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Facility concepts

Here you will find answers to the following questions:

  • Are there facility designs that make GMP economical?
  • What points must be observed with regard to facility designs such as CIP (Cleaning in Place), isolator technology and facility chains?

In order to satisfy the special GMP requirements, a range of facility concepts has been developed. These concepts were developed to provide an economic means of protecting and ensuring the quality of the product. Several important designs that are applicable for all dosage forms are described as examples.

1 CIP (Cleaning in Place)

Cleaning in Place was developed for sterile production and represents state-of-the-art technology in this area. This principle has also been adopted in other areas, e.g. solid dosage forms. CIP refers to the cleaning of production equipment using stationary attached cleaning nozzles or heads thus dispensing with the time-consuming process of dismantling the facility.

Figure 1 Regulations for CIP systems

Regulations for CIP systems

  • Observing the requirements for purified water systems
  • Specification of pipes: dimension, flow rate, permissible length of stubs (3 to 6 x diameter), material, welding seams, surface quality, passivation procedure
  • Complete emptying capability of all facility parts, particularly pumps, fittings, valves, pipes, measuring instruments and possibly exhaust devices
  • Sterilisability of the entire facility, including all its components
  • Type of cleaning heads
  • Cleaning principle (high pressure 10-100 bar, low pressure < 2 bar)
  • Cleansing agent (acid, alkaline)
  • Final rinse: distilled water
  • Suitable measuring instruments for purified water: to measure flow rate, temperature, pressure, pH value, etc.
  • Possibility of mechanical separation of CIP system from purified water loop should fast separation be required in the event of reverse microbiological contamination
  • Sampling nozzle at representative point
  • Suitability of control for validation (see chapter 9 Computer Validation)
  • Controllability of all valves, pumps and actuators for qualification of the facility

The criteria that must be checked are cleaning effectiveness, contamination of the product with cleansing agent, and microbiological growth (see chapter 8 Cleaning Validation). The details to which particular attention must be paid are listed in figure 1.

2 Isolator technology

The significance of isolator technology in the pharmaceutical industry is steadily increasing. Authorities have also responded positively to this technology as verified by clause 7 onwards in Annex 1 of the EU GMP Guideline: "The utilisation of isolator technology to minimise human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment."

Figure 2 Evaluation criteria, isolator  

Evaluation criteria, isolator

Isolator
(class A/B)

Clean room
(class A/B)

Qualitative factors

  • Product protection
  • Personnel safety
  • Sterilisation
  • Availability of facility
  • Operation of facility
+ +
+ +
+ +
+
-
+/-
+/-
+/-
+ +
+ +

Investment costs

  • Construction
  • Building services
  • Production machines
  • Start-up
  • Qualification/validation
+
+
- -
- -
-
-
-
+ +
+ +
+

Operational costs

  • Air-handling technology
  • Personnel requirements
  • Sterile clothing
  • Monitoring
  • Sterilisation
  • Maintenance
  • Requalification
+ +
+/-
+ +
+ +
+ +
+/-
-
- -
+/-
- -
- -
- -
+/-
+

Evaluation: ++ = very good, + = good; +/- = satisfactory; - = poor; -- = very poor

An isolator is a miniaturised self-contained sterile chamber into which the user may reach by means of gloves integrated in the appliance. The benefits of this room-in-room solution are the protection of persons and products with a minimum of air-handling effort.

The areas of application range from microbiology (implementation of sterility tests) to aseptic filling through to the processing of highly potent substances. The investment and operational costs are highly dependent on the intended purpose. In general, the investment costs for an isolator are higher than for a conventional clean room: the opposite applies to the operational costs (see figure 2).

As this technology is not yet as widespread as the clean rooms which are normally used, special requirements must be observed, particularly in relation to validation. Critical aspects from the GMP standpoint are listed in figure 3:

Figure 3 Critical aspects of isolator

Critical aspects of isolator

  • Docking procedures for the transfer of materials
  • Leak-tightness of gloves
  • Embrittlement of gloves and other plastics due to decontamination gases (H2O2)
  • Ease of cleaning inside isolator
  • Validation: The degree of sterilisation is dependent on the duration, the H2O2 concentration, the flow rate, the temperature and the loading of the isolator, amongst other factors.
  • Frequent product or format change

3 Connected facilities

Connected facilities are used particularly for solid dosage forms, and in this case, for reasons of product and personnel safety. Ideally, materials are transported between individual facility components installed on different storeys using gravity. This facility concept can even influence the architectural design of a production building. Details to be considered are: cleanability by CIP or dismantling as well as information flow of product data. (See chapter 3.C.1 Material flow.)

Summary

A range of facility concepts exist that provide economic GMP-compliant solutions. CIP, isolator technology and connected facilities are only a few examples of applications for a variety of dosage forms. Costs are reduced and errors minimised through reduced personnel expenditure and increased automation. Additional cost savings may be achieved for isolator technology and facility chains by reducing the room air-handling requirements.



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