Richard Denk is Head Sales Containment at SKAN AG, www.skan.ch, Richard.Denk@skan.ch.

Richard Denk

The Future Robotics Special Interest Group (SIG) of the DACH (Germany, Austria, Switzerland) affiliate of the International Society for Pharmaceutical Engineering (ISPE) was founded in 2019 and is headed by Richard Denk of SKAN AG and Charly Coulon of Invite GmbH. The group’s aim is to formulate requirements in the pharmaceutical industry and, working in smaller groups, to develop possible solutions for including robotics in a user requirements specification (URS). The group will examine all processes and related issues that are required by robotics or that enable or simplify its use. To this end, an evaluation was conducted with various pharmaceutical companies to determine where robotics could be used most effectively in pharmaceutical manufacturing. A workshop was also held in November 2021, in which small groups discussed further scenarios for the use of robotics. Subsequent ranking of the scenarios then led to the various workstreams. The individual scenarios showed a trend toward the use of robotics in aseptic manufacturing. As a result, the SIG sub-group “Facility of the Future of Robotics for Aseptic Manufacturing” was established. The group brings together all ongoing workstreams related to this topic, with the ultimate goal of achieving fully automated aseptic manufacturing.

Converting Injectable Therapies to Combination Drug-Device Products

Read this article in the Trends in Manufacturing ebook.

1. EC, Draft Revision to “Annex 1, Manufacture of Sterile Medicinal Products,” (Brussels, 2020).

2. BioPhorum, “Robotics Biomanufacturing Roadmap, Draft Version 1,” presentation at the Pharmaceutical Mobile Robotics Conference (London, UK, April 21-22, 2022).

Richard Denk is senior consultant for Aseptic Processing and Containment at SKAN AG. Julien Janda is Head of Process and Technology at Takeda. Markus Stuebchen is Robotics Network Team Lead at Roche. David Wolton is Global Engineering Technology Lead at Takeda.

When referring to this article, please cite it as R. Denk, J. Janda, M. Stuebchen, D. Wolton, “Using Robotics in the Aseptic Manufacturing Facility of the Future,” 

Pharmaceutical Technology Trends in Manufacturing

Articles

Several steps need be taken to achieve lights-out, fully automated operations.

Using Robotics in the Aseptic Manufacturing Facility of the Future

A revised draft of the European Union (EU) good manufacturing practice (GMP) Annex 1 was published in February 2020 (1), and a final version is expected in 2021. The GMP guidance includes several key points related to isolator design and operation, which are illustrated in 

As the author discussed in the first part of this article series, the design of an isolator is the basis for compliance with GMP in aseptic processing and in cleanability (2). Isolator design also affects surface decontamination. 

 Contamination control for sterile operation in isolators. Figure is courtesy of the author. 

Hygienic design and cleaning to remove particulate and microbiological contamination are important attributes for surface decontamination of the inner surfaces of isolators and of their installations (e.g., a vial or syringe filling line, an incubator, or other utilities for manufacturing cell and gene therapies). Consider section 4.24 of the new EU Draft GMP Annex 1, which says (1):

For RABS [restricted access barrier systems] and isolator systems, decontamination methods should be validated and controlled within defined cycle parameters. The cleaning process prior to the disinfection step is essential; any residues that remain may inhibit the effectiveness of the decontamination process:

i. For isolators, the decontamination process should be automated and should include a sporicidal agent in a suitable form (e.g., gaseous, aerosolized, or vaporized form) to ensure thorough microbial decontamination of its interior. Decontamination methods (cleaning and sporicidal disinfection) should render the interior surfaces and critical zone of the isolator free of viable microorganisms.

This section has two messages in terms of isolators: decontamination methods should be validated and controlled within defined cycle parameters and the process should be automated and should use a sporicidal agent.

In most isolators, surface decontamination is carried out with vaporized or sprayed hydrogen peroxide (H

) as the sporicidal agent. Direct spraying of micro-nebulized H

 into the isolator system produces a quick distribution with a smaller amount compared to vaporizing H

The decontamination cycle, using the selected agent, must be validated in accordance with GMP to generate a reliably aseptic atmosphere inside the isolator. The phrase “controlled with defined cycle parameters” does not mean solely the amount and time of the H

 in the isolator system; the following questions should be considered:

How homogeneous and quick is the distribution of the sprayed or evaporated H

, including at difficult-to-reach positions (worst case observation)?

