning procedure for
the drums
- On the finished product facility :
- Received some shipment of this
contaminated API , resulted in the
contamination of FBD’s bag .
- Turn led to cross contamination of the
lots produced at that site
- No adequate validated cleaning
procedure for the FBD
7

GMP REQUIREMENTS
Chapter IV : Equipment ( CPOB 2012 )
Clausul Description
4.24 Equipment and utensils should be cleaned ,stored and where appropriate
sanitized or sterilized to prevent contamination or carryover of a material that
would alter the quality of product …..
4.25 Where equipment is assigned to continuous production or campaign
production of successive batches of the same product and intermediates ,
equipment should be cleaned at appropriate intervals to prevent buildup and
carryover of contaminants ( degradants or objectionable levels of microorganism )
4.26 Non-dedicated equipment should be cleaned between productions of

different products to prevent cross-contamination
4.27 Equipment should be identified as to its contents and its cleanliness status ….
4.28 Log books should be kept for major or critical equipment recording ,as
appropiriate ,any validation , cleaning including the dates and identity of
people who carried these operations out
8

COMMON CASES……..
Product y
• Equipment A • Equipment
• Equipment B • Equipment A A
• Equipment • Equipment B • Equipment
C • Equipment C B
Product x Product
• Equipment z
C
The same equipments may be used for processing different products
To avoid contamination of the following medicinal product, adequate

cleaning procedures are essential
9
Cleaning Validation
DEFINITION
DEFINISI PRINSIP
• Tindakan pembuktian • KETANGGUHAN
yang didokumentasikan PRODUK terhadap
bahwa – Kontaminasi silang (al.
– prosedur pembersihan produk lain, air-borne
yang disetujui partikel, debu )
– akan senantiasa – Kontaminasi mikroba
menghasilkan peralatan – Kontaminasi deterjen
bersih yang sesuai untuk • Pemakaian ulang
pengolahan obat
peralatan
Glossarium CPOB 2012 • Persyaratan _ sesuai
CPOB
10
Cleaning Validation
OBJECTIVES
CLEANING VALIDATION
• “ Removal ” of contaminants • A CONFIRMATION of an
associated with
– Previous products, EFFECTIVE and RELIABLE
– Other Material eg. equipment cleaning
dust,lubricants, air-borne procedure ,
particles etc.
– Residues of cleaning agents
• Omitted or reduced analytical
and monitoring in the routine
The “ Control “ of operations
– potential microbial • Provide equipment which is
contaminants
suitable for processing of the
On the equipment surfaces following product
which contact with the product • Taking into consideration
during production process . taking
into consideration batch size, batch size, dosing, toxicology ,
dosing, toxicology , equipment Note a risk-based
equipment size etc. employment
size etc.
11
Fundamentals of Cleaning
Cleaning depends upon process
parameter control…
T ime
A ction
C oncentration /
Chemistry
T emperature
Cleaning also depends upon the

conditions of cleaning…
W ater
I ndividual Performing Cleaning
N ature of Soil
S urface Being Cleaned
12
Cleaning Validation
CLEANING PROCEDURE -1
Written procedures (SOPs) of equipment cleaning

process are required
• For each major equipment :
– Cleaning between different batches of the same
product
– Cleaning between product changes
– Cleaning for dedicated equipment when it is
difficult to clean or hazardous
13
Equipment Categories
Major Equipment - Attributes of Each Category

equipment critical to the Generally large and significant
manufacturing process contributor to overall
contamination
(usually has a unique
May be dedicated
identification number)
Minor Equipment - Generally small but may be used

apparatus and utensils (such for highly concentrated materials
as scoops, hoses, beakers) Not a significant contributor, but
we can’t leave them out of our
which perform a support program
function May or may not be dedicated
14
Cleaning Validation
SOP’s for cleaning of equipment shall be strictly followed

