When GEA supplied a complete oncology manufacturing line to a customer in India, they didn’t just ensure the health and safety of the operators — complying with internationally recognised standards — the company also increased yields, reduced production cycle times and implemented an ultimate containment solution.
Contained Solid Dosage Production
Containment issues are becoming an increasingly important aspect of solid dosage form production. Active pharmaceutical ingredients (APIs) are becoming evermore efficacious, with more than 50% of all new chemical entities (NCEs) being classified as potent; at the same time, the health and protection of operators, all over the world, is being put under an increasingly intense spotlight. In addition, navigating the maze of available hardware components and the huge variety of containment solutions has made it progressively more difficult to select the most appropriate equipment for the specified task.
This was the dilemma facing Zydus Cadila, the innovative global pharmaceutical manufacturer based in Ahmedabad, India; the company intended to improve its solid oral dosage form production processes for highly potent drugs. Planning to use high containment equipment, the company approached GEA. Having supplied single pot processors to the pharmaceutical industry for more than 25 years, GEA is a leader in the field and has a proven track record as a system integrator for single pot, high containment projects for oncology and hormone applications.
Not only does GEA have a long history of expertise and an unparalleled depth of experience in the field of containment, they have also built numerous similar plants for low-volume production in Europe; this was a major influencing factor for Zydus Cadila, who were convinced that UltimaPro single pot processors would provide the ideal solution and enable the company to safely handle occupational exposure band (OEB) 3 and 4 drugs without risking the health and safety of its operators.
Several key technology requirements had to be met: Zydus Cadila needed processing units that could handle their highly potent drugs without exposing their operators to any health or safety risks. In an ideal world, operators would not be exposed to a single harmful molecule. In reality, however, this is simply not possible. Three main factors dictate how much containment is required and, therefore, which method of containment is most appropriate: the nature and potency of the API; the type of process to be done; and the working environment of the operators.
Non-specialist equipment suppliers may make spurious claims about their containment equipment or offer figures based on poorly defined test conditions. Where GEA excels as a solution provider as opposed to a pure equipment supplier is, having invented split valve technology (GEA BUCK® Valve), the company then went on form an ISPE expert working group (comprising pharmaceutical companies, engineering companies and containment equipment suppliers) who developed an accepted test procedure guideline in which all the previously discussed parameters are defined.1 The accepted test procedure uses a defined-grade lactose, places the equipment in a specific environment (humidity, temperature, number of air changes) with a number of sample-collecting filters in precise positions. The test involves doing the intended task and collecting air samples for 15 minutes. Analysing the filters gives the quantity of lactose in a measured amount of air, which is the containment performance of the equipment.
At Zydus Cadila, all product transfers to the production environment had to be effectively contained to avoid contamination of the product or the surrounding atmosphere. At the end of the process — and during product changeover — a fully validated clean-in-place (CIP) cycle was required to avoid any product contact. The whole process had to be compliant with current good manufacturing practice (cGMP) requirements and, not surprisingly, any loss in (expensive) product yield had to be avoided. The following points illustrate important criteria that were examined during the vendor selection process:
The potency of a substance is generally characterized by the occupational exposure limit (OEL) or the acceptable daily intake (ADI). The ADI describes the absolute amount of a specific drug substance that an operator can absorb without a negative health effect. Similarly, the OEL describes the maximum concentration of a drug substance that can be tolerated in the air of the production room. Values for established substances are listed in textbooks (for example, paracetamol is 10 mg/m3 and ethinyl estradiol is 35 ng/m3), although these values are based on certain assumptions and may alter during the lifecycle of a substance.2,3 If an OEL for a substance cannot be obtained from the literature, the value can be determined mathematically.4
Additionally, drug potency can also be classified from 1 (less potent) to 5 (most potent). This allows production equipment to be classified as suitable for the production of a class X compound, and it clearly shows operators the potency of the substance. However, when discussing this “simple” classification system, two important facts must be considered: it is not universal as nearly every company has its own classification system; and, factors such as dilution by excipients and the number of cycles/operations per shift are rarely taken into consideration.
2. Containment Risks
During most of the manufacturing process, APIs remain within airtight machines or vessels. The main risk of material loss occurs whenever a connection between those pieces of equipment needs to be made or broken, when a sample needs to be taken and when the machines need to be cleaned at the end of a manufacturing campaign. Even in the most state-of-the-art multi-product facilities, however, cross-contamination will happen. The critical question is how much cross-contamination is acceptable and how can it be kept below the acceptance limits.
Acceptable cross-contamination limits are dictated by the potency of the products. By definition, in the maximum daily dose of product two, only 1/1000 of the minimal daily dose of the active of product one should be found. The European Medicines Agency (EMA) has recently published new guidelines on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.5 Common ways to reduce the level of cross-contamination in multi-product facilities include separate production rooms, air locks and pressure cascades. These are perfectly appropriate for less critical products; but, when highly potent substances are handled, strict containment is the only way to protect both operator health and the integrity of other products.
The selection of the material handling system for potent APIs is of paramount importance; it fundamentally determines the containment performance of the entire installation and comes down to two choices: stainless steel or disposable systems. Intermediate bulk containers (IBCs) with split butterfly valves are the most commonly used material handling systems for dealing with potent APIs.6 The material required for a batch is loaded under a laminar flow booth, for example, into the IBC in the dispensing area. This IBC is then moved into the granulation area where it is docked using a split butterfly valve connection to a discharge station. The raw material, once milled to break up any lumps, is loaded either by gravity or by vacuum conveying into the granulator.