If an uneven enrichment of the sprayed or evaporated H

 takes place, what consequences does this have for the decontamination cycle to be validated? Are surfaces exposed for a shorter or longer duration with a lesser or greater amount of H

How is the concentration distribution of the H

 in the overall isolator system? Is a uniform H

 film created on all surfaces without undesirable droplets forming on surfaces?

What materials are used in the isolator system and what is their influence on the surface decontamination? Stainless steel has a different decontamination factor (D-value) than glass or polymers, for example. These parameters need to be taken into account as well in the cycle to be validated.

Are moveable parts located in the isolator system? How are transfers into and out of the isolator accomplished and what influence do these transfers have on the decontamination cycle?

Are surfaces exposed during the production process and during work in the isolator system that are not sufficiently exposed during the decontamination cycle?

The phrase “defined cycle parameter” also contains quality-by-design (QbD) attributes in regards to the variable parameters in the isolator system. Consider questions such as the following when developing a validated decontamination cycle:

In which defined acceptance criteria (e.g., temperature range, relative humidity range, quantitiy and concentration of H

, air velocity and speed range if used) does the decontamination cycle function?

Additionally what influence do the criteria have on the decontamination cycle? For example, what is the effect if the temperature is 15°C instead of 20°C or if the relative humidity is 30% instead of 40%?

Automation, including robotics, can make manufacturing of sterile products more efficient, quicker, and safer. Robotic systems are mentioned specifically in section 2.1 of the new EU Draft GMP Annex 1, which says (1):

The manufacture of sterile products is subject to special requirements in order to minimize risk of microbial, particulate and pyrogen contamination. The following key areas should be considered:

i. Facility, equipment and process design should be optimized, qualified, and validated according to the relevant sections of the Good Manufacturing Practices (GMP) guide. The use of appropriate technologies (e.g., Restricted Access Barriers Systems (RABS), isolators, robotic systems, rapid microbial testing and monitoring systems) should be considered to increase the protection of the product from potential extraneous sources of particulate and microbial contamination such as personnel, materials and the surrounding environment, and assist in the rapid detection of potential contaminants in the environment and product.

Robotic work processes are widely used in pharmaceutical packaging, and their use has been expanding; they are now employed for handling sterile products, free of any manual interventions. The International Society for Pharmaceutical Engineering (ISPE) DACH [Germany/Austria/Switzerland] Future Robotics special interest group (SIG) was founded by the author in 2019. The SIG concerns itself with possible new work processes for robotic systems, the facility of the future using robotics, and the regulatory requirements from the EU GMP Annex 1 Draft for using robotics.

For example, a new work process for robotic systems is to place molded parts in transport containers and transport them to the washing machine and, after washing, back to the isolator. This process needs to take into account transfers between individual cleanroom grades.

Another work process is aseptic filling and automated handling of sterile finished products by means of robotic systems in isolators, as well as implementing their technical and regulatory compliance with current good manufacturing practice (CGMP). It is necessary, for example, to adapt viable monitoring to fully automated robotic solutions in aseptic manufacture. In the Draft Annex 1, the application of rapid microbial monitoring is mentioned, but the technical and organizational measures needed to replace the current monitoring methods using settle plates with rapid microbial testing methods need to be redefined. This topic will be addresed by the ISPE Future Robotics SIG in 2021.

The production of highly active and hazardous substances in the biopharmaceutical industry has increased rapidly in recent years, requiring consideration of environment, health, and safety protection. Viral vectors, for example, require high protection for the employee as well as prevention of cross-contamination with other substances.

Consider section 4.14 of the new EU Draft GMP Annex 1, which says, regarding the topic of containment of highly active and dangerous substances (1):

… Particular attention should be paid to the protection of the critical zone. The recommendations regarding air supplies and pressures may need to be modified where it is necessary to contain certain materials (e.g., pathogenic, highly toxic or radioactive products or live viral or bacterial materials)…

In addition to the pressure concept, the following aspects need to be taken into consideration for fill/finish of parenteral pharmaceuticals in an isolator system:

Is there an Accepted Daily Exposure (ADE) or Permitted Daily Exposure (PDE) that sets a limit value for exposure, such as that found in the European Medicines Agency’s guideline on setting health based exposure limits (3)? This limit value is important for calculating cleaning limit values as well as for determining how to protect employees during manufacturing.