and shall :
– Assign responsibility for cleaning
– Describe in sufficient details ,
• Schedules
• Methods
• Equipment
• Materials to be Used
To prevent ,
• contamination that would alter the identity, strength,
quality, efficacy and/ or safety of the drug product
beyond
the official or established requirements
15
Cleaning Validation
CLEANING PROCEDURE - 3
In addition to Responsibilities, Schedules, Methods,
Equipment, Materials to be used , other details should
include:
– Methods of Disassembling and Reassembling to
ensure proper cleaning and maintenance
– Instructions for removal or obliteration of previous
batch identification
– Instructions for the protection of clean equipment
from contamination prior to use
– Inspection of equipment for cleanliness immediately
before use
– Establishing the maximum time between the
completion of processing and equipment cleaning
16
Cleaning Validation
• Records of cleaning process performed should be

kept and the following informations are readily
available ;
– the area of equipment cleaned
– the persons who carried out the cleaning
– when the cleaning was carried out
– the SOP defining the cleaning process
– the product which was previously processed on the
equipment beeing cleaned
– training record and level of experience of the cleaning
operator
• The cleaning records should be ,

• signed by the operator who performed the cleaning ,
• the person who responsible for Production ,and
• reviewed by Quality Assurance
17
Cleaning Validation
GENERAL REQUIREMENTS -1
• For Cleaning validation process , requiring :
– Cleaning validation protocols
• Sampling
• Analytical methods
• Limits ( “acceptable level” )
– Final report
– Approval by management
• IQ / OQ Elements to consider,
– Examination of equipment design especially when using CIP
– Assure proper identification of process equipment to ensure
correct implementation of cleaning procedures
18
Cleaning Validation
• Cleaning validation should confirm effectiveness of
cleaning procedures;
• The rationales should be logical for selecting :
– Limits for carryover of drug product residue,
cleaning agents and microbial contamination
Should be based on material to be cleaned
• Sufficiently sensitive validated analytical methods
should be employed
19
Cleaning Validation
• Only cleaning procedure for product contact

surfaces of the equipment need to be validated ;
although non-product contact parts should be
considered , such as
• seals,
• flanges
• mixing shafts
• fans of ovens,
• heating elements
• Cleaning intervals should be validated for :

– Time between use and cleaning ;
– Time between cleaning and reuse
20
Cleaning Validation
• Worst-case approaches for similar materials /
processes may be employed
• Typically three consecutive applications of the cleaning
procedure should be performed à shown to be
successfull to prove that the procedure is validated
• “Test Until Clean” is not an appropriate substitute for
cleaning validation
• Products which simulate the physiochemical
properties of the residues may be used where such
materials are either toxic or hazardous
21
Cleaning Validation
GENERAL REQUIREMENTS - 5
• “In establishing residual limits, it may not be adequate
to focus only on the principal reactant since other
chemical variations may be more difficult to remove….
the issue of impurities / by-products needs to be
considered if equipment is not dedicated.”
• “When cleaning is between batches of the same
product (or different lots of the same intermediate in a
bulk process) the firm need only meet a criteria of,
"visibly clean" for the equipment. Such between batch
cleaning processes do notShould
require validation.”
be considered cleaning agent,
microbe and areas in which equipment cleaned ,
stored etc.
22
Cleaning Validation
• Microbiological aspects of equipment cleaning should be

considered; there should be some evidence that routine
cleaning and storage of equipment :
• does not allow microbial proliferation;
• equipment should be dried before storage
• “When variable residue levels are detected following cleaning,
one must establish the effectiveness of the process and
operator performance.”
• “Indirect testing, such as conductivity testing, may be of
some value for routine monitoring once a cleaning process
has been validated. … Any indirect test method must have
been shown to correlate with the condition of the
equipment.”
23
Cleaning Validation
GENERAL REQUIREMENTS - 7
• Manual cleaning methods should be reassessed at

more frequent intervals than Clean-in-place ( CIP)
systems
Revalidation
• Facilities, systems, equipment and processes,
including cleaning, should be periodically evaluated to
confirm that they remain valid; a review with evidence
that still meet the prescribed requirements may suffice
if no significant changes were made
24
Types of Cleaning
Attributes of Each Type
Manual Cleaning
• Adaptable to varying soil loads
Eg. scrub brushes and high
pressure hoses used by an • Highly dependent upon training
operator to remove product
residue
Automated Cleaning • Reproducible if equipment is qualified
(eg. Clean-In-Place) - cleaning for use
performed by a control system or
microprocessor which automatically • Will not recognize variability in the
controls functions of wash, rinse and incoming soil condition
dry
Semi-Automated Cleaning
• Often combines strengths and
(eg. COP – Clean-Out-of-Place) - weakness of the above
performed in a parts washer or sink;
often requires manual intervention or • May depend upon accurate load
disassembly; may be automated placement / disassembly for proper
cleaning
25
Preparation for cleaning validation

