Cleaning validation in the pharmaceuticals industry

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Ferrum – Supplier of Centrifuge Technology Solutions for Solid/Liquid Separation

Category: Centrifuge Technology Solutions

Good pharmaceuticals manufacturing practice requires from pharmaceuticals companies that rooms and apparatus such as centrifuges and other devices must be cleaned according to written methods (“Good Manufacturing Practice” or GMP).

The most suitable method must be validated by the respective pharmaceuticals company on the basis of regulatory requirements [1] and their own expertise and technological advances in apparatus engineering. This takes place as part of cleaning validation; and this is precisely where the innovations of Ferrum in the area of vertical scraper centrifuges offer further alleviations.

Not without “my” risk assessment

The word cleaning validation represents a real challenge to the pharmaceutical, apparatus and plant engineering industries. This does not just simply involve complying with regulatory standards. The safety of pharmaceuticals, feasibility and efficiency are main aspects.

At the start of every cleaning validation is the validation plan, which can be divided into three phases, see also [2], [3]. The providers of centrifuge technology solutions can make an essential contribution in all three phases towards realisation and efficiency. This can only be achieved by working together and harnessing all available relevant knowledge available.

The three phases can be briefly described as follows:

1)Internal status inspection of planned production line
This concerns the question of which active and inactive ingredients are to be produced or used? The product change frequency has a considerable influence on the efficiency. One must therefore know which cleaning agent and method should or can be used.

This is where the latest innovative VBC centrifuge technology comes in; based on the expertise of the machine supplier in apparatus engineering and construction in line with the latest advances in mechatronics as well as design aspects and process sequences of solids-liquid separation and cleaning. The machine supplier is not responsible for the active ingredients however.

2)Risk assessment of products and facilities
The internal pharmaceuticals status inspection must be followed by risk assessment for all products, the aim being to identify substances that are a particular hazard. Responsible is the pharmaceuticals company, see graphic “worst-case” analysis according to Borchert [6].
Centrifuge manufacturers can make a valuable contribution with their expertise and years of experience in the assessment of design-related cross-contamination (e.g. difficult to access or absorbent surfaces, dead ends in pipes and extraction points, etc.).

3)Determination of extent of validation
On completion of the internal status inspection and joint risk assessment (machine supplier and pharmaceuticals company), the extent of validation can (must) be determined by the pharmaceuticals company, see also [4].

In this phase, Ferrum is able to offer the possibility of validating design-related critical points in its own assembly halls following assembly and so reduce by this verification item, time-consuming validation within the pharmaceuticals company. By means of a so-called riboflavin test, for example, the effectiveness and wettability within the centrifuge can be verified or also the effectiveness of CIP cleaning of inert material at “critical points”.

It is therefore in the interest of the pharmaceuticals company to complete validation quickly and if possible in the phase prior to commissioning. This is only possible in cases where existing facilities are duplicated. As maximum flexibility in the manufacture of pharmaceuticals is of the essence today, apparatus such as centrifuges must be appropriately flexible in design.

Precisely this step was taken at Ferrum with the latest VBC vertical pharmaceutical centrifuge. The processes of rinsing, washing, spraying, measuring, analysing, scraping, blowing out and even flooding have been greatly improved in the new generation of centrifuges over that which was state of the art a few years ago. The special advantage of Ferrum centrifuge technology solutions is that many of the different function modules can be integrated flexibly both in the initial design of the machine as well as retrofitting. The cleaning process can be optimally adapted to the respective production sequence in a highly flexible manner.

It is therefore extremely important that the experienced and innovative centrifuge supplier is included in process selection already in the planning phase.

Cleaning procedure validation and selection

In order to locate fouling on machine parts, specific samples are taken before and after the cleaning procedure. In the PIC document PI 006, sampling procedures using the wipe or swab test and flush or rinse test are considered suitable. [5]

One advantage of the swab test is that it provides information on where the fouling is located, e.g. in bends or branches of pipe systems.

Useful is the inclusion of global analytical methods. An example is TOC determination for organic loading, conductivity measurement for ionic residues and ph measurement for cleaning agent residue detection. These analytical methods can be included as online measurements or installed in the centrifuge. Such analytical methods can be used for multifunction systems to provide maximum flexibility during commissioning, as all possible active and inactive ingredients are often not known. Offered is a retrofitting option; this is usually possible in the majority of cases without redelivery to the manufacturer’s workshop due to the modular design of the VBC.

