Sterile manufacture

Sterile manufacture

Scope

All terminally sterilised medicines produced in hospitals are made under a manufacturer’s specials licence, except in a few cases where PLs have been obtained. The range of products made generally reflects gaps in the portfolio of licensed products available from the pharmaceutical industry. The limited number of specialist sterile manufacturing units remaining in the NHS pro-vides an essential service in making available sterile parenteral and topical products that are not commercially viable for industry to produce. Such products include non-standard concentrations and presentations of injections and eye drops, specialist injectables for paediatrics, anaesthetics and palliative care, and various sterile topical products.

In some cases, NHS hospital sterile product units have developed prod-ucts to support pharmacy CIVAS units. These include electrolytes for addition to TPN feeds such as concentrated sodium chloride injection, potassium phosphate injection and zinc sulphate injection. A range of sterile bulk solutions for filling into syringes and other devices is also produced. These include bupivacaine injection, morphine sulphate injec-tion and fentanyl injection. Sterile manufacture also supports research, and small runs of experimental drugs in parenteral formulations are prepared for clinical trial use.

The container and filling technologies employed in hospital units encom-pass glass vials, glass ampoules, glass bottles and polyvinyl chloride infusion bags for parenteral products, and a variety of glass and rigid plastic containers for topical solutions. No lyophilised presentations are available since freeze-drying technology is beyond the scope of hospital sterile product units.

Facilities and equipment

In general, the weighing and solution preparation areas required would be similar to those described previously for non-sterile manufacture. However, the filling, sealing and capping stages must be accomplished in a higher-quality environment, usually EU grade A, to minimise particu-late contamination and reduce the microbiological load prior to sterilisa-tion. This is usually achieved by local laminar flow of high-efficiency particulate air-filtered air at the filling zone. After filling and sealing, containers and their contents are sterilised by steam in an autoclave (aque-ous solutions) or by dry heat in a hot-air oven (non-aqueous liquids, powders). The sterilisers and associated monitoring equipment can be located in a lower-grade environment and are normally sited so that maintenance staff can access them without the need to enter critical pro-duction areas.

Dedicated space for reinspection of the finished product, labelling, pack-ing and quarantine is also required. Regulatory requirements for sterile pro-duction facilities and sterilising equipment are strictly defined and require extensive validation. The design and construction of sterile manufacturing units should only be undertaken by specialist contractors. The increasing use of automated systems, particularly for filling, sealing and reinspecting ampoules, and the sophistication of modern steriliser technology have con-tributed to the rapid rise in capital and maintenance costs associated with sterile manufacturing units. National coordination and strategic planning of new units are essential to maximise the cost-effectiveness of these expensive but important resources.

Process

In addition to the processes outlined under non-sterile manufacture, above, sterile production normally includes a filtration process (for liquids) and sterilisation of the product. These processes are critical to product quality and require rigorous validation and control. The microbiological bioburden must be minimised, particularly in the case of injectables, to reduce the release of bacterial pyrogens into the product, because these will not be destroyed by sterilisation. This is achieved by limiting the number of viable microorganisms in starting materials and by minimising the time between preparations of the bulk product, filling and sterilisation.

The sterilisation cycle for each batch is clearly monitored to ensure that all containers in the batch have received the pharmacopoeial-approved temper-ature and time combinations. Printouts of the load temperature, usually taken at the coolest location of the autoclave or dry-heat oven, are recorded throughout the cycle and are scrutinised as part of the release process. Additional measures are taken to ensure that products sterilised by autoclave or hot-air oven are not at risk from microbial contamination of cooling water or non-sterile air, respectively, which could enter through closures during the cooling phase of the cycle. Figure 6.3 shows an autoclave and its control systems in a large sterile production unit.

The QC of sterile products includes analysis of active components, sterility testing, subvisual particulate measurement and tests for the absence of bac-terial pyrogens. This means that batches must be quarantined for at least 14 days (the time taken for sterility test incubation) before release. Production managers and users of sterile products need to consider this when drawing up production schedules and managing stocks.