Strategies And Technical Solutions
The development of tablet presses with clean-in-place (CIP) features in the mid 1990's was one of the first steps on the road to producing a truly contained solid dosage production system.
IMA, a company at the forefront of solid dosage technology, has been developing systems with CIP capabilities for some time and has recently taken the design of such systems even farther with the addition of technologies to ensure complete containment when processing compounds with highly active substances.
This article will discuss some of the latest technologies to contain, transfer, process and subsequently clean solid dosage equipment used to process these highly potent and in many cases, toxic compounds.
Development of Tablet Presses With Clean-In-Place Capabilitiies
With the development of Comprima tablet presses in 1994, and of Imatic capsule filling machines in 2000, IMA was one of first suppliers of solid dosage equipment to produce machines with CIP capability1. Automatic cleaning systems were developed with the aim of reducing cleaning times and thereby also non-production times. From the very beginning CIP machines were particularly suitable for containment applications.
The basic feature of CIP equipment is a complete isolation of the processing area, so that neither the powder nor the cleaning media (water and/or detergent) can pass in the mechanical area. The reduction of contaminated parts, the possibility to wet all parts before dismantling and the completely automatic and validatable CIP of the processing area are all features that are required when processing high potent products.
The increase in the number of highly active substances (approximately 50% of new Active Pharmaceutical Ingredients) and more restrictive regulations in terms of operator and environmental safety have brought a significant growth in the demand for containment installations world-wide.
Since the delivery of the first Comprima for product category IV2 in 1998, IMA has supplied over 45 different installations for dispensing, handling, tableting and capsule filling of category III, IV and V products, both for production and R&D applications. Through the years, a number of containment strategies, different systems and technical solutions have been developed, allowing solid dose production without the need for the operator to wear personal protection equipment.
Containment strategies on equipment
As a general statement, high containment has to be designed taking into consideration the whole manufacturing flow, and not only the production process itself: this means that product feeding and discharge, sampling and cleaning operations have to be considered.
Containment measures on the processing steps usually include:
Use of isolators for operations requiring close contact of the operator with the active ingredient (e.g. dispensing), or for complementary production operations (in-process-control, capsule/tablet dedusting and metal checking, sample collection, etc.). In this case the isolator is used to enclose wettable accessories and peripheral equipment.
Use of isolated processing areas inside the machines: a series of technical solutions, including gaskets, V-ring seals, inflatable seals and negative pressure inside the operating area, are applied, enclosing the product in a limited space, so that the machine working area itself becomes an isolator.
Safe access into an isolated area during production can be achieved by means of glove ports, rapid transfer ports (RTP) and/or bag-in bag-out devices, allowing the operator to work in the protected area without breaking the containment. The quantity and positioning of glove ports, rtps and bag-rings can be evaluated upon operation requirements.
Although these systems allows safe access to the processing area and contained sample collection, different strategies are increasingly used to control high containment manufacturing processes by means of indirect methods, thus limiting, if not eliminating, the number and quantity of samples to be collected. These strategies include 100% net weight check through compression force, NIR systems or other PAT techniques like image analysis for the determination of granulation/drying end point, a check of mixing uniformity, content uniformity, etc.
All the internal, contaminated parts of a contained area (either inside an isolator or inside an isolated machine working area) should be wetted, in order to reduce airborne particulate, prior to the operator accessing the area for size change and/or for cleaning operations. Besides the wetting function, an increasing number of production machines are fitted with a completely automatic cleaning system, adjustable to different product characteristics and including a drying phase: in this case no final manual intervention is necessary to achieve a complete cleaning of the equipment, and the cleaning process can be validated.
Containment strategies on air treatment
When handling highly active substances, special technical solutions have to be applied to the treatment of the air exhausted from the processing area, for drying (in granulation or coating processes) and/or dust extraction (in granulation, tableting, encapsulation, or coating processes).
These containment measures can be limited to the application of one of the dust collection units available on the market and specially designed for high containment installations, like bubbler dust collectors, where water filtering of the air is automatically wetting the active product, or dust collectors with standard filters and bag-in/bag-out systems for safe changing.
Additional technical innovations are also available, such as metallic filters, which can be applied on both high shear mixers and fluid bed processing equipment. They feature a patented unclogging and cleaning system, represented by a rotary device combined with a bottom drain valve. The bottom valve, pneumatically actuated, can be opened to discharge water and fragments of insoluble products during the cleaning cycle.
A complete CIP process of the whole machine can therefore be achieved without dismantling the filters.
Containment strategies on product transfer
Besides machines and their auxiliary equipment, one of the most critical issues when processing highly active substances is the connection between different pieces of equipment, and the transfer of product from one step of the process to the next.
The use of intermediate bulk containers (IBCs) are the preferred method of product transport, as a standard bin can be easily fitted with isolation valves to guarantee a contained product loading/unloading. Product blending is generally performed on a bin tumbler, so that no product feeding and discharge is required.
When a process has to be performed on a line of different machines (e.g. an high shear mixer connected to a fluid bed dryer for granulation), high automation and closed systems are applied to product transfer. The use of high containment valves is particularly important to achieve containment in connections and product transfer operations, including dust-tight docking systems for machine feeding and discharging. An example of this technology is the ZANCHETTA TwinValve.
The TwinValve system is composed of a passive valve (a standard sanitary butterfly valve), and an active valve, where the standard sanitary butterfly valve is fully integrated in a cylindrical mini-hopper: a small chamber is therefore created, which can be cleaned before and after product discharge.
A telescopic, orbital rotating spray head is used to clean the chamber, with compressed air and/or water and/or other fluids. When water and/or other fluids are used, a drying phase is also performed. The system also includes an aspirating port, to keep the chamber under vacuum during each phase of the cleaning cycle.
The TwinValve structure ensures that the containment performance is maintained without depending on perfect positioning and continuous maintenance operations. Additionally, as the passive valve is a standard butterfly valve, the TwinValve can be easily retrofitted on existing installations.
As one of the first producers of Solid Dose equipment dealing with the contained manufacture of products containing Highly Active Pharmaceutical Ingredients, IMA has developed through the years a reliable knowledge in this field. This experience has led to the development of a number of technical innovations and specific solutions which can be applied to new installations. IMA is also very aware that containment must be approached as a global issue, where the solution to individual specific problems is found by facing them as part of a wider production system, including customer products, existing structures, manufacturing needs and procedures.
1 P. Colombo, P.L. Catellani et al., Clean-In-Place System Evaluation of a Rotary Tabletting Machine, Pharmaceutical Technology Europe, vol. 9 nr. 4 (1997). P. Colombo, R. Bettini et al., Validation of a Clean-In-Place System on a Capsule Filling Machine, Pharmaceutical Technology Europe, October 2003.
2 S. Kaplan, Containment: Reducing Operator Exposure, Pharmaceutical Engineering, March/April 2000.
3 see also P. Gurney-Read, M. Koch, Guidelines for Assessing the Particulate Containment Performance of Pharmaceutical Equipment, Pharmaceutical Engineering, May/June 2002.