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Pharmaceutical Manufacturing and Packing Sourcer

Working in Isolation

Life science companies are increasingly seeking to expand their global reach by bringing novel drugs, therapies and combination products to market to treat diseases both rare and widespread. Firms are under pressure to provide technologies that ensure product quality and protection, as well as efficiency and operator safety. For drug makers, barrier isolation is a critical tool in aseptic filling operations for vials, syringes and ampoules, and serves as containment for cytotoxic agents when processing biopharmaceutical and anti-viral therapies. In addition, these sterile mini-environments are used in hospitals and pharmacies for drug compounding.

Fuelling the demand for barrier isolation technology are FDA regulatory guidelines, and in particular ‘Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice.’ Equally influential is the US Pharmacopeia Convention’s Chapter 797, Pharmaceutical Compounding – Sterile Preparations. Recommended practices from many scientific industry organisations, including the Parenteral Drug Association (PDA) and the International Society for Pharmaceutical Engineering (ISPE), also continue to bolster the benefits of barrier isolation technology.

The growth in barrier-isolation technology is likely to continue, as it is regarded as the most cost-effective system for maintaining the sterility assurance levels of drug products and for protecting operators and technicians from hazardous compounds. Compared with cleanrooms, isolator systems can improve product quality, reduce operating costs, allow for longer production campaigns and remove the possibility of harm to personnel.Yet there are several important parameters to consider to get the most out of an investment in isolation technology, including key features and total systems design, which we will further explore in this article.

Barrier Isolation Technology Benefits

Compared with cleanrooms, the advantages of barrier isolation technology include:
  • Better protection of the product from contamination risk through humans
  • Improved protection of operators from potentially hazardous compounds
  • Considerably higher sterility assurance level (SAL)
  • Lower risk assessments with isolators than cleanrooms when highly potent substances are being processed
  • Potential cost savings due to lower overall classification (isolators usually operate in cleanrooms with GMP Grade C)
  • Cuts in labour, gowning and other associated cleanroom costs, resulting in an overall lower total cost of ownership (TCO)
Some providers of isolation technology offer packages of value-added services that can make the switch from cleanrooms more seamless. In-house process departments, for instance, can help to develop and optimise key processes around barrier systems.

In addition, suppliers with validation facilities can assist in qualification and validation. Leading pharmaceutical equipment manufacturers can now provide complete support and testing laboratory services, including: development space for new equipment and processes; GMP and isolator training; cleaning validation support labs; and platforms for new validation services. Suppliers that offer these services collectively can help manufacturers test and refine requirements prior to delivery, cut lead times due to broad in-house expertise and ensure a fully integrated, one-stop-shopping approach.



Ensuring Safety and Security

When selecting isolation technology, easy validation and maintenance are essential to ensure efficiency as well as protection of the sterile environment, and certain features can produce real benefits. Secure seals are a must and testing is paramount. One of the most reliable and simplest methods for the testing of integrity is the pressure decay test, which can be applied to the overall barrier system through door seals, mouse holes and dampers as well as glove testing.The measurement principle helps detect leakages in gloves and cuffs.

Bio-decontamination of all surfaces inside the isolator is crucial to ensure safety and product quality. Decontamination with H2O2 vapour is a recognised procedure for the inactivation of microorganisms in the entire isolator interior. For an efficient bio-decontamination cycle, the isolator atmosphere has to be prepared during the dehumidification phase.Then, once the highest possible concentration of gas has been reached, this concentration has to be held over a defined period of time during the bio-decontamination phase. After this phase the entire system must be flushed with air to completely remove remnants of hydrogen peroxide vapour from the isolator.

As this decontamination process has to be performed before each filling, short cycle times are paramount to ensure high efficiency and sustained output.To achieve these short cycles, fast and complete evaporation of H2O2 is crucial so the highest concentration inside the barrier can be reached quickly. In addition, shorter bio-decontamination cycles lead to faster aeration phases as absorption of H2O2 inside the isolator is reduced. Filling itself requires uncompromised cleanroom conditions. To guarantee a trouble-free operational filling sequence, ergonomics and integration are important.These factors should be considered during line design (see Systems Approach section below).

