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Consider equipment design, transfer systems, and maintenance when operating isolators for sterile manufacturing of pharmaceutical products.
In sterile manufacturing and aseptic fill/finish of pharmaceutical products, isolator technology offers the ability to achieve high sterility levels. Pharmaceutical Technology spoke with two experts to learn about best practices in specifying and operating isolators. Richard Denk is senior consultant for Aseptic Processing & Containment at SKAN AG, which designs and manufactures isolators, isolator process solutions, and cleanroom equipment. Denk founded the Parenteral Drug Association (PDA) Isolator Expert Group, which has published guidelines for isolator design and cleaning. Denk was also responsible for writing about transfer systems and isolator design for PDA’s technical report on isolators, which will be published in 2020, and is chair of the International Society for Pharmaceutical Engineering Germany/Austria/Switzerland (ISPE D/A/CH) Affiliate’s Containment Expert Group, which published the ISPE Containment Manual. Steve Nole is vice-president of operations at Grand River Aseptic Manufacturing (GRAM), a contract development and manufacturing organization (CDMO) for parenteral pharmaceuticals. GRAM is building a new aseptic processing facility, near its existing facility in Grand Rapids, Michigan, that uses isolator technology from SKAN. The company is currently in the process of equipment qualification, with good manufacturing practice (GMP) production planned for start-up in September 2020.
PharmTech: What do you see as the advantages of isolator technology for aseptic manufacturing? When are isolators a good choice compared to restricted access barrier systems (RABS)?
Nole (GRAM): The main advantage for isolator-based technology is that it removes the most significant source of contamination from the aseptic environment by eliminating direct interventions by gowned employees. Typically, with an isolator system, a higher sterility assurance level (SAL) is achieved. Also, isolators can be placed in a Grade C surround, which requires less cleanroom real estate, whereas RABS require a higher level of air classification and additional airlocks, more stringent gowning requirements, and support to operate and maintain a Grade A/B RABS system.
Both isolators and well-designed RABS systems can achieve very high SAL. Isolators may be a better choice for a new greenfield building because you can achieve a higher SAL, operate in a Grade C space, and recognize lower operating expenses due to a smaller cleanroom and less gowning requirements; however, isolators require a higher initial investment for equipment costs. RABS may be best suited for upgrading existing equipment already within a Grade A cleanroom. Lastly, a company may choose RABS/isolator lines based on the company’s existing technology and training. For example, a company with existing RABS lines may stay with RABS for consistency and training of the workforce.
Denk (SKAN):Isolators most comply with the regulatory requirements of the pharmaceutical authorities, such as FDA or the European Medicines Agency, with regard to sterile manufacture. If you look at the Draft Annex 1, which was published in December 2017, you will find the term ‘isolator’ 34 times throughout the document (1). Draft Annex 1 is a European document, but [global regulatory] members, such as FDA, WHO [World Health Organization], and PIC/S [Pharmaceutical Inspection Cooperation Scheme] are involved in this document, which also makes the document of international importance. The advantage of isolators is the barrier between the operator in production and the sterile product to be manufactured. The operator is seen as the highest contamination risk to the sterile pharmaceutical product. Compared to the RABS, which is decontaminated together with the room, the isolator has its integrated decontamination system, which offers significant advantages. As a result, the aseptic area is also reduced inside the isolator chamber, decontamination can take place more quickly, and the decontamination cycle can be validated. This setup also has advantages for the operators, since they can work in a reduced GMP environment of ISO [International Organization for Standardization] class 7 or 8.
PharmTech: What are some of the keys in choosing/specifying isolators and surrounding equipment?
Nole (GRAM): Factors to consider include decontamination cycle time, changeover, residual vaporized hydrogen peroxide after decontamination, and where/how the vaporized hydrogen peroxide is introduced (below or above the HEPA [high efficiency particulate air filter]). Other significant items for GRAM were whether the isolator and equipment vendors worked together in the past, how many installations they have fully commissioned in the United States, and support and service capabilities. These factors become even more critical if the OEM [original equipment manufacturer] is responsible for routine maintenance and requalification activities.
Denk (SKAN): In the fill/finish area of sterile manufacturing, isolators are primarily selected and specified to ensure an aseptic environment in the filling process. In addition, if the pharmaceutical product is a highly active or highly hazardous substance, there are additional protective factors on the isolator to secure the operators during production. The topic of cleaning to avoid cross-contamination in a multi-purpose system is becoming increasingly important. The permitted daily exposure (PDE)/acceptable daily exposure (ADE) levels are getting lower; especially in the fill/finish area, any external contamination in the vial or syringe, for example, can quickly exceed the PDE/ADE. In order to prevent this, I founded a PDA expert group in 2015 that has now published two PDA publications on the subject of cleaning and avoiding cross-contamination. The first publication, Isolator Surfaces and Contamination Risk to Personnel and Patient, deals with the limit values for cleaning of non-direct product contact surfaces inside and outside of isolators with the associated equipment such as the filling line (2). In the second publication, Preventing Cross Contamination During Lyophilization, cleaning and its limit values for surfaces not in contact with the product within a lyophilizer were considered (3).
