According to the FDA (Food and Drugs Administration), pharmaceutical manufacturing has been well known for its inefficient and costly operations (2004). Recently, the need to increase efficiency and reliability has developed the necessity for improving the Quality by Design (QbD) of the solutions adopted by this traditional market. However, the main challenge for the pharmaceutical industry in moving towards cost-effective manufacturing is to design new operational procedures and workflows that comply with all regulatory requirements, but at the same time support continuous improvement by minimizing costs, time and resources needed (O’ROURKE & GREENE, 2006).
Fedegari Group was chosen as the preferred supplier of contamination control systems for a multinational pharmaceutical company with a new sterile antibiotic powder plant. The requirements for the new pharma plant emphasized the need for Grade A continuity in the manufacturing process with a barrier between operator and sterile process. The main challenges of the customer were to optimize the powder filling process and benefit from the cost-effectiveness of process integration with the best ergonomic design for the operators as well as ensuring a reliable and, contained pharmaceutical process.
1. PROCESS INTEGRATION
Fedegari Engineering Team has worked with the customer for developing the most efficient and reliable solution that would allow to fill Al- kegs in the safest way for the product and for the operators. The outcome is a complete plant that combines in a modular way various subsystems that have been individually tested by Fedegari for different applications thus minimizing the risks typically associated with novelties. The solution also represents the most compact design for this type of operations. Fedegari was choosen as the only manufacturer able to supply the process equipment (Washersterilizer) integrated with RABS and surface bio-decontamination with hydrogen peroxide MAL (Material Air-lock).
A Washer-sterilizer integrated with RABS and surface bio-decontamination with H2O2 MAL applied to the powder dosing station. The washer unloads on module 2 – RABS.
Module 1: Washing/sterilization
Module 2: Washed kegs unloading station
Module 3: Empty kegs buffer station
Module 4: Manual powder dosing, capping and bagging with automatic pneumatic lifting device. Packaging materials and tools are introduced through the H2O2 MAL connected to the module.
Module 5: Filled and packed kegs unloading station Thema4 process controller delivered to the customer can be completely integrated with SCADA system.
Thema4 process controller delivered to the customer can be completely integrated with SCADA system.
Figure 4 – Integrated Solution for Filling Al-Kegs with Sterile Antibiotics. (Source: Fedegari Group)
2. PROCESS FLOW
2.1 Classification of Containment Systems
The handling of active pharmaceutical ingredients (APIs) increasingly requires the implementation of directives. This has become particularly important when the European Community Good Manufacturing Guide has incorporated the subject in the Annex 18. Respectively, implementing handling and containment measures capable of increasing the safety levels in the production of intermediates and APIs is crucial to define operator exposure limit/operator exposure band (OEL/OEB) levels 1 through 5. (DENK, 2008). OEL (Occupational Exposure Limit) is the average load of concentration of a substance in the air at the workstation measured over a defined time period so that no acute or chronic harms to the health of the employee is expected. Since bulk solids can be dangerous/sensitive at different levels, containment systems are categorized according to their application and field of use. While customer and regulators body determine product specific limit values, the classification of containment systems allows the selection of the appropriate containment strategy and operating procedures for each product. There is a distinction between the following classifications or limit values:
Figure 2 – Containment Strategy Triangle. (Source: Fedegari Group)
3. THE PROJECT
Considering the target of an OEB equal to 3, the strategy chosen was a down flow system integrated into RABS because of the required sterility of the product. The system was designed for dosing of bulk sterile antibiotic powder into clean and sterile Aluminum Kegs.
