Amer Gamal Pres Session11

Equipment Design Consideration
for
Cleaning & Cleaning Validation
Gamal Amer, Ph. D.

Principal
Premier Compliance Services, Inc.
All rights reserved. Do not copy without permission. 1

Cleaning and Cleaning Validation
Life Cycle*
The Overall Picture
Design/Development
Phase
Cleanable Equipment and
Operating Facility
Information and Cleaning Procedure and
Monitoring Data
Validation Protocol
Validated
Procedure Execution &
Implementation
& Maintenance Qualification
Phase Phase
* Based on FDA Guidance on Process Validation of January 2011

Life Cycle
The Development Phase
Information from execution &
Implementation phases
Science, Technology and Risk Knowledge
Equipment/Facility
Define required level Develop/modify
Design as cleanable &
of cleanliness cleaning procedure
with cleaning in mind
To execution Develop cleaning Test cleaning

phase validation protocol SOP capability
Method Method
Development Validation

Life Cycle
Execution & Qualification Phase
Repeat
From
Implementation or No
Development Clean and validate Pass Investigate
Phase the cleaning
Yes
Need for
Cleaning validation Develop Validation Change
Complete report
Change
To implementation management?
phase
Back to
development
Life Cycle
Implementation and Maintenance Phase
Back to Execution Change
or Development Phase Management Yes
Modification?
No
From Execution
Phase Clean using Monitor Review Identify
validated SOP effectiveness of trends & possible
cleaning issues
Back to Information for

Development continuous process
Phase improvement

The Cleaning Continuum
Dedicated Equipment..vs. .Non-dedicated
Single Product Use .. vs. ..Multiple Products Use
Single Product Facility .. vs. ..Multiple Products Facility
Existing/Established Product .. vs. .. New/unknown Product
Low Risk/Potency Drug .. vs. .. High Risk/Potency Drug
Sterile Operation/Product .. vs. .. Non-sterile Operation/Product
_____________________________________________
PDA Points to Consider for Cleaning Validation, Tech Report 29, August 1998

The Cleaning Continuum (Cont.)
Solid Formulation .. vs. .. Liquid Formulation
Manual Cleaning ..vs. .Automated Cleaning
Product Contact Surface .. vs. ..Non-Products Contact Surface
Bulk Ingredient .. vs. ..Finished Pharmaceutical
Early Processing Step .. vs. .. Final Purification Step
Active Ingredient .. vs. .. Non-Active Ingredient
_____________________________________________
PDA Points to Consider for Cleaning Validation, Tech Report 29, August 1998

Implications
You need to consider all these factors when
designing a piece of equipment
A piece of equipment must be tailored to specific
cleaning challenges
You must consider the entire operation & facility
when designing equipment
You must consider the material you will be
cleaning during the design
You must consider where within the process the
equipment is used
You must consider how you will clean
Categories/Types of Equipment
1. Off the shelf

2. Unique/made to order
3. Hybrid

Off the shelf
Equipment available and meets user
requirement
Short lead time for delivery
Established and known
Lower cost
Purchase from experienced quality suppliers
Limited possibility to modify
User must define any required minor or limited
modifications early on and work with supplier
on implementing
Unique or Specialized
No vendor or off-the-shelf equipment
available to meet requirements
User develops the design
Need an equipment fabricator
Involvement of many groups
Long lead time
Increased cost

Hybrid
Normally Off-the-shelf requiring considerable

modification to meet user requirements
Requires extensive collaboration with
equipment manufacturer to define
modifications
Lead time is somewhere in between
Cost somewhere in between

Issues to Consider Prior to
Designing the Equipment
Intended Use of Equipment (determines the need to
clean, etc.)
How toxic or potent is the material to be

processed? (determines residue allowed in next product)
How difficult it is to clean the material? (based
on solubility in cleaning agent and intrinsic difficulty of cleaning)
How do you plan to clean the equipment?

Where will you clean the equipment?
Intended Use
Will equipment be used for multiple products or
single product (Cleaning requirement)
Will equipment be dedicated?
Processing volume (equipment size and location, can it be moved for cleaning
vs. in place cleaning, etc.)
Where within the process is the equipment used

(early step, late step, step with further purification, Bulk, finished, etc.)
Material to be processed and its risk level to the

public wellbeing (Should it be cleaned? Should it be dedicated? Risk analysis)

Risk Analysis
Risk associated with cleaning can be
determined by defining three factors:
Residue allowable R (1 large amount - 5
very small amount)
Solubility in cleaning agent S (1 very
soluble - 5 highly insoluble)
Cleaning difficulty C(1 easy to clean - 5
difficult to clean)

Risk Analysis
Cleaning Risk Priority Number
CRPN = R x S x C
Low Risk 1 - 20
Medium Risk 21 - 60
High Risk 61 - 125
How toxic/potent is the material?
Defines the level of cleanliness that must be reached
Analytical methods that can detect material at low
levels accurately
Ability to sample the surface and the cleaning
solutions and collect sufficient samples for analysis
Multiple use design in cases where contaminants are
not excessively toxic/potent
Closed equipment to prevent compound migration
Possibly dedicate equipment

