To maximize return on investment (ROI) and operational efficiency, packaging lines need to be capable of handling new products, different product counts, and packaging changes with minimum retooling. Modular design and quick-changeover features help deliver this level of flexibility on integrated lines from original equipment manufacturers such as Uhlmann Packaging Systems and Bausch + Stroebel Machine Co. 

For parenteral products, Bausch + Stroebel has devised a lock-and-key system to simplify removal and replacement of VarioSys modules within a Class A isolator from Skan. An inflatable seal in the L-flange hermetically seals the connection between each production module and the isolator. Production modules lyophilize product; fill and seal nested syringes, vials or cartridges; and fill and/or close bottles and vials. Filling occurs via peristaltic pump, valveless rotary piston pump, or auger and is compatible with single-use systems. Options include tub unpacking and modules for stability tests and product formulation. 

Similar flexibility is available for solid dosage forms. Uhlmann’s Integrated Bottle Packaging Center (IBC) 120, for example, handles round, rectangular, and oval bottles ranging from 45 to 200 mm in height and 25 to 125 mm in diameter. A monoblock design mounts all functions on one frame in a length of less than 5 m, and a single touchscreen user interface centralizes controls for all the stations. When the operator identifies the product to be run, the machine automatically adjusts all the necessary stations, including desiccant feeding, tablet counting, tablet inspection, cotton insertion, and capping. "In a conventional layout, these processes would be performed with multiple machines—usually from multiple suppliers—with each using different operating systems,” said Ralf Klotz, regional sales manager for Uhlmann Packaging Systems, in an interview with 

. A library in the controller stores previous run data and machine settings. “The library allows users to duplicate the last run settings identically,” said Klotz. 

Changeover-related downtime is reduced by hygienic machine design, which eliminates product hiding places and areas where moisture or debris can collect and expedites the cleaning verification process. With no open conveyors between stations, cleaning involves a simple wipe and inspect, and there is no downtime associated with disassembly, reassembly, and manual adjustment of conveyor links. 

Once the machine is clean, changeover between various shapes and counts of capsules, tablets, and gel caps involves swapping a few format parts. Format parts and tooling are plug-and-play, with each designed to fit precisely in its station. “Quick disconnects, ball detent locking, and pneumatic unclamping will speed removal and replacement of change parts,” reported Klotz.

Feeding systems and electronic tablet counter(s) are format independent and adjust automatically using stepper motors. If settings are not already stored in the controller’s library, Klotz said, “Operators simply ‘teach’ a new product into the controller by defining length/width/shape and counts, and the system self-adjusts to optimize performance.” Changeover to a different bottle diameter can be completed in six minutes and requires no hand tools. 

A master shift register tracks each container, minimizes rejects, and supports serialization requirements. The modular design of the IBC 120 dedicates an area for coding and related inspection prior to the next process step. “Any failure in the process disables the next process steps through the shift register,” reported Klotz. This means that if the code is not legible, no filling occurs, and only faulty bottles are rejected. “This significantly minimizes rework,” he notes. It also minimizes network traffic since only verified bottles are passed downstream. 

Hallie Forcinio is Pharmaceutical Technology's packaging editor, 

Articles

Packaging

Modular design and quick-changeover features help deliver flexibility and maximize return on investment.

Flexible Packaging Machines Maximize Efficiency

Sterile transfer of components and other materials from one confined space to another has always been a concern in pharmaceutical production. A solution lies with isolation technology, which allows materials to be transferred between two closed chambers, or for two chambers of like ambiance to be connected without altering their environmental and containment properties. These exchanges use rapid transfer port (RTP) systems installed on enclosures such as isolators or production lines. Getinge-La Calhene’s DPTE system, the precursor in sterile transfer systems, has become an industry standard.


   
  The DPTE system is made up of two distinct parts: the “Alpha” part, fixed to a barrier (e.g., isolator surface) and the mobile “Beta” part, which is attached to a container (rigid or flexible) or to a transfer isolator. Each of the two parts has a door that functions both to close and to seal the device. 

 shows the operating principle of the transfer system. 