Modularity in use

Passive contribution towards cleanliness in scraper centrifuges

It may sound simple, but good access to the centrifuge is a precondition for its cleaning and analysis, even when fully automatic CIP systems are usually installed. The modular design of the VBC vertical pharmaceutical centrifuge takes this into account. The design of the cover opening, the position of the outlet and the basket drive can be selected in a wide range of variants and combinations. This enables the machine to be optimally adapted to local space conditions at the site of installation without additional expenditure; this is something that will be appreciated by structural engineers and plant constructors as well as those responsible for maintenance.

Until now, only so-called horizontal centrifuges where considered suitable for installation in a clean room. With the introduction of the VBC, a vertical scraper centrifuge now meets all requirements for installation in a clean room concept, as the complete drive can be arranged below the vibrating plate. This allows the technical area to be separated from the clean room area by means of a membrane in the floor/ceiling.

This method of installation complies with the wishes of many pharmaceuticals companies as the entire production flow takes place gravimetric vertical. The VBC vertical scraper centrifuge thus requires less space than a conventional horizontal centrifuge, as this additional clean room area is required for opening the horizontal housing and positioning the pipes with respect to the vertical product flow into the horizontal machine.

A further important item in the design of the VBC is the one-piece concept of the housing and base plate, avoiding numerous edges and transitions with the advantage of less fouling.

Active contribution towards cleanliness in scraper centrifuges

The function modules that contribute towards active cleanliness include CIP nozzles. The principle applies: As much as necessary, as little as possible. Especially in the case of multifunction systems, the use of an additional CIP nozzle may be necessary. In the modular concept of the VBC centrifuge, this does not present a problem as the CIP nozzles are flanged and easily retrofitted (during production) without welding. It goes without saying that these flanges are all provided with GMP compliant seals.

Those responsible in pharmaceuticals companies can face a far greater problem if the cleaning process must subsequently be changed from CIP cleaning to flood cleaning with a change of product, see “worst-case” analysis. This is another problem that can easily be solved with the design concept of the VBC, as the complete bearing and sealing system is in a modular design. The so-called bearing cartridge can be prefitted as a floodable version and exchanged for the fitted cartridge (during production); and all this without removing the complete centrifuge and sending it to the manufacturer’s works. After the conversion, the complete centrifuge can be flooded up to the cover.

A further important innovation measure was achieved by the optimal use of pneumatic drives for operating the scraper and cover, whereby movement is effected by self-locking spindle drives. All hydraulic oil is thus banned from the pharmaceuticals area and a further risk factor eliminated.

Conclusion

Innovation in the engineering industry today is based on a large proportion of modularisation of functional units. An innovative and modular design in combination with the latest control concept enables users in pharmaceuticals production to adapt machines precisely to suit their individual requirements and to bring function and costs into accord.

A technical feature does not often produce the best result with regard to reducing consumption costs. Only the sum total of all activities in one solution enables costs to be minimised within a production plant. In short, Ferrum “Centrifuge Technology Solutions.

SMOL Schneider; Dipl. Phys. ETHZ, Ferrum Marketing& Sales, Business Unit Centrifuge Technology /29.2.04

Bibliography
[1] EG-GMP Guide, Appendix 15

[2] Jörg Koppenhöfer; Efficient and cost-saving cleaning validation in the area of active ingredients and substances in multifunction systems, gempex, GmbH, Mannheim, Source: http://www.gempex.com/

[3] Dr. Bernd Köhler und Dr. Carsten Richling; Planing, implementation and documentation of cleaning validation in the pharmaceuticals industry, SWISS PHARMA 25 (2003) No. 9.

[4] FDA Guide for inspection of the validation of cleaning processes; http://www.fda.gov/ICECI/Inspections/default.htm

[5] PIC/S PI 006; Recommendations for validation master plan; GMP Consultant, GMP-Verlag, Schopfheim (2003)

[6] D. Borchert; Cleaning validation (Bd. 1, Chapter 8.B-8.K), GMP Consultant, GMP-Verlag, Schopfheim (2003)