Pharmaceutical Cleaning and

Cleaning Validation
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Who Am I?
Jeff Phillips
Sr. Manager, Science and Marketing
20+ Years Pharmacology, Pharmaceutical,
Medical Device and Validation Experience
Alconox, Inc. (New York, USA)
jphillips@alconox.com
++(914)948-4040
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Chemistry of Cleaning

How Does One Chose a Cleaner?

Chemistry of Cleaning

Easy to Choose Aqueous

Water is relatively cheap, safe and abundant
Starting with the universal solvent (water), by
blending ingredients, virtually any soil type can be
cleaned
Modern aqueous cleaning know-how goes back
over 70 years; soap based cleaning goes back
millennia.
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Chemistry of Cleaning

Hard to Choose Which Cleaner

Thousands of cleaner suppliers
Quality levels ranging from appearance grade
to semiconductor quality
There are formulations for gross soil removal
and fine trace soil removal
Formulations change for economy,
performance or marketing claims
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Chemistry of Cleaning

Aqueous Cleaner Selection

Variables for consideration
Cleaning method
Soil type
Substrate type
Safety
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Detergent Selection
So for best performance (and Cleaning Method)
choose a detergent for a specific soil, substrate, or
machine/method
Environment - minimize disposal concerns, or
optimize for recycling
Safety - maximize worker safety
Economy - synergistic economical blends
Residue potential - minimum amount of synergistic
blend - least cleaner residue.

Chemistry of Cleaning

Cleaning Method & Cleaners Required

High-agitation needs low-foam, dispersing,
rapid chemical attack
Pressure spray washing (cabinet washers, conveyer
washers, dishwashers, parts washers)

Low-agitation with high-foam, emulsifying,

enzyme, digesting
Immersion (soak, manual, ultrasonic)
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Chemistry of Cleaning

Soil Type
Natural Oils - higher alkaline cleaners
Synthetic and Petrochemical Oils - wetting,
emulsifying; typically mild alkaline
Salts, Oxides, Metals - alkaline chelating,
sequestering cleaners, best with acid cleaners
Particulates - dispersant cleaners
Protein/biofouling - protease enzyme cleaners; mild
alkaline with wetting agents
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Chemistry of Cleaning

pH and Residues Removed

(next slide Pharma)

Type Cleaner pH
Mineral acid 0-2
Mild acid
2-5.5

Typical Soils
heavy scales
salts, oxides,
metallic
Neutral
5.5-8.5 light oil and particle
Mild alkaline 8.5-11 oils, particles, films
Alkaline
11-12.5 natural oil, fat, resin
Corrosive
12.5+ heavy grease/soils
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Chemistry of Cleaning
Alkaline High pH
Generally Best cleaned by Alkaline Detergents ( in order)
Oils, fats, greases, Alcohols, Amino Acids, Some Proteins
Diols, Triols, Phosphates, Organic Acids, Acid Salts

Either Alkaline or Acidic

N-heterocyclics, Polysaccharides. Proteins, Ferments, Steroids
Sugars, Ethers, Ketones, Pyrrolidines, Pyridines
Generally Best Cleaned by Acidic Detergents
Amines, Alkaloids, Amphoteric Proteins, Starches, Carbonates
Bicarbonates, Metal Complexes, Metal Oxides/Hydroxides
Acidic Low pH
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Chemistry of Cleaning
Alkaline (High pH) cleaning mechanisms
Saponification reacting with fats, oils and esters to break
them and form water soluble salts ie. potassium hydroxide
reacts with trilauryl glycerate to form water soluble
potassium laurate and glycerine
Alkaline Hydrolysis- alkaline labile proteins are broken in to
smaller more water soluble fragments or amino acids by
alkaline attack on peptide bonds in the proteins
Alkaline Deprotonation alkaline reaction with weak acids
and alcohols to form more water soluble alkoxide salts
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Chemistry of Cleaning
Acidic Cleaning Mechanisms
Protonation acid reaction with amines, N-heterocyclics,
Pyridines, and Pyrolidines to form water soluble cationic
amine salts which are more polar molecules with greater
water solubility
Acid hydrolysis- acid reaction with starches to smaller more
water soluble monosaccharides, disaccharides and smaller
polysaccharides
Acid chelation formation of water soluble more polar
compounds with metal oxides, salts and complexes
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Chemistry of Cleaning
Residues that are both acid and alkaline labile:
proteins, polysaccharides (some cross link in alkaline)
and amine compounds

Residues that are pH indifferent and get cleaned by

other cleaning mechanisms
Sugars, steroids, acid insoluble metal oxides and
complexes, inert particles

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Cleaning Validation

Cleaning Validation Slides Start Here

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Overview of Cleaning Validation

Cleaning Validation as Defined by the Health Sciences
Authority:
Cleaning Validation is documented evidence that an
approved cleaning procedure will provide equipment that
is suitable for processing of pharmaceutical products or
active pharmaceutical ingredients (APIs).
The objective of the Cleaning Validation is the
confirmation of a reliable cleaning procedure so that the
analytical monitoring may be omitted or reduced to a
minimum in the routine phase.