Which biological safety level (BSL) is required, and which technical and organizational measures are necessary to achieve this BSL?

Is this a monoproduction or a multi-purpose system? On a multi-purpose system, the necessary cross-contamination requirements have to be observed. For products with an ADE/PDE, these requirements are determined by toxicologists. For viral vectors, there currently are no defined limit values, so a no-tolerance level from the previous to the subsequent product is assumed.

A quality risk management (QRM) process is needed that covers the requirements of GMP for product protection as well as protection of employees and the environment. A contamination control strategy CCS is derived from the QRM. Furthermore, prevention of cross-contamination and containment strategies must be developed.

Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities,

 EMA/CHMP/CVMP/ SWP/169430/2012 (London, 2014).

Richard Denk is senior consultant for Aseptic Processing and Containment at SKAN in Switzerland and is a member of the ISPE Commenting Team of the new draft of EU GMP Annex 1.


Vol. 45, No. 4
April 2021
Pages: 30–33

When referring to this article, please cite it as R. Denk, “Understanding the Impact of Annex 1 on Isolator Operation,” 

Decontamination, automation, and containment are important considerations
for aseptic manufacturing in isolators.


Understanding the Impact of Annex 1 on Isolator Operation

The first draft of the European Union (EU) good manufacturing practice (GMP) Annex 1, “Manufacture of Sterile Medicinal Products” was published for comment on the December 20, 2017 (1) and generated great interest internationally, as it was the first adaptation to the full EU GMP document on the manufacture of sterile medicinal products since November 20, 2008 (2). And, as during the creation of the document, the Pharmaceutical Inspection Cooperation Scheme (PIC/S) and the World Health Organization (WHO) were also involved. The previous applicable document of Annex 1 was completely revised and contained many changes, adaptations, and new contents, which resulted in a large number of comments (6400 in total) to the European Commission. The second published draft of the EU GMP Annex 1 appeared just two and a half years later, on February 20, 2020 (3). For the new draft version, stakeholders such as the International Society for Pharmaceutical Engineering (ISPE), Parenteral Drug Association (PDA), and others were contacted for comments. The comments on the second publication of the draft document concluded in July 2020, and the final version is expected to be published in the beginning of 2021.

Barrier systems in Annex 1: RABS and isolators

The expressions “Contamination Control Strategy (CCS)” and “Quality Risk Management (QRM)” are mentioned frequently in the document, along with barrier systems, such as isolators or restricted access barrier systems (RABS). This article describes the impact on isolator design for aseptic processing and how contamination control strategies are observed in relation to isolators.

Compared to RABS, isolators have a closed barrier between the surroundings and the interior of the isolator in which the sterile product is processed. During production, access to the interior of the isolator is only possible through validated transfer systems, such as decontamination airlocks (e.g., using hydrogen peroxide [vH

]), or e-beam, dry heat tunnels (i.e., depyrogenation tunnel), rapid transfer ports (RTPs), or through interventions via the gloves attached to the isolator.

The most important points in the draft EU GMP Annex 1 with regard to isolators are illustrated in 

. The starting point for every CCS is the risk observation of the design of the isolator system, including the installation of equipment in an isolator, such as a fill/finish machine for vials, syringes, etc. Most of the design failures could occur during the risk observation of the isolator System. The design forms the basis for cleaning in order to prevent a possible particulate or microbiological contamination of the sterile products, or to avoid cross-contamination in the case of a multi-product system. The entire design is also important for the subsequent surface decontamination with vH

. A high degree of automation reduces the manual interventions in the aseptic area through the gloves attached to the isolator. If highly active/toxic substances are to be manufactured in the isolator (or substances with an increased bio-safety factor), the protection of employees is a further important factor.

Consider section 4.3 of the draft Annex 1, which says (3):

Restricted Access Barrier Systems (RABS) and isolators are beneficial in assuring the required conditions and minimizing the microbial contamination associated with direct human interventions in the critical zone. This use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators should be justified.

The document expressly indicates that RABS or isolators should be used, which means that RABS or isolators are the favored technologies of the future for handling sterile products.