General Principle for Validation Approach
High Toxicity
Increasing Therapeutics dose /
Cleaning Validation Cleaning Validation

Required (may use Required PER
Matrix approach) product
Toxicity (LD 50%)
Medium Toxicity
Cleaning Validation Cleaning Validation

may not be Required (may use
Low Toxicity Required Matrix approach)
Very Soluble Slightly Soluble Practically Insoluble
Decreasing Solubility in Water
26
Where to start?
• Collect the necessary data!
27
Gathering Data -1
Data Required Required For
Formulation Attributes Analytical method selection
(eg. dosage, toxicity, concentration, Sampling method selection
excipients, degradants, impurities) Limits determination
Worst-case determination (if grouping / bracketing)
Segregation requirements (if hazardous)
Equipment Characterisation Materials of Construction (MOC) for Recovery Studies

(eg. materials of construction, Surface Area for Limits Determination
geometry, surface area, cleaning Hard to clean sampling locations or “hot spots”
procedure, cleaning agent,
Sampling locations where non-homogeneous
disassembly requirements, likely or
contamination is likely or critical sites
“critical sites”)
Worst-case determination (if grouping / bracketing)
Segregation requirements (if highly difficult to clean
effectively)
28
Gathering Data - 2
Data Required Required For

Process Attributes Residue selection
(eg. batch size, upstream Limits determination
/downstream, extreme Sampling location selection
temperatures / holds times, etc.) Worst-case determination (if grouping /
bracketing)
Segregation requirements (if hazardous)
Standard Operating Procedures Process parameters for validation

Inspection requirements
Sampling locations
Grouping / Bracketing (if applicable)
29
Scientific Rationales Will be Needed for …

• Product grouping / bracketing rationale
• Equipment grouping / bracketing rationale
• Residue selection criteria
• Limit selection and calculation rationale
• Analytical approach (specific / direct vs. non-specific/ indirect /
screening)
• Sampling method selection
• Sampling site selection criteria
• etc.
Scientific rationales should be documented well , as these will

serve as the guideposts for future personnel or auditors
navigating your cleaning validation program
30

EVALUATION OF CLEANING PROCESS
Evaluate on :
• How the residues cleaned ?
– Eg : disolving , physically , reduce surface tension
• What are the cleaning agents ?
– Water (+ Surfactant/Acid / Base)
– Organic solvent
• Cleaning method
– Manual , semi-otomatic or fully automatic CIP ( Clean-in-place)
• Critical cleaning parameter
– Temperature , action, cleaning agent concentration , time
• Cleaning process condition
– Water quality
– Personnel who performed the cleaning process
– Nature of soil
– Surface to be cleaned ( MOC)
GOAL
APPROPRIATE CLEANING PROCESS TO BE VALIDATED
31

ACCEPTANCE CRITERIA
Scientific Limits Determination
• Determine residue limits:
– Sensitivity of analytical methods is critical to establish valid limits
– Logical, practical, achievable and verifiable
– Scientifically justifiable
• Three examples of limits are given:
• as percentage of contamination eg. 10ppm,
• associated with the nature of the substance being cleaned (in
other words, its pharmacological properties) , and
• organoleptic levels eg. visually clean
• Cleaning Agents - “...no or very low detergent levels
remain after cleaning...”
32

SAMPLING METHOD
• “There are two general types of sampling methods
that have been found acceptable.
– The most desirable is the direct method of sampling on the
surface of the equipment
– Another method is the use of rinse solutions ”
• “The analytical method should be challenge in
combination with the sampling method(s) used to
show that contaminants can be recovered from the
equipment surface and at what level, i.e. 50% recovery,
90%, etc.”
33