How toxic/potent is the material?
Multiple use equipment require a design that is
easy to clean
High potency or highly toxic compounds should
warrant extra vigilance when applying the
principles of equipment design outlined later in
this presentation.
Accessible, No difficult to reach, no areas where
contaminants can accumulate, Smooth surfaces,
eliminate appendage that are difficult to reach and
clean, etc.
How difficult it is to clean the
material
Defined based on R&D work
The nature of the material defines cleaning
methodology (manual, automated, etc.) thus
establishing needs for ports, connections, and
manholes
Establishes the cleaning agent and the conditions
for cleaning thus possibly dictating the material of
construction

How will the equipment be
cleaned?
Manual cleaning
Automated cleaning
Semi automated or combined manual and
automated cleaning

Manual Cleaning
Large opening to access interior (hand holes,
manholes)
Lighting for viewing capability
Dismantle-able equipment for cleaning (clamps,
fittings, gaskets, etc.)
Movable would require easy disconnect &
connect capability, wheels, etc.
Movable equipment would affect facility design
(wash room, storage room, size and finishes of corridors)

The Facility
Air Flow
People Flow
Soiled Equipment Flow

Clean Storage Wash Storage Dirty
Clean
Return Corridor
Buffer &
Fermentation Isolation
Degown Media Prep
Utilities
Clean Corridor
Gown
Packaging Finishing
Storage &
Staging
Rounded corners

Automated Cleaning
Washers and dryers for cages, glassware, small
equipment, tools and utensils, etc. must be sized
appropriately for such
Utilities for automated cleaning should be
available at the locations where the cleaning
would take place
Equipment to be properly sized for the washer
Layout of equipment to allow for access of
personnel or equipment for washing.
Automated Cleaning
Automated cleaning in place dictates the
equipment be equipped with spray ball & nozzle
connections, drainage capability, and their
location.
Defines some of the controllers and the logic
Quick-connect ability from the exterior.
Equipment to be capable of complete draining.
Locating the equipment within the space close to
drainage, near needed utility, etc.
Automated Cleaning
Again, piping of the utilities to where the
equipment is located and providing proper
drainage in the facility.
Floor drains to be piped to appropriate
containment.
Floor pitched towards drains
Wall and floor finishes to withstand excessive
liquid use and draining.
Affects room size and equipment layout to allow
CIP skid movement.
Semi-Automated Cleaning
Some components are cleaned in a washer
and other parts will be cleaned manually
Require dismantling
Require moving parts to washer
Cleaning parts in place or moving to sink
Requires reassembly with clamps, fittings,
gaskets, etc.
Where will it be cleaned?
In-Place
For large equipment
Many of the details outlined in automated cleaning
would apply (spray balls, coverage, drainage,
connections, etc.)
Manholes and hand-holes as well as access to them
(no exterior obstacles) to clean difficult to reach
spots
Short pipe runs without sharp bends to make it easy
to access for cleaning
Where will it be cleaned?
Remotely
Equipment reasonable in size and weight to
allow for moving
Equipment with wheels if too heavy to carry or
load on cart
Ability to disassemble for washing
Open design in case of remote washer use

Once all the factors associated with
cleaning the equipment have been
identified, the following general
consideration for designing and
specifying a piece of equipment
should be addressed.

General Design Consideration
Material of Construction and Surface Finish
Material to withstand processing conditions or
cleaning conditions which ever is harshest
Material should be inert to content
Should not deteriorate over time
Surface finish quality and smoothness (prevent
contaminant accumulation and microbial
contamination)

Material of Construction and Surface Finish
(cont.)
Cost of material and of finer surface finish should
be balanced with the process and cleaning
requirements Use a risk assessment approach
Expected life of equipment may dictate material
thickness to allow for future resurfacing
Request supplier provide coupons for cleaning
studies of the material when ordering the
equipment
Disassembly and reassembly
Sanitary design implies ease of disassembly and
assembly
Use of clamps, threads, and/or pressure fittings
for easy connecting and disconnecting
Small equipment design to dismantle to basic
components for washing in a washer or sink
Large equipment dismantle hard to reach
appendages, inlets, outlets, pipes, covers, and
possibly agitators to wash separately
Accessibility of all surfaces
Through hand-holes, manholes, to spray balls
and nozzles
Ensure no unreachable surfaces where
contamination accumulates
Lighting to assist with manual cleaning (sight
glass or hook to hang a light)
Proper location of spray ball or nozzle usually
established empirically

Visual inspection consideration

Cleaning and its validation necessitates
ensuring equipment is visibly clean
Design to provide ability to visually inspect
Sight glass, lighting capability, opening to
look-in and their location, ease of access to
openings for inspection

Sampling consideration for cleaning
Ports to withdraw samples of rinse solutions,
cleaning solutions, product, etc.
Sizing of sampling ports and location are
important design consideration
Cleaning and sanitizing sampling ports
considerations
Sterilize-able ports for microbial sampling
(ability to steam)

