Compliance with the measures for production hygiene is an indispensable requirement for pharmaceutical manufacturing. The type of measures for cleaning rooms and their facilities is based on the cleanliness grade that must be achieved. This is prescribed by the production method or the dosage form. The maximum permissible microbial counts for the different pharmaceutical preparations are stipulated in the European Pharmacopoeia (see figure 11.C-2).

The type of cleaning depends on the type of contamination. This trivial statement, however also conceals a knowledgeable, detailed consideration of the production sequences. On the one hand, the cleanliness grade prescribed by the production step is specified as the cleaning target, and on the other hand the bordering areas must also be considered from a hygiene perspective. So, for example, finished medicinal product warehouses and warehouses for primary packaging material should be included in the consideration. The cleanliness requirements must be complied with in particular at interfaces to the production area.

11.C.1 Sources of contamination

Not only are personnel an influencing factor, as previously mentioned, but the following additional sources of contamination are also evaluated:

• Surfaces (premises, facilities)
• Raw materials (including water)
• Processes
• Utilities (nitrogen gasing)
• Ambient air

Surfaces

• Premises and facilities
  The GMP requirement for suitability of the rooms and facilities is important not only from a production perspective, but also from a hygienic perspective. For cleaning, the term sufficiently large means sufficient room for movement by the cleaning staff as well as accessibility of all possible points. Experience shows that small rooms are often set up in such a way that cleaning is made difficult, due to the best possible utilisation of the available space. Thus, for example, machine parts that are located near the walls are difficult to reach during cleaning (3.38 EU GMP Guideline) (see chapter 11.D.1 Cleaning procedure for rooms).
  As part of the product-specific cleaning validation, the parts that come into contact with the product are subject to critical analysis and are differentiated in a risk assessment. Parts which do not come into contact with the product are only investigated in exceptional cases. If contaminated areas remain due to inadequate cleaning results (machine parts, walls, floors or ceilings), there is a risk that subsequent products may become contaminated.
  It should be possible to clean technical facilities such as pipes, light fittings, etc. (3.10 EU GMP Guideline). This requires fully wainscotted environments as far as possible, e.g. through integration in suspended, sealed ceilings. This avoids classic problem areas such as pipes and hanging light fittings, which could potentially form dusty surfaces. (See chapter 3.E Construction elements.)
  Only cleaned, faultless equipment, machines, containers or aids may be used. Microbiologically critical materials or objects, e.g. wooden pallets and cardboard boxes, must therefore not find their way into production.
• Drains
  From a hygiene perspective, waste water disposal is critical. The construction must prevent a jam or back flow of waste water. This also means there must be a sufficient number of drains of an adequate size. The capacity should be designed during room planning in view of production. Drains that are too small will cause blockages despite a sufficient pipe diameter. In any case, a back flow flap must be provided for safety reasons (3.11 EU GMP Guideline), as the hazard from the entry of standing, contaminated water is high. The last section of the drains in the floor should be arranged with a slope to the outlet. The remaining floor areas should be level, in order to avoid puddles. It goes without saying that this slope must not cause risks to safety at work.
  The drains must be disinfected regularly, for the residual waste water standing here offers an ideal reproduction basis for microorganisms. This is not only significant for sterile operations, but also for non-sterile production areas, e.g. in solid dosage forms productions. Here, residues of solids, which act as a culture medium for various cultures, are washed away with the waste water (e.g. starch, cellulose, lactose, etc.). As a certain initial contamination is present in the raw materials, especially from a plant-based origin, a big increase in the bioburden must be reckoned on here. Disinfection is thus indispensable. The disinfectant should be changed regularly in order to counteract the development of resistances (see chapter 11.C.3 Disinfection).
• Lighting
  The requirement for good lighting in the rooms is also significant for cleaning. Only in adequately lit up rooms can visual clean be carried out, i.e. an acceptable cleaning result be achieved.
• Sanitary facilities
  Sanitary facilities carry a high hygienic risk due to the potential entry of organisms. Here, there is a discrepancy between workplace regulations and the GMP requirement. On the one hand, the immediate proximity of toilets to the place of work is prescribed, and on the other hand, this cannot be accepted for hygienic reasons. Ideally, there should be no toilets in the production area without locks. They should at least have an anteroom which enables cleaning and disinfection of the hands and the removal of the pharmaceutical clothing.
• Recreation rooms
  To avoid an excessive entry of microorganisms, rooms that are used for food consumption or smoking must be completely separated from production (3.30 EU GMP Guideline). It is crucial that locks be installed with prescribed change of clothing, in order to prevent contamination of clothing and the consumption of product dust (by inhalation or with food).
• Pest control
  Pest control in the entire surrounding area (warehouse, direct environment around the manufacturing sites, within the plant) makes it possible to estimate a possible hazard through different small animals (insects, rodents) and the measures to be taken. This should be undertaken by competent persons, as the location of the installation and the type and number of traps require zoological or behavioural biology knowledge. Assignment to specialist service providers offers a good alternative to internal installation and evaluation. The results should be evaluated by quality assurance or the head of production.