Designing an isolator should start with an analysis both of the end-user’s needs and of the manufacturing process requiring protection, particularly in terms of ergonomics and functional features. The ensuing design solution should be validated by the construction of a full-scale mock-up that is tested by the client and the end-users (see 

). This design process, which has been applied for more than 30 years by Getinge-La Calhène, has provided substantial feedback on recurring ergonomics issues encountered by isolator users.

Feedback analysis shows that repetitive sterile transfers can become an issue for the end-user even though the system has been designed with simple operating principles for ease of use. Productivity has risen, with a consequent increase in the number of transfer operations, from one per day in the 1990's to as many as six per hour today. Clearly, the ergonomics and security issues posed by transfer systems are becoming a challenge to pharmaceutical production industries, and transfer system manufacturers will have to address these new concerns. 

 Positioning and accessibility of the transfer system on the isolator wall are two major factors that are taken into account when improving working conditions for operators. The Beta part must be correctly positioned to connect to the Alpha part; this first phase of the sterile transfer operation often requires the Beta part to be lifted into position then connected by rotation onto the Alpha part. This may be particularly onerous when the Beta part is voluminous or heavy, or when the Alpha door is poorly positioned on the isolator wall; it may be too high or it may interfere with other items of equipment. Getinge-La Calhène's standard is to place sterile transfer ports 1.2 m high. In production units, footstools may be positioned to assist some end-users. New, 3D design tools will enable clients to experience working with their chosen layout and revise it as required to avoid interference with other equipment in use. Although reducing the weight of the Beta part is not an option in most cases, mechanical or hydraulic lifting systems may be installed for large containers and presterilized bags of components. 


Once the container has been attached, the two doors (now a double door) are opened to connect both chambers. This is done manually via a manipulation system (glove and glove port) which must be positioned close to the sterile transfer port and within the operator’s reach (see 

). The standard position for two glove ports, based on experience and user feedback, is to have a 600-mm distance between the ports.


Some systems, in which the Alpha part is rotated and/or the system is automated, have been devised to solve some of the issues raised by the rotation of the Beta part and the manual intervention required to complete the connection. These systems are, at present, limited in use because of issues with maintenance, cleanability, and footprint. New concepts, however, are being designed and developed by isolator manufacturers to overcome these limitations. 

 Manipulation inside the isolator using glove ports raises the risk of breaking confinement, which could cause costly and lengthy delays or could contaminate the operator if toxic products are involved. The protective sleeves and gloves can hamper the user’s movements and may reduce their field of vision or break their concentration. In the future, however, mechanized systems will make glove ports next to sterile transfer systems obsolete.

Christophe Dufour is Transfer Systems product manager and Chloé Guilmet is Innovation manager, both with 

Troubleshooting

Isolators should be designed to enhance working conditions for end-users.

Ensuring Ergonomic Design in Sterile Transfer Ports

 annual equipment and manufacturing survey collected industry feedback on trends and the utility of equipment used in finished drug-product manufacturing. Respondents to both solid-dosage and parenteral drug manufacturing questions indicated overall satisfaction with existing equipment and equipment innovation. Data indicated that process analytical technology (PAT) is growing in use, but some users also noted a need for improvement in existing PAT equipment and in new solutions. 

Existing solid-dosage equipment is generally meeting industry needs. Only one area-PAT/in-process testing-was indicated as poor or inadequate by more than one-third of respondents (see 

). Nearly one quarter of respondents also indicated that innovation is lacking in this area. This dissatisfaction is up from 2013, in which 22% indicated existing equipment was poor or inadequate and 16% said innovation was poor (1). It is interesting to note that use of PAT also increased over the past year among those surveyed. Process control/automation and powder transfer/materials handling were also flagged as needing significant improvement in existing equipment (25% and 21%, respectively) and in innovation (17% and 12%); these areas were also noted in 2013.


  The majority of parenteral-equipment respondents indicated that existing equipment is good or excellent, as shown in 

. These respondents also agreed that innovation is generally keeping pace with most, if not all, of their needs. Innovation was rated as excellent or good in lyophilization (95%), barrier isolation (91%), disposables (91%), vial and cartridge fill-finish equipment (92%), and prefilled-syringe fill-finish equipment (85%). Process control and automation was a weaker area, similar to 2013, with approximately 25% saying that existing equipment is either poor or inadequate, and 18% saying that innovation is poor.