Overview of Cleaning Validation

Cleaning Validation
Cleaning procedures must strictly follow carefully
established and validated methods of execution.
This applies equally to the manufacture of
pharmaceutical products and active
pharmaceutical ingredients (APIs). In any case,
manufacturing processes have to be designed and
carried out in a way that contamination is reduced
to an acceptable level.

Overview of Cleaning Validation

Focus on the objective of the cleaning validation
and answer questions such as
At what point does a piece of equipment or system
become clean?
Does it have to be scrubbed by hand?
What is accomplished by hand scrubbing rather than
just a solvent wash?
How variable are manual cleaning processes from
batch to batch and product to product?

Overview of Cleaning Validation

Validating the Use of a Cleaner
Set Residue acceptance criteria
Validate the cleaning process with the new
cleaner
Including design of experiments for optimal process
Including three consecutive cleaning trials
Including the Validation Report

Write procedures and train operators

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Overview of Cleaning Validation

Validating the Use of a Cleaner
Identify Cleaner Residues
Select a Residue Detection Method
Choose a Sampling Method
Validate a Residue Detection Methods
Construct Recovery Studies

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Overview of Cleaning Validation

GUIDE TO INSPECTIONS VALIDATION OF CLEANING
PROCESSES
The two most important points:
the test of any validation process is whether scientific data
shows that the system consistently does as expected and
produces a result that consistently meets predetermined
specifications
This guide is intended to cover equipment cleaning for chemical
residues only.

Overview of Cleaning Validation

Incidents that brought cleaning validation to the
forefront
Historically speaking, FDA was more concerned about the
contamination of nonpenicillin drug products with penicillins
or the cross-contamination of drug products with potent
steroids or hormones.
A number of products have been recalled over the past
decade due to actual or potential penicillin crosscontamination.

Overview of Cleaning Validation

One influential event in 1988 recall of a finished
drug product, Cholestyramine Resin USP.
The bulk pharmaceutical chemical used to
produce the product had become contaminated
with low levels of intermediates and degradants
from the production of agricultural pesticides.

Overview of Cleaning Validation

Reuse of recovered solvents
Culprit: Reused drums to hold solvents used for
pesticides
Not adequate control over drums or cleaning of them
Pesticides contaminated bulk drug
FDA instituted an import alert in 1992 on a foreign
bulk pharmaceutical manufacturer which
manufactured potent steroid products as well as nonsteroidal products using common equipment.
Company only looked for the last compound made

Overview of Cleaning Validation

FDA Requirements:
FDA expects firms to have written procedures (SOP's)
detailing the cleaning processes used for various pieces of
equipment
FDA expects firms to have written general procedures on
how cleaning processes will be validated.
FDA expects the general validation procedures to address
who is responsible for performing and approving the
validation study, the acceptance criteria, and when
revalidation will be required

Overview of Cleaning Validation

Equipment:
Be careful of large systems with intricate equipment
that employs automatic CIP systems.
Ex. Ball valves Difficult to clean

People properly trained to clean the systems?

Do Validated cleaning procedures identify difficult
systems and addresses them?

Overview of Cleaning Validation

Microbiological aspects of equipment cleaning should
be considered.
This consists largely of preventive measures rather than
removal of contamination once it has occurred.
There should be some evidence that routine cleaning and
storage of equipment does not allow microbial
proliferation.
e.g. equipment should be dried before storage, and under no
circumstances should stagnant water be allowed to remain in
equipment subsequent to cleaning operations.

Overview of Cleaning Validation

Written Procedures
Documentation is based on the complexity and type of
systems used
General SOPs and Master Validation Plan
Batch record or log sheet requiring documentation at each step
In complex systems always document critical steps, the cleaning
process and any special information (where to clean, how, who
and when
Other factors
Cleaning history
Residue levels after cleaning
Variability of test results
Establish effectiveness of process and operator

Overview of Cleaning Validation

Analytical Methods
What is most important?
Specificity and Sensitivity residues, contaminants

Selection of method based upon need or what

could be on the equipment
Never 0 always below limit of detection or below
limit of quantitation
Always challenge analytical method and sampling
method (recovery study)