Starting materials

The raw materials used in production must comply with the specifications of the valid pharmacopoeia. In terms of the permissible microbial contamination, herbal extracts should be considered as critical starting materials. Water as a raw material is of great importance due to the volume in which it is used and its ubiquitous application. (See chapter 5 Pharmaceutical Water) Threshold values for microbial loading can lead to violations of the specifications in the further course of production in terms of the microbial count of the final product. Alert limits must be defined.

Cleansing agent and disinfectant

The cleansing agent and disinfectant to be used must be matched to the circumstances. Thus, even for non-sterile manufacturing, disinfection may be necessary, e.g. after drying herbal extracts. The effectiveness of the procedure is reviewed during monitoring. They must not cause contamination. This must be reviewed as part of the evaluation.

To avoid contamination through cleansing agents, the first parts of a batch for partial discharges (e.g. ointment filling, tablet presses) are discarded. This is advisable as possible contaminations, such as traces of grease, can be removed during assembly of components in this way. Cleaning through neutral fillers, such as placebo compounds, is not recommended, as it must be proven that there is no cross-contamination. For parts which do not come into contact with the product, such as table tops, it must be ensured that no influence is exerted.

Primary packaging material and excipients

Handling of primary packaging materials exerts a great influence on the microbiological stability of the product. Particular care must be taken here. Opened containers must be sealed properly. (See chapter 13.A Packaging material.)

If the use of aids such as lubricants, which could come into contact with the products under adverse conditions, is unavoidable for technical reasons, the conformity or official approval (e.g. FDA conformity certification) of the grease used must be ensured, in addition to its compatibility with the product.

Processes

Production processes can lead to an increase in microbial counts. Thermal manufacturing steps (solution batches, drying processes) in combination with humidity usually lead to increased microbial reproduction at temperatures of 20-50 °C or to a reduction in the microbial count at temperatures above 80 °C. This is especially significant for long processes. Examples of this are insufficient heating during the manufacturing of ointment or gel, or the preparation of a suspension or solution with heating or drying of moist granulates on trays. It must be ensured that no residues of compounds with a high starting contamination are left for a long time after production, e.g. weekend. Prompt cleaning and disinfection must be ensured in this case.

Manufacturing waste should be removed as quickly as possible. The containers should be emptied into collection containers outside the production area (prevention of contamination). The containers must be adequately labelled. It is recommended to use colours with a signalling effect throughout the plant for clear identification.

Utilities

These include process gases, such as nitrogen for inertisation or compressed air that comes into contact with the product. The purity of these utilities must be checked during monitoring.

Ambient air

Ventilation systems create air with low microbial and particle counts. Compliance with the requirements is supervised through monitoring. (See chapter 3.H Heating Ventilation Air Conditioning (HVAC).)

11.C.2 Cleaning

Aim

The task of cleaning is to remove organic and inorganic contamination. This results in an uncontrolled and random microbial count reduction (wash away effect). In terms of disinfection, cleaning is carried out to remove dirt, polysaccharide, lipids and proteins, as these reduce the effectiveness of the disinfectant through embedding effects.

