Michael Moussourakis-Vice President of Technical Marketing & Strategy, Alconox Inc.; Stacy Silverstein- Senior Director, Strategic Programs, Alconox Inc.; Jeff Phillips- Senior Director, Business and Product Development, Alconox Inc.; Malcolm McLaughlin-Senior Vice President, Alconox Inc.
What makes this Handbook different than other books and cleaning guidance information out there? Where can it be found?
Michael Moussourakis: At Alconox Inc. we are dedicated to manufacturing critical cleaning products and take pride in our technical expertise. This is demonstrated throughout the book. Updated from the previous version to meet the changing needs of critical cleaning industries, I am proud to be a part of this effort and thank the other authors and contributors for their efforts. The Aqueous Cleaning Handbook 5th Edition is currently found on the alconox.com website and epub outlets like Amazon and Barnes & Noble. During this introduction period, the electronic copy can be obtained completely free of charge from our website.
Can you give us a brief overview of the changes/ updates made to the Handbook since the last version was published?
Michael Moussourakis: Much has changed since the last edition over 15 years ago. New regulations, new environmental concerns, new identifications of hazardous chemistries, new and more precise residue detection methods, and even new industries. These include cosmetic manufacturing, medical cannabis and other botanical processing, solar and photovoltaic, 3D printing and of course others. Each of these new areas is a source of questions from our customers and an opportunity for solutions for Alconox Inc. to provide.
Malcolm McLaughlin: The book has significantly updated information about applications in pharmaceutical cleaning including the latest techniques for silicone oil, titanium dioxide, and zinc oxide removal. The latest changes in guidelines for cleaning validations are reviewed and explained including the use of Acceptable Daily Exposure/ Permissible Daily Exposure based acceptance limits for pharmaceutical cleaning validations. Material expanding on the old TACT (Time, Agitation, Chemistry and Temperature) variables in cleaning is expanded to BATH-O-CARD (Before, Agitation, Time, Heat, Orientation, Cleaner, After, Rinse, and Dry) cleaning variables.
Stacy Silverstein: Readers of past editions will recognize the chapter titles as familiar but there is a ton of new, updated content in each chapter. It’s all well worth the read. Chapter 6 gained six new application subsections (Ultrasonic Cleaning Systems, Clean-in-Place (CIP) System, Cleaning GMP Washers/Dryers, Passivation Cleaning, Filter Cleaning, and Biofilm Cleaning) and new industries such as Cannabis and Foodservice. Major updates can be found in Chapter 8 on pharmaceutical cleaning validation chapter as well as Chapter 9 Wastewater Treatment and Waste Minimization and Chapter 11 Environmental Health and Safety Considerations. Our job is to respond to the ever-changing landscape of aqueous cleaning regulations, protocols, and best practices to educate and inform our readers with the most accurate and up to date information. In addition to the content, the appendices were refreshed with a new resource-oriented appendix to assist the reader with their own research. The Alconox Inc. detergent selection guide is incorporated into the appendix as well as a useful tool to understand types of detergents industry and application, and offer specific recommendations.
What are some critical industry issues facing the pharmaceutical industry in regards to their cleaning/disinfection processes?
Jeff Phillips: Today the pharmaceutical industry worries about critical cleaning more than ever before. There is an ever-increasing number of large molecules being manufactured that include biosimilars. This explosion of different types of molecules puts ever greater pressure on price and, hence manufacturing throughput. The old paradigm of go with what has been used is dying. Getting better detergents with optimized process parameters becomes crucially important. The first step to optimize a critical cleaning process should be to read The Aqueous Cleaning Handbook 5th Edition. The second, contact us at Alconox Inc. to optimize your critical cleaning process.
As the pharmaceutical industry has grown to be more international/global in nature – can you tell us how international cleaning/sterilization needs have evolved over time?
Jeff Phillips: Pharmaceutical companies outside the US, especially areas outside of the EU, Japan, and Canada have an accelerated focus on product quality to rival the US. A better focus on quality issues such as critical cleaning help focus manufacturing on meeting requirements of high-quality medication needed around the world. Successful pharmaceutical manufacturers around the world learn and partner with companies such as Alconox Inc. and learn from material such as The Aqueous Cleaning Handbook 5th Edition to succeed in an ever-increasing complex world.
How does Alconox provide the same standard of cleaning/sterilizing processes to pharma companies that operate all over the world?
Michael Moussourakis: Understanding how our cleaning chemistries interact with particular residues and surfaces is vital. That is the foundation of what we do every day. Next, we help ensure good quality product – appropriate QC, cGMP, and continuous improvement throughout our manufacturing process. Finally, we partner with our international customers and dealers to help make sure regulatory needs are met.
Malcolm McLaughlin: Alconox Inc. detergents are manufactured in all locations to the same FDA regulated quality standards. The products are sold with tamper evident seals and are distributed all over the world by a network of international dealers. A customer in Shanghai or Costa Rica gets the same quality detergent as a customer in New Jersey.
Biofilms
What are biofilms and where are you most likely to find them in a pharmaceutical facility?