Use of disposable liners
Hoppers in tablet filling machine could be lined
with disposable liner to reduce the burden of
cleaning
Design to consider equipping with appropriate
fasteners for the liner
Design for easy introduction and removal of the
liner
Design so that liner fits snuggly

Avoiding or minimize sharp corners
Where surfaces meet should be rounded
Smoothed weld and other protruding elements
and maintain level with general surface
Requirement should be outlined in specification
Confirm that it was achieved through inspection
and certification

Gaskets and connections
All gaskets and connections must be flush with
surface
Must be accessible for cleaning
Tight to prevent leaking and accumulation of
materials within
Gaskets should be easy to remove and clean or
disposable (low cost)

Pipes and valves
Pipes within the piece of equipment should be
of short runs to allow for cleaning and draining
Should be slanted to allow for proper and
complete draining
Venting to allow for complete draining of pipe
runs
Avoid dead legs within the pipes, near valves,
and near sampling ports

Pipes and valves (cont.)
Avoid sharp (90) bends which would be
difficult to clean
Proper valve selection such as diaphragm
valves and not globe valves
Use sanitary valves and pipe fittings

Diaphragm valve
Surfaces
Flat surfaces should be slanted towards drain to
avoid pooling of liquids
Appropriate smoothness/finish to prevent
accumulation of contaminants & microbes
Sufficient thickness to allow resurfacing
depending on the expected life of equipment
Testing ability for glass lined equipment to
identify if cracks exist

Documentation to Support Cleaning
Validation and Operation
Documentation for equipment is required for
GMP compliance and needed to prepare and
execute cleaning validation protocols.
Should be considered during the design stage.
Many are produced prior and during the
design/development phase.(user requirements,
specification, drawings, Cleaning SOP)

Documents needed to support cleaning Validation:
User requirements
Equipment specification
Engineering and design drawings
O&M Manual
Cleaning procedure
Certifications (material, finishes, welds, passivation)
Equipment cleaning log
MSDS for material being processed and cleaning agents

Always order sufficient number of documents
to address the needs of the operation as well as
the validation requirements.
Store one set in a controlled area.
Ensure documents are in the appropriate
language.
Ensure they are correct from a syntax point of
view if translated.

Pre-Installation Testing of
Equipment
Factory Acceptance tests (FAT)
Spray ball coverage, operation and pressure
Weld testing and scope visualization
Confirmation of sanitary pipes, valves, gaskets,
finishes, etc.
Leak testing during SAT
Many of the design aspects related to
cleaning to be confirmed during IOQ testing
Analytical and Testing
Consideration
Validate analytical procedures and methods for
analysis of residuals and cleaning agents
Insure critical aspects of method such as LOD,
precision, linearity, selectivity, recovery-
spiking, consistency of recovery, are
addressable.
Coupons for swab recovery studies should be of
same material and finish - order with equipment
Analytical and Testing
Consideration
Surface sampling techniques and recovery
confirmation (e.g. Swab Recovery Studies)
Rinse solution analysis and relation to
residue on surface
Surface examination procedures
Sampling methodology and proper
sampling ports.

Checklist for Equipment Cleaning
Design Considerations
Choose proper material of construction.

Define appropriate surface finish
requirement.
Define appropriate welding requirements.
Ensure awareness of pipe length limitations
and avoid unnecessary log pipe runs

Minimize or eliminate dead legs.
Ensure all surfaces and pipes are slanted to
promote draining.
Design equipment so that it could be
dismantled if necessary.
Equipment should have accessibility to the
interior.
Equipment should have appropriately
located sampling ports.
Equipment should be designed to give the
ability to inspect its interior.
Ensure that the equipment is equipped with
lighting for the interior.

Spray balls and/or nozzles should be located

in such a way to provide full coverage of
the surface to be cleaned.
Can liners or throw-away bags be used to
reduce the cleaning requirements?

If disposable single use implements are to

be used how will they be used?
Documentation requirements and number of
copies.

In Summary
Equipment design is the first step in the life cycle
approach to cleaning Validation
When designing a piece of equipment you must
consider its use and how to clean it
Design of the equipment may dictate some of the
design aspects of the facility
Ensure proper development of necessary
documentation during equipment design
Insure proper (equipment and material specific)
analytical techniques are developed and validated.

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Equipment Design Consideration

Gamal Amer, Ph. D.

All rights reserved. Do not copy without permission. 1

* Based on FDA Guidance on Process Validation of January 2011

To execution Develop cleaning Test cleaning

All rights reserved. Do not copy without permission. 3

Back to Information for

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1. Off the shelf

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Normally Off-the-shelf requiring considerable

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How toxic or potent is the material to be

How do you plan to clean the equipment?

Where within the process is the equipment used

Material to be processed and its risk level to the

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Soiled Equipment Flow

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Visual inspection consideration

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Choose proper material of construction.

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Spray balls and/or nozzles should be located

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If disposable single use implements are to

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