The following differences between RABS and isolators should be mentioned:

RABS are installed in a grade B room, while isolators are installed in a grade D room. The installation of an isolator in a grade D cleanroom means more comfort for the operator when wearing the required cleanroom clothing. Training employees for a grade D cleanroom is also less intensive than training them for a grade B cleanroom.

RABS systems are classified into the following systems: passive RABS, active RABS, or closed RABS. Apart from the closed RABS, the operator always has access to critical areas within the RABS. With the isolator, access is only possible using gloves at the isolator, just like with the closed RABS.

In most cases, RABS are decontaminated via the room. With isolators, there is an integrated and validated decontamination system, for example, with vH

With the isolator, the aseptic critical zone is self-contained, while with most RABS, the aseptic critical zone is opened to the surrounding room during interventions.

Isolators are suitable for handling highly active, toxic substances or for substances that require a higher biosafety level, and they can also handle substances with an extremely low acceptable daily exposure (ADE) or permitted daily exposure (PDE) when further technical measures are implemented.

The use of isolators in sterile manufacturing, in particular, has rapidly increased over the past 10 years. The main reasons are the increased safety of the product in the isolator, as well as the large number of highly active substances that have entered the market in recent years or are expected to do so in the coming years.

 shows that manufacturing control starts with the aseptic engineering design. The design of an isolator system, including its installations, is the basis on which all further requirements, such as cleaning or surface decontamination, are built. The design plays an important role in a variety of ways.

Consider section 4.4 of the draft GMP Annex 1 (3); the following description applies to the interior of an isolator:

Grade A zone: The critical zone for high risk operations for making aseptic connections by ensuring protection by first air (e.g., aseptic processing line, filling zone, stopper bowls, open ampoules, and vials). Normally, such conditions are provided by a localized airflow protection, such as unidirectional airflow work stations, RABS, or isolators.

The hygienic design plays an important role in ensuring this first air within the isolator system. No installations should be located, and no handling carried out, above critical operations that could lead to possible contamination of the sterile product. When observing critical operations, consider all transfers, interventions, movement sequences in the isolator, and so on. The investigation of every individual process steps on a GMP Annex 1 compliant aseptic hygiene design plays an important role here.

Other important points when it comes to aseptic engineering design are cleaning and surface decontamination. With regard to surface decontamination by means of vH

, all surfaces should be structured and designed so that the vH

 reaches them quickly and completely. Dead spaces, areas with difficult accessibility, feed-throughs from the room into the isolator, screw connections, and so on, should be avoided. 

 illustrates a hygienic design of a filling line. The walking beam is designed with easy to clean surfaces and with couplings to allow a fast removal of all components. Dead legs or areas not easy to access are eliminated.

The aseptic engineering design also plays an important role in cleaning with regard to avoiding contamination and cross-contamination. Consider section 5.4 of the new EU Draft GMP Annex 1, which says (3):

The cleaning process should be validated to:

i. Remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting agent used.

ii. Minimize chemical, microbial, and particulate contamination of the product during the process and prior to disinfection.

In this paragraph special attention should be paid to the wording: “The cleaning process should be validated”. Many of the process systems within an isolator are cleaned manually. To be able to perform this manual cleaning in a validated way, a process and system design are required that permit validation. In addition, highly qualified employees are required to carry out this validated cleaning process. In the future, the author expects that complex and unwieldy manufacturing/filling processes will be simplified and a suitable hygienic design used. A hygienic risk assessment is certainly a beneficial tool for simplifying the system design.

An optimal process and isolator hygienic design also enables the handling of highly active toxic pharmaceutical products or pharmaceutical products that require an increased biosafety level. For several years the quantity of these substances has been increasing steadily. The prognosis for the next few years shows that many new substances currently in the preclinical or clinical phase are being classified as highly active, toxic, or with an increased biosafety level. As well as the process and isolator hygienic design, further important aspects play a role in the cleaning of these pharmaceutical products. It is important to consider the following questions:

Which PDE or ADE limit value is required?

Can the materials that are used in the isolator and their surface qualities be cleaned to the required PDE or ADE, and which surface limit values should be considered?

