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During regular freeze-drying in vials you still have the implication of product loss and fly-out. In addition, the staff and product are under contamination risk.
Further, aseptic development and/or manufacturing for clinical studies is difficult and expensive to achieve.
The Teclen® Lyoprotect® Solution
A tray (or frame) is used to accommodate the filled vials. These are arranged in the middle of the tray, and the stoppers are in the drying position. Open space in the tray should be filled with empty vials. The vial/tray assembly is placed into a Lyoprotect® Bag, which is closed and secured with the closing stick.
If aseptic criteria must be met, filling of vials, placement and closure of the Lyoprotect® Bag need to take place under a laminar flow / at a work bench. All required accessories (vials, stoppers, bag etc.) must be sterile. When the bag is closed, the assembly can be moved to a freeze-drier in the facility.
When the drying process is finished, the vials are securely closed with the stoppers. This is done within the freeze-drier by lowering the shelves. The flexible materials of the Lyoprotect® Bag follow the movements and mechanical loads when the stoppers are pushed in. If decontamination of the outside of the vials is needed (e.g. H2O2), this can be done with the bag still in place. After decontamination you can remove the closed vials for crimping.
The Heraeus Pharmaceutical Ingredients Business Line
Within the globally active Global Business Unit Heraeus Precious Metals, the Business Line (BL) Pharmaceutical Ingredients has specialized in the process development and production of highly potent active pharmaceutical ingredients (hAPIs). This ranges from the synthesis of cytotoxic compounds to registration and market launch. All hAPIs for cancer treatment are fully developed and manufactured at the company’s headquarters in Hanau, Germany.
Pharmaceutical Ingredients has been US FDA-approved for more than 25 years and in 2018 once again received an award for the high quality and safety standards applied to the production of their hAPIs.
The R&D team of BL Pharmaceutical Ingredients is a CDMO (Contract Development and Manufacturing Organization). It develops custom-order chemical synthesis and purification processes, where the staff members research and work with platinum-based and organic active ingredients for chemotherapy. Hence, a reliable protection is indispensable for the staff members as well as the environment. Furthermore, the active ingredients must be protected from contamination or cross-contamination.
Heraeus manufactures active pharmaceutical ingredients in compliance with GMP. Often only a few grams up to 100 grams of these highly toxic APIs are required per batch. This relatively small amount is a particular challenge for the lyophilization of active ingredients, as a laboratory or pilot freeze-drier is frequently not located inside an isolator or does not have the necessary CIP/SIP equipment. Due to capacity utilization or cross-contamination risks, switching to a suitable production facility is difficult or not possible at all.
The Solution: Lyoprotect® Cup
Under discussion between the R&D team of Pharmaceutical Ingredients, the responsible QA representative, and staff members of Teclen GmbH, it soon became obvious that the
Lyoprotect® Cup would be a good solution in order to avoid contamination risks. However, the cup still had to be customized.
The team selected the high-grade, resistant stainless steel 1.4404 (ANSI 316L) as material. By polishing, a mean roughness of Ra £ 0.4 µm is obtained and the cup can be even more easily cleaned without leaving any residues. The QA representative liked details such as the radius between bottom and sides as well as a consecutive serial number.
The Lyoprotect® expanded PTFE membrane ensures that no contaminants can enter from the outside and that toxic dusts remain inside the container. Due to the very porous structure of the membrane, water vapor can escape easily during freeze drying. Freeze-drying parameters determined on an open container can be transferred to the Lyoprotect® Cup with Membrane without limitation. The same filling level must be applied.
The screw-on ring cover and a silicone O-ring with FEP sheathing ensure tightness of the cup system. The FEP O-ring is resistant against acids, caustic soda and solvents.
The R&D team of BL Pharmaceutical Ingredients agrees:
“We have expanded our performance spectrum and can now lyophilize highly toxic custom-order APIs in our laboratory in Hanau, Germany, in compliance with GMP. The Lyoprotect® Cup with Membrane is a principal item of the freeze-drying process.”
Starting out as a regional company, Lactosan has become a globally active specialist in the production of lactic acid bacteria.
In addition to special products on the basis of living lactic bacteria, Lactosan also produces probiotics for farm animals, strains for human probiotics as well as starter cultures for food. The services offered also comprise contract manufacturing of more than 40 different enzymes for the food or pharmaceutical industry.
With the R&D laboratory and pilot plant, research projects and process developments can be realized in a target-oriented way. The pilot plant permits the production of smaller quantities up to a scale of 300 l for testing purposes.
Mr Mag. Bernhard Hofbauer, working at the R&D department of Lactosan, verified the suitability of the Lyoprotect® Tray for contamination-free freeze-drying of bacteria strains in the course of an internal qualification process. This way, Lactosan would be able to lyophilize different products in one drying cycle in the future. In the event of success, this could save time and money.
During this test, the drying parameters and subsequently the drying results were scrupulously examined in the pilot laboratory. Needless to say that special attention was paid to possible cross-contamination. The aim was to provide evidence that by using the Lyoprotect® Tray, different bacteria strains can be freeze-dried side by side without contaminating each other.
The picture above demonstrates the setup of the test, which was carried out by Mr Hofbauer in the pilot laboratory:
The Lyoprotect® Tray on the left contained bacterial strains of the type Lactobazillus plantarum. These strains were freeze-dried under aseptic conditions and were then examined for the most common pathogenic bacteria as well as for cross-contamination.