    In the five manufacturing areas surveyed, the use of PAT increased significantly since 2013 (see 

), with 32-46% of respondents in 2014 indicating that they currently use PAT compared to 13-21% of respondents in 2013 (1). The primary drivers for using PAT (multiple answers possible) include better process understanding (56%), increased efficiency (39%), reduced costs (34%), and shorter process times (30%). The use of PAT should continue to grow; between 20 and 30% of respondents in 2014 indicate plans to implement PAT in the coming year. Approximately one-third of respondents (33-37% depending on the application), however, do not currently use PAT and do not plan to implement it in the coming year. 


Given these plans to implement PAT and the respondents who said that existing PAT tools do not meet their needs, as discussed previously, PAT is an area ripe for suppliers to develop new and improved instruments.

 for the complete survey analysis, which includes responses to questions on quality by design, metrics, continuous manufacturing, and manufacturing of highly potent drugs.

Production Trends

Pharmaceutical Technology’s survey collected industry feedback on trends and the utility of equipment used in finished drug-product manufacturing.

Survey Shows Importance of Process Analytical Technology

A corrosion-resistant, plastic combination (PC) conveyor chain from FB Chain is designed for pharmaceutical manufacturing and meets EU hygiene standards. The chain is constructed from detection-grade engineering plastic inner links, supported by 304-grade stainless-steel bearing pins and outer link plates. The PC chain matches the strength of standard stainless-steel chain but has a much lower friction coefficient, eliminating the need for lubrication and increasing wear life. The PC chain is also quieter and lighter than stainless-steel chain. The bushed design of the plastic inner link eliminates the risk of residue becoming trapped between the chain components in wash-down applications. FB Chain’s PC chain is dimensionally interchangeable with stainless-steel chain; no adjustments to sprockets or other existing conveyor components are required to accommodate it. 

A hygiene-grade conveyor chain from FB Chain improves wear compared to stainless-steel chains.

Plastic Combination Conveyor Chain Increases Wear Life Without Lubrication

Gerresheimer's patent-pending Gx G-Fix adapter integrates prefilled glass syringes with polymer-based autoinjector devices. Most autoinjectors contain two main modules: the injector itself and the prefilled syringe. The modules are combined in one assembly, but combining two different materials is a challenge, because glass prefilled syringes have different tolerance requirements than plastic devices. The plastic adapter attaches to the syringe shoulder and provides a precisely defined interface to the device.

In the past, the high dimensional tolerance of the glass syringe only permitted limited control of the injection needle’s position in the front opening of the autoinjector. Because Gx G-Fix is specifically adapted to the autoinjector, it allows accurate needle positioning and improves control of the injection process. The adapter also protects the syringe against breakage. Conventional products coupled the syringe with the finger flange. When triggered, the structurally sensitive flange is subjected to a lot of pressure and can easily break. With Gx G-Fix, however, attaching the syringe at the sturdier shoulder minimizes the risk of breakage. 

The Gx G-Fix is assembled in conjunction with ready-to-fill syringe processing at the syringe manufacturer’s facility. Device integration and RNS positioning with Gx G-Fix can be used individually or in combination in the autoinjector. Plastic syringes can also be easily fitted with the adapter. Autoinjectors with Gx G-Fix are therefore suitable for both plastic and glass syringes and can be used for a variety of drugs. No changes to the customer’s filling station are necessary.

Gerresheimer's Gx G-Fix adapter integrates prefilled glass syringes with polymer-based autoinjector devices.

Equipment and Processing Report-07-16-2014

Flexible Packaging Machines Maximize Efficiency

Ensuring Ergonomic Design in Sterile Transfer Ports

Survey Shows Importance of Process Analytical Technology

Plastic Combination Conveyor Chain Increases Wear Life Without Lubrication

Adapter Aids Positioning of Syringes in Autoinjectors