Intraocular preparations should be prepared in a horizontal or vertical Laminar Flow Cabinet (CFL) (according to the risk assessment of the medication) in a controlled environment: in a EU-GMP grade A cabinet (or ISO 5 class according to the UNE-EN ISO 14644-1 at rest or in operation) and a grade B working area environment (or class ISO 5 at rest) if starting with non-sterile material, or a grade C working area environment (or ISO class 7 at rest) if all starting materials are sterile. During aseptic preparation it is also possible to work in a positive pressure pharmaceutical isolator (if the substance is not hazardous) in a grade D environment (or ISO 8 class at rest)4.

The presence of materials that can release fibres should be minimized in clean areas, and so the use of sterile drapes instead of gauze is recommended.

The materials used, such as types of needle, filters, or syringes, will be suitable for the starting substances and the type of preparation, while always checking for their compatibility. For example, during the process of syringe preparation, the filtration of bevacizumab should be avoided26.

In the case of the preparation of terminal sterilization products, 0.22-μm filters suitable for the type of solution to be sterilized should be used. Due to risks inherent to the intraocular route, double sterilizing filtration should be performed before filling the final container4.

In the case of starting with sterile substances, and only if the substance is compatible, 5-μm particle filters should be used to prevent glass particles from the ampoules or elastomers from the vials from entering the preparation. Providing the substance is compatible, 0.22-μm filters can be used prior to filling the final container in order to increase the sterility of the preparation and thus its safety. Particles would also be removed during this sterilizing filtration process.

In the case of preparations in which a prior dissolution or dilution of the medication at a certain concentration is needed for intravitreal administration, such as in the preparation of antibiotics, syringes will be filled through the hub of the syringe with the syringe already loaded with the solution, and filtered using the appropriate filter which is compatible with the substance. The resulting syringes will be capped with sterile plugs and the intravitreal administration needles will be attached to the syringes in the operating room.

If divided doses obtained from high-cost biological medication vials are required, a possible approach would be as follows:

• 1)

  Leave the vial to rest for a few seconds in an upright position on the surface of the cabinet to allow all the medication to slide down the walls to the bottom of the vial.

• 2)

  Extract the medication in the syringe through a needle with a suction filter ensuring compatibility between the substance and the filter membrane.

• 3)

  Load the volume of medication agreed upon with the ophthalmology service into fixed-needle dead-space-free syringes. The size of the syringe and needle will be that agreed upon with the ophthalmology service because the ophthalmologist will directly administer the medication with this syringe via the fixed needle. The technique would be as follows: Using the fixed-needle dead-space-free syringes, directly extract the required volume through the hub of the syringe loaded with the medication. In this case, precautions must be taken to prevent the microneedle of the dead-space-free syringe from rubbing any surface of the syringe containing medication. Extraction through the hub of the dead-space-free syringes can be facilitated by the use of a pipette holder to hold the syringe loaded with the medication in an upright position.

The vials of the monoclonal antibodies must not be shaken and the medication should be carefully transferred to the syringe to avoid protein aggregation. It should be ensured that there is no turbidity because this would indicate aggregate formation26.

The formation of bubbles and the introduction of air into the syringes should be avoided because this can lead to protein instability26.

Prepared syringes should never be labelled directly on the barrel of the syringe, and they should be packaged inside the LFC in sterile self-sealing bags which will be labelled.

Depending on the particular working method (procedure, personnel involved in opening the bags and taking the syringe to the operating room), it could be advisable to use a double sterile bag to package each syringe. That is, each bag containing the syringe will be place inside a second sterile bag. In this case, this second bag will be the one to be labelled. The need for the second sterile bag must be previously agreed with the ophthalmology service.

Finally, all labelled bags will be packaged in a lightproof bag for conservation and transportation.

It is highly recommended that auxiliary support staff are available in the sterile area to check the volume of the syringe, bag labelling, and so on, thus preventing the person preparing the syringes from taking his/her hands away from the sterile areas and touching non-sterile material.

According to the GBPP, medium-risk preparations prepared in a LFC with a controlled environment have a microbiological shelf-life of 9 days in a refrigerator (2 °C – 8 °C) and 45 days in a freezer (≤ -20 °C), provided that their physical and chemical stability is not less than the aforementioned periods and that the substance can be kept in a refrigerator or freezer4.

Likewise, when using open systems or preparing non-sterile products or materials, high-risk preparations prepared in a LFC with a controlled environment have a microbiological shelf- life of 3 days in a refrigerator (2 °C – 8 °C) and 45 days in a freezer, provided that their physical and chemical stability is not less than the aforementioned periods and the substance can be kept in a refrigerator or freezer4.

Biological medicines should not be frozen because they may undergo alterations in their molecular structure26. It is recommended that the divided doses should be prepared closer to the time of administration.

Shelf-lives longer than those established in the GBPP may be assigned when:

• –

  They are documented in a high-impact publication and the formulation is the same as that documented in the literature4;

• –

  Or when the responsible pharmacist performs the final sterility test to validate the preparation and routinely performs periodic tests to ratify the assigned validity4.

All starting materials and packaging materials must undergo visual inspection before use to ensure that they meet all specifications4.

Sterility test: When preparing a batch of more than 25 units of high-risk preparations, the batch must undergo microbiological analysis. In high-cost preparations, it is not economically feasible to waste 1 or more units in order to reach the volume needed to inoculate the culture medium. In these cases, other measures are applicable to ensure the continuous quality of the preparation process, such as validating the aseptic technique by simulating the preparation with a culture medium that replaces the medication, preparing it with the same procedure27.

If a product is prepared for administration to a single patient, the only aspects that have to be checked are its appearance and the final clarity of the finished product4. The PiC/S guide to good practices for the preparation of medicinal products in healthcare establsihments28 recognizes that it is unnecessary to perform sterility tests in individual extemporaneously prepared medicinal products per patient, because this process would involve handling the final product.

It is recommended that these substances are prescribed for outpatients using the computer application available to the hospital. This prescription will also serve to confirm the scheduling of surgery and for managing dispensing per patient.

With the agreement of the ophthalmology service, and in order to help ensure the traceability of the preparations, it is recommended to send a label identifying the batch and shelf-life of the preparation so that it can be attached to the patient's medical record.

An alternative technique for preparing divided doses from vials of high-cost biological medicines would be to previously extract the plunger of the dead-space-free syringes and load through the inlet part of the plunger. In this case, precautions should be taken when replacing the plunger and extracting air from the syringe to ensure that medication is not wasted. It is essential to ensure the absence of bubbles in the preparation.

The use of a decapper to remove the metal top of the vial would prevent the release of its particles into the contents of the vial and the needle, and would also contribute to better use of the vial, because this approach would prevent wastage of medication on the walls of the rubber stopper29.