Cross-contamination: coming to terms with new regulations

Recent changes in both European and American pharmaceutical regulations are gradually replacing conventional quality control and assurance with risk-based procedures.

Cross-contamination forms one of the potential major risks and is the subject of particular attention from the regulatory authorities. Of the last 33 warning letters from the FDA, 13 related to cross-contamination identified during audits on production sites. The two main regulations relating to cross-contamination are the US cGMPs CFR 21 part 211 and the European BPF (cGMP/CEE) brought together in Volume 4 of the Eudralex. In following the stages of a production process (figure 1), the two regulations define the technical measures, particular arrangements and precautions to be taken in order to prevent the risk of cross-contamination. Certain additions are specific to particular categories of medicines. The US cGMPs are more general than the European texts, except for the sterile products cGMP issued in 2003 by the FDA and the EMEA. In Volume 4, section 5.18 of the European cGMPs specific reference is made to the need to avoid accidental cross-contamination arising from the uncontrolled release of dust, gas, steam, aerosols or organisms from the raw materials or products during the course of production; or from residues arising from equipment and operator clothing. It goes on to qualify the cross-contamination risk according to both contaminant and product. The highest-risk contaminants are stated to include highly-sensitising substances; biological preparations containing, for example, living organisms; certain hormones; and cytotoxics or other high potency drugs. Those products especially at risk are indicated as injectables, and medicines taken in high dosages or over a long period. The cGMPs also outline a range of technical or organisational preventative measures, including: a) the separation of production areas (required for products such as penicillins, live vaccines, live bacterial preparations and certain other biological products), or production in time-separated stages followed by appropriate cleaning; b) the installation of airlocks and air extraction systems, and the reduction of contamination risks caused by the recirculation or re-use of ventilation air that is insufficiently treated or untreated; c) the wearing of specialised protective clothing in areas where products at high risk of cross-contamination are produced; d) the employment of cleaning and decontamination procedures that are known to be effective (insufficient cleaning of equipment being a frequent source of cross-contamination); e) the use of "closed systems" of production; f) checking for the absence of residues, and using labels indicating the "cleaned" or "not cleaned" status of equipment. Section 20 of Chapter 5 also advises that a defined procedure should exist that allows cross-contamination avoidance measures to be checked for effectiveness and usability. Other references to cross-contamination risks are made in the premises section (Chapter 3) of the European cGMP, starting with the fundamental principles that the facility design avoids the build-up of dust or dirt and allows for effective cleaning and maintenance, thus assisting the minimisation of errors. Risks will be further reduced if:

• premises are positioned in locations that do not create or enhance risks of cross-contamination; • special segregated premises are created for materials that are highly sensitising (e.g. penicillins) or biologically active (e.g. live vaccines); • the layout of premises is arranged so as to minimise confusion and the potential mix-up of materials at differing stages of production; • naturally-dusty areas, such as those used for sampling, dispensing, dry product handling and packaging, are separated or provided with controlled systems that minimise the spread of dust, avoid risks of cross-contamination and reduce the need for cleaning; • quality-checking laboratories are designed with sufficient space and with a view to minimising confusion; • production equipment is designed to facilitate cleaning and avoid cross-contamination between sequential products or batches, while equipment used for washing and cleaning of such equipment should also be designed to prevent such risks.

The production operations themselves are also considered in the context of cross-contamination risk avoidance. Two stipulations define these risks and their avoidance: production areas should not be used for simultaneous or consecutive production activities involving different products, unless the risk of cross-contamination is known to be absent; and during production, products should be protected from microbiological or other contamination. The risk of contamination, particularly for aseptic processes, is so important that it has accelerated the employment of single use, disposable devices, which essentially reduce the risk of cross-contamination caused by unsatisfactory cleaning of production equipment. Furthermore, their use reduces the number of equipment items to be cleaned or sterilised and eliminates the associated validations. This disposable equipment is of particular interest in the production of cytotoxics and other high potency compounds, where the economic balance between the extra cost of single-use components is greatly offset by the increased risk of potential contamination. The cleaning of equipment between each type of product is obligatory, and the process must be validated; while the use of detergents, disinfectants and other chemical products is sometimes necessary. Equipment will be cleaned by production personnel, or other personnel specifically employed, who will note its status on the accompanying record documents. The cleaning equipment for cleanrooms should be dedicated to these areas. Cleaning procedures must have defined frequency and equipment to be used, and products and methods based on rules that are easily followed: e.g. clean from the most contaminated area towards the less contaminated area. In facilities for the production of sterile products, all the surfaces of the premised should be cleaned and disinfected each day, the greatest attention being paid to the entrance airlocks for personnel. The floors of production facilities should be cleaned each day, including in non-sterile facilities. The use of strict clothing procedures, adapted to the particular class of product, and the use of simple rules – such as the use of different colours of clothing for personnel working in the disparate areas – assists in reducing contamination risks. In response to all the requirements for protection and control of contamination, the concept design of production facilities should be adapted to the dual requirements of:

• segregation of products which present a potential contamination risk (space separation); • arranging the operation in accordance with a sequential flow that avoids any risk of confusion and mix-up of the products (time separation).

The preliminary phases of the concept design of a production facility will therefore consist of an analysis of the expected activities according to the nature of the products to be made and the critical stages of the process at which the product is exposed to a risk of cross-contamination. According to their characteristics, products may be handled either in common areas, or in separate, dedicated areas, (figure 2). The "step by step" study of the process will allow the definition of successive functions, common areas and zones to be separated, (figure 3). It will also allow their classification for particulates, necessary proximity links, associated services, and the detailed technical specification for each area to be created. This stage of concept design should include a Preliminary Risk Assessment (PRA) in accordance with a HACCP-type system or equivalent, in order to evaluate the probability of defects in the systems defined and the impact of failure on the level of quality of the products. The risk of cross-contamination can thus be identified and corrective measures included within the concept design. The golden rule of "forward progression" ensures that risks of confusion and of the mixing of products at different stages of their development are limited, (figure 4). The flow of materials, of personnel and of wastes should be clearly identified, and cross-flows should be avoided. The appropriate treatment of air in production areas is one of the most effective means of protection of products against cross-contamination. Depending on the evaluation of risk of contamination, it will be advisable to work completely with fresh air, or with partially recycled air with levels of filtration on supply and return, adapted to the level of cleanliness required, which is defined in accordance with the ISO standard 14644-1. A barrier effect can be generated by air pressure systems; or the containment of an area achieved with access limited by one or more airlocks with appropriate change of clothing. In the case of products associated with particular risk (for example, sterile or toxic materials), the area concerned should be provided with a dedicated air handling system. To prevent the product from coming into contact with an external contaminant, closed systems are preferred (figure 5), particularly during transfer operations (e.g. dedicated vessels, pipework and pumps for liquids and pastes; tight-shutting valves for powders). If a stage of the process requires the product to be exposed to the atmosphere (weighing; filling), the preferred solution in keeping with the need for containment becomes the isolator. Isolation technology provides the answer to several problems: it protects humans and the environment from possible contact with a hazardous product; it protects the product from the environment; it avoids the risk of external and cross-contamination. The impact of the new cross-contamination regulations on the concept design of areas and the organisation of production, is leading towards dedicated areas and equipment dedicated by product and type of activity. The size of cleanrooms will therefore tend to reduce, in favour of small, specific, modular areas, and perhaps isolators able to guarantee complete containment and allowing for the planning of production by stages.