Up until a few years ago, there were still no cleaning recommendations for surfaces that did not come into contact with the product, but there were already requirements from an EU GMP directive. Section 5.21 of Part 1 of these GMP guidelines (4) mentions:

Depending on the contamination risk, verification of cleaning of non-product contact surfaces and monitoring of air within the manufacturing area … in order to demonstrate effectiveness of control measures against airborne contamination or contamination by mechanical transfer.

Especially in isolators with the associated process systems for aseptic filling in vials, syringes, etc., most surfaces are considered non-product contacting. A PDA expert group, led by the author of this article, was established in 2015 to look into this topic; the group published “Isolator Surfaces and Contamination Risk to Personnel and Patient” (5) and “Preventing Cross-Contamination during Lyophilization: GMP and Occupational Cleaning Requirements for Nonproduct and Indirect Product Contacts Parts” (6) that provide recommended limit values for cleaning surfaces that do not make contact with the pharmaceutical product. 

 summarizes some of these recommendations.

This article reviewed considerations for aseptic design and cleaning. A second article to be published will consider surface decontamination, automation, and considerations for environmental health and safety when operating isolators.

EC, Draft Revision to “Annex 1, Manufacture of Sterile Medicinal Products,” (Brussels, 2017).

EudraLex Volume 4: Good manufacturing practice Guidelines

, “Annex 1, Manufacture of Sterile Medicinal Products,” (Brussels, 2008).

EC, Draft Revision to “Annex 1, Manufacture of Sterile Medicinal Products,” (Brussels, 2020). 

, “Part 1, Chapter 5: Production,” (Brussels, 2014).

R. Denk et al., “Isolator Surfaces and Contamination Risk to Personnel and Patient,” 

Richard Denk is senior consultant for Aseptic Processing and Containment at SKAN in Switzerland and is a member of the ISPE Commenting Team of the new draft of EU GMP Annex


Vol. 44, No. 11
November 2020
Pages: 34–37

When referring to this article, please cite it as R. Denk, “Understanding the Impact of Annex 1 on Isolator Design,” 

An optimal engineering design is crucial for aseptic operation and cleaning.

Understanding the Impact of Annex 1 on Isolator Design

	The manufacture of highly active or highly hazardous pharmaceutical substances involves a complex interplay between the required threshold values, such as the permitted daily exposure (PDE), which is used to calculate the occupational exposure limit (OEL) and the maximum carry-over from one product to the next. In addition to these threshold values, a risk assessment of the overall process and the associated containment transfer systems, cleaning, and staff training are also important. An account of this complex interplay and how it can be successfully implemented has now been published in the first edition of the International Society for Pharmaceutical Engineering (ISPE) 

	A group of experts came together in 2008 to establish an ISPE Community of Practice (CoP) in Germany, Switzerland, and Austria (DACH), which laid the foundation for a comprehensive document about containment. After almost six years of intensive collaboration, with numerous meetings, working group sessions, workshops, and reviews by industry, the 

 was presented and distributed to participants at the ISPE Containment Workshop in Germany in November 2015.

 is the most comprehensive document to date on the topic of containment, and it comprises an introduction followed by 10 different chapters that cover the principles of containment, risk assessment, the lifecycles of containment solutions, process requirements from API manufacturing to the packaged tablet, technical systems such as isolators, secondary containment, filter systems, occupational hygiene validation, cleaning/waste treatment, and staff training. Selected chapters are outlined in the following.

	How are OELs calculated? The chapter entitled "Fundamental Considerations" focuses on defining the relevant terms. From establishing the critical effect to establishing the no observed effect level (NOEL), which is then used to calculate the acceptable daily exposure (ADE) or, in accordance with the new EU GMP guideline for shared facilities (2), the PDE.

	The relationship between the ADE/PDE and the OEL can also be seen in the containment pyramid (see 

). Along with the OEL, the ADE/PDE is used to calculate threshold values for cleaning residues and for product carry-over from one substance to the next. The threshold values calculated using the PDE also replace, in Europe, the 10 ppm and the 1/1000 of the daily dose criteria previously applied (2).

	A further point relating to the principles of containment is the distinction between primary and secondary containment. Primary containment refers to all of those technologies that enclose the substance and prevent it from spreading. Examples of this include isolators and endless liner systems. Secondary containment, on the other hand, involves preventing any further spreading of the substance that could not be held back through primary containment.