ANALYTICAL METHODS
Scientific Design of Analysis
• Determine the specificity and sensitivity of the analytical
method(s) used to detect residuals or contaminants
– Testing of rinse solutions should include testing for residues
or contaminants rather than for water quality
• Challenge analytical methods in combination with the
sampling method(s) to show recovery
• Sampling techniques include direct surface sampling
and sampling of rinse solutions.
– “Test until clean” systems should not be used. The need for
retesting may indicate that the cleaning process is not validated.
34
Master Planning for Cleaning Validation

Master Plan Approach
• Validation Master Plan • Separate Master
incorporates all Plans for various
validation activity topics
– Qualification In this session we will talking
about a Master Plan for
– Process Validation Cleaning Validation
– Cleaning Validation
– Computer Validation
– etc
35
Why Do We need a Master Plan?

To Design an Effective Program we
How the Master Plan addresses the
need
need
• Single source for • High Level Philosophy

information • Framework for consistent risk
• Consistent understanding based decision-making
by all team members • Overview of actions and
projects, resource planning,
• Assessment of what needs
scheduling
to be done and by whom
• Location to consolidate our
• Effective control of scientific rationales
strategies to ensure that • Single source for regulatory
they are consistent review
• Less time spent by
regulators in our facility
36
What are Typical Master Plan Sections?
1. Introduction Objective and Scope

2. Description and Background
3. References
4. Responsibilities
5. Validation Approach
– Strategy and organization
– Inventory of qualification activitues to be accomplished
6. Acceptance Criteria ( as appropriate )
7. Procedures &Format ( as appropriate )
8. Risk / Hazard / Failure Analysis ( or may be in separate document )
9. Reference on how to manage change, deviations, continued
verification
10. Appendices :
– List of company guidelines (esp for larger companies)
– Equipment/Product Matrix
– Planning & Scheduling (a high level summary of the actions
needed and when they will be done)
37
Master Plan Contents -1

• Introduction Objective and Scope
– Goals of the Master Plan and brief content insight as
well as boundaries of the Validation Project and of the
Master Plan
– Typical scope boundary elements:
• Production areas included as appropriate:
marketed production, clinical trial materials, R&D,
laboratories, contract manufacturer / packagers
• Types of Residues / Analysis included: chemical,
microbiological
38

• Description and Background
– Overview and orientation to the facility, process,
technology or project; may include product overviews,
as appropriate
– Typical elements:
• Program progress to date or significant iterations
• Dosage forms, primary manufacturing processes,
significant attributes of products (eg toxic, potent),
production characteristics (eg batch, campaign)
39

• References
– pertinent internal and external documents (maybe in the
appendix)
Examples include:
– Scientific rationales, SOPs, risk analyses, literature supporting
key rationales or strategies
– Avoid excessive generic references (e.g., GMPs)
• Responsibilities
– High level overview of key project participants
– Sufficient detail here may supersede the need to
continue to reiterate responsibilities in protocols
40

Example Responsibilities
Department Responsibilities
QA / Validation Protocol and Report Preparation
QC Methods Validation
Recovery Studies
Analysis of Samples
Engineering Surface Area Calculations
Materials of Construction ID
Production / Operations Cleaning in accordance with SOPs
Collecting samples
Important : this will be specific to your organisation’s structure,
personnel and their experience
41

• Validation Approach
highlight the key elements of the validation program
• Scientific rationales – the basis for the selection of
the validation testing and trade-offs
• Basis for the selection of validation priorities (most
likely risk based – e.g., New product introductions,
worst-case products, multi-purpose equipment,
etc.)
• List of validations to be accomplished or already
accomplished in support of the plan (may be in
appendix)
42
Master Plan Contents-6
• Acceptance Criteria
– The acceptance criteria section typically refers to the
way in which the acceptance criteria will be calculated
– If more than one criterion is to be used the document

needs to define how the terms will be applied
(e.g. lowest, type of product, etc)
43

• Procedures and Format
– Often outlines the relevant procedures at a high level
and refers to another document for detail (either in
the reference section or the appendix)
– Will often stipulate what types of documents need to
be prepared and the formats to be followed
– in some cases specific documentation samples or
outlines of document headings may be included
44
• Risk / Hazard / Failure / Criticality / Impact Analysis

