Passivation validation

• Introduction
• Purpose and explanation of passivation and validation
• Regulations
• Risk Evaluation
• Standards
• Cleaning and Passivation Tests
• Passivation Modalities
• The Chemistry
• Drafting the Document
• Process Options including sanitization and derouging

Just because you don’t see it, doesn’t mean it’s not there.
If you can’t measure it, you can’t improve it.
-Peter Duker
Picture from Pexels, Cameron Readious

The passivation process of new equipment or installations in the
pharmaceutical industry is frequently an oversight; after all, it is just a
small cost and requires a short execution time compared with the
total construction project.
Additionally, the pieces of evidence of corrosion or contamination
related to lack of passivation or an elementary passivation practice
usually happens after some or many years of operating equipment
and systems as per the "Standard Operating Procedures."
This presentation will provide additional knowledge to the
pharmaceutical industry's regulation, standards, basic passivation
and documentation practices.

Passivation of stainless steel is to clean its surface with
an acid for the purpose to remove free iron and create a
chromium rich surface.
FeFe FeFeFe
FeFe FeFe
Cr Cr
CrCrCr

Free Iron means reactive iron, iron that
will form iron oxide or rust, iron that
will contaminate the product. The free
iron react easily with water, steam,
saline solutions, sanitizers and other
raw materials and products in the
pharmaceutical industry.

• The FDA requires that processes be “Under Control”
• The PROOF of “Under Control” = Validation
• Validation is Defined by the FDA as:
“Establishing documented evidence that a specific
process will consistently produce a product meeting its
predetermined specifications and quality attributes with a high
degree of assurance.”
• Written proof that your process can repeatedly do what
you say it can do

The PassivationValidation may be
included in
• IQ - Installation Qualification
• PM - Preventive Maintenance Procedures
• Change Control
D I O P
Q Q Q Q

General Explanation of cGMP’s
• Facilities used for manufacture, processing, holding or distribution of
a drug product must be properly designed, operated and maintained
• GMP’s are mostly “ubrella” regulalations, indicating “What” must be
done. The specific “How” is left to the manufacturer
• The “c” is for the “Current” practices
and interpretations of the “How”
• The cGMP’s are always evolving
cGMP’s

“Equipment shall be constructed so that surfaces
that contact components, in-process materials, or
drug products shall not be reactive, additive, or
absorptive so as to alter the safety, identity,
strength, quality, or purity of the drug product
beyond the official or other established
requirements.”
21CFR211.65(a)
shall not be reactive,

“No person shall sell any drug that
(a) Was manufactured, prepared, preserved
packaged, or stored under unsanitary conditions”
In Canada the Food and Drugs Act requires:
No
unsanitary conditions

I will use a
risk-based
approach to
mitigate the
consequences
of corrosion
and product
contamination.
Risk Assessment Methodology:
Step Description
1 Generate list of risks
2 For each risk estimate the probability of
occurrence.
3 Estimate the consequences on quality,
equipment damage or product liability
4 Use Risk Rating Table to assign initial
risk rating.
5 Assess risk tolerability / acceptance.
6 Introduce control measures to mitigate
risk.
7 Reassess probability and consequences
with new control measures implemented.
8 Assign new impact rating and assess risk
tolerability / acceptance
9 If the residual impact rating is adequate
continue and assess next risk
10 If the residual impact rating is not
adequate the hazard must be re-
evaluated.

! Risk:
Particles and construction debris going into the
product for example metal shavings.

Probability of Occurrence
Score Probability Example
1
Rare
Seen every
10-30 years
2
Unlikely
Seen every
5-10 years
3
Possible
Seen every
1-5 years
4
Likely
Seen to occur more than
once a year
5 Almost Certain Several times a year

Impacts Guidelines
Score Impact Consequences
1 Negligible
• No regulatory issue.
• No effect on and not noticeable by patient.
• Equipment can be operated.
2 Marginal
• May require notification by the authority.
• Decision to release product not compromised.
• Direct or indirect damage to equipment <$5,000 USD.
3 Moderate
• Authority inspection may identify a major concern but deficiency quite
easily resolved.
• Limited product recall possible.
• Unlikely product liability.
• Direct and indirect repair cost $5,000 - $100,000 USD.
4 Critical
• Authority inspection may conclude a serious non-compliance
• Likely product recall from one or more markets
• Likely product liability.
• Direct and indirect repair cost $100,000 - $1M USD
5 Catastrophic
• Major enforcement action, such as consent decree, product seizure, plant
shutdown, criminal persecution
• Global product recall
• Product liability
• Direct and indirect repair cost exceed $1M USD
Source: This table has been amended from Forty-seventh report of the WHO Expert Committee on specifications
for pharmaceutical preparations. (WHO technical report series ; no. 981)