Various granulation options exist. With potent APIs, only a small percentage of the formulation is “active.” Such low dose recipes are not well suited to dry methods, such as roller compaction: containment is difficult and achieving even API distribution is problematic. Wet granulation methods are preferred. Post-granulation, an outer phase/coating is added by discharging the dry milled granules into an IBC, adding the outer phase, tumbling the IBC in a container blender to achieve homogeneity and then feeding the tablet press. When dealing with highly potent substances, tablet compression is probably the most challenging stage of the manufacturing process for the following reasons:
- the complex mechanical design and construction of the inside of a tablet press
- the continuous flow of materials in and out of the press
- the need to clean a very complex system during product changeover (including upstream and downstream equipment)
- the multiple interfaces between the tablet press and its environment (air inlet, tablet outlet, powder inlet, dust extraction), each requiring a contained interconnection
- the need for frequent tablet sampling, either manually or automatically.
To compress potent materials, GEA’s MODUL™ tablet press, with its exchangeable compression module (ECM), offers an unbeaten solution. The ECM is a completely sealed box; it contains all product-contact parts and is easy to remove and clean. Depending on the product and manufacturing requirements, it can be constructed in normal containment or dust-tight (C) or high containment (HC) options. During production, the ECM can be removed and cleaned offline while a second ECM is used, which significantly reduces machine changeover time.
Taking all these factors into account and, after suitable consideration, GEA recommended the use of two Single Pot Processors in a set-up that met all the key requirements: for the development laboratory, an UltimaPro™ 10 (10 L processing bowl) equipped with Hicoflex® technology for containment; and for production, an UltimaPro™ 75 (75 L processing bowl) equipped with Hicoflex® and MC valves. Both Single Pot Processors were equipped with all the available drying techniques, including microwave, to ensure flexible processing, higher yields and shorter cycle times.
Single Pot Processor: Flexibility and Containment
A single pot processor combines the process advantages of a high-shear granulator with a minimal surface area and the built-in facility of CIP to offer extremely fast changeover times. The available drying techniques for a single pot processor are vacuum drying, gas-assisted vacuum drying (Transflo™), microwave drying and swinging bowl. By equipping the machines with all these techniques, the most suitable drying parameters can be selected to ensure high yields and short cycle times. Using microwaves, for example, significantly reduces the drying time and enables the bowl temperature to be controlled to prevent the product sticking to the vessel wall. The single pot processor concept inherently ensures contained processing by avoiding product transfers and allowing the unit operations of mixing, granulation and drying to be done in one machine.
To monitor and analyze the process in a contained way, several options are available: one is to install a sampling valve into the processing chamber and adapt it to different containment levels; this obviates the need to stop the machine, open the bowl or a port in the lid. The sample container is completely contained and allows the sample to be transported to the QC lab without exposure to the atmosphere. For smaller equipment, the Hicoflex® sampling system can be used. Another option is to provide PAT ports for the use of online analytical probes; this allows real-time process monitoring, enabling real-time release and avoids the need for sampling.
With CIP playing an integral part of the containment strategy, the UltimaPro™ can be supplied with a wide range of washing-in-place and fully automated CIP options, such as retractable spray nozzles and downstream equipment such as a mill. A complete CIP report for the UltimaPro™ is available online.
Benefits for Zydus Cadila
GEA was able to supply the company with a complete oncology manufacturing line. The hardware solutions provided — particularly the split valves and the tablet press — represent the state-of-the-art when it comes to handling highly potent APIs. The entire project was managed in-house, beginning with a risk analysis regarding the amount of containment required, progressing through the overall design of the building and solution to installation and start-up. In addition, it was also managed in situ, in India, by local colleagues; only key components, such as the split valves, tablet press and single pot processor, were sourced from Europe. By choosing the UltimaPro™ 10 and 75, equipped with all the available options, and with Hicoflex® technology and MC valves, Zydus Cadila has ensured that it will be able to produce their OEB 3 and 4 drugs in a safe, cGMP-compliant environment and guarantee maximum yields with reduced cycle times.
Mr S.G. Belapure, President, Operations, commented: “Dealing with highly potent, solid oral dosage forms, we were looking for processing units that were safe, cGMP-compliant and protected the health and safety of our operators. We also wanted to maximise yields, prevent expensive product loss and reduce cycle times. These were the key factors that influenced our decision to purchase this technology and work with GEA."
- ISBN 07176 2083 2 EH40/2002 OEL 2002
- ISBN 07176 2172 3 EH 40/2002 Supplements 2003.
In the UK, COSHH rules state: “It is the first duty of the employer to protect (the health) of its employees.” Even though the regulatory situation differs from country to country, this statement should be seen as general guidance when handling potent substances. Given that approximately 30% of all people in western societies will develop some form of cancer during their lifetime, if one of these had been exposed to a carcinogenic substance whilst working for a pharmaceutical company, there is the potential for a legal claim against the company. This could result in high cost compensation and in very bad publicity, unless the company can prove that the employee had been protected using best available technology. COSHH rules show a clear hierarchy of control measures:
- Elimination at the source
- Substitution with a less hazardous material or form
- Reduction of the quantity below critical limits
- Engineering controls to prevent intolerable operating staff exposure (contained handling)
- Administrative controls
- Use of Personal Protection Equipment (PPE).
In many other countries, no legislation enforces this hierarchy. Most western countries will monitor the conditions under which operators have to work in the countries from which they import as it is seen as highly unethical to support practices that create health and safety risks in other areas of the world.