Terminal sterilisation

Pharmaceutical manufacture may involve the contracting out of certain operations in the process, such as packaging and labelling, terminal sterilisation of products. 

Manufacturing process Aseptic manufacture/sterile filtration (terminal sterilisation by autoclaving not possible ... 

The unit dose is either glass or plastic, with the use of plastic form-fill-seal equipment being dominant. However, glass is considered more elegant pharmaceutically in some markets, and can be terminally sterilised where this is a requirement. With form-fill-seal processes, a strip of ampoules is produced, with the neck being much easier to break than glass. The plastic is pervious to moisture transmission, which will occur on storage, especially in dry environments thus an aluminium overwrap may be necessary. 

Like suspensions, ointments can be more difficult to manufacture in sterile form. They can be terminally sterilised alternatively, they must be manufactured from sterile ingredients in an aseptic environment. Filtration through a suitable membrane or dry heat sterilisation is often used. 

According to the decision trees, where it is not possible to carry out terminal sterilisation by heating due to formulation instability, a decision should be made to utilise an alternative method of terminal sterilisation, filtration and/or aseptic processing. If this alternative route is taken, then a clear scientific justification for not using terminal heat sterilisation will be required in the NDA/MAA dossier. Commercial reasons will not be acceptable because terminal sterilisation offers the highest possible level of sterility assurance. 

It will be necessary to conduct preliminary feasibility studies to establish an acceptable and effective method for sterilisation of the product. There is a clear responsibility with the manufacturer to provide evidence to the regulatory agencies that the product can or cannot be terminally sterilised. Preformulation studies will indicate whether the candidate drug and proposed formulation can withstand the sterilisation process using small samples of product. 

Process development studies showed that terminal sterilisation of the gel was not possible. Heat sterilisation and gamma irradiation methods both caused unacceptable physical degradation of the gel and also caused chlorbutol hydrolysis. Aseptic filtration was not possible because the drug was suspended in the gel vehicle and viscosity would also have been a problem. The process described below was therefore developed with consideration of the sterilisation of the product components and the maintenance of asepsis throughout manufacture. 

Sterilisation is the finite method for microbial control and can be achieved either by sterilising each component (product and packaging materials) followed by assembly, i.e. aseptic processing, or by a terminal sterilising process which involves both product and pack. The latter is the preferred method as it entails less risk of a non-sterile product being produced. 

Gamma irradiation of 25 kGy or above and accelerated electrons tend to cause similar changes to the product/pack. These processes are normally used as part of an aseptic process to sterilise the pack components before use, since many products tend to degrade if terminally sterilised. Some contact lens solutions and normal saline products can be satisfactorily gamma irradiated in a suitable plastic or metal pack (aerosols). 

Although certain products can be terminally sterilised by moist heat, gamma irradiation or accelerated electrons, these tend to apply to relatively few pharmaceutical applications where flexibles are involved (the last two are more widely used for medical instruments in pouches or sachets). 

Moist heat sterilisation can be used to sterilise packaging components for aseptic filling or to terminally sterilise both the product and the pack. Because of this, various factors have to be noted. 

Some regulatory authorities request that certain types of product, e.g. IV solutions, be subsequently subjected to terminal sterilisation. However, there is still an advantage in that a cleaner product is achieved, as the container is made, filled, sealed with the minimum of exposure and handling. Virtually all the risk is related to machine stoppage, clean-down after operating and the start-up period. 

The need for higher standards of cleanliness and hygiene has already been mentioned. Since the safety factors for aseptic processes and terminal sterilisation processes rely on a low initial bioburden, attempts will continue to minimise contamination. Packaging manufacturers of materials, components and containers will therefore slowly adopt GMP procedures currently found as part of the Orange Guide in order to lower both bioburden and particulates. Cleanliness and improved hygiene are an order of the day, in terms of facilities, procedures and training. 

The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area Manufacturing operations are divided into two categories firstly those where the product is terminally sterilised, and secondly those which are conducted aseptically at some or all stages. 

Grade Examples of operations for terminally sterilised products (see para 11)... 

Blow/fill/seal units are purpose built machines in which, in one continuous operation, containers are formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine. Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment, provided that grade A/ clothing is used. The environment should comply with the viable and non-viable limits at rest and the viable limit only when in operation. Blow/fill/seal equipment used for the production of products for terminal sterilisation should be installed in at least a grade D environment... 

Filling of products for terminal sterilisation should be done in at least a grade C environment. 

In cleanroom suites in which both terminally sterilised and aseptically prepared products are made, it is preferable for both types of product to be processed in accordance with the standards required for aseptically prepared products. 

Filling and sealing of products intended to be terminally sterilised C ... 

Each batch of terminally sterilised LVP product should be sampled immediately after filling and closing and tested for viable microbial content An action level for viable microbial content, above which special action is required to determine the source of contamination should be defined. This level should be no greater than 1 CFU/mi. 

In the case of terminally sterilised products, from representative sites within the steriliser, including the sites shown by validation studies to be least accessible to the sterilising agent except that samples may be taken representatively from across each sterilising lot if ... 

First those where the preparation is terminally sterilised, sealed in its final container, and second those which must be conducted in an aseptic way at some or ail stages. 

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