Risk Rating
Probability Negligible Marginal Moderate Critical Catastrophic
Almost Certain
5 10 15 20 25
Likely 4 8 12 16 20
Possible 3 6 9 12 15
Unlikely 2 4 6 8 10
Rare 1 2 3 4 5
Source: Forty-seventh report of the WHO Expert Committee on specifications for
pharmaceutical preparations. (WHO technical report series ; no. 981)
https://www.who.int/medicines/areas/quality_safety/quality_assurance/Annex2TRS-
981.pdf?ua=1

RISK TOLERABILITY / ACCEPTANCE TABLE
Risk Rating by Colour Remedial Action and Timescale
Unacceptable Risk (>10)
Work shall not be started or continued until the risk has been reduced. If it is not
possible to reduce the risk even with unlimited resources, work shall remain
prohibited.
Moderate Risk (5-10)
Work may proceed but efforts should be made to reduce the risk below this
level. The resources/costs required for prevention should be carefully measured
and limited. Risk reduction measures and remedial action shall be implemented
as soon as practicable..
Low Risk (1-4) Risk Acceptable. No action required.

!
Risk:
Particles and construction debris goes into the product for example
metal shavings.
• This is a common problem, and you can easily confirm by looking for
FDA warning letter metal shavings.
• We need to understand that the standard cleaning procedures are
designed to clean common residues and not matter like metal shavings
• Construction debris must be removed in the pre-operational cleaning,
which includes the passivation.
• The severity of the consequences are related with the type of final
product, topic, solid, injectable, etc.
• The probability depends of the specific company practices, procedures,
quality controls etc. The selected ratings are based on common
industrial practices and occurrence frequency across the industry.
RISK RESULT HARM TO INITIAL RISK CONTROLS RESIDUAL RISK
Construction
Debris
Damage to
equipment with close
clearances such as
mechanical seals,
valves.
Product liability
Reputation
Regulation
authorities will
require remediation
actions
Equipment,
customer,
product,
reputation
Probability
(3) Seen
in 1 – 5
years
Impact and
consequences:
(4) critical
Risk
Rating
12
• Construction
procedures,
• control turbulence and
time when flushing
pipes during
preoperational
cleaning,
• use of filters or
screens during
preoperational
cleaning,
• Install metal detectors
Probability
(1) Rare
Impact and
consequences:
(1)
Negligible
Risk
Rating
1

!
Risk:
Microbiological contamination associated to corrosion or biofilm in
critical water and steam systems
• The risk is related with the system design and operation. It is more
frequent in cold systems, and systems without sanitization procedures
for all the elements in the water treatment line.
Microbiological
contamination
Contamination not
detected by quality
control
Contamination
detected by quality
controls
Regulation
authorities will
require remediation
actions
customer,
product,
reputation
Probability
(3)
Possible
Seen
every 1-5
years
Impact and
consequences:
(4)
Moderate
Risk
Rating
12
• Improved sanitization
procedures
• Include derouging,
passivation and
chemical sanitization in
the maintenance
procedures
• Use specific analytical
methods to detect
biofilms,
Probability
(1) rare
Impact and
consequences:
(4)
Moderate
Risk
Rating
4

!
Risk:
Corrosion in internal and external surfaces in contact and not in
contact with product
• Frequently external surfaces that are not in contact with the product are
not passivated
• The severity of the consequences are related with manufacture process
for example corrosive environments, use of corrosive sanitizers,
autoclaves and lyophilizers can contaminate the packing or the product.
• The probability depends on the specific company practices,
procedures, quality controls etc. The selected ratings are based on
common industrial practices and occurrence frequency across the
industry.
Corrosion
Damage to
equipment
Contamination in the
product or packing
Regulation
authorities will
require remediation
actions
Equipment,
customer,
product,
reputation
Probability
(4) Seen
to occur
more than
once a
year
Impact and
consequences:
(3)
Moderate
Risk
Rating
12
• Use of non-metallic
construction materials
• Use of no-corrosive
sanitizers
• Construction
procedures,
• Better passivation
procedures
Probability
(2)
possible
Impact and
consequences:
(1)
Negligible
Risk
Rating
2

• ASTM A380
Standard practice for cleaning, descaling and passivation of
stainless-steel parts, equipment and systems
• ASTM A967
Chemical passivation treatments for stainless steel parts
• ASME BPE
Bioprocess Equipment

!
Keep in mind some of the limitations of standards such as:
•the are difficult to understand
• The passivation conditions on the standards are general and do not
apply to all circumstances
•Meeting the standard does not equal to meet the project goals.
Passivation that meets a standard does not equal a corrosion or
contamination-free system or equipment.
A standard provides a good starting point; however, the passivation
methods and conditions available to the public have limitations in the
following circumstances:
• used equipment
• Equipment and systems that are not manufactured with the best
practices
• Metal with specific contaminants.
On the other hand, proprietary passivation chemistry may not
provide enough evidence about the chemicals involved and the
quantitative control of passivation.

