Johannes Rauschnabel is a director of process engineering and a coordinator for barrier systems and the PharmaLab at Bosch Packaging Technology.

Johannes Rauschnabel

Packaging machinery suppliers describe how changes in regulations have driven developments in packaging and look ahead to coming challenges. 

Serialisation is among the major trends and future challenges for the pharmaceutical industry. Growing internet sales, outsourcing of production and more complex supply chains require at least national, if not international, legislation to secure pharmaceutical products and, most importantly, to protect patients from counterfeited medicines. Currently, new guidance and legislation are being developed and implemented by numerous countries, such as Argentina, China and Brazil, whose health surveillance agency, ANVISA, adopted a new resolution at the end of 2013.

The United States Food and Drug Administration (FDA) requires pharmaceutical producers to apply a standard numerical identification (SNI) to the packaging of all prescription drugs in a step-by-step approach beginning in 2017. The European Union’s Falsified Medicines Directive (2011/62/EU) also stipulates uniquely coded, serialised packs for almost all prescription drugs. Moreover, the EU has defined a second layer of security to be provided by tamper-proof closures that indicate whether a package has been previously opened or tampered with.

Pharmaceutical manufacturers will be—and are already—facing enormous challenges to implement the respective regulations within the given timeframe. And this implementation is not going to be an easy task. Most companies must develop and apply a global strategy for the consistent serial-number assignment, management and storage on all levels—from devices, line processes and line management to production and enterprise control. Such solutions must be compatible with in-house processes, such as manufacturing execution systems, which in turn require the adaptation of highly demanding packaging processes.

These solutions must be compatible with existing line concepts, and they must be extendable to all possible aggregation levels, including bundling, shipping cartons and pallets. The safest approach undoubtedly consists in a multilayer machine and software concept, which should take all requirements into account and combine all necessary processes in one modular, yet complete system that complies with the industry’s demand for consistent and high-quality operations and with patients’ demands for higher safety. 



Johannes Rauschnabel, PhD, is chief pharma expert at Bosch Packaging Technology. 

Articles

Pharmaceutical manufacturers will be-and are already&mdashfacing enormous challenges to implement the serialization regulations within the given timeframe.

Serialisation, Aggregation and Authentication

Patient safety often requires that drug products be filled and packaged in sterile conditions. Sterile cleanrooms and isolators prevent contamination during the filling process. The use of cleanrooms is well established, and isolators are gaining increased acceptance. Each method, however, has its drawbacks such as making process interventions more difficult. In certain applications, restricted-access barrier systems (RABS), which can provide a level of aseptic quality near that of isolators, offer an efficient alternative and more process flexibility. 

The aseptic processing of parenteral drugs and other sterile products such as opthalmic medicines and inhalers requires sterile handling to prevent the product from coming into contact with particulate and microbial impurities. For this reason, processing usually is performed in sterile rooms (see Figure 1). 

 Figure 1: Equipment in a cleanroom. Curtains mounted to the sterile air manifold or a safety partition separate the aseptic area from the cleanroom. The machine often will have its own filtration.			

Production equipment such as filling machines must have a hygienic design and must be sanitized regularly. In addition, operators cannot enter the sterile room until they change their clothing and are disinfected. Despite the precautions, experience with this methodology has shown that the major contamination source for the product continues to be the operators themselves. Incomplete disinfections, inappropriate operator actions, and problematic machinery that requires frequent manual interventions can cause viable contamination. Any biological contamination of a processing line and its associated drugs may pose a risk to patients receiving the product. 

To prevent such risk, the production areas, production machinery, and processes must be validated for aseptic quality. For example, operators must work according to precise, certified standard operating procedures (SOPs), which require special training programs. In addition, the production technology must function reliably to minimize operator interventions. The sanitation procedures must ensure the maximum removal of microbial impurities. Complete sterilization (the removal of all divisible organisms) of the entire machine and the entire area is hard to achieve with open-cleanroom methodology (1). 

The pros and cons of isolator technology. 

Products with higher standards and greater security requirements necessitate the use of isolator technology, which completely encloses the aseptic working area (see Figure 2). 

Figure 2: Equipment in an isolator. Air is prepared and recirculated in the isolator through double-window systems or return-air ducts.			

The high air-purity cleanroom (ISO class 5) inside an isolator is limited to the space above the machine's baseplate (2). The surrounding external area can have a lower air quality (a minimum of class 8) as long as the physical separation is maintained (3–5). This separation can be achieved using:  					

a separation wall between the aseptic area and the surrounding area (

 a plastic curtain [soft wall] or a metal partition with glass windows [hard wall]);

gloveports in the separation wall for manual interventions such as materials handling for microbiological monitoring or for responding to process disruptions;

sterile-transfer mechanisms for moving production components, tools, and monitoring material (double-door transfer systems are common);

mouseholes with format-specific parts to minimize the space around incoming and outgoing containers;

positive interior pressure relative to the surrounding room. 