Jeff Phillips: Microbes embedded often in mucoid extracellular matrix often along piping though cell adhesion in water systems. These microbes are often water born bacteria. When in the pharmaceutical industry water systems, this microbial contamination may bring manufacturing to a halt. When one manufactures parenteral medications where one not only has strict microbial contamination specifications but has endotoxin levels needed < 0.25 endotoxin units [EU] per milliliter [mL]. This necessitates a well thought out preventive maintenance program to prevent biofilm formation and remove it quickly when formed.
How can biofilms affect the quality of pharmaceuticals in production?
Jeff Phillips: Biofilms can have bacteria and endotoxins “fluff off” and contaminate pharmaceuticals. In injectable medications this can be catastrophic.
What tests are used to identify biofilms?
Jeff Phillips: It is recommended to use a lab that is ISO17025 certified as a gauge of an organization’s commitment to quality. The tests that are often run to determine and identify the type of biofilm are the following: Single Tube Method, the Drip Flow Biofilm Reactor, the CDC Biofilm Reactor and the Minimum Biofilm Eradication Concentration or MBEC. Consult with the testing lab about the best methodology to use based on your situation.
In general, what methods are used to reduce and control biofilm build-up?
Jeff Phillips: One robust method would involve a combination of using an enzymatic cleaner such as Tergazyme® Enzyme-Active Powdered Detergent to break down and remove much of the biofilm. Cleaning should be followed by a disinfectant such as our stable hypochlorous acid solution.
What methods can be implemented to prevent biofilm build-up in the first place?
Jeff Phillips: A comprehensive preventive maintenance program that is employed usually once a quarter to once a month depending upon your circumstances is advisable. Tergazyme detergent followed by our stable hypochlorous acid solution is a good method. Otherwise cleaning with Solujet® Low-Foaming Phosphate-Free Liquid alkaline detergent, rinse, clean with Citrajet® Low-Foam Liquid Acid Cleaner/ Rinse detergent, and finishing with our stable hypochlorous acid solution are good methods.
Ultrasonic Cleaning
What is ultrasonic cleaning and how can it be used for pharmaceutical cleaning applications?
Michael Moussourakis: An ultrasonic cleaning system traditionally consists of a tank or series of tanks filled with an aqueous cleaning solution. Ultrasonic pulses are sent through the cleaning solution to create agitation at the surface of parts and wares, allowing for a very effective, efficient cleaning process. Pharmaceutical equipment including laboratory instruments, and process parts including presses, dies, and stamps are all regularly cleaned in ultrasonic apparatuses. This newest edition of the book has a section specifically dedicated to ultrasonic cleaning technology.
What are the benefits to using ultrasonic cleaning?
Michael Moussourakis: From the perspective of aqueous cleaning, employing an ultrasonic cleaning system allows for the use of higher foaming, better emulsifying detergents. But unlike other clean-out-of-place (COP) methods where foaming detergents are used, the ultrasonic cleaning method is automated. This reduces cleaning variability from run to run. While some cleaning applications require more manual COP methods, the automation, reliability, and reproducibility provided by an ultrasonic system is a definite asset.
How is ultrasonic technology used in conjunction with cleaning agent?
Michael Moussourakis: Alconox Inc. experts work with our customers to ensure the most appropriate cleaning chemistry is chosen for the residue and material/substrate being cleaned. This can be verified if there are concerns (such as in the cases of uncommon residues or surface materials) on bench top or small-scale ultrasonic unit testing. We then work with customers to ensure scale-up accuracy and provide cleaning validation direction and guidance. Using our relationships with ultrasonic unit manufacturers we can often ensure the right Alconox Inc. detergent is specified at the onset.
Are there any cleaning situations where the use of ultrasonic technology is not recommended? What are these situations and what is done when they are encountered?
Michael Moussourakis: There are some. Certainly, any solvents that are flammable, explosive, or combustible should not be used in an ultrasonic. Alconox Inc. aqueous detergents are not. Other times parts are too large to accommodate or accommodate cost-effectively. They may be cleaned with scrubbing or large soaking tanks. Other times, parts with complex geometries cannot always be effectively cleaned in an ultrasonic. At these times other technologies are employed such as Vacuum Cyclic Nucleation.
Measuring Cleanliness
Is it possible to measure cleanliness? If not, what is actually being measured?
Stacy Silverstein: There is not really a way to directly measure cleanliness, as defined as the absence of residue. What you really measure is amount of detectable residue or amount of detectable surface altering residue.
Specifically, what types of testing are available, what are their benefits, and, are there certain situations where they are best used?
Malcolm McLaughlin: The book reviews the use of 8 different techniques for measuring at the 10 mg/cm2 level of cleanliness; 11 different techniques for measuring at the 1-10 mg/cm2 level of cleanliness; and then 12 techniques for measuring at levels below 1 ug/cm2 . You want to match technique to level of desired detection. Some techniques give you broad information about the fact that something is there, but not much specific information about what it is. Other techniques can very specifically identify what the residue is, but perhaps not identify anything else. For getting good adherence with surface coatings, cleaning down to 10 mg/cm2 levels can be sufficient using surface energy sensitive test methods such as an atomizer test or water break test. Perhaps augmented by a tape test or “white glove” test. More demanding applications require more sensitive tests.
