Non-sterile manufacture

Non-sterile manufacture

Scope

The manufacture of traditional non-sterile oral liquids and topical prep-arations, usually in accordance with British Pharmaceutical Codex formulae, has declined in the hospital sector over recent years. This is largely due to the commercial availability of licensed products and also the growth of non-sterile specials manufacturing services operated commercially. How-ever, a non-sterile production service is still required to support several clinical specialties, particularly dermatology and paediatric. Many dermatol-ogists have their own variants of standard preparations, often differing only in the type of diluents or base used or in the concentration of active components. Although there is little scientific evidence to support the use of these non-standard preparations, custom, practice and clinical experience have, until recently, provided a continuing demand. Attempts are being made to reduce the range of products used to allow standardisation and simplification. The British Association of Dermatologists’ preferred list was issued in 2008 to support this approach.

Conversely, the clinical justification for using medicines outside their licensed indications for adults in the paediatric setting is well accepted. The unit dose of commercially available preparations of medicines designed for adult use is usually too large for paediatrics. Also, some of the larger tablets and capsules would be difficult for children to swallow. Safe and reproducible paediatric dosing therefore requires preparations of lower dose, usually in the form of oral liquids, suspensions or powders.

Department of Health information reported in 2002 suggested that dermatology preparations (coal tar, salicylic acid and dithranol) were the most frequently prepared non-sterile products by hospital pharmacy depart-ments, although in recent years most of these preparations have become commercially available. Some hospitals have developed commercial non-sterile manufacturing units to supply other hospitals and community phar-macies. This type of activity helps to offset the costs of maintaining facilities of a high standard and meeting the regulatory requirements of MHRA specials licences.

In some hospitals, dispensary services have been reorganised and extem-poraneous dispensing work has been transferred to the technical services section. A wide range of non-commercially available extemporaneous prep-arations is required for individual patients, including oral liquids, creams, ointments, powders, suppositories and pessaries. This approach provides variety and clinical interest for manufacturing staff and ensures that extem-poraneous products are produced in accordance with the principles of good manufacturing practice.

Facilities and equipment

Typically, non-sterile manufacture is carried out in a European Union (EU) grade D environment with a single stage change. Although some units require production staff to wear sterilised coverall gowns, most centres rely on clean two-piece gowns of low-lint-shedding material, over-shoes, hats and gloves. To reduce the microbiological bioburden, drains and potable water supplies are excluded from production areas and all surfaces should have a smooth impervious finish to facilitate effective cleaning. Weighing areas should be separate from the main production area (linked to it with a pass-through hatch) and should be fitted with localised dust extraction. Although containers for non-sterile products are not reused, a facility for washing and drying containers before use may be required. Separate areas should be provided for labelling and reinspection of products.

The Rules and Guidance for Good Pharmaceutical Manufacture and Distribution strongly recommend the use of stainless-steel measures and mixing vessels to avoid the risk of contaminating product with spicules from glass equipment.⁸ Large-scale manufacture will require the use of industrial mixers and homogenisers. Automated liquid filling lines may be deployed for large-scale liquid handling and some units with a significant output of creams and ointments have also invested in tube-filling and seal-ing equipment. Figure 6.2 illustrates small-scale non-sterile manufacturing facilities.

Process

All raw materials, containers and labels used in the production process must be approved by the person responsible for QC. To reduce the micro-biological bioburden, limits are placed on the level of microbiological contamination of raw materials and only sterile water (usually water for irrigation BP) or freshly distilled water is used for manufacture. All prod-uct formulae, storage conditions and shelf-life assignments require prior QC approval.

The manufacturing process is controlled through the use of approved standard operating procedures and batch documents. Particular care is re-quired to ensure that mixing processes produce a homogeneous product for distribution into the individual containers that constitute the batch. This process must be validated for each product type to ensure uniformity of content in the finished batch. The avoidance of cross-contamination between different products is also essential. Only one batch may be prepared in a designated work area at any one time and the cleaning of equipment and work surfaces must be carefully validated and monitored.

Filled containers should be visually inspected for product homogeneity and the absence of any extraneous matter. The security of container closures should be checked and the quality and accuracy of labels determined against a master label for the product. It is essential that the batch documentation includes reconciliation between the amounts of raw materials, number of containers and number of labels used in the process and the yield of finished product. All variations must be recorded and investigated.

Although some regulators have attempted to discourage non-sterile manufacturing in hospital pharmacies, there are compelling reasons why sufficient capacity in this activity is retained. The ongoing need for paedi-atric doses of both new and existing medicines that are commercially avail-able in adult doses must be recognised. There is also a requirement to formulate medicines for patients with particular clinical needs, such as patients with dysphagia. It is preferable for these medicines to be produced by trained pharmacy staff in appropriate facilities, using fully documented procedures, than to have undocumented manipulation taking place in clinical areas by nursing staff.