Another important aspect of isolator technology is that it requires the biodecontamination of all machinery and isolator surfaces in the aseptic-process area before each production run. Biodecontamination is necessary because the isolator typically is opened for maintenance, format changes, cleaning, and product changeover. Opening the isolator removes the physical separation of the cleanroom and the potentially contaminated surrounding area. The most common biodecontamination systems for isolators use H

 vapor is introduced into the sealed isolator until it reaches a specified concentration. Next, H

 is held at this concentration for a specific duration. Finally, during the aeration phase, the H

 vapor is removed by purging the isolator with fresh, filtered air. This process can take 3–10 h, depending on the biodecontamination system, isolator size, surface areas, and air-filter size. During this period, the process line cannot be used, although other procedures such as cleaning and steaming in place of the filling system can be performed during aeration. 

The long duration of a biodecontamination cycle reduces operational flexibility when working with an isolator. This procedure, however, does guarantee that each production run begins with a biodecontaminated system, which is nearly sterile (demonstrating a 6-log inactivation of biodecontaminants). 

Table I: A comparison of cleanrooms, restricted-access barrier systems (RABS), and isolators.			

Manual operations within the aseptic area are more difficult with isolators. Gloveports must be used in place of direct operator access. This technique requires greater reliability and automation for process machinery inside an isolator than is required in a traditional cleanroom. All interfaces, gloveports, mouseholes, and transfer ports must be integrated into the physical barrier because they separate the clean process area from the potentially contaminated exterior areas.  

Isolators always have their own air-handling system to maintain production conditions and achieve the optimal conditions for the biodecontamination cycle. 

The restricted-access barrier system (RABS) can be an alternative to isolators and cleanrooms. The RABS concept entails a physical barrier between operators and production areas, but the barrier is limited. A limited barrier is acceptable because RABS always must be set up in high-class cleanrooms (at least ISO 7). Thus, RABS do not require their own biodecontamination system (6). 

To date, no specific standards or regulations for RABS have been developed. Manufacturers should follow existing norms and regulations for the basic processing of sterile pharmaceutical products. Operators can consult ISO Standard 14644, Part 7 for guidance when using RABS as a protective solution (5). Appendix A of Part 7 features a diagram that shows the reliability of a separation 

 the separation method. It demonstrates that RABS can be considered an aerodynamic measure that has a high physical separation. The system's interior atmosphere can be controlled, but pressure control is limited. In contrast, the diagram shows that isolator solutions have a small leak rate and appropriate positive or negative pressure control. 

Figure 3: Vial-filling line with a passive RABS.			

The US Food and Drug Administration is the first authority to offer preliminary definitions of the approximately 75 existing RABS installations worldwide (6). A working group of industrial experts drafted a definition of RABS and guidelines for RABS operation for FDA. This draft emphasizes that:  

				"RABS can operate as 'doors closed' for processing with very low risk of contamination similar to isolators, or permit rare 'open door interventions' provided appropriate measures are taken (7)."			

Opening the main doors during production is permissible and only requires in-depth documentation in exceptional cases. The same is not true for the transfer doors because the physical and aerodynamic barrier to the external area is only guaranteed when the doors are closed. Sometimes, industrial safety concerns prohibit the opening of RABS doors during production, regardless of aseptic considerations. 

Appropriate guidelines, manuals, and drafts for isolators are available in the three major pharmaceutical markets: the United States, Europe, and Japan. The recently rewritten FDA guidelines, Annex 1 of the European Union good manufacturing practice guidelines, and the detailed PIC/S recommendations are helpful for the planning and use of an isolator (3, 4, 8). The Japanese admission authority also is presently working on an appropriate document. 

RABS are more than just a safety covering for production machines. Incoming air passes through suspended high-efficiency (of at least HEPA Class H14) filters and is distributed evenly by a sterile manifold. The doors of the RABS are locked, and the gloveports are the only means of access. Users must transfer materials and components by means of special aseptic transfer systems. Air flows out of RABS the same way it does with simple barriers: through openings underneath the doors or through holes in the lower sections of the doors. The air returns to the same room from which it came. In a closed RABS, air is prefiltered and recirculated through ducts.

Figure 4: Machine in an active RABS. The RABS has its own air-handling system that draws air from the area and through openings below the product transport. 

RABS can be classified as either active or passive systems. A 

RABS does not have its own air recirculation, filtering, or conditioning. Its high-purity air supply comes from the cleanroom. Air flows downward from the ceiling and returns to the surrounding room through openings under the doors. The air from the room returns through air ducts to the room air-handling unit (see Figures 3 and 4). 			

RABS typically has an air-handling unit directly attached to it. This unit always contains a HEPA filter and provides even air-flow distribution with the help of a sterile air manifold. A cooling system also can be integrated for temperature-critical products. Air-conditioning expenditure is limited because fresh air is drawn from the cleanroom (see Figure 4). 

Figure 5: Machine in a passive closed RABS. Air is recycled from the room air-handling system. A prefilter also is used, which helps prevent contamination of the air-handling system.			

 RABS also may be passive systems that use the cleanroom's ventilation system and filter ceiling. The air does not return to the surrounding area, it passes through prefilters and ducts into the room's airconditioning system (see Figure 5). Because closed RABS concepts are used with toxic and dusty product applications, operators must pay special attention to cleaning the return air ducts and changing the prefilters without contaminating them (see Figure 6). 

