The entire design concept of a facility is subject to the choice of suitable containment systems, which requires careful attention to the different flow behaviors of the product. This report examines one such solid material handling and containment solution…By Richard Denk
The production of active pharmaceutical ingredients (APIs) requires the implementation of prevailing directives such as the ICH Q7A, which has strengthened its importance by being incorporated as Annex 18 in the EC GMP Guide. Equally important, however, is the implementation of the improvement for human safety in the production of intermediates and APIs.
Collective Safety MeasuresPlacing collective safety measures (closed systems) ahead of personal protective equipment is not merely a lawful claim by the EU Guideline 89/391 EEC. Even the new Act for Hazardous Goods demands collective safety measures. For effective operator safety, it is paramount to enclose the product at the location where it is produced and to maintain such an enclosed condition from the first step of the process until the product's final packaging.
A critical phase often emerges while changing processing facilities and transportation receptacles such as containers, drums, sacks, and big bags. If transports become indispensable, an OEL/OEB classification is undertaken (determination of workplace boundaries) in order to select the appropriate transfer system. The OEL/OEB classification refers to operator exposure limit/band. See Figure 1 for more details.
As soon as OEL/OEB values of a new API and/or workplace boundaries for chemical products have been determined, the technical effort involved can be defined with the effect to keep investment and operating costs at a minimum.
Containment defines the process of the enclosure of a biological agent or another substance within a defined space. In the pharmaceutical industry, the keywords of "total containment" protect human beings and the environment and prevent cross-contamination.
For the OEB values 1, 2, 3, 4, and 5, as shown in Figure 1, the toxicology of the pure substance is taken into consideration. Target is a plant classification by selecting appropriate production facilities and operating procedures for the respective product. OEL defines an average concentration load (µg/m3) by an API, which is measured over eight hours in the respiratory areas of the operators.
Facility PlanningFigure 2 shows a facility for the contained handling of highly potent APIs. The set-up of the production facility includes two reactors and a centrifuge dryer. The reactors are located on the second floor with the dryer on the first floor. The transfer of the solid starting material and the intermediates at several production stages takes place on the second floor. As for the highly potent APIs, the solid material transfer and the filling of the final product are executed on the ground floor by means of containment systems.
Production Area 2, Ground FloorIn a cleanroom of class D (100.000), there is a combined high containment filling station, where big bags (for intermediates that are discharged back into the reactor) and drums with in-liners (for APIs) are filled. Upon classification of the toxicity of the API, the product is filled into an endless liner (OEB 2-4).
Big Bags, Production Area 1Flexible receptacles such as big bags are low-cost containment systems. Big bags are able to deliver workplace boundaries of small 200 nanograms/m3. Especially in the containment business, the use of flexible disposable receptacles such as big bags pays. Apart from the low purchase price of big bags and in contrast to containers, there are no cleaning expenses. Moreover, the discharge performance of flexible receptacles offers major advantages compared with rigid ones. As shown in the example, large amounts of 25 kg or more are discharged into the process by big bags. For this purpose, the big bag discharge stations were equipped with Hecht lifting columns in order to accommodate big bags of different sizes and to lift them while being discharged and, thus, allow the product to exit easily. In addition, the big bag discharge station includes an agitation unit in the form of a rocker, which is adjustable in height. The rocker massages the bottom of the big bag and accomplishes the discharge of even the most bridging products. The height of the agitation unit is adjustable in order to enable the rocker to trail the bottom of the big bag while it is stretching.
Isolator, Production Area 1
The core of the big bag discharge station are the docking systems developed by Hecht Anlagenbau that allow the big bag outlet to be connected to the isolator with two integrated in-liners. By means of this advanced technology, it is possible for the first time to discharge a big bag in a completely contained manner. A workplace boundary of small 200 nanograms/m3 is achievable. No other technology with flexible receptacles currently is able to accomplish such containment. Small quantities up to 25 kg are connected to the RTP with the help of a canister, entrained to the interior of the isolator and discharged into the reactor subsequently.