Overview of Cleaning Validation

Sampling
Direct sampling by swab and rinse sampling
Direct swab sampling
Most advantageous
Allows for sampling of difficult areas
May use physical force to remove dried or insoluble
contamination onto swab
Make sure swab does not interfere with analysis (e.g.
adhesive)
Sample medium and solvent are appropriate for solvating the
contaminant

Overview of Cleaning Validation

Rinse sampling
Advantages
Can cover a large surface area
Tough to reach areas or equipment difficult to take apart
may be sampled CIP
Disadvantages
Occluded or dried/ insoluble contaminants
Look at the clothes not the wash water
MUST USE DIRECT METHOD IN INITIAL VALIDATION recovery
Its not okay to simply test the rinse water

Overview of Cleaning Validation

Routine Process Control
Indirect testing such as conductivity Especially
when processing bulk
Indirect testing must have shown correlation with
the condition of the equipment
Need to document that testing unclean
equipment gives failing results

Overview of Cleaning Validation

Excipients to test cleaning
It is often a good idea to run a placebo batch and
test placebo for contaminant
Do not assume uniformity of contaminant
Often in initial discharge portion

Not a replacement for swab/rinse

Overview of Cleaning Validation

Detergents often do not have ingredients
listed on material safety data sheet
Get a non disclosure agreement with the
detergent manufacturer for a full disclosure of
ingredients

Detergent need to be easy to remove

Need to test for their removal

Overview of Cleaning Validation

Keep cleaning until you pass your acceptance
criteriaNO
This is a sign of a poor cleaning program and
one that was not validated

Overview of Cleaning Validation

Visually Clean
Include visual inspection
Complements rinse and/or swab sampling
Key is to not have cleaning residues left behind
Issues
Background variations
Rouge may be indicative of a maintenance problem,
but generally not a cleaning problem

Overview of Cleaning Validation

Visual Determination of Clean
Based on European guidance, some may utilize
visually clean alone as the most stringent criteria
May apply in non-potent drugs, API manufacture
Generally not applicable for potent drug products

Key items to consider

Angle, distance, lighting, viewer

Typical level is 1-4 mg/cm2

Must relate visually clean to actual levels in
spiking studies

Overview of Cleaning Validation

Representative Product: most difficult to clean
Basis of selection
Historical
Solubility data
Lab/pilot study

Overview of Cleaning Validation

Residue limit selection

Lowest limit among group
OR

Validate most difficult to clean (at its limit)

and most toxic (product with lowest limit)

Overview of Cleaning Validation

Terms to Avoid
Avoid the use of the terms
No Residue
None Detected
0

Confusion in use of term limit

10 ppm of what measured in what?
How low can or should you go?

Overview of Cleaning Validation

Challenges For three Performance
Qualification (PQ) runs for a cleaning
validation
Process conditions (within normal process
conditions)
Different operators for manual cleaning
Bioburden
Dirty hold time
Clean hold time

Overview of Cleaning Validation

Dirty Equipment Hold Time
What?
Time between end of manufacture and beginning of cleaning

Why?
Manufactured product may be harder to clean (dries, bioburden
growth)

Issues
Sometimes cleanability does NOT change with time (e.g., dry
products)

What do?
Specify a maximum hold time in cleaning
Challenge worst-case condition in validation (at least one run at
maximum)

Overview of Cleaning Validation

Clean Hold Time
What?
Time from end of cleaning to beginning of
manufacture
Sometimes called expiry period

Why?
Equipment may become re-contaminated
during storage (bioburden, dust)
Issues
If dry and sealed, should not be re-contaminated

Overview of Cleaning Validation

What done?
Specify maximum hold time in Standard Operating
Procedure (SOPs)
For extended storage, attempt to dry equipment (as
part of cleaning SOP)
For extended storage, seal/wrap equipment
appropriately
Measure residues before and after storage (may be in
separate protocol)
Usually are measuring bioburden and visual
cleanness; may also use Total Organic Carbon (TOC)
Criteria is change from baseline

Overview of Cleaning Validation

Product Grouping to reduce number of
validations
By product (soil)
By equipment

Also called matrixing, family approach, bracketing

to determine the worst case residue and worst
case equipment
Rationale
Simplify amount of validation work with scientific
rationale to support

More common for older drugs

Overview of Cleaning Validation

Equipment Grouping Continued
Must be similar type
Identical equipment (identical for cleaning
purposes)
May involve simple equipment of different sizes
Example:300L, 500L and 1000L tanks

Alternatives
Validate separately largest & smallest sizes
Validate together testing extremes

Overview of Cleaning Validation

Conditions to meet for product grouping

Similar product type
In some equipment train
Identical cleaning process
Cleaning agent
Cleaning method
Process parameters