– Usually best to reference a separate document to
substantiate scientific rationales , priorities ,trade-offs
• Change Control, Deviation Management, Continuous
Verification
– Interfaces to other quality system elements, such as
change control, deviation management etc should be
provided in the document. The approach to
Continuous Verification should also be outlined
45
Master Plan Contents- 9

• Appendices
Include such items as…
– Planning & Scheduling – include or reference a project schedule
for major milestones
• If referenced, ensure that a document exists
• If included, keep it high level otherwise the master plan
becomes impossible to manage
– Equipment/Product Matrix
– Other appendices may include
• sample flow diagrams for key processes,
• specimen documentation formats,
• data tables of key product attributes including product-
specific limits, etc…..
– The structure and content of the appendix varies greatly from
company to company
46
Managing the Master Plan

• Maintain a Revision History
Ø It is recommended to spend time on fully capturing the reasons
for change when revising the document
• Circulate approved copies of the Validation Project Plan
to all involved departments (especially important for
large companies)
• Keep the Master Plan up to date with regard to changes
in priorities and schedule
Ø Make sure there is clear responsibility for this task
• Place the Master Plan on a periodic review cycle (at
least annually)
Ø to ensure that scientific rationales and the approach to
validation are kept current ;
Ø plan vs actual are kept on schedulle if not justification should
be define
47
Summary Reports for Master Plans

• In some cases, where a plan is developed for a specific
project such as the commissioning of a new plant, a
summary report to the plan means for project closure
between commissioning and routine operation
• In other cases, an annual summary report provide a

convenient update for management on activities from
prior year and providing highlights of goals for next
year including:
– Demonstrate closure of activities during a
regulatory inspection
– Mechanism to discuss/defend project deviations
48
Thank You
Terima kasih
49

Preparing For Cleaning Validation

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FITHRUL FARMASIINDUSTRI.

PREPARING FOR CLEANING

CLEANING VALIDATION SEMINAR

Sayekti Sayekti Sulisdiarto

Why Cleaning Validation

Other Material Medicinal

Why Cleaning Validation

construction Suitable location :

to facilitate cleaning, maintenance, and proper operations.

Why of Cleaning Validation

Why of Cleaning Validation

Why Cleaning Validation

4.26 Non-dedicated equipment should be cleaned between productions of

Why Cleaning Validation

The same equipments may be used for processing different products

To avoid contamination of the following medicinal product, adequate

Cleaning also depends upon the

Written procedures (SOPs) of equipment cleaning

Major Equipment - Attributes of Each Category

Minor Equipment - Generally small but may be used

SOP’s for cleaning of equipment shall be strictly followed

• Records of cleaning process performed should be

• The cleaning records should be ,

• Only cleaning procedure for product contact

• Cleaning intervals should be validated for :

• Microbiological aspects of equipment cleaning should be

• Manual cleaning methods should be reassessed at

Preparation for cleaning validation

Cleaning Validation Cleaning Validation

Cleaning Validation Cleaning Validation

Very Soluble Slightly Soluble Practically Insoluble

Decreasing Solubility in Water

Equipment Characterisation Materials of Construction (MOC) for Recovery Studies

Data Required Required For

Standard Operating Procedures Process parameters for validation

Scientific Rationales Will be Needed for …

Scientific rationales should be documented well , as these will

Preparation for cleaning validation

Preparation for cleaning validation

Preparation for cleaning validation

Preparation for cleaning validation

Master Planning for Cleaning Validation

Why Do We need a Master Plan?

• Single source for • High Level Philosophy

What are Typical Master Plan Sections?

1. Introduction Objective and Scope

Master Plan Contents -1

Master Plan Contents -2

Master Plan Contents -3

Master Plan Contents -4

Master Plan Contents -5

Master Plan Contents-6

– If more than one criterion is to be used the document

Master Plan Contents-7

Master Plan Contents-8

• Risk / Hazard / Failure / Criticality / Impact Analysis

Master Plan Contents- 9

Managing the Master Plan

Summary Reports for Master Plans

• In other cases, an annual summary report provide a

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