PTS and DCS, Production Area 2High containment can be obtained with PTS/DCS vacuum conveyor systems. The product inlet system of the reactor is equipped with a PTS. It forms the lock for the transfer of solid material into a pressurized vessel with preloaded solvent. The PTS is based on the same pressure as the reactor (6 bar). It extracts the oxygen from the powder inside its chamber and subsequently discharges the contents into the reactor by using nitrogen. The PTS effectively improves the safety in the reactor on account of the oxygen-free transfer of solid materials.
The PTS is connected with two different powder transfer systems. Large quantities (50 kg and more) are added via a big bag discharge station. Small quantities (up to 50 kg) are added via a DCS. For this purpose, a drum with two in-liners is necessary. Those two in-liners are connected with the DCS: the outer in-liner at the bottom of the DCS and the in-liner, which is filled with product, inside the DCS. To carry out such operation, there are two integrated gloves at the DCS. The product is evacuated from the drum by means of a capped suction lance that is connected to the PTS. The DCS achieves a workplace boundary of small 1µg/m3.
For cleaning purposes, both the PTS and DCS are equipped with cleaning-in-place (CIP) units, allowing the cleaning fluid to be emptied directly into the reactor.
SAS, Production Area 2
Here's a brief explanation of the principle behind the protective liner system. There is a liner depot with about 15 m of protective liner centrically on top of the product guide pipe. The end of the protective liner envelopes the product guide pipe. Before opening, the in-liner of the big bag is connected and clamped dust-tight to the protective liner with a disposable ring. The protective liner is redrawn from the liner carrier. Upon discharge, the operator tapes off in-liner and protective liner above and below the disposable ring and separates the liners in the middle of the tape. The product guide pipe is sealed again, and the contaminated protective liner is discarded.
This procedure makes sure that no product escapes into the environment at any time. A workplace boundary of small 1 µg/m3 is achievable with this protective liner system. As a result, this system also qualifies for carcinogenic, mutagenic and reprotoxic substances. The suction shoe for the connection to the conveyer tube of the PTS contains a lump breaker.
Automatic SamplingA spoon integrated into the centrifuge dryer loosens, if need be, adhering product from the centrifuge drum. Once loose, the product precipitates into a collector, is evacuated by a mini powder transport system (MPTS), and then removed from the centrifuge dryer in a contained manner. The MPTS empties the product taken as reference samples into the vessel provided. The example examined here employs a glass. The MPTS is located in a glove box so that the filled glass can be undocked safely from the MPTS and sealed. The sealed glass is extracted from the glove box via an RTP. Just like all other systems, the MPTS also provides a CIP system.
Intermediates, Production Area 1
APIs, Production Area 2Finally, let's examine high containment filling of APIs into drums with an endless liner. The facility is equipped with a sieving machine, a metal deposition represented by a permanent magnet, plus an in-line metering system for the accurate filling of the drums without moving parts in the product-contact area. The metal deposition and the metering system rest on a lifting column. After cleaning, the lifting column may lower the systems to operating height for maintenance work. Again, the core of the filling facility is the Hecht endless liner filling head for the contamination-free filling of product. It is a special filling head to accommodate a liner package holding up to 50 m of liner. The design to provide the liner centrically to the product outlet makes sure that the filling head never is open to the environment. The liner is pulled down in sufficient length, according to drum size, from the carrier and is filled with product. Once the product is filled in the liner bag, the liner is sealed twice by an integrated bag sealer. Following the automatic separation between both sealings, the operator closes the drum. The drums are extracted on roller conveyors through a material lock into the storage area. In the material lock, there are air jets to clean the drum surfaces. The same system is to be found in the operator lock.
Richard Denk is the head of the pharmaceutical department at Hecht Anlagenbau GmbH. Hecht Anlagenbau GmbH has developed systems for all OEL/OEB levels (workplace boundaries) and all major transportation receptacles. Additional information is available by contacting him at firstname.lastname@example.org. KMPT USA, Florence, KY, is the exclusive North American distributor for Hecht containment systems. More information is available at www.kmpt.net or 859-547-1002.
APIs: active pharmaceutical ingredients
DCS: drum containment system
MPTS: mini powder transport system
OEL/OEB: operator exposure limit/band
PTS: powder transfer system
RTP: rapid transfer port
SAS: protective-liner-connecting system