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It can be disheartening to design and build a new pharmaceutical facility with shiny new stainless steel process vessels and tubing only to see what appears to be rust appearing exactly where you don’t want it. However there is hope and you are not alone. Rouging in process equipment is very common and in some cases is considered quite stable. This blog post will not pretend to present the various chemical reactions in the rouging process. Nor will there be any definitive statement of what course of action a company should take given that each process, effect on product and severity of occurrence is unique.

What causes Rouge?

There are many positions on what causes rouging. One thing that everyone can agree on is that Rouge is a form of Iron Oxide. Yes, this means it is a form of rust, not what you want to hear when you need to assure your process to not be Reactive, Additive or Absorptive to protect product Safety, Identity, Strength, Quality and Purity (SISQP) (CFR21 Subchapter C, Part 211 Subpart D Section 211.65).

Rouge can begin to form on surfaces that have been damaged from cavitation (pumps and turbulent tubing arrangements), dented tubing, impingement (from sprayballs), improper surface Ra (roughness) and from plain old scratching and gouging of surfaces during routine maintenance and processing.

Rouge Classifications

There are three types of rouge;

Class 1:  Limonite, FeO (OH). Rouge that originated outside of the system where it was discovered. This type of rouge can then migrate to the affected system through process streams and more commonly WFI and Clean Steam. This type of rouge is your typical reddish-orange.

Photo Credit: Ateco Tobler AG

Class 2: Hematite, Fe2O3.  This type forms in place, within the affected system.  This can be the result of surface damage within a stainless steel vessel or associated stainless steel tubing.  Hematite is brownish in color.

Class 3: Magnetite, Fe3O4.  This is the type that typically forms in high temperature steam systems.  This class of rouge is blackish in color an can be powdery or glossy.

 

 

Photos Credit: CPP Chemical Plants and Processes

Where to Expect Rouge

For the rouging process to occur you must have water present. This means that high purity water systems often are the source of Class 1 rouge found throughout processing systems. The distributed nature of Water for Injection (WFI) means that rouge can quickly migrate throughout multiple processing areas. Other sources of Class 1 rouge can be improper Material of Construction (MOC) fittings upstream from a system or from improper surface finish such as surfaces with an Arithmetic Average Roughness (Ra) measurement above 15-20 Ra. In some cases a process requires Electro-Polished (EP) surfaces which in conjunction with surface roughness are expressed as RaEP. Electro polishing is a process by which the “peaks” of a surface are removed through the use of an electric current and electrolyte. This provides a surface that has less surface area for reaction and fewer crevices for migrating rouge to take hold.

Turbulent water flow and cavitation can also damage the surface finish in tubing and pump housings resulting in a surface where the chromium oxide layer has been removed and exposure of the stainless steel surface higher in iron. As could be expected, rouge will form in these situations and this will also find its way into your process vessels.

Class 2 rouge is often the result of a damaged, previously passivated surface. CIP sprayballs can be the culprit in pinpoint rouge spots within a vessel as a result of high flow rates. Often times these spots will occur on the dome of the process vessel where they are not visible from sight glasses. This gives them time to form undetected and it’s not until rainbow-colored streaks of discoloration are noticed making their way down the vessel walls that their presence is discovered.

Photo Credit: Spray Balls by John C. Tverberg March 26, 2012

The air/liquid interface is also a prime location for rouge development as you have air and water, the key contributors. This is something to keep an eye out for in processes that require long wet vessel hold times and for vessels that are held for long periods of time prior to CIP post use and or are left wet post use.

Another scenario can be rouging from a damaged vessel wall or bent process tubing. Bent tubing may not be appear as an immediate concern however when one considers the surface of the tubing inside at the bend point, there could well be a change in the surface character by which underlying stainless steel layers are now exposed along with the higher iron content. A damaged surface example could be when a sight glass is being removed and a nut falls into the vessel and pings around a bit. The bottom outlet is removed and the wayward nut is removed from the vessel. This may seem like the problem is solved however the surface where the nut made impact is most likely damaged and no longer meets the required surface finish specification. An Ra measurement should be obtained or at a minimum this event should be recorded. Doing so will aid in the investigation should rouge begin to appear at the bottom of the vessel. If damage has occurred and the surface is not re-electro polished then pitting can occur that will require more extensive corrective measures such as grinding and filling with 316L rod followed by electropolishing.

Class 3 rouge is common in clean steam systems and less alarming that class 1 or class 2 rouge as it often in the stable form of Magnetite. Unless there is a powdery nature to the rouge, these systems can be operated for years with this rouge present without negatively impacting your process.

Rouge Remediation

Removal of rouge should be decided on a case by case basis. Some companies choose to establish monitoring programs by which the presence of rouge is observed and recorded for any changes in appearance or proliferation. This coupled with quality testing of product can often be sufficient to ensure that the presence of the rouge is not impacting product Safety, Identity, Strength, Quality or Purity.

Another approach has been to aggressively pursue the removal of all visible rouging from process systems. This should only be attempted after thorough investigation including classification of rouge present and best determination of sources. If the sources can be identified, in cases such as improper MOC fittings or pump cavitation due to non-optimal operating parameters, then it goes without saying that these identified causes should be addressed prior to overall system remediation.

Once the path of remediation has been decided on, there is really only one preferred method, Citric Acid Passivation. Other options exist such as Nitric Acid passivation and possibly even manual cleaning coupled with De-rouging CIP cycles. These latter two options have their drawbacks however.