What are some best practices to be employed to measure cleanliness?
Malcolm McLaughlin: For pharmaceutical cleaning validations, it is best to use a sensitive method that can specifically identify residues of concern. In a detergent cleaning validation residue detection you want a technique that had a limit of quantitation that is below the acceptance criteria for the residue, ideally at least 50% below the acceptance limit. Typically, you would use HPLC or UPLC analytical methods with swab sampling to achieve these goals. Other techniques can be used, but this would be the best practice.
Stacy Silverstein: In non-cGMP industries, best practices for measuring cleanliness or the absence of residue ranges anywhere from visual inspection, rinse water pH testing, to simply “squeaky” clean surfaces. Following your specific industry’s guidelines is the way to go.
Combination Devices
Can you give us a general definition of a combination device?
Jeff Phillips: A combination device is a pharmaceutical and medical device in one. This can be an inhaler, autoinjector, or drug eluting stent.
Why are they becoming more popular?
Jeff Phillips: There are different reasons for popularity of combination devices. In the case of drug eluting stents there are studies that show increased health outcomes from stents that elute drugs such as Paclitaxel.
What are their benefits to patients?
Jeff Phillips: Better health outcomes, routes of administration, and often ease of use.
What are some unique challenges to cleaning combination devices?
Jeff Phillips: Some of the most difficult cleaning issues are having to meet medical device and pharmaceutical standards. The code of federal regulations for pharmaceutical quality management system (QMS) is 21CFR211 and 21CFR210, while medical device QMS is 21CFR820. These QMS have some differences and similarities. Navigating these quality and specifically ways of thinking about cleaning and cleaning levels requires knowledge of both industries. Teaming up with a company like Alconox Inc. goes a long way to avoiding problems and facilitating optimized critical cleaning.
Environmental and Regulatory Issues
With environmental and green issues making headlines, what types of aqueous products are available that minimize environmental issues?
Malcolm McLaughlin: Aqueous products formulated from ingredients that are on the US EPA safer choice list minimize environmental issues. These ingredients are safer for human health and the environment and will typically have better sustainability profiles.
Stacy Silverstein: At the operational level, drain safety is a big concern. Aqueous cleaners that are mild alkaline or mild acids can be easily disposed of down the drain without the hazard and headache of neutralizing. The Alconox Inc. aqueous detergents have the added benefit of being biodegradable and safer for workers.
Are environmentally safe cleaning agents as effective as those that aren’t safe for the environment?
Malcolm McLaughlin: The history of detergent chemistry has been one of starting by making products that clean well. Then sometimes environmental concerns are raised about these formulations. Improvements in the environmental status are often made at the expense of cleaning performance. After several potential iterations and time, a product is designed that has improved performance while maintaining a good environmental profile. Then the tension between environmental concerns and performance continues to repeat to respond to evolving environmental concerns.
Stacy Silverstein: In some cases, “environmentally safe” cleaning agents are just not as effective cleaners as some more hazardous cleaners. It’s a risk reward scenario. How much risk do you want to put your staff, equipment and the ground water in to get the most effective cleaning? There are plenty of safer products in the marketplace that balance both safety and effectiveness. Detergent raw material suppliers continue to introduce new, more environmentally friendly ingredients. Working with a manufacturer that prioritizes these innovations brings more reward for prioritizing safety concerns and pristine results.
Are there any special considerations that need to be addressed when using environmentally-safe products?
Malcolm McLaughlin: Depending on where the product you are using is on the historical environmental development cycle, it is possible that it will be a somewhat more poorly performing product. To compensate for this, you may need to optimize other variables that impact cleaning performance such as before cleaning handling, amount of mechanical agitation, cleaning time, and cleaning temperature.
What points should be considered when evaluating the environmental health and safety of a proposed cleaning process?
Malcolm McLaughlin: The safety of the operators using the cleaning process and the environmental impact of the effluent from the process is very important to consider.
Stacy Silverstein: Another point to consider in addition to Malcolm’s is the life of the processing equipment itself. Often products that are more hazardous and harsher on the environment also produce faster wear and tear of capital equipment.
How do issues such as energy and resources used factor into the use of aqueous cleaning systems?
Malcolm McLaughlin: Energy and resources used are critical factors to consider in any evaluation of the sustainability of an aqueous cleaning system. By optimizing chemical energy in a cleaning process, you can minimize the need for other forms of energy and resources required.
Are there specific regulations that govern the use of solvents for aqueous cleaning? What governing bodies oversee the use of cleaners?
Malcolm McLaughlin: In the United States, the Occupational Safety and Health Administration (OSHA) governs the use of solvents and cleaners in the workplace. The US EPA governs the use, reporting and discharge from cleaning processes. Numerous State and Local waste regulators or Departments of Environmental Protection govern permissible discharge in to waste treatment plants. In the US, the Toxic Substances Control Act (TSCA) and Resource Conservation and Reclamation Act (RCRA) regulate the use of solvents, including those used in cleaners. Internationally there are comparable organizations to those found in the US.
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