The participants were given a special kind of “food for thought” at the GMP Symposium hosted by Maas & Peither – GMP Publishing at the beginning of October 2014. For example, a talk by Richard Denk (SKAN AG) entitled “Preventing Cross-Contamination” in the morning of the first day rounded out the challenging agenda. Denk has been dealing with this field for almost twenty years, also serving on the board of the ISPE Containment Group. By his own account a “passionate containment specialist”, Richard Denk focused his talk on the various risk factors for cross-contamination, the influence of highly active substances and in particular the opportunities offered in this connection by hygienic design.
The first risk of contamination according to Richard Denk involves handling open or partially open products. With good reason. “Because,” in his own words, “at some point in the manufacturing process, everyone is confronted with a situation like this, and open products always entail the hazard of contaminating the room, equipment and personnel. Dry, powdery substances, for example, spread quickly and settle on everything located in the room. ”It is sometimes simply dreadful to see how even supposedly simple actions can cause a person to become contaminated “from head to toe.” At this point Denk suggested that it was about time to question the common practice among employees of wearing white protective clothing. For example, contamination with light-coloured powders is instantly recognisable against dark colours.
Many kinds of starting materials also pose risks. Suppliers, contract manufacturers and distributors - insofar as they also repackage - provide the first opportunities for contamination of a product. Experience shows that hygienic notions and standards or cleaning practices can differ greatly from one country to the next. Richard Denk: “Perhaps the customer should always insist on being informed about what substances were manufactured on an installation preceding the customer’s own product.”
Production facilities are another potential source of contamination, regardless of whether in mono or multi-material operations. Faulty design is a frequent source of impurities. However, danger lurks even in immaculate areas with easily cleaned surfaces. For example, substances can easily infiltrate through ventilation equipment or with the entry and exit of personnel.
One of the greatest risk factors for contamination in the production area consists in inadequate training of the staff. Carelessness when changing clothes or mishaps caused by inadvertently touching contaminated places are common occurrences. Richard Denk presented an impressive comparison: “It is similar to the transmission of pathogens. The disease is usually not transmitted by direct contact, but rather, for example, when someone touches the same doorknob.”
The design of processes and equipment is important for preventing cross-contamination. Even if the actual reaction chambers often appear to be immaculate, problems do arise, for example, if product spreads over into seals. “Risks of contamination lurk in areas where they are not expected. Process equipment is usually under a certain amount of pressure and the powder migrates to the most unlikely of places, which the cleaning fluid never reaches,” explained Richard Denk. The pipes through which nitrogen is conducted for inertisation are a classic example. They are rarely checked, and yet fine powders can be detected as far as 1.5 metres into the nitrogen pipe.
There are vast differences in surface quality, depending on how long a facility has already been in operation. With time, scratches and grooves inevitably occur in the mixers and rotary tools in use. The surfaces become dull, a characteristic which carries a potential risk of product spreading. Richard Denk: “Why is there no revalidation of the surface quality from time to time or at least an examination of the surfaces when the product is changed?”
Fig. 1: Risk of cross-contamination as function of different factors
Highly active substances are steadily gaining in importance. Even now, almost half of all newly developed pharmaceutical products are classified as being highly active or extremely hazardous. Suitably low limit values for workplaces are in place to protect personnel, while suitably highly stringent requirements relating to the maximum permissible contamination are in effect to protect patients.
Two terms are significant in this connection: OEL and OEB. OEL stands for Occupational Exposure Limit. It defines the average concentration load on employees over time by a medicinal product or an active substance. Measurements are taken inside the breathing range of the employee over a period of eight hours (with a 40-hour work week). Incidentally, in the pharmaceutical industry, internal workplace limit values have long been calculated without regulation by the authorities. Occupational Exposure Band (OEB) takes the toxicology of the pure substance into consideration. The goal is to create a facility categorisation in which production equipment and a work process suitable for a product are selected.
Values in the microgram per cubic metre range that may not be exceeded are often defined for highly active substances. The following illustration shows this magnitude and provides a feeling for the requirements that must be met when highly active substances are being handled.
Fig. 2: 1 microgram/m3 corresponds to one gram per million square metres. In a “visible dimension”, that would be equivalent to one sweetener tablet in the Empire State Building. Within the nanogram range, which can certainly be the case for highly active substances, even one sweetener tablet in 1000 skyscrapers would be possible.
The decisive question is still how these minimal limit values affect the production of pharmaceutical substances. One thing is clear to Richard Denk: “We must think about whether or not the facilities and processes used today can meet such requirements. Or is it not up to other processes to be better able to deal with these substances?” A key factor for preventing cross-contamination in the future will be - and experts agree on this point - Hygienic Quality Design (HQD). That means:
Consistent implementation of HQD is complicated and not without a price. “Quality is always planned from the inside out,” according to one principle. That means that a good facility defines itself first on the inside, where contact with the product occurs. This calls for highest degree of precision with regard to accessibility, user friendliness, ease of cleaning, dismantling capability and maintenance.
Richard Denk, talk held on 08 October 2014 at the GMP Symposium in Freiburg i. Br.
Maas & Peither AG - GMP Verlag