Facilities for sterile cytotoxic reconstitution

Facilities for the sterile reconstitution of cytotoxic agent need to ensure both the protection of the product and the protection of the drug handlers. Aseptic drug manipulation must take place in a controlled environment to ensure the sterility of the end product. Additional protective measures are required to guarantee the safety of the operators. Centralized preparation of parenteral cytotoxic drugs should be implemented to protect the final product against microbiological and particulate contamination and to protect handlers against exposure to hazardous drugs. Taking into account the pharmaceutical analysis and quality control implemented, centralized preparation improves the entire quality of the preparation and thus the safety of patients is enhanced. Centralization of services also provide economic benefits. Centralization is commonly located in the pharmacy department.

Many institutions sites the preparation facility within an oncology outpatient department or close to the inpatient ward where chemotherapy is most commonly administered that is a satellite pharmacy. This offers advantages in terms of ease of transport of cytotoxics as well as enhanced communication between pharmacy, medical, and nursing staff. The satellite pharmacy must be under the control of a pharmacist. Remember, under no circumstances should nursing staff be permitted to prepare, reconstitute cytotoxic agents on the ward. Due to the risk of contamination, cytotoxic reconstitution must be performed in a room dedicated solely to that task with similarly dedicated equipment. Access to the room where cytotoxic preparation is performed must be restricted to trained and validated pharmacy personnel.

The cytotoxic facility should be designed to allow easy and adequate access for personnel, equipment, and cleaning. The room surfaces should be designed to minimize particle shedding and to prevent the build-up of particulate matter. The design must facilitate effective cleaning. Walls must be lined with a smooth, durable surface, lighting recess into the ceiling, and the room should contain a few projecting ledges or shelves as possible. Floors should be poured and seamless if possible. Vinyl tiles have been shown to trap and hold drugs. This classification take into account both particulate and microbiological contamination.

The room shall be designed tofacilitate asepsis in the handling and preparation of cytotoxic drugs, and shall also be designed to provide containment of cytotoxic drugs, particularly in the event of the failure of the biological safety cabinet or isolator or spillage outside the cabinet or the isolator. Sterile cytotoxic preparation using aseptic technique must be performed in a Grade A environment. The Grade A environment corresponds approximately to the ISO Class 5. Both laminar airflow hoods and isolator are able to guarantee a Grade A environment. For terminally sterilized product, the background environment for filling these products is at least Grade C.

Note that an anteroom leading to a positive pressure room may be ISO Class 8 but an anteroom leading to a negative pressure room shall meet at least ISO Class 7 This table shows the airborne particulate classification. Sterile cytotoxic preparation using aseptic technique must be performed in a Grade A environment. Characteristics of a Grade A environment are shown in the Table. This Table summarizes the relationship between the ISO classification the EudraLex Classification, and the US Federal Standard 209E with regard to particulate contamination. According to USP〈797〉,

Hazardous drugs as Compounded Sterile Preparations: The ISO Class 5 Biological Safety Cabinet or Compounding Aseptic Isolator shall be placed in an ISO Class 7 room that is physically separated, that means a different room, separated from other preparation areas, and optimally has no less than 0.01-inch water column negative pressure to adjacent positive pressure ISO Class 7, or better, anterooms, thus providing inward airflow to contain any airborne drugs. This slide we talk about pass-through hatches. A pass-through hatches is essential to prevent direct access between the cytotoxic cleanroom and the external environment. There are two possibilities for the location of such hatches. These hatches may either be between thecleanroom and anteroom or between the cleanroom and external environment.

If the latter option is selected, then interlocking doors must be used and the unit must be HEPA filtered. Hatch doors should preferably be fitted with an audible or visual alarm to prevent doors being opened simultaneously. In order to minimize cross contamination, separate hatches for entry and exit of products are preferable. This slide we talk about storage room. According to USP USP〈797〉, hazardous drugs shall be stored separately from other stock in a manner to prevent contamination and personnel exposure. Such storage is preferably within a containment area such as a negative pressure room. The storage area must have sufficient general exhaust ventilation, for example, at least 12 air exchanges per hour to dilute and remove any airborne contaminants.

An ongoing monitoring program should be established. In controlled workplaces, the parameter to be monitored are microbiological contamination, particulate contamination, HEPA filtration, air velocity, and pressure differentials. Visual inspection of the surfaces and joints should be performed regularly for cracks or other damage. A check list should be used to assess the conformity of the room and equipment before daily use. Pressure differentials must be checked before entry into the cleanroom. Consideration should be given to the installation of manometer alarms, preferably visual, which alert staff to inadequate pressure differentials. Particulate contaminations and air velocity should be assessed on a regular basis. Microbiological contamination should be checked on a daily basis by sampling surfaces.

Passive air sampling should be done daily with settle plates and active air sampling done on a regular basis. Testing must be carried out more frequently if any abnormality in any test is detected, or if any maintenance or repair work is carried out.

Because of the large quantity of details, I would like to provide recommended references for further details. You could look for ISOPP guideline. It is published in 2007. And USP 800, it is published just last year, 2016.

You could search the internet and get them all free. In the second section of this topic, we will continue to talk about following issues, including personal protective equipment, special devices, for example, closed system transfer devices.

Then we will also focus on non-sterile hazardous preparation. Very important, we want to mention WHO recommendations for resource-poor area. And finally we will give the summary and conclusion for this topic.