In API (Active Pharmaceutical Ingredient) production, it is essential to use filter elements that comply, among other requirements, with FDA requirements (CFR Title 21, extractables, etc.) and/or the relevant European directives, as well as biological safety requirements for plastics (USP Class VI).
They must also be guaranteed non-cytotoxic in accordance with the MEM Elution Test, ISO 10993-5, and comply with European and US guidelines relating to the minimization of the risk of transmission of BSE/TSE agents.
Expert advicce
BSE/TSE: A filter element is considered compliant if it meets the “European guideline on minimizing the risk of transmission of animal spongiform encephalopathy agents via medicinal products for human and veterinary use” (EMEA/410/01 Rev. 3 – July 2011), adopted by the Committee for Medicinal Products for Human Use (CPMP) and the Committee for Veterinary Medicinal Products (CVMP).
The filter elements most commonly used in API production are filter cartridges, filter bags, and to a lesser extent, lenticular modules.
Issues related to filter media, structure, and sealing gaskets
These components can be divided into three parts: the filter media, the structural components (core, cage, end caps, collar, etc.), and the sealing gaskets. The main challenge lies in the chemical and thermal compatibility of all constituent parts of the filter element. Indeed, it is not always possible to supply a fully homogeneous element (i.e. 100% single polymer).
Either the filter media have been very little developed, for example at certain filtration ratings, in specific polymers (notably polyester), or the structural parts (mainly obtained by thermoplastic injection molding) are not available, for reasons of production volume and associated costs, in certain polymers.
The issue of gaskets is easily addressed through the use of FEP- or PTFE-encapsulated seals (readily available on the market as standard O-rings).
Expert advice
For each chemical product to be filtered, it is therefore necessary to consider the appropriate combination of each component (filter media + structural components + seals) in order to achieve the best possible technical–economic ratio.
Another parameter to be considered is the “position” of the filter element within the process. Indeed, filter elements located further upstream (for example, solvent prefiltration during transfer to reactors) may have to retain a wide range of particle sizes. In other words, the particle size distribution of the fluid is broad (often with a fairly Gaussian shape) and may extend over several tens (or even hundreds) of microns.
By contrast, filter elements used further downstream in the process, which are more related to safety filtration, excluding the retention of fines (carbon, catalysts, …), normally have a low particulate concentration to retain, with a narrow distribution centered around a specific cut-off.
For each type of filtration, whether upstream or more advanced, different filter elements will be selected according to the position of retention within the process:
- “Depth” upstream
- “Surface” in the latter case
These “depth” characteristics (sometimes referred to as clarification) and “surface” characteristics (sometimes referred to as classification) must be adjusted according to the chemical compatibility of the available materials and the nature of the fluids.
Depth filtration
For “depth” filter cartridges, the two most commonly used synthetic media are polypropylene and nylon.
The core, which is always required for mechanical support, particularly during differential pressure increase, may also be made of polypropylene or nylon (and more rarely of glass fiber–reinforced material or stainless steel).
The ratings generally available range from 0.5 µm to 200 µm.
By default, we consider only so-called absolute efficiencies, i.e. greater than 99.98%, sometimes referred to as Beta 5000.
Surface filtration
For “surface” filter cartridges, the range of options is broader and generally covers all chemical compatibilities. Depending on requirements, filter media may be made of polypropylene, nylon, glass fibers, polyethersulfone, Halar® (ECTFE), or PTFE. Limitations are more often related to the structural components and available parts.
However, polypropylene, nylon, Halar® (ECTFE), and PTFE are readily available. Although these filters are available with filtration ratings above 5 µm and up to 100 µm, they are normally used for submicron filtration or bacterial retention. This typically refers to filtration at 0.05 µm, 0.1 µm, and 0.2 µm (or 0.22 µm).
Regardless of technical, industrial, and commercial choices, it must be kept in mind that an API is the primary component of a medicinal product. As such, an API acts directly on the human body.
Quality assurance is obviously provided by Good Manufacturing Practices (GMP) and all international regulations (for the record, the pharmaceutical industry is the most heavily regulated of all, with legally binding requirements).
And yet, within this rigid framework, several approaches are possible in the management of filtration—or rather, of filtrations.
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