Buildings and facility

The size of the facility will depend largely upon the volume and variety of the radiopharmaceutical manufacturing programme and R&D activities, if any.

A PET only facility will obviously be much smaller than a national accelerator facility engaged in manufacturing products for the entire country. As a general principle, the manufacturing facility should be designed to ensure adequate space availability and suitability for pharmaceutical manufacturing. An additional requirement in case of radiopharmaceutical manufacturing is radiation protection and radiation level monitoring (discussed in detail in Section 9). It is suggested that even in a small facility, operations should be performed within specifically designated areas to avoid mix-ups and cross-contamination (for example, segregation of incoming raw materials from the tested and approved materials). The flow of materials in a logical pattern generally achieves good results.

The most critical factor in aseptic processing is the microbial cleanliness and particulate quality of the air in production areas. At the most vulnerable points where sterilized containers and closures are exposed (critical areas), the air should be of Class 100. The layout of the facility should be designed to ensure that the required air classification in the critical areas can be kept by maintaining the surrounding areas with specific air classification. All clean areas should be carefully and frequently monitored for assurance of conformity to the required specifications.

In general, the facility should be maintained in a clean and sanitary condition through an effective cleaning routine and monitoring. Some additional considerations for a radiopharmaceutical manufacturing facility are highlighted below:

— Space planning and utilization should take into consideration radiation protection of the worker, along with protection of the product quality.

Radiation protection dictates negative pressure in the area where the product is in relation to the area occupied by the operator, while the product protection (microbial contamination) necessitates the opposite.

Careful designing of air flow patterns and the pressure differentials are the challenges in radiopharmaceutical handling as both requirements must be accommodated in the same location.

— Some of the other areas with specific designation include: quality control lab; sterility testing lab; aseptic processing areas; and raw materials receipt, testing, and storage areas. Furthermore, these areas should be separated from one another to avoid cross-contamination and to facilitate smooth work and materials flow.

— In production areas, attention should be given to the nature of the interior surfaces (walls, floors, and ceiling), ensuring smooth and hard composition allowing easy cleaning and disinfection. This is particularly applicable to the aseptic areas.

— For aseptic processing, isolation rooms (clean rooms) should be made available, where room air is filtered through HEPA filters under positive pressure. Access to the aseptic areas should be through personnel airlocks and material airlocks with interlocking doors. HEPA filters should be monitored and replaced at regular intervals.

— One often neglected subject is the storage area. This area should be of sufficient size for orderly storage of components, both radioactive as well as non-radioactive materials.

8.5. EQUIPMENT

A manufacturing facility will have a wide range of equipment with designated purpose. Unlike conventional pharmaceuticals manufacturing, radiopharmaceuticals manufacturing is often achieved using specialized and dedicated equipment. Whether the equipment is used in preparation of glassware (e.g., pyrogen oven, glassware washer) or in manufacturing (for example autosynthesizers, dispensing machines) or in the QC laboratory (dose calibrators, HPLC), selection should be based upon key performance attributes such as suitability for the intended use, reliability and ease of operation and serviceability.

Consistent production and the product quality depend upon consistent and reliable performance of the equipment. Therefore, all equipment having a bearing on product quality should be validated for performance at the time of installation and at a regular interval thereafter. Furthermore, equipment should be well maintained and in general should be in good working order at any given time. Defective equipment should be kept from inadvertent use.

Currently, several autosynthesizers have become available for production of PET radiopharmaceuticals. GMP compliance manufacturing and product quality require careful practice in aseptic handling, in addition to reliable performance of the equipment.

8.5.1. Validation and calibration

Equipment should be selected for its suitability for the intended use. New equipment must not be used until it has been properly installed, evaluated for its performance, and validated for suitability of its application. Furthermore, all equipment, in particular the critical equipment, should be continuously monitored and revalidated at a regular interval ensuring continued suitability and reliability.

It is necessary to have written procedures for validations, revalidations, and calibrations. Calibration procedures should define how often it is to be done, by whom, and the exact methodology to be used. Equipment used in measurements may need to be calibrated prior to use or at a regular interval for confidence in results. The frequency of calibration is usually determined by type of equipment and criticality of the measurement.

Accurate data of validations and calibrations should be maintained, and should be readily available for data analysis.

8.5.2. Maintenance and cleaning

A sound preventive maintenance schedule, as opposed to reactive and remedial maintenance, not only reduces the down-time, but also improves the production output. Spare parts availability may become an issue in some Member States; hence, it is recommended that an inventory of critical components and consumables be identified and stocked at the facility to reduce down-time. Following a major repair or maintenance, revalidation of the equipment is necessary to ensure equipment performance and suitability.

General cleanliness in laboratories and specific cleaning of the equipment utilized in product manufacturing require careful planning and implementation. Documentation of equipment usage and a maintenance log are a useful exercise for reliable service.

8.5.3. Computers and software

Modern equipment (for example, PET autosynthesizers) is often operated and controlled with PCs. The computer systems and the software running the automated equipment require control and safeguarding, ensuring that no inadvertent or even deliberate changes have occurred.