In addition to these factors for the selection and specification of isolators, other factors such as the surrounding equipment also play an important role. How do the stoppers and caps get into the isolator? Or if ready-to-use (RTU) primary packaging, such as nested vials or syringes, are used, how are they introduced and the packaging removed?
PharmTech: What are some ways to address challenges for moving material in and out of the system?
Denk (SKAN): Transfers in and out of an isolator are areas that should be examined closely in a risk assessment, because they have an impact on sterility and containment. The risk assessment should be performed in the beginning (during mock-up) and include GMP and EH&S [environment health and safety] requirements. Different decision criteria play an important role in the selection of the suitable transfer system. Is the intention for a large-scale production or smaller batch sizes, and mono-production or multipurpose production? Will reusable units such as a stopper processor or single-use packaged units be used? Is a high degree of flexibility required when selecting different format sizes, for different vials, for example? Once these decisions are made, there is the right transfer system for each unit. In 2020, PDA will publish a technical report for isolators. The report also describes, among other things, transfer systems and how they work safely in an aseptic environment.
Nole (GRAM): You need to have a robust system in place that provides flexibility. GRAM can use a combination of dedicated parts that are autoclaved and transferred into the isolator via rapid-transfer canisters, or preassembled and gamma-irradiated assemblies in bag-in-bag-out with rapid-transfer ports. This setup allows us to assemble and sterilize our own assemblies or source preassembled material from a third party.
PharmTech: What are best practices for cleaning/decontamination of isolators?
Nole (GRAM): All removable size parts and dedicated parts are removed and cleaned per batch. Any materials that can be autoclaved (bowls, hoppers, tracks) are autoclaved and set in place with a plastic (Tyvek) cover in place. Once the line is set up, the isolator and all materials inside undergo a decontamination cycle with vaporized hydrogen peroxide. For multi-product filling lines, best practices are to have a multi-product risk assessment to determine risk mitigation practices, and to create a program for routine monitoring of the cleaning efficiency.
Denk (SKAN): The new Draft Annex 1 describes that the surfaces should be validated as cleaned before they are disinfected or decontaminated. In my opinion, complex surfaces as well as a multitude of flexible connections, inaccessible areas, etc. are difficult to clean and to validate. I have been dealing with the subject of cleaning and hygiene design of surfaces for many years. In order to be able to clean processes in a reproducible and valid manner in the future, the technical implementation has to be rethought to reduce the components that are installed within an isolator to a minimum and then make them easily accessible for cleaning. Building on the hygienic design, surface decontamination in the isolator is then carried out using evaporated or sprayed hydrogen peroxide. When it comes to surface decontamination, I am a big supporter of integrated systems in the isolator, since the technology is in line with the process and isolator design, and the hydrogen peroxide is brought to the surface to be decontaminated as quickly as possible. There are two different systems here: evaporation of the hydrogen peroxide by means of an evaporator plate and distribution in the isolator chamber by means of recirculation. Another possibility is the direct spraying of the hydrogen peroxide with a two-component nozzle, using SKANFOG technology. With this nozzle, the liquid hydrogen peroxide and compressed air are mixed and micro-droplets are generated. These micro-droplets are distributed at a high speed in the isolator and, due to the fast atomization, form a uniform film on all surfaces, resulting in short decontamination times of a few minutes.
PharmTech: What are some of the best practices for maintenance of isolator technology?
Denk (SKAN): The best practice for maintenance of isolators is predictive maintenance. The isolator is the aseptic barrier between the sterile product and the environment. The better this barrier works, the safer the sterile product. Some maintenance personnel are particularly distinguished in keeping the isolators in good shape for a very long time. I’m often surprised seeing isolators installed many years back that still look like new. We have a SKAN Academy where all of our service people are trained, as well as the operators of our customers if they have no experience with isolators or would like to enlarge their skills. Most of our customers have a service contract and are thus informed about their upcoming maintenance to be coordinated with their production cycle.
Nole (GRAM): Most OEMs offer routine preventive maintenance and decontamination-cycle requalification packages until a company has in-house expertise. Finally, one crucial best maintenance practice is a glove maintenance/management program. Understand your glove change frequency and have six to 12 months of inventory on the shelf-gloves have long lead times.
1. European Commission, EudraLex, Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products, December 2017.
2. R. Denk et al., PDA Letter, Nov. 6, 2017, www.pda.org.
3. R. Denk et al., PDA J Pharm Sci and Tech 73 (6) 487-495 (2019).
Vol. 44, No. 2
When referring to this article, please cite it as J. Markarian, “Best Practices in Using Isolator Technology,” Pharmaceutical Technology 44 (2) 2020.