!
Example:
• Tubing and fittings used for pharmaceutical piping, especially if
they are electropolished, will pass a water break, ferroxyl, copper
sulfate or potassium Ferricyanide-Nitric Acid tests without any
cleaning or passivation.
The tubing sample on the right is
without question a positive
ferroxyl test. On the left there is
a sample of electropolish metal
without cleaning or passivation;
however, in this circumstance,
the ferroxyl test gives a false
negative result.

!
Example:
• The amount of organic matter in sanitary tubing and fittings is
minimum, but other stainless-steel components that are machined
or forged can be more contaminated.
The machining of stainless
steel requires cutting fluids.
Traces of cutting fluids can be
found in machined parts.

!
Example:
The aluminum oxide used to polish stainless steel will be a
contaminant in new equipment and piping.
EDTA at alkaline pH has a better ability to remove aluminum than
citric acid, caustic or detergents.
Aluminum oxide is frequently used
to polish sanitary-stainless-steel
tubing.

!
Example:
Calcium and Magnesium compounds that are common in water can
leave residues.
EDTA solutions can remove Calcium and Magnesium compounds
better than solium hydroxide and citric acid solutions.
Bild-up scale inside of a
pharmaceutical still is
frequently insoluble residues
of Calcium and Magnesium
from purified water.

!
Example:
Welds require more demanding conditions for passivation than other
parts of the metal.
The ferroxyl blue stains
in welds are a failure,
though the tubing pass
the test.

Each test of cleaning and passivation has advantages and
disadvantages that are included in the following charts, be sure to
address the method limitations in the cleaning procedure.
Cleaning Testing
Method Advantages Disadvantages
Visual inspection,
borescope inspection
Easy to implement Required qualified
inspectors with
experience in
pharmaceutical
industry.
The areas that can be
inspected are limited
by accessibility
Wipe test Easy to implement
especially suitable to
identify polishing
residues and excessive
biofilm
by accessibility

Cleaning Testing
UV Light Low cost
Easy to implement
specially suitable to
identify large amounts
of organic matter
Not all matter is
fluorescent under UV
light.
by accessibility
Roboflavin spray
coverage
Use food grade
compounds
Common test in the
industry
Scope is usually limited
to document spray
coverage.
Water break free
surface test
Easy to implement In most of the cases do
not identify the level
of cleanliness required
in the pharmaceutical
industry.

Passivation Testing
Ferroxyl Test or
potassium
Ferricyanide-Nitric
Acid
Low cost
Easy to implement and
visual test
Chemical test
Do not measure the
quality of the passive
layer
by accessibility
Uses toxic compounds.
Limited sensitivity in
electropolish and high-
quality stainless steel.
Copper Sulfate Low cost
Easy to implement and
visual test
Chemical test
Limited sensitivity in
high-quality stainless
steel.
Do not measure the
quality of the passive
layer
by accessibility
Uses toxic compounds.

Passivation Testing
Salt Spray /
immersion
Laboratory test
Visual results
Is a standard method
that can be automated
No quantitative
Visual interpretation
may depend on the
person
Electric-pen
passivation testers
Laboratory or field test
Calibrated instruments
Low cost
Meassures the
corrosion potential
Proprietary technology
Frequently a
qualitative test
Auger Spectroscopy A quantitative analysis
that measure the
composition of a
surface in atomic
layers
Specialized laboratory
test
Price
Qualified people shall
perform the test and
interpret the data.
Other spectroscopies Can measure the
composition of a
surface
Specialized laboratory
test
Price
Qualified people shall
perform the test and
interpret the data.

In the United States is common to use a colorimetric method to
measure dissolved iron in citric acid solutions for passivation.
This method is not included in the standards. On the other hand, it is
very accurate, qualitative, fast, is not limited by the sample’s
accessibility and has been compared with surface analysis methods.

Iron Readings from the QA log
Reading 1 2 3 4 5 6 7 8 9
Time 8:40 9:20 10:00 10:40 11:20 12:00 12:40 13:20 14:00
Iron ppm 0.98 1.36 1.29 1.36 1.50 1.53 1.56 1.56 1.56
The iron concentration increased to 1.56 parts per million and stabilized. The
iron removal from the surface indicates an improvement in the chromium to
iron ratio and increases corrosion resistance. The iron concentrations'
stabilization demonstrates that the passivation process has removed all the
available free iron at the surface, and thus the metal is passive.