Overview of Cleaning Validation

Maintenance of Cleaning Validation
Monitoring
Change control
Deviations
Revalidation
Preventative Maintenance (PM)

Overview of Cleaning Validation

Monitoring During Cleaning

May monitor key control parameters
Time(s)
Temperature(s)
Cleaning agent concentration
Pressure

May monitor key indicators of control

Rinse water TOC or conductivity

Visual examination

Overview of Cleaning Validation

Change Control
Change control Standard Operating Procedure
(SOP)
Planned vs. unplanned changes
In cleaning process
In manufacturing process

Key
Evaluate impact of change
May require lab work and testing to support change
Document

Overview of Cleaning Validation

Process Deviations
Deviation of process once cleaning process is
validated
Look for
Their investigation into causes & effects
Corrective or preventive action

Overview of Cleaning Validation

Revalidation
Repeat of Performance Qualification (PQ) on any
significant change
On a regular basis, evaluate consistency based on:
Monitoring date
Change control date
Deviations
Quality records

Overview of Cleaning Validation

Cleaning Validation for What Product?
Dilemma: If I do Cleaning Validation for Product A, what is
more important?
Measuring residues after cleaning of Product A
Measuring residues after cleaning of previous product

In one sense, to say cleaning validation is complete for

product A, should have both
General approach is to start with cleaning validation
measuring residues after new products and add older
products later
Once cleaning validation is done for all product in
manufacturing train, then before and after is covered.

Overview of Cleaning Validation

Other Considerations
Training records
Operators
Samplers
Analysts
Validation specialists

Computer validation

Overview of Cleaning Validation

Process Analytical Technology (PAT) for

Cleaning Validation
Focus in on control of process, not
necessarily rapid Quality Assurance (QA)
release of equipment
Avoid time based control
Example, rinse to certain conductivity

Old process: control by time, monitor

conductivity
PAT: control by conductivity monitor time

Online Tool for Calculating Acceptable

Residue Limits

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The Tool
Calculator For Residue Acceptance Criteria
Limits For Alconox Inc. Detergents
http://www.alconox.com/calculator.html

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The Tool

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The Tool
Data needed
Detergent brand
Patient body weight
Safety Factor
Smallest next manufacturing batch
Biggest daily dose of pharmaceutical
Size of shared equipment

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The Tool
Detergent brand
Brand determines the toxicity from which a
safety based limit is determined

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The Tool
Patient Body Weight
70 kg adult
35 kg child
5 kg infant
Worst case is typically infant
Use adult or child weight if pharmaceutical is known
to only be directed at those populations

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The Tool
Safety Factor
Typically 1,000 to 10,0000
For detergents which are typically not very
hazardous, usually you use 1,000

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The Tool
Smallest next manufacturing batch
Worst case is whatever the smallest amount
that might be manufactured in the shared
equipment

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The Tool
Biggest daily dose of pharmaceutical
Use the worst case maximum daily dose.
Typically a multiple of the recommended daily
dose

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The Tool
Size of shared equipment
Measured in cm2 or L of pharmaceutical
produced

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The Tool
The calculations
Acceptable daily intake (ADI)
Safety based acceptable residue limit (ARL)
10 ppm carryover acceptable residue limit
(ARL)
Compares and selects the lower of the two

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The Tool
The calculations
ADI = LD50 mg/kg * Body Weight kg / Safety
Factor
Safety based ARL = ADI mg * smallest next
batch kg / (size of shared equipment cm2 or L
* biggest daily dose of next batch mg *
1kg/1000000 mg)
Result expressed as mg/cm2 or mg/L
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The Tool
The calculations
10 ppm carryover ARL = 10 mg residue / 1 kg
next product * (smallest next batch kg / size of
shared equipment cm2 or L)
Result expressed as mg/cm2 or mg/L

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Alconox, Inc. Overview

Privately held 65+ yr old company
Third generation family ownership
Detergent manufacturer serving
Laboratories
FDA: pharma, medical device, healthcare, food
Precision manufacturing; solar aerospace electric

Over half a century of global distribution

Expert technical support
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Alconox, Inc. Overview

Just a Few Quick Slides About Alconox
HeyIt Pays the Bills

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Alconox, Inc. Overview

Our 65-year track record is unparalleled.
Industry leaders count on us to meet their
precision cleaning needs.

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Regulatory Support
Comprehensive cGMP compliance support
Recordkeeping documentation
Lot traceability of cleaners
Oral toxicity data
Ingredient reactivity information
Cleaner shelf-life testing
Cleaning validation support
Written cleaning procedures
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Unsurpassed Technical Expertise

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The End

Are There Any Questions?

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