	Every planning process begins with a risk assessment, which takes the overall manufacturing process into account, from delivery of the API to the finished and packaged pharmaceutical product. The procedure involves assessing the risks that may arise and the extent of the immediate hazard for users and the environment. In addition to the immediate hazard associated with product transfer systems, cleaning, maintenance, and repair should also be taken into account. During cleaning, for example, it must be noted that dust exposure is possible when opening containment or process systems at critical points. Maintenance work, for its part, involves the risk of visible product deposits being left on shaft seals when parts are disassembled, for example. As part of the risk assessment, all experienced individuals who are familiar with the manufacturing process should sit together with suppliers to discuss critical areas, risk reduction, and risk acceptance.

	The lifecycle of a containment installation does not end when it goes into operation-it is only just beginning. More precisely, the lifecycle starts with the planning process for manufacturing a highly active or highly hazardous pharmaceutical product, together with its specifications, and ends with decommissioning. There may be a significant period of time in between, during which the containment installation and its safety function will need to keep pace with the relevant requirements. One of the most significant factors for ensuring compliance is maintenance and repair. Consumables used in pharmaceutical manufacturing are subject to a constant process of wear, and this wear can vary according to process, frequency, and product. Based on these requirements, it can be necessary to shorten the inspection and maintenance intervals. Ideally, the OEL measured on the installation (referred to as the DEL, or "design exposure limit") should be significantly below the required OEL. It is, in any case, essential to note the point in time at which the first effect level is reached, or alternatively to ensure that this does not occur. The first effect level is reached when the DEL becomes very close to the required OEL. Maintenance plans and instructions help to secure the lifecycle of the containment.

	As a rule, the processes involved in API manufacturing or pharmaceutical formulation are considered to be closed and hence safe. There are, however, several important points to take into account when it comes to planning functioning process containment. One of these is product residue, as shown in the following example.

	A high shear mixer is a process device that is closed while the product being manufactured is processed. It must be noted, however, that this technology is not completely self-emptying. It may be necessary to open the system to remove (potentially expensive) product residues from surfaces and make them available for further processing. These systems also have shaft feedthroughs from the exterior to the interior, and these feedthroughs are subject to wear, even when equipped with the best seals and air flushing. In particular, when the product is abrasive and friction against the seal is intensified by the rotation of the mixing paddle, product may be carried over into the seal. Inerting with a noble gas can also result in residue. Flushing the gas with low pressure can result in air turbulence at the point where the gas enters into the process, making it possible for product dust to be deposited in the gas pipe against the direction of flow.

	In addition to describing the functions of the individual process systems, the 

 also lists the possible technical containment systems that can be used for this process together with the critical areas to be considered in each case. The term "containment" primarily refers to product transfer systems such as isolators. These technical systems are intended to ensure that highly active or highly hazardous substances do not escape. Further product transfer systems include double valve systems, film connection systems, endless liner systems, rapid transfer ports (RTPs), film isolators, and various others. All of these systems have their merits and are used in the pharmaceutical manufacturing of highly active or highly hazardous substances.

Isolators are undoubtedly the most frequently used form of containment system. They can be put to various different uses and can achieve a high level of containment down to the low nanogram range. Achieving this result in the low nanogram range, however, needs a significant amount of experience in isolator manufacture and design. Here, the glove port design and glass door seals also play an important role, in addition to hygienic design. 

 shows an example of an isolator with high containment.

	The filter technology used for inlet and outlet air is a further important factor. In many cases, bag in/bag out or push–push systems are used. With bag in/bag out systems, the low nanogram range cannot be reached due to technical limitations. While this is possible with push–push filters, they are a concern from a GMP perspective, as they involve pushing the contaminated filter cartridge into the cleaned isolator. However carefully this procedure is carried out, the risk of contamination within the isolator cannot be ruled out, nor can the risk of contaminating the new filter. 

Isolated filter cartridges called “FiPa” are the better option in this regard. The FiPa, shown in 

, is constructed in a similar way to the isolator itself; it is completely sealed before use and is connected to the isolator in this state. Once the FiPa has been connected, the cover plate is opened from the outside into the isolator so that the contaminated air flows inwards and the dust is collected. Before the isolator is cleaned, the cover plate is closed to seal the highly active or highly hazardous substance within the filter housing. The FiPa is disconnected and disposed of once the cleaning process is complete. Sophisticated technical solutions are required to ensure that the low nanogram range can be reached in a secure installation.