Figure 6: Aseptic powder-filling line in passive closed RABS.			

Active closed RABS have air-filtration and air-conditioning systems (see Figure 7), which are needed to keep conditions constant within the aseptic area, especially when air cooling is required. 

Closed RABS can be operated with positive or negative pressure, which requires good sealing and pressure control. In these applications, a closed RABS is similar to an isolator (see Figure 8). 

Figure 7: Machine in active closed RABS. The RABS has its own air-handling unit. If necessary, recirculating air is prefiltered over mechanisms that permit a contamination-free filter change.			

The next level of aseptic operation and production safety is not attainable with RABS because of the lack of a biodecontamination system and the reduced air sealing. Closed RABS, as opposed to isolators, also require additional expenditures that must be considered (

 the surrounding area must be an ISO class 7 cleanroom). Each RABS installation balances pharmaceutical security, industrial safety, building support systems, operational flexibility, and the money invested in the system.  

If the RABS is operated according to the guidelines, the component-transfer techniques, sanitation processes, format-change procedures, and maintenance procedures required are different from those of a cleanroom installation. 

Before the beginning of a production run, the integrity of the barrier must be guaranteed. In particular, the gloves must be tested for leakage and damage regularly. To reduce dependence on SOPs, a regular physical testing method should be used in addition to the visual examination of the gloves. Two options for examination are: 					

testing the gloves before mounting them on the RABS and sterilizing them;

testing the gloves in the mounted position.

Both options have advantages and disadvantages. When the gloves are mounted, the entire glove assembly, including the mounting ring, can be tested. When the glove is tested before mounting, the isolator can be prepared for production, thereby reducing setup time. The sterile installation of the gloves is a challenge in each case. The gloves must be pre-sterilized, transferred into the cleanroom, and installed to the mounting ring in a sterile manner. 

Glove sterilization can occur in an autoclave bag. The material of the glove is a key factor for sterilization. Common glove materials such as chlorosulphonated polyethylene (Hypalon) will physically change after 8–10 cycles in an autoclave. More-stable materials such as ethylene propylene diene monomer, however, are stable for a nearly unlimited number of cycles in an autoclave. Assembling the gloves at the glove-mounting rings in a sterile way is difficult and requires experienced operators. Reversing the mounting ring can facilitate this operation by allowing the glove to be mounted from outside the isolator, rather than from inside. This arrangement reduces the length of the glove, however, so longer gloves may be necessary. 

Figure 8:  Active closed RABS with pressure-zone control.			

 Components, tools, and growth media for monitoring the microbiological state of the air in the RABS must be transferred in a sterile manner. A RABS can incorporate systems such as double-door transfer and steam sterilizers. A transfer chamber or simple transfer door also can be used. Transfer chambers possess inner and outer doors that are interlocked so that only one door can be opened. The interior of the transfer container, from which components such as stoppers are taken out of bags and introduced into the production process, should be ISO category 5. Simple transfer doors should be installed below the process level to reduce the influence of ambient air on the aseptic area. Opening the main doors to transfer components is not permissible, according to FDA's draft definition, because a RABS has no positive-pressure plan that could prevent outside air from entering the system. Closed RABS can be operated with positive pressure, but opening the doors during operation is not permitted for industrial-safety reasons. 

 The sterile assembly of filling-machine product-contact parts, including containers and component-holding parts, is difficult, especially when the component size is considered. For example, after a production run, a stopper sorting bowl was cleaned, dried, packed into a sterile bag, and autoclaved (

 in the material lock). Afterwards, the packaged bowl was taken from the air lock. The bowl was unpacked outside the sanitized RABS because of its physical dimensions. The heavy and bulky sorting bowl subsequently had to be installed into the aseptic area through an open RABS door. The draft of the RABS definition states: 

"Sterilization-in-place (SIP) is preferred for contact parts such as fluid pathways. Where this cannot be achieved, such parts should be sterilized in an autoclave, transferred to the RABS 

 a suitable procedure and aseptically assembled before processing (6)." 

 The sanitation of a RABS is substantially more complex than that of a machine with no barrier system. More surfaces and larger surfaces must be sanitized, and some surfaces are harder to reach because of the barrier. Operators try to achieve aseptic conditions with a RABS, which is impossible with open production systems. 

The draft RABS definition refers to a "'high-level disinfection' of all nonproduct contact surfaces within the RABS with an appropriate sporicidal agent before batch manufacture" (6). The draft defines 

 as a microbiological disinfection that increases product security and is a precondition for long production runs. A partition between operators and aseptic production areas is insufficient for better product security. The correct interface solutions and the correct handling are highly significant. RABS allow long production runs, but impose more restrictions than isolation systems. The definition draft carefully states: 

Filling machines often are installed in sterile rooms and separated by isolators to prevent contamination. These methods have certain drawbacks, including making interventions more difficult. Restricted-access barrier systems are an alternative that ensures sterility and facilitates interventions.