Introducing a clean room for creating sterile preparations

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Bernard Vanhoutte
Hospital and Industrial Pharmacist
AZ Sint-Jan AV, Bruges
Belgium

Since October 2007, all non-toxic preparations have been prepared in a clean room in our pharmacy facility. The room is built to the Pharmaceutical Inspection Co-operation Scheme (PIC/S) standard 20061 and has an area of 100m2. It is used for the production of both named patient preparations and for batch preparations. The reasons for introducing the clean room were twofold – to help satisfy increased production demands 
in the current hospital, and pending legislation that would authorise hospitals to produce for other hospitals. The new legislation (a Royal Decision),2 which came into force on 29 January 2007, outlined what could be done in terms 
of producing preparations for other hospitals and includes:

• Preparations containing toxic 
(that is carcinogenic, mutagenic, teratogenic and/or potentially harnful) registered medicines
• Preparations containing toxic 
raw materials
• Preparations containing allergenic products (for example histamines)
• Preparations containing penicillins and cephalosporins
• Repackaging (in unit dose)
• Central sterilisation
• All sterile preparations.

The legislation covers what can, 
and cannot, be produced but does not indicate which good manufacturing practice standards,2 must be followed. This directive is forthcoming and will most likely follow the PIC/S standard 
for batch preparations and possibly 
the US Pharmacopeia (USP) 797 (or also the PIC/S standard) for named patient preparations.

PIC/S is stringent and does not differentiate between batch preparations and patient named preparations. USP 797 differentiates according to risk analysis (preparations starting from no sterile products and 0.22 µ filtration, mixing of sterile products for one preparation, mixing of sterile products and filling multiple recipients, etc) and also on the basis of temperature of conservation (such as room temperature, refrigeration or freezing).

What preparations do we provide for other hospitals?
A licence is usually required for each activity/type of preparation for external organisations. Our facility only produces non-toxic sterile batch preparations for other hospitals and also unit dose packaging for the Henri Serruys Hospital in Ostend, with which we merged in January 2009, resulting in an increase in the number of beds from 907 to 1234 and which led to the increased demand for preparations in our organisation.

What is the PIC/S standard for the different types of preparations?
Preparation autoclaved after filling
The preparation must be done in a Class C or Iso 7 clean room
Filling must be done in a Class C if filling and closing is quick and starts from a closed container; otherwise filling must be done in a Class A (Iso 5) with a Class C (Iso 7) background
Autoclaving must be carried out as soon as possible after filling.

Preparation filtered with no end sterilisation
This must be carried out in a Class A (horizontal laminar airflow; HLAF) cabinet with a Class B background.

Preparation in isolators
Background must be at least a Class D.1

Our procedures
Batch preparations in vials with end sterilisation

• Preparing and mixing in an Iso 7 environment
• Filling by 0.22 µ filtration and closing in a Class A environment; HLAF placed in a Class C background
• A peristaltic pump guides the solution through the 0.22 µ filter placed as close as possible to the filling point
• Autoclaving as soon as possible after filling/closing.

Batch preparations in syringes

• Preparing the solution and mixing 
in a Class C
• Filtration through the wall of the isolator and filling in 5l bags (guided by an outside peristaltic pump)
• The bags are dispensed into syringes; this process is automated controlled by a filling machine – the SmartFiller® – placed in the isolator
• The isolator is placed in a Class C environment).3,4

Adding solutions to infusions (also batch preparations)

• As above, but in another isolator
• Addition to the infusion is performed with a Flexicon Pump (a peristaltic pump placed in the isolator)
• Control is through weighing; a balance is incorporated into isolator (electronics displaced outside the isolator)
• The Isolator is placed in a Class C environment.

