passivation in the pharmaceutical industry
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STAINLES STEEL PASSIVATIONFOR THE PHARMACEUTICAL INDUSTRY
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
STAINLESS STEEL SURFACE
Cr Cr
CrCrCr
The most common stainless steel alloys used to manufacture pharmaceutical equipment in North America are types 316L, 316, 304 and 304L as per American Iron and Steel Institute.However above alloys are mostly iron.
316L 316 304L 304
Iron 62.1-69.1 62.0 -69.1 66.6 -71.1 64.2-71.1
Chromium 16.0-18.0 18.0 - 20.0
Nickel 10.0-14.0 8.0-10.5 8.0-12.0
Molybdenum 2.00-3.00 ---------
Manganese Max 2.00
Silicon Max. 0.75
Phosphorus Max. 0.045
Sulfur Max. 0.030
Carbon Max. 0.030 0.080 0.030 0.080
CHEMICAL COMPOSITION % WT.
In the 300 series stainless steel, the corrosion resistance is given by a molecular layer called passive layer.
The passive layer does not have the same composition as the bulk alloy. It has mostly iron and chromium in the form of chromium oxide.
Alloy as per standard composition
Molecular Passive Layer
If the passive layer has more iron, is more prone to corrosion
Fe Fe FeFeFe Fe
Alloy as per standard composition
Fe CrOX CrOX
Corrosion starting point
If the passive layer has more chrome, is more corrosion resistant
FeFeFe Fe
Alloy as per standard composition
FeCrOXCrOXCrOXCrOX
In the 300 series stainless steel the chromium oxide in the passive layer is created spontaneously with the air, but his composition is enhanced by some acids such as nitric or citric.
The 316 alloy is more corrosion resistant than 304.
The L grade will improve the properties of welds.
“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.”
Regulation21CFR211.65(a)
“No person shall sell any drug that
(a) Was manufactured, prepared, preserved packaged, or stored under unsanitary conditions”
RegulationIn Canada the Food and Drugs Act requires:
“C.02.005
The equipment with which a lot or batch of a drug is fabricated, packaged/labelled or tested shall be designed, constructed, maintained, operated, and arranged in a manner that
(b) prevents the contamination of the drug and the addition of extraneous material to the drug;”
RegulationCanadian Good Manufacturing Practices (GMP) Guidelines - 2009 Edition, Version 2 (GUI-0001)
Some substances common in the drug manufacturing process are corrosive even to the 316L alloy. Those substances are:• High purity water (purified water, WFI etc.)• Pure steam• Saline solutions• Chlorine compounds (Benzalkonium chloride, hydrochloric
acid, etc.)
To improve the chemical resistance of stainless steel this one must be passivated.
It is a common industrial practice that all stainless steel surfaces in contact with raw materials or finish product should be passivated to prevent any potential reaction with the alloy
Interior of a tank used to prepare large volume parenterals
Pump casing after 1 year in service pumping pure water
Inside of a clean steam system
The two most common chemistries to passivate stainless steel in the pharmaceutical industry are:1) Nitric acid passivation2) Citric acid passivation
Nitric acid was the first acid to be use to passivate stainless steel, and it has the following advantages: Low cost It can be use cold Require less contact time than citric acid Same nitric acid solution can be used many times
Disadvantages:o Hazardouso Additional to dissolve iron, also dissolve heavy metals that are
toxico It must be disposedo Will not keep the metals dissolved after neutralization
I strongly recommend to avoid nitric acid for passivation in the pharmaceutical industry, however if some one is interested in use nitric acid for passivation I recommend the following standards ASTM A967 / A967M - 13 Standard Specification for Chemical Passivation Treatments for Stainless Steel PartsASTM A380 / A380M - 13 Standard Practice for Cleaning, Descaling, and Passivation of Stainless Steel Parts, Equipment, and Systems
Citric acid is very common used to passivate stainless steel in the pharmaceutical industry, and it has the following advantages: Food grade and USP grade Not hazardous Dissolves only iron, not the heavy metals that enrich the alloy Its performance can be enhanced using other chemicals to
generate passive layers better than nitric acid It will keep the iron dissolved after neutralization Biodegradable
Disadvantages:o More expensive than nitric acido Low concentrations solutions will require to be heated up to 180 F ⁰
(80 C)⁰
Passivation Approaches: Recirculation (very useful to clean pipes and internal
surfaces of equipment designed to hold liquids) Immersion (good for parts which can be deep it in chemical
tanks) Spray (god for tanks, or other parts, reduces the amount of
required chemical) Foam (useful for surface which can not be cleaned by
recirculation or immersion, when foam is used the liquid remains in contact with the surface longer times than sprayed solutions)
Gel or pastes (useful for surfaces that can be reach by hand)
Passivation can be complemented with:
Alkaline cleaning or degrease Passivation Rinse
Pickling
SanitizationOr Strong oxidation
Dry
Leak test Pressure test
Preservation
Pickling
Required to clean welds not performed in a inert gas, or when iron oxide is present (the case of equipment in service)
Pressure or leak testingA leak test can be more sensible than a pressure test, specially on large or complex pipe systems. It will require clean air.A pressure test can:• Verify system integrity• Confirm that system will stand the pressure• Can be done with water or air
Alkaline cleaning
• Can remove cutting oil and grease left in the construction process of pipes and equipment.