Both Citric and Nitric acid passivation effectively remove surface contaminants from stainless steel and increase the Chromium Oxide to Iron Oxide ratio. However, Nitric Acid passivation can release toxic gases and must be disposed of as hazardous waste. Citric Acid on the other hand is organic and safe to use and does not require that it be treated as hazardous waste. Furthermore, with temperature elevation, Citric acid can accomplish passivation in a shorter period of time while Nitric Acid is more dangerous at high temperatures.

With regards to manual cleaning, this choice is not optimal as it subjects the vessel to possible damage. The process of entering a vessel for manual cleaning can be abrasive to the surface and increase the potential for scratching and gouging. This option is often chosen regardless of the drawbacks when there is substantial rouging that requires removal.

De-Rouging CIP cycles can all be used utilizing higher percentages of acid in the cycle. These ~5% acid cycles have proven to be effective in milder cases of rouging and as part of a preventative rouge program.

Conclusion

Despite our best efforts, rouging is here to stay. Though we decide on differing approaches to how to handle its presence, the fact remains that we can expect to see this uninvited guest in our process equipment and utilities. At least we can take comfort in knowing that this is happening industry wide and we can potentially learn from each other’s efforts.

Written B: Joe Herrick, Managing Consultant

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Method transfer is a regulatory requirement that is performed between two sites. It is a documented process to verify a certain laboratory’s capability of performing the analytical testing method’s intended use. Method transfers are performed for validated methods for which complete analytical methods and validation data are available.

Method transfer between laboratories and different company sites is needed throughout all pharmaceutical testing. Results have to be consistent throughout all testing being performed no matter where the testing takes place. For results to be considered valid all methods and test plans must be validated. As an example transferring a method from research and development to the quality group for a new a new product that will shortly be produced in manufacturing. It is important to properly have all acceptance criteria developed. After bringing the new method to your lab criteria on validating the method to ensure that it will work as planned must be determined. Once the new method is transferred to the new laboratory for testing all personnel that will be executing the method must be trained in the procedure.

Written By: Daniel Gabrault, Consultant

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Cleaning Validation (CV) is driven by regulatory expectations to ensure that residues from one product will not carry over and cross contaminate the next product. Regulatory scrutiny is more rigorous in a multi-product facility compared to a single product establishment. Companies are usually cited either for not having a sound cleaning validation or not meeting the protocol acceptance criteria. Because failing protocol acceptance criteria is considered a substantial regulatory risk, companies tend to spend money and resources even though there is minimal or no product risk.

Visual inspection is a tool commonly used during cleaning validation. Visual inspections are used to verify there is no residue or excessive water pooling etc.

Cleaning Validation is handled by taking rinse water samples and by taking Total Organic Carbon (TOC) swab samples of the equipment. There are four different samples taken to be tested by Quality Control (QC) and they are Bioburden, Endotoxin, Conductivity and Total Organic Carbon (TOC).

Written By: Tim Cronin, Consultant II

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Integrated Commissioning & Qualification Corporation (ICQ) is a leading provider of commissioning, qualification and verification services to companies in the life sciences and pharmaceutical industries. We develop programs and procedures that promote, facilitate and ensure compliance with stringent regulatory standards and our clients’ own internal quality standards. During our history, teams of ICQ consultants have played a central role in the commissioning and qualification of multiple manufacturing plants in the New England area as well as North Carolina. ICQ consists of eighty plus employees all qualified in the different areas of the industry that we as a company specialize in.

We thrive on the long-term success of our clients. We at ICQ make every effort to establish strong continuing relationships. Our company strives to blend in at the client site and become an extension of each client company we work with. ICQ offers many services from the start-up and commissioning of new facilities, utilities, process equipment and processes to decommissioning or project planning. No matter which service you require we have an experienced professional to place into our client sites.

◊ Equipment/Facilities CQ &V ◊ Process Engineering ◊ Process Validation ◊ Manufacturing Operations ◊ Quality Systems and Remediation ◊ Consent Decree Remediation ◊ Construction and Program Management ◊ Project Planning and Scheduling ◊ Compliance Support ◊ Quality Control and Assurance ◊ Re-Qualification ◊ Decommissioning ◊ Commissioning Activities (IV, OV, IQ & OQ) ◊ Engineering Change Management ◊ Cycle Development (CIP & SIP) ◊ Engineering Test Plans ◊ Start-Up and Turn-Over ◊ Shake Down Activities ◊ Project Execution ◊ Cleaning Validation (CIP/COP) ◊ Sterilization Validation (SIP/SOP) ◊ Process Validation ◊ Mixing Validation ◊ Clean/Dirty Hold Validation ◊ Expiry Validation ◊ Cleaning Verification (CV) ◊ Validation Maintenance ◊ Assistance with Compliance Audits ◊ Development and Management of Compliance Action Plans ◊ Regulatory Readiness Inspections and Training ◊ Response to Regulatory Citations and Warning Letters ◊ Design of Quality Systems for New Facilities or New Process Lines ◊ Ongoing QA/QC Support ◊ Preparation of Regulatory Filing and Review Documents ◊ Implementation of Quality by Design (QbD), ICH-Q9, ICH-Q10, ASTM E2476, ASTM E2500 Principles and Approach ◊ Project Managers ◊ Project Leads ◊ C&Q Technical Leads ◊ C&Q Consultants ◊ C&Q Engineers ◊ C&Q Specialists ◊ Documentation Specialists ◊ Construction Managers

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