Once the filling process is complete, safe wash-down processes are essential to ensure all product traces are removed safely.Wash-in-place (WIP) technologies are a way of ensuring all surfaces potentially contaminated with product remains are cleaned so employees are protected. Smooth and even surfaces with easy-to-clean corners allow for fast and efficient cleaning of the entire line.

Choosing the Right Isolation Technology

To ensure that the barrier system meets the needs of the particular product and facility, it is important to consider the different options available in this field. The two most common isolation technologies used by pharmaceutical firms are restricted access barrier systems (RABS) and isolators. Isolators guarantee the best microbiological status, and do not require operators to wear personal protection equipment, leading to higher safety. They constitute fully enclosed, sealed and pressurised units, and allow air to be re-circulated by returning it to the integrated air handlers though sealed ductwork.

RABS units are rigid wall enclosures supplied with high efficiency particulate air filters (HEPA) to yield an ISO 5 classified space, with all air handling equipment built into the system. Glove port access for personnel is standard with RABS as well as isolators and glove ports, sleeves and gloves should be secured to the walls using well designed and reliable seals. RABS technology helps to improve aseptic quality over open cleanroom processing and has become the barrier of choice for retrofits and existing cleanrooms. If operated properly as an integrated system, RABS technology can approach the microbiological quality of an isolator. It does, however, require a highly classified ISO 5 environment. Isolators offer the benefits of automatic cleaning using washing-in-place (WIP) and cleaning-in-place (CIP) systems while RABS generally have to be cleaned and bio-decontaminated manually, which can make validation more challenging.

Systems Approach

Incorporating barrier isolation technology requires some front-end early involvement by facilities, process, quality assurance and validation personnel. Moreover, the enclosed system must be fully engineered and integrated with process equipment in order to adequately address critical process and service requirements. Integration is perhaps one of the most critical components of isolation technology deployment. For example, complex filling lines require competent management of the interaction between filling machine, isolator system and subsequent machines, such as freeze-drying systems or overseal capping machines.

Successful system design requires partnering with a supplier that provides barrier isolation technology solutions for custom applications. Challenges include the safe functioning of the interfaces, the simplicity of the overall controls system and the simplicity of operation of the individual components. Additionally, a streamlined, smooth and harmonious overall system layout is paramount. Locations for glove ports, transfer systems and other equipment can be determined using full-scale system mock-ups.These mock-ups allow manufacturers to be involved in the process from the beginning and ensure that the final layout and system meet their needs.

By reducing interfaces, standardising components and opting for a single operating software, processes are managed with greater efficiency, reliability and safety.To ensure proper integration with filling and processing equipment, a total systems philosophy should be employed when designing barrier isolation systems, including:
  • A single unit design, so that the facilities engineers do not have to deal with several suppliers and components which do not match
  • Integration of the control systems from the filling equipment, barrier equipment, bio-decontamination system and ancillary equipment
  • Single HMI (human-machine interface) for the entire barrier and filling system
  • Integrated hardware and software
Conclusion

Life science players, from manufacturers to pharmaceutical compounders to the many regulatory and standards agencies involved, will continue to struggle with the ever-evolving complexities of drug development and production.These new treatments call for more aseptic potent or cytotoxic drugs, which can have an extremely adverse effect on personnel if they become exposed. At the same time, these drugs must be protected from contamination, the largest source of which is people.

Choosing the right contamination control platform, whether RABS or isolators, is a task that requires a great deal of research into what the product needs for an effective process design. If barrier isolation technology fits the bill, it is essential to partner with a supplier who will not only provide a complete system, but also the regulatory knowledge and know-how to ensure effective therapies get to the market. For those manufacturers at the frontier of the latest developments for treatments of diseases rare and widespread, barrier isolation technology is not only the right contamination control choice, it also makes sense.


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Mathias Kreher started at Robert Bosch GmbH, Packaging Technology, Product Division Pharma in 1998. Working as a mechanical engineer in the applications department for special projects, his main focus was on syringe and cartridge projects as well as on isolated filling lines. From 2003 to 2005 Mathias was in charge of the development of product management for Barrier Systems at Bosch Packaging Technology North America in Minneapolis. After returning to Germany he became project manager of a key account project for isolated high speed filling lines. Since September 2007 Mathias has been responsible for product management for barrier systems worldwide within Bosch. Email: mathias.kreher@bosch.com
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Mathias Kreher
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