• A tailored alkaline solution can remove biofilm
• EDTA can remove aluminium compounds used to polish stainless steel
Sanitization or strong oxidationHydrogen peroxide can create the chromium oxide instantaneously, reducing the required time to be in contact with the air by some proceduresHydrogen peroxide or peracetic acid also can reduce bacteria or virus in contaminated systems or microbial introduced to the system with passivation solution. Hydrogen peroxide also reduced the amount of organic compounds, very useful when total organic carbon will be used as part of the acceptance criteria.
Rinse
Only high purity pharmaceutical water must be use for rinse.The quality of rinsing water will determine the final level of cleanness. For example if we are using purified water (water with less than 100 colony form units), it is impossible that a system will be sterile after rinse.
Dry
System that will handle solids or gases will need moisture be removed. Usually dry is measure by drew point.Systems which will not be in service immediately after passivation also are recommended to be dry to reduce microbiological grow.
Preservation
If a system not going to be in service for several months it can be keep it free of environmental moisture and microbiological grow, injecting nitrogen.
Passivation Conditions for a recirculation or immersion approachIf stainless steel has been welded, the welding area is affected and this will require a longer passivation times than the ones find them in the ASTM standard.
A good approach for process pipes, tanks and valves are: 5% citric acid solution 80 ⁰C 2 hours contact time
It will be necessary to confirm that all the components in the system can resist this temperatures, for example some positive displacement pumps are not designed for high temperatures
Passivation Quality Control
From all the methods to confirm passivation in the ASTM A380 standard, the Ferroxyl method is the most suitable, however the chemicals involved are toxic, and is not recommend to do the test in surfaces that will have contact with raw materials or products. It will be better to do the test in samples of the same construction materials, like welding coupons.
Ferroxyl Test• Add 2 ml (60 -67% solution) of
nitric acid to 50 ml of distillated water
• Add 3g of Potassium Ferricyanide• Add water to complete 100 ml of
solutionThe solution should be rubbed on the surface to be tested.If the solution turns blue after a minute, it is an indication of free iron and poor passivation.The solution must be discarded after 2 hours.
The blue color in the swab is an evidence of free iron.The bottom swab shows the ferroxyl solution after a minute in contact with passivated stainless steel
Passivation Quality Control:Iron Concentration in passivation
solution
An analytical method uses a Hatch portable colorimeter and their procedure to determine Total Iron FerroVert®.This method measure the iron concentration in the passivation solution, this iron concentration will be increased up to reach a plateau. When the iron concentration do not change after 1 hour, is an evidence that metal is passivated.
Passivation Quality Control:Iron Concentration in passivation
solution
30 60 90 120 150 180 210
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0.1
0.2
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0.4
0.5
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0.8
0.9
Time [min]
Iron
Conc
entr
ation
ppm
Two consecutive readings after 30 min. with +/-0.03 ppm of iron are evidence of passivation.
Measuring the iron concentration in the passivation solution has the following
advantages:
• It is extremely sensible• Confirms the passivation of all the
surfaces in contact with passivation solution
• Is a non destructive test
Other Quality Control Points
• Measure water conductivity after rinse, this should be no more than 0.2 µS/cm than water used for rinse.
• TOC less than 500 ppb or + 100 ppb of rinsing water
• pH very rough test, to identify residues of alkaline or acid stage
• Microbiological test, when passivation is part of a sanitization process
Mauricio Gonzalez has more than 7 years of experience executing passivation, pickling and sanitization projects in the pharmaceutical industry.
My experience include trouble shooting high purity generation and distribution systems when passivation, derouging or sanitzation may be required.