The level of purity to be achieved for product contact surfaces is defined by the requirements in the cleaning validation. (See chapter 8.E Acceptance criteria and limit calculation.) Bordering areas, e.g. corridors, are cleaned according to the visual clean criterion, taking into account the monitoring results.

Procedure

All procedures are to be fixed in writing in order to enable reproducibility. By nature, this is easier in automatic procedures than in purely manual cleaning processes. (See chapter 8.B Validatability of cleaning procedures.)

Even with surfaces that do not come into contact with the product, the factors of mechanics, time, temperature and concentration of the rinsing solution are important for the quality of the result. Excessively high concentrations of rinsing concentrate lead to massive adsorption effects, especially on stainless steel surfaces. The compatibility of the cleansing agent with the surfaces to be cleaned must be ensured in order not to cause any damage.

After rinsing, product contact surfaces are subject to a final rinse with water of the highest cleanliness grade in the procedure. This is not necessary when cleaning areas that do not come into contact with the product.

It should be possible to blow through rinsing pipes in order to prevent standing water after the rinse process is completed. This also applies for feeds into facilities. Facilities may have to be dismantled in order to dry the components (e.g. ball valves). Under no circumstances should water remain standing, as this would cause a massive growth in bacteria. Feed pipes used for self-conserving, highly viscous syrups, are not emptied if there is a short standing time. A multiple ampunt of the pipe volume is rejected as start-up waste.

The effectiveness of the cleaning process is proven during cleaning validation and is reviewed through ongoing monitoring and optimised as required. (See chapter 8.E.3 Determination of the microbial status and chapter 8.F.5 Microbiological testing of surfaces.)

The respective cleaning and disinfection measures are documented in the log books of the machine and room cleaning records. Confirmation of the measures is recorded in the batch records.

11.C.3 Disinfection

Aim

It is the task of disinfection to achieve a specified reduction in the microbial count. The target microbial count is prescribed by the cleanliness grade. Sterilisation procedures may also be necessary to achieve the desired target. This may depend on the average starting contamination and on the production cleanliness grade (see figure 11.E-3).

Procedure

The factors that apply for cleaning are generally also valid for disinfection. The method of application and the acting time are important aspects for sufficient effectiveness of the disinfection procedure. Dilution and evaporation effects lead to a massive loss in effectiveness of the disinfectant.

The effectiveness of the procedure is reviewed as part of the monitoring and optimised as required.

Annex 1 of the EU GMP Guideline on the manufacturing of sterile drugs gives detailed information on the handling of disinfectants.

• A key principle for avoiding the build up of resistance is to regularly change the disinfectant. Although the combination of different disinfectant types does not lead to any scientifically proven development of resistance, there can be problems with the effectiveness of the disinfectant due to application errors and gradual breeding of an internal flora. The frequency, e.g. monthly, and the sequence of the change are defined and recorded in the cleaning procedures and in order to enable retrospective assessment.
• Storage containers which are partially empty, e.g. after changing the disinfectant, must not be refilled. This is partly due to the notion of batch purity, but also the hazard of contamination through the layer formation of disinfectants is high. This applies especially for dilutions that are produced from concentrates. Under certain circumstances, e.g. in central dosing facilities, dilutions for use can become microbially contaminated, in particular if they are underdosed for a long period of time. A so-called biofilm could form, which protects the microoorganisms against the direct attack of the disinfectant. Sources for this are usually the water-carrying piping of the dosing facility. The dissolution of such a film can be very problematic.
• If long-term storage is necessary, sterilised containers should be used in order to counteract the hazard of the breeding of resistant strains.
• Disinfectants must be sterile at the time of application (for cleanliness grades A-D). The disinfectants now available commercially are usually irradiated with gamma rays, in order to offer the necessary sterility. Alcohols should be sterile-filtered before being brought into the sterile room, provided they have not already been filtered by the vendor, as spores in alcohol are not killed. With the dispersion of the alcohol, the spores are distributed and can multiply again.

The disinfectants used should be approved by the respective national test centre. This checks and evaluates them according to different methods and effectiveness requirements in circumstances relatively close to practice. This ensures their basic suitability. Medical and safety data sheets are available.