Patient safety always is the most important concern for drug manufacturers, how to prevent cross contamination of highly potent active pharmaceutical ingredient (HPAPI) is the increasing critical part for a safe manufacturing process.
Drug products are typically formulated of several components, the most significant of which is the active pharmaceutical ingredient (API). According to the FDA definition, the intended function of an API is to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body 1.
Efficacious at much lower doses than APIs, high potency active pharmaceutical ingredients (HPAPI) represent a rapidly growing market, driven mainly by their utility within cancer treatment and efficacy as antibody drug conjugates (ADC). However, along with high potency, HPAPIs often exhibit high cytotoxicity, therefore efforts to prevent cross-contamination are essential to a safe manufacturing process which protect employees, the environment and the patient.
What are High Potent Active Pharmaceutical Ingredients (HPAPI)?
The definition of an HPAPI has not yet been standardized, however an API that is considered highly potent can be placed into one of the following four categories 2:
? A pharmacologically active ingredient or intermediate with biological activity at approximately 150 μg/kg of body weight or below in humans (therapeutic daily dose at or below 10 mg)
? An active pharmaceutical ingredient or intermediate with an occupational exposure limit (OEL) at or below 10 μg/m3 of air as an 8-h time-weighted average
A pharmacologically active
ingredient or intermediate with high selectivity (i.e., ability to bind to
specific receptors or inhibit specific enzymes) and/or with the potential to
cause cancer, mutations, developmental effects, or reproductive toxicity at low
? Or, by default, a novel compound of unknown potency and toxicity
To minimize the risks associated with manufacturing and handling these substances, it is vital that procedures are put in place to mitigate any hazards.
Engineering Controls within HPAPI Manufacturing
There are increasing pharmaceutical companies and their contract partners who manufacture and process high containment compounds taking the exposure limits of operators, environment protection as well as containing of cost into consideration when they select equipment, design processes and procedures, how to deploy appropriate containment technologies.
Applying engineering controls is the preferred methods of reducing the risks of contamination in the manufacturing environment and controlling employee exposure during the manufacturing process. Occupational hygiene monitoring techniques and methods of analysis can then be used to verify the performance of the engineering controls. Separate guidelines are required for the design and construction of the facilities in which high containment compounds are handled.
Equipment Selection Based on Occupational Exposure Band (OEB)
To identify the Occupational Exposure Limit (OEL) incurred during manufacture of an HPAPI, factors including the quantity of material to be handled, the percentage of this that is active (i.e. the relative proportions of the HPAPI and any excipient components), the dustiness of the material, and the task duration should all be considered.
Factors on HPAPI Manufacturing Process
There are a multitude of factors to consider when selecting an HPAPI manufacturing process. Considerations regarding equipment for HPAPI manufacturing are many and varied. Standardization of valves and containers, and compatibility with upstream and downstream processing can contribute significantly to the selection of a suitable containment strategy, while equipment cleaning and maintenance should also be assessed.
For cleaning purposes, decisions should be made regarding whether a process is dedicated or not, which cleaning materials will be used for deactivation, and the types of cleaning methods that will be employed. While clean-in-place methods rely on automatic procedures which require no manual intervention, wash-in-place techniques necessitate some manual involvement. Ergonomics is yet another factor to consider, with accessibility, the capacity to make any necessary equipment adjustments, and the ease of equipment cleaning and maintenance all requiring evaluation.
Tofflon R ★EVOLVE ? Tilting PFD for HPAPI Manufacturing
In the production process of solvent crystalline high potency active pharmaceutical ingredients (HPAPI), R ★EVOLVE ? Tilting PFD equipment is very important. Conventional Pressure Filter Dryers has limitations such as residual materials, leakage, low drying efficiency and manual intervention requirement, etc. Traditional filtering washing and drying equipment cannot meet HPAPI manufacturing process Due to the above problems, and the new flip-type multi-functional filtering washing and drying equipment can solve the above problems.
Structure of R ★EVOLVE ? Tilting PFD Equipment Equipment
In recent years, we proposed the concept o R ★EVOLVE ? Tilting PFD.
? It simplifies the internal design of the equipment and eliminated the hydraulic system. Driven by the motor, dynamic
production process is realized;
? The design concept combines the technical features of traditional filtering washing and drying equipment, single cone and double cone equipment, which is a game-changing design that integrates the technical advantages;
? Heat medium is not required for the stirring shaft. Horizontal working position is used for drying. The drying efficiency
can be increased by 30%-50% under the same conditions;
? The discharge port is designed at the upper head to ensure complete discharge and complete sealing after discharge;
? The material trap is eliminated to ensure the effect of CIP/SIP but reduce cross-contamination.
R ★EVOLVE ? Tilting PFD has remarkable advantages such as low investment cost, low operating cost, dynamic process production, low material residue, high drying efficiency, thorough cleaning, and sterilization, etc. based on the scientific and reasonable design concept and actual project operation.
High Drying Efficiency
The filtering washing station of the new flip-type filtering washing and drying equipment is shown in Figure 5, which is the same as that of the traditional filtering washing and drying equipment. In this station, materials are filtered and washed, while the main difference between the new and traditional equipment is the design of drying station and discharging station.
The material drying by the R ★EVOLVE ? Tilting PFD is automatically controlled by PLC, where the materials are flipped to approximately the horizontal position for drying. The stirring blade moves up and down and rotates forward and backward to ensure the full contact of the materials and cylinder wall and rapid drying.
? After filtering and washing, it is flipped to the horizontal drying station by PLC control, with materials at the upper head to increase the heating surface area;
? The stirring blade moves up and down to scrape off the materials adhered to the filtering floor as well;
? The stirring blade rotates forward and backward to allow the full contract of the materials to the cylinder wall. During the process of stirring and forward and backward rotation, the agglomerated materials can be broken up to achieve uniform heating of the materials.
Thorough Discharge, No Residue
The new flip-type filtering washing and drying equipment is automatically controlled by PLC and flipped to approximately the inverted position, and the stirring blade moves up and down, forward and backward. The materials are quickly discharged driven by gravity and stirring blade.
(1) Automatic flipping and automatic limit
(2) In the beginning, the materials will be automatically discharged under the action of gravity. In the later stage, the materials are thoroughly discharged by the forward/reverse rotation and up/down movement of the stirring blade;
By flipping and inverted discharge, it is a dynamic discharge process, which can ensure that the materials between the stirring blade and cylinder wall and those on the stirring blade can be thoroughly discharged;
R ★EVOLVE ? Tilting PFD simplifies the design through technological innovation and solves a series of risks such as huge residual amount, low drying efficiency and leakage of the traditional Pressure Filter Dryers, thereby improving the quality of drugs produced. In addition, it is more in line with the requirements of the regulations and a significant technical breakthrough. Its seal residue rate and other characteristics are ideal equipment for HPAPI manufacturing process.