Depending on the size, geometry and resources there are different options
to passivate a metal, this options include:
• Immersion
• Spaying
• Recirculation
• Use of paste
• Use of foam

Know what are you using for cleaning your system:
If you use a commercial brand their composition should be known to the
user and their removal should be demonstrated. The drug manufacturer
should ensure that they are notified by the chemical supplier of any changes
in the formulation of the chemical.(1)
Many passivation chemical suppliers will not provide specific composition,
which makes difficult for the user to evaluate residues(2).
PASSIVA Pass-1
Passivation for Stainless Steel
Ultra Gel
Passivation Pickling Paste

Limit the use of Nitric Acid, is toxic and a significant health concern. There
are passivation products that are food grade and less hazardous.

You can get similar or better results with the right chemistry, using food
grade chemicals.
Here is a list of chemicals commonly used to clean stainless steel and their
function.
• Citric Acid- Passivation, chelanting agent, best performance at pH=3
• Ascorbic Acid AKA as vitamin C- reduction agent really good to remove
Fe3+ and Fe2+ compounds.
• Erytorbic Acid, is a steroisomer of ascorbic acid, and has same
antioxidant properties as vitamin C.
• Sodium EDTA salts-are strong chelants, depending on pH they can
remove Aluminum, Calcium, Magnesium and Iron
• Sodium Phosphates-Excellent cleaners, they will remove organic matter
including grease and oils.
• Sodium Gluconate- Chelanting agent used to remove metals
• Tween 80 MR- Is a non ionic surfactant really helpful to keep the
insoluble matter and small particles suspended.
• Sodium Hydroxide- Strong base good to remove organic matter
including oils and fats, very useful to remove biofilms and adjust pH or
neutralize acids.

You can get similar or better results with the right chemistry, using food
grade chemicals, here is a list of chemicals commonly used to clean
stainless steel and their function.
• Potassium Hydroxide- Strong base good to remove organic matter
including oils and fats, very useful to remove biofilms and adjust pH or
neutralize acids.Potassium Hydroxide can remove oils faster than sodium
hydroxide.
• Formic Acid- Is the strongest of organic acids, used to adjust pH and
increase solubility of metals.
• Oxalic acid- Organic acid, it can dissolve iron oxides.
• Phosphoric acid- A mild inorganic acid suitable for passivation, remove
organic matter and iron oxides.

The following chemicals are not available or expensive in food grade,
however, are useful for precision cleaning, it use must be careful and its
quality documented.
• Ammonium Bifluoride- With acids will generate Hydrogen fluoride, this
compound is able to dissolve silicates and stainless steel. The electronic
grade is about 99% pure with few impurities.
• Formic Acid- Is the strongest of organic acids, used to adjust pH and
increase solubility of metals. Industrial grade 85% purity, 10 ppm
maximum or iron
• Hydrogen Peroxide- Strong oxidizer and sanitizer, 50% industrial grade.
• Peracetic acid- sterilant, very useful to remove biofilms, industrial grade
or use recognized trade mark as Mincare.
• Sodium or Potassium Hydroxide – industrial grade or membrane grade
with a maximum content of 0.05% chlorides.
• Thickening and emulsifying agents use cosmetic grade, no chlorides or
other corrosive compounds.

1. Include all the necessary information to identify the validation document
such as: Name of your company, Location, Project, System, Who create
the document, who check the document, dates, signatures, approvals,
and any other suitable information.
2. Objective, for example:
This document describes the procedures to clean and passivate
stainless steel fluid and gas handling equipment and piping of the
system, in order to ensure that the internal surface is suitable for
production of high purity products under regulatory agency approval.
3. Scope
Define what will be cleaned as accurate as possible a water loop, a
pump etc. are inaccurate limits, for example the water loop includes the
hook ups, or the pipe between the generation system an the water loop.
Some common practices to identify the scope are highlight flow paths in
the Pipe and Instruments Diagrams, dimensional drawings, serial
numbers, pipe line numbers, weld numbers etc.