The right tray remained uncovered for comparison purposes. It contained bacteria strains of the type Enterococcus faecium. By means of agar plates, which were placed in the freeze-drier, fly-out during freeze-drying and contamination of the environment was verified.
The components of the Lyoprotect® Tray comprise an aluminum tray with accurately fitting fixing frame, a vapor-permeable membrane and a silicone flat gasket.
The tray was assembled under a laminar flow and subsequently filled with the Lactobazillus plantarum suspension.
Then, the Lyoprotect® Membrane was positioned and secured with the fixing frame. As next step, the Lyoprotect® Tray and the open tray were placed side by side in the freeze-drier. Both were freeze-dried with the parameters which had been determined for the open tray in the past. After completion of the drying process, the chamber was ventilated. The bacteria strain freeze-dried in the Lyoprotect® Tray was then examined for common pathogenic germs and cross-contamination.
Survival rate after freeze-drying of Lactobazillus plantarum in the Lyoprotect® Tray was 80%. Microbiological testing with selective culture mediums showed that the product was free from cross-contamination by Enterococcus faecium. Pathogenic germs were not detected, either.
The behavior of the closed Lyoprotect® Tray is identical to that of an open tray with regard to freeze-drying of bacterial suspensions. No differences were found with respect to powder, survival rate and speed.
Mr Hofbauer concluded that contamination-free lyophilization products can be obtained by using the Lyoprotect® Tray.
”With Lyoprotect® we can now freeze-dry different formulations together in the same cycle. This saves a considerable amount of time when developing product variants for our customers.“
ProJect Pharmaceutics uses Teclen Lyoprotect® Bags for lyophilization of innovative cytotoxic drugs
ProJect Pharmaceutics GmbH (PJP) offers optimized formulation and process development for pioneering drug products to the international pharmaceutical and biotech industry. PJP was founded in 2010 and is located in Martinsried / Munich. The company has become the leading European service provider for the pharmaceutical development of cancer drugs, especially of so-called Antibody Drug Conjugates (ADCs). With these innovative agents, a highly cytotoxic agent is linked to a monoclonal antibody, which is to direct the active substance to the cancer cells in a targeted manner. For this type of drugs, PJP does not only develop formulations but also efficient and robust manufacturing processes, which are scaled up from in-house pilot installations to industrial sterile manufacturing. In the process, PJP pursues a consequent “Quality by Design” approach, so that the drugs can be processed smoothly and in consistent high quality in the production plant.
The PJP team approached Teclen GmbH, who offers different products for contamination-free lyophilization, with this problem.
Freeze-drying is an essential step in the development and manufacturing of many drugs in order to increase the stability of active ingredients and to get a storable finished drug product. Especially cancer drugs with highly sensitive active ingrediences often imperatively require freeze-drying to avoid degradation and reduction of the effectiveness during storage. So far, the products have been freeze-dried in open glass vials. In this process, the contamination of the freeze-drier by potential fly-out of toxic material from the vial or by glass breakage poses a risk for the staff, and the higher cleaning effort and frequent change of the vacuum pump oil leads to a considerable increase of production costs. Trials to seal the lyophilizate in sterilization bags and to perform lyophilization from within such more or less gaspermeable bags were not successful. The considerable obstruction of the sublimate downflow at the bag’s membrane leads to massive changes in the process quality – efficient lyophilization is no longer guaranteed.
The solution: Lyoprotect® Bag
When Dr. Andreas Schütz of PJP explained their present approach to Rolf Lenhardt of Teclen GmbH, a joint solution was found within no time:
The freeze-drying process was to be identical to the lyophilization process in an open vial to the extent possible. At the same time, it was to ensure total protection of the product and the environment. The specific Lyoprotect® Bag offers this advantage:
The entire assembly (usually a metal tray) of the vials can be inserted into the bag, the open side is closed with a special clip system. Subsequently, lyophilization of the vials is possible with exactly the same drying parameters used for lyophilzation with open containers. It has been demonstrated that there is no obstruction of the sublimate downflow. Depending on the requirements, the bag can be sterilized in an autoclave before it is filled.
For vials and bulk
The Lyoprotect® Bag is characterized by an excellent vapor permeability; at the same time it reliably prevents bacteria, germs or particles from passing through the membrane.
As the Lyoprotect® Bag is very flexible, the vials can also be closed directly in the bag with the lyo-plugs by lowering the shelves, thus securely closing the vials.
Thorough tests performed by PJP confirm the excellent suitability of the Lyoprotect® Bag for lyophilization. By means of extensive test series, it was possible to verify the particle tightness of the bags even under extreme conditions. The drying process of sample vials within the Lyoprotect® Bag was completely equivalent to the drying process with open vials. PJP now uses Lyoprotect® Bags for all projects with toxic ingredients and for all batches for the production of sterile preclinical samples.
“We’d already tried out several sterilization bags, but always had to compromise on the drying parameters. With Lyoprotect® our drying philosophy of the Single-Step-Cycle can now be realized much better – we also consider the Lyoprotect system fit for GMP production of lyophilized drugs.” (Dr. Andreas Schütz, Managing Director at ProJect Pharmaceutics)