	An essential factor in the success of a containment installation is the production team that operates the facility once it has been successfully commissioned. The production team should be selected at the early stages of planning and integrated into the decision-making process. Intensive and recurring training during commissioning and the initial stages of routine production is significant when it comes to complying with the required OEL.            

	The development and manufacture of highly active substances are becoming increasingly common. While in the past, these were primarily APIs and products in the pharmaceutical manufacturing of oral solid dosages, they are now also being used increasingly in biotech, such as in antibody drug conjugates. The 

 will support those planning a new, high-potency API facility or modernizing an existing production facility.

	1. ISPE Germany/Austria/Switzerland Affiliate, 

Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities 

	Richard Denk is head of the Containment Group at SKAN AG, 

:
	When referring to this article, please cite it as R. Denk, "Understanding Containment," 

The new ISPE Containment Manual is a summary of the process involved in the manufacture of highly active or highly hazardous pharmaceutical substances.

Understanding Containment

	The manufacture of highly active or highly hazardous pharmaceutical substances involves a complex interplay between the required threshold values, such as the permitted daily exposure (PDE), which is used to calculate the occupational exposure limit (OEL) and the maximum carry-over from one product to the next. In addition to these threshold values, a risk assessment of the overall process and the associated containment transfer systems, cleaning, and staff training are also important. An account of this complex interplay and how it can be successfully implemented has now been published in the first edition of the International Society for Pharmaceutical Engineering (ISPE) Germany/Austria/Switzerland (D/A/CH) Affiliate's 

	A group of experts came together in 2008 to establish an ISPE Community of Practice (CoP) in Germany, Switzerland, and Austria, which laid the foundation for a comprehensive document about containment. After almost six years of intensive collaboration, with numerous meetings, working group sessions, workshops, and reviews by industry, the 

	1. ISPE Germany/Austria/Switzerland (D/A/CH) Affiliate, 

	Antibody drug conjugates (ADCs) are a new class of highly hazardous substances used for cancer treatment. Most ADCs have an occupational exposure limit (OEL) of less than 0.1 μg/m

) and, therefore, require the most stringent containment classification (see 

).  The manufacture of pharmaceutical products in this range represents a  challenge, particularly to aseptic production processes, which must be run in overpressure to meet GMP requirements for protecting the product, while also actively protecting operators from the substance. 

Isolators have been used successfully for many years for product protection in aseptic manufacture, and now they are also being required to provide active personnel protection.  In aseptic manufacture, isolators are operated in overpressure to protect the product. Containment, however, calls for negative pressure in the isolator to protect personnel by preventing the hazardous substance from escaping. High-performance aseptic isolators can do both, but innovative solutions, such as FilterPatrone (FiPa) filter technology and specific sealings on the gloves and glass panel, are needed to enable an isolator operated in overpressure to remain below an OEL of 0.1 μg/m

. This OEL can be verified on the basis of the International Society for Pharmaceutical Engineering (ISPE) Good Practice Guide "Assessing the Particulate Containment Performance of Pharmaceutical Equipment," also known as SMEPAC (1).

Integrated filter technology plays an important role in achieving this low level in an isolator operated in overpressure. As a rule, filters are installed after the exhaust air channels and then changed using bag in/bag out (BiBo) technology, but this arrangement has two serious problems. Not only do the exhaust air channels become contaminated, but BiBo technology does not offer the necessary level of containment in the nanogram range. Nanogram-level containment  requires a technology that captures and filters the particles in the critical containment area to prevent them from reaching the exhaust air channels in the first place. Such technology is provided by a new type of isolation filter known as FiPa, which is shown in 

. These filters are positioned in critical areas in such a way that particles released during production can be captured safely and via the shortest possible route. FiPa filters take the form of a mini-isolator in their own right, and they come with an integrated filter cartridge. During a product change, the FiPa can be sealed and removed safely for disposal.

ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment


	Richard Denk is head of the Containment Group at SKAN AG, 

Manufacturing of antibody drug conjugates requires high-containment solutions, such as high-performance aseptic isolators.