4. .Description of the equipment to be used

5. Include the procedure and the chemistry
A procedure is not a Job Safety Analysis, is not a check list.
It is a detailed description of the steps to passivate the stainless steel,
includes: chemistry, quality control, logs, certificates, drawings,
attachments, risk analysis, responsibilities,

6. Include safety considerations such as Risk Assessment, Material Safety
Data Sheets, required Personal Protection Equipment, specific site
requirements etc.
7. Include calculations or other engineering considerations that support the
process requirements
8. Define responsibilities
9. Document waste disposal

10. Some Quality points to be considered:
a. The procedure must be submitted for revision in advance.
b. Sampling
b1 Direct Surface sampling, Do not use Ferroxyl test on product contact
surfaces, discuss with your vendor of passivation testers the way to
document the removal of the chemicals to perform the test. Sice many
passivation test are destructive or need to be performed in the
laboratory is better to use welding coupons using the same construction
materials or a sample of stainless steel from the same heat number and
finish as the equipment.
b2 Rinse samples “Two advantages of using rinse samples are that a
larger surface area may be sampled, and inaccessible systems or ones
that cannot be routinely disassembled can be sampled and evaluated
(1)”
c. Define the acceptable quality of water for the process, for example
conductivity no larger than 2 mS/cm
d. Inspect the temporary equipment to be used for passivation
e. Inspect the condition of the system or equipment to be cleaned
f. Include batch number and quality certificates of the chemicals to be
used
g. Include calibration certificates of critical instruments
h. Define the acceptance criteria, for cleanliness, passivation, rinse etc.

Critical Process Parameters or Control Points
Since the quantity of impurities and
cleanliness conditions of the stainless steel
is difficult to determine, the passivation
process conditions will usually exceed the
worst-case scenario. For this reason, there
is some latitude in the process parameters
and may not be a control point or critical
process parameter. Additionally, depending
on the process's rationale and chemistry,
some of the parameters may not be
critical.

Critical Process Parameters or Control Points
pH
Passivation
Validation

pH may not provide enough evidence
that all the chemicals has been removed
to an acceptable level for these reasons:
a) USP purified water commonly
used for passivation has a pH 5- 7.
pH=5 shows that are some acids
present
b) There are some salts that yield a
pH=7, however this salts are not
acceptable residues in a
pharmaceutical process equipment
Conductivity is more sensitive than pH to
show chemical residues, if we use
organic compounds for passivation TOC
is more sensitive than conductivity. 7

A certificate of analysis allows us to trace
chemicals with lot numbers.
An MSD is issued for safety purposes not for
quality purposes, and it is not the same as a
certificate of analysis or quality certificate.
Lot/Batch
602294
Lot/Batch
602294

Instruments that measure a critical parameter
shall be calibrated.

Passivation
Passivation Process
•Alkaline Cleaning
•Passivation
•Oxidation

Pressure Testing
Used to confirm there are no leaks, equipment
integrity and reliability.
Water Flushing
Used to remove construction debris.
Alkaline Cleaning
Used to remove organic matter, biofilms and
other impurities soluble at high pH.
Passivation
Removes free iron to create a ‘non-reactive”
surface.
Derouging
Removes corrosion products such as iron
oxides
Disinfection
Eliminates microorganism, biofilms, viruses
and pyrogens.
Clean Stainless Steel
Definition of clean stainless steel required

(1) Health Canada, Cleaning Validation Guidelines (Guide-0028)
https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/good-
manufacturing-practices/validation/cleaning-validation-guidelines-guide-0028.html
(2) FDA, Validation of Cleaning Processes (7/93)
https://www.fda.gov/validation-cleaning-processes-793
(3) A Risk-Based Approach to Stainless Steel Equipment Maintenance
February 2, 2017 Elizabeth Rivera , Paul Lopolito , Dijana Hadziselimovic PharmTech,
https://www.pharmtech.com/view/risk-based-approach-stainless-steel-equipment-maintenance
(4) ASTM International, A967–13,Standard Specification for Chemical Treatments for Stainless Steel Parts (West
Conshohocken, PA, 2013).
(5) ASTM International, A380 / A380M-13, Standard Practice for Cleaning, Descaling, and Passivation of Stainless
Steel Parts, Equipment, and Systems (West Conshohocken, PA, 2013).
(6) ASME, “Nonmandatory Appendix E: Passivation Procedure Qualification,” in Bioprocessing Equipment, BPE–
2014 (New York, 2014).
(7) Chelants Prove Practical for Cleaning and Passivation of Stainless Steel Parts, Kenneth. B. Balmer and Martin
Larter
http://www.nmfrc.org/pdf/pc1294a.pdf
(8) Operation and Maintenance of Thermal Power Stations, Energy Systems in Electrical Engineering,
Appendix A The Operational and Safety Aspects of Chemical Cleaning of Thermal Power Plants
P. Chanda and S. Mukhopaddhyay,
http://link.springer.com/content/pdf/bbm%3A978-81-322-2722-9%2F1.pdf

Questions and comments
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Passivation validation

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