Automated filling of the syringes
Before SmartFiller, syringes were filled with a peristaltic pump in a HLAF; this was a slow, multi-step process which increased the possibility of infecting the syringe. The SmartFiller apparatus (Added Pharma)5 is able to fill up to 350 60 ml syringes per hour (see Figure 1). We use three kinds of syringes: 3ml; 10ml; and 60ml (all from Becton Dickinson with Braun stoppers). The SmartFiller can be adapted to deal with different volumes or to fill syringes from other manufacturers (for example Braun, Terumo). The SmartFiller saves our facility the cost of one pharmaceutical assistant a year. Syringes are delivered in packs of 25 or 50 with a stopper on the syringe. The 10ml and 3ml syringes are packaged in plastic and are sterilised by radiation. The 60ml syringes are packed in laminate bags and sterilised with ethylene oxide.

Patient named non-toxic preparations

• Preparation in a Class A or Iso 5 (HLAF)
• Background is a Class C (Iso 7), but this can be upgraded to a Class B (now 30 air changes per hour for a Class C; for Class B needs a minimum of 
75 air changes per hour are required).

Patient named cytostatic preparations

• These formulations are not prepared in a real clean room
• The preparation itself is done in a negative pressure room in a biohazard cabinet (vertical laminar air flow (VLAF) with negative pressure).

Classification of the room is an Iso 8 (Class D). Upgrade to a Class B is not possible here. For this we will have to build a real clean room for biohazards (Class A), with a Class B background or isolators (the most cost-effective solution) that will need to be placed in the existing room.

For the moment there is no direct communication between the prescription order and a pharmacy preparing module, so that we have to ‘transcribe’. Also there is no weighing control. CATO (Computer Aided Therapy in Oncology), a software programme for cytostatic preparations from Cato Software Solutions, could be the answer to this.6

Our facility uses the Tevadaptor® apparatus as a needle-free, closed drug reconstituion and transfer system.7 We still have a spike connection to the infusion (connection line), which is filled with neutral solution. We aim to use infusions with double luer lock connections to be able to produce a ‘dry’ connection to the infusion line, which will improve security.

Monoclonal antibodies (MABs) 
are not prepared in the cytostatic preparation room, but in the clean room for patient named non-toxic preparations. There is an increasing body of literature indicating toxicity of MABs and that 
the formulations are best prepared in biohazard cabinets (although employing 
a different type of cabinet for the preparation of classic cytostatics).

Evolution of the preparations

• Delivery to other hospitals is included in the number of recipients of the batch preparations
• The increase in the number of 
patient named preparations is 
because of MABs and the 
preparation of study medication
• Non-toxic patient named preparations can increase to an amount of about 20,000 a year, and the MAB preparations will go to the cytotoxic preparations in the future, so there is an opportunity there
• The increase in the number of batch preparations is a result of the expansion of our hospital (from 907 
to 1234 beds) and the delivery of preparations to other hospitals
• The number of cytotoxic preparations is stable (for seven years between 13,000 and 13,600 preparations) but will increase if the MAB preparations are carried out in our facility
• Batch preparations can be doubled or even tripled. This part of the clean room is occupied only three days a week. There is a possibility to work in two periods of eight hours for five days a week, so the production capacity can be increased, with an increased number of personnel. Our facility employs 
four full time pharmaceutical assistants for the non-toxic sterile preparations (batch plus patient named preparations), included their vacation and recuperation times
• A solution must be found for the cytostatic preparations. Two pharmaceutical assistants are required every day (taken from a pool of 10 assistants). If MABs are to be included in the cytostatic preparation, 2.5 assistants will be required daily.

Batch preparations
Table 1 shows the products in batch preparation in 2010.

Conclusions
Introduction of PIC/S in Belgium will enhance the quality of hospital pharmacy sterile preparations. Small hospitals might not be able to install their own clean rooms so larger hospitals must 
help them, because the industry is not likely to be interested in producing small batches or individual preparations. We hope other hospitals will follow in the footsteps of our facility and produce for other hospitals.

References

1. www.picscheme.org
2. http://reflex.raadvst-consetat.be/reflex/pdf/Mbbs/2007/02/23/103228.pdf
3. www.eurobioconcept.fr
4. www.ccsbe.com
5. www.addedpharma.com
6. www.cato.eu
7. www.tevadaptor.com
8. www.stabilis.org
9. Trissel LA & L Goldberg. Handbook on injectable drugs 14th edition; 2008