- Product potency: OEL 65 μg/m3
- Occupational Exposure Band OEB: 3
- Containment Performance Target: 25 μg/m3
Rules and Standards for sterile production are evolving continuously. Clean areas require strict contamination control because of very critical operations taking place. An integrated approach to operations inside clean areas leads to the concept of integrated machinery as presented in this case study. Every load needs a specific washing equipment and its design plays a fundamental role on obtaining an effectively clean load. The use of steam in the cleaning process minimizes the use of detergents as well as energy and water consumption, reducing operational costs and improving washing performances. The door is equipped with a silicone inflatable seal, with a specific design to ensure the perfect drying of the surrounding area, at the end of the cycle. A close loop piping recirculates cleaning water without the need of a buffer tank and steam injection during pre-washing softens most of the soil thus reducing the detergents typically needed as well as utilities and energy in general. A Conductivity sensor was installed on external water circulation circuit to check cleaning effectiveness and prevent sensors contamination. The conductivity meter controls the process to end the washing/rinsing phase when the desired set point is reached. The additive is initially dosed up to a specific quantity (ml) selectable by a programmable parameter. During the washing, a refilling of additive is performed up to a specific conductivity value checked by the conductivity sensor and a pressure transducer detects possible failures or malfunctions of the circulation pump or the spray nozzles.
Figure 6 – Washing cycle development. (Source: Fedegari Group)
3.3 H2O2 MAL – Hydrogen Peroxide Vaporizer
An innovative design which provides real time biocide concentration control (over traditional estimated calculations) has been applied to the Material Air-lock used to transfer packaging materials and tools inside the RABS.
The use of Fedegari vaporizer with control loop (PID based) provided superior reliability and repeatability for easier process validation. The same process controller (Thema4 ) that manages the washing machine is used to control the bio-decontamination with hydrogen peroxide.
Applying Quality by Design (QbD), this solution helped the customer to achieve the desired ergonomic results on manual operations reducing the risks of contamination due to the integration of different machines connected by RABS into one unique system managed by a single process controller. Since continuous improvement requires a higher level of process understanding (FDA, 2004), Fedegari knowledge on pharmaceutical processes has been crucial to support pharmaceutical companies on the design of cost-effective solutions for process optimization and improved workflows.
|Batch size||600 kg (aprox. powder density 0,5 kg/l)|
|Kegs volume||25 l|
|Line output||12 Kegs/h|
|Line footprint||60 m2|
|Washing/Sterilization customized cycle||approx. 1,5 h|
|Washing batch||16 Kegs|
|Buffer area||32 Kegs|
- ERGONOMIC DESIGN – Unloading system designed to work at the same level (height) throughout all the modules – from washer to RABS (Figure 7).
- SIGNIFICANT TIME AND COST-SAVINGS by easily handling the kegs through sequential workflow inside the gloved isolator.
- CUSTOMIZATION – A fully modular and custom-made loading rack was designed for the specific load configuration and the spray pattern was optimized, thus improving process validation. The washer was designed to prevent any water stagnation by means of dedicated draining points. The washing cycle was developed considering the nature and quantity of the residues adapting washing temperature, time interval, additive concentration, number of rinses and phase sequence to achieve the highest performance.
COST-EFFECTIVENESS – Time and cost-savings on training and maintenance due to standardization of components, procedures and process controller. Thema4 process controller delivered to the customer can be completely integrated with SCADA system.
Figure 7 – Sequential workflow inside the RABS. (Source: Fedegari Group)
Figure 8 – FOWS Washer-sterilizer with Unloading Rack. Material Air-lock Inside the RABS. Aluminum Kegs in the Working Flow. RABS. (Source: Fedegari Group)
By Chrissie Fuchs, Marketing & Communication at Fedegari Group, and Sergio Mauri, Director, Marketing & Business Intelligence at Fedegari Group
Learn more: https://www.fedegari.com/en/latest-developments/
DENK, Richard. Containment System Concepts for OEB1 through OEB5. February 1, 2008. http://www.powderbulksolids.com/article/containment-system-concepts-oeb1-through-oeb5
O’ROURKE, Dermot and GREENE, Anne. Lean Manufacturing practice in a cGMP environment. Pharmaceutical Technology Europe PTE. Volume 18, Issue 10, 2006. http://www.pharmtech.com/lean-manufacturing-practicecgmp-environment
FDA, Innovation and Continuous Improvement in Pharmaceutical Manufacturing. Pharmaceutical CGMPs for the 21st Century -The PAT Team and Manufacturing Science Working Group Report. February 8, 2004. https://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4080b1_01_manufSciWP.pdf