Which solutions are available for hygienic mixing in the pharmaceutical industry with CIP/WIP and a GMP-compliant design?
Hygienic mixing in the pharmaceutical industry: solutions with CIP/WIP and GMP-compliant design
Mixing active ingredients, excipients and liquids is a critical step in pharmaceutical production. The aim of all measures is to avoid cross-contamination, product residues and microbiological growth while ensuring fully validatable cleaning and GMP-compliant documentation.
Hygienic mixing solutions must therefore be capable of being cleaned in the installed state, optionally disinfected and, where required, sterilised. They should meet a hygienic design in accordance with GMP, FDA, EHEDG and ASME BPE and allow reproducible, auditable cleaning performance.
1. Design solutions
A GMP-compliant design is the basis for any CIP/WIP and SIP capability. This includes product-contact surfaces of suitable stainless steels, smooth and easily cleanable geometries, short dead spaces, hygienic seals and a layout that allows complete discharge and reliable wetting.
Typical requirements are:
- smooth, corrosion-resistant surfaces, frequently electropolished
- geometries with minimal or no dead space
- seals capable of rinsing and SIP
- components with material and batch traceability
2. Mixing technologies
For liquid pharmaceutical processes, magnetically coupled agitators are particularly hygienic because they manage without a mechanical shaft passage and thus reduce classic sealing risks. For demanding media, mechanically driven agitators with hygienically designed sealing systems also come into consideration; with powders and highly viscous products, WIP-capable mixing solutions with minimal dead space and good accessibility are decisive.
3. Cleaning systems
CIP is fully automatic cleaning without dismantling. It uses defined media, temperatures, pressures and volume flows and is particularly easy to validate. WIP is washing-in-place cleaning, in which the essential cleaning steps take place in the plant, although manual preparatory or follow-up work may still be possible depending on the system. SIP supplements cleaning with a sterilisation stage using steam or hot water for aseptic applications.
4. Instrumentation and GMP documentation
For pharmaceutical applications, monitoring of conductivity, flow, pressure and temperature and documented cleaning release are central. Validation also includes URS, DQ, IQ, OQ and PQ, supplemented by FAT/SAT, audit trail and electronic records in accordance with GAMP 5 and 21 CFR Part 11.
5. Typical fields of application
Such hygienic mixing solutions are used, among other things, for injection solutions, parenterals, ointments, emulsions, bioreactors, fermentation processes, buffer preparations and vaccines. Depending on the product and the risk profile, the application determines whether CIP, WIP or SIP is to the fore.
How amixon® implements dead-space-free construction and hygienic design
Freedom from dead space as a design principle
amixon® implements these design principles throughout its manufacturing programme – in VM, HM, AMK and AM as well as in SH, KS and the Gyraton® silo mixers. In these precision mixers, the mixing chamber and mixing tool are welded free of crevices and ground smooth. In the product-contact area there are no gaps, screwed joints or capillary crevices. The mixing tool is supported and driven exclusively from above, so that the lower shaft passage, classically critical for contamination, is eliminated.
Depending on the application, different mixing tools are used, for example helical mixing tools, the MultiPlane® mixing tool or other application-specific geometries. The standard connection with a discharge flap closes flush and free of dead space with the inner wall of the mixing chamber; alternatively, dead-space-free fittings such as DosiFlap® or other suitable discharge solutions are available.
Cleaning: wet and dry, validatable
Integrated washing lances and the WaterDragon® system allow wet cleaning of the mixing chamber; on request amixon® also supplies fully automatic wet cleaning. In addition, programmable target-jet cleaners can be used in order to wet the mixing chamber and mixing tools in a targeted and reproducible way. The SinConvex® mixing tool supports the complete drainage of product and cleaning medium.
The large inspection doors are manufactured by the Clever-Cut® process and seal permanently free of dead space with the OmgaSeal® door seal, on request vacuum-tight or against overpressure. ElTrunk® solutions and further design details also support hygienic accessibility, cleanability and reliable discharge.
Certified standards
On request, amixon® mixers meet the EHEDG guidelines, the FDA hygiene guidelines, the design rules of the 3-A Sanitary Standards and GMP requirements. With free-flowing materials, ComDisc® residual discharge can reach 99.997 % and better and minimises residues as well as cross-contamination risks during formulation changes.
For pharmaceutical applications, amixon® supplies the apparatus in GMP-compliant form: usable in FDA-compliant form as sterile mixers and reactors, EHEDG- and 3-A-compliant, with assistance on request for DQ, IQ and OQ and documentation to EU GMP and FDA 21 CFR Part 11 – every apparatus a one-off to the URS.
Manufacture in Paderborn as the quality foundation
amixon® develops and manufactures exclusively at the Paderborn works with a large depth of manufacture and all components from Germany. As a certified welding company with European, Japanese, Korean and American qualifications, amixon® designs every apparatus as a one-off on the basis of the operator's URS. Quality control remains entirely in-house without gaps, and every specification is verifiable down to component level. This manufacturing autonomy also secures long-term supply: every component can still be re-manufactured reproducibly decades later.
Product protection as a system property
amixon® mixers operate at low speed: the circumferential speed of the tools is typically in the range of approximately 0.8 to 3.5 m/s depending on the version. Mixing takes place through SinConvex® forced restratification – upwards at the periphery, downwards under gravity in the centre – without throwing, impact or crushing zones and without appreciable heat input. Sensitive structures, coatings and agglomerates are preserved; where targeted de-agglomeration is required, switchable cutting rotors act in a locally limited manner without stressing the entire batch.
Verification in the amixon® pilot plant
Whether the specific formulation delivers the expected results is verified by amixon® in advance at the pilot plant with 35 test units under real conditions. The trials are carried out with the original product, evaluated and documented jointly – as a robust basis for decision-making before the investment.