GERPAC conference report

One recent publication showed that 100% of vials of carboplatin were contaminated, noted Dr Crauste-Manciet. Exterior contamination of vials is a source of contamination both inside the working area – isolator or biological safety cabinet (BSC) – and in the immediate environment. Despite implementation of corrective measures by manufacturers – washing the exterior surface of vials and protective over-wrapping – there is still a residual risk of contamination. Washing of the exterior surfaces of vials is now routinely undertaken by pharmaceutical companies during the manufacturing process.

However, this process is unable to remove potential contamination between the flip-off cap and rubber stopper. The surface contamination risk was originally identified in 2004 and at a GERPAC debate in 2009, manufacturers of cytotoxic drugs confirmed that it was a widespread problem. In addition, the outer packaging of vials can also be contaminated and when different products are packed in the same manufacturing plant, cross-contamination can occur. The levels of contamination found on vials in the different studies are variable, from no contamination (under the detection limit of analytical method) to detectable contamination with microgram quantities. 

Shrink-wrapping reduces exterior vial contamination considerably but does not eliminate it – contamination under the flip-off cap is still an issue. The safest way to deal with this is to remove the flip-off cap in the protected environment of an isolator or BSC. The space between the flip-off cap and the rubber stopper is not sterile and needs to be disinfected by swabbing. The next step is to implement procedures to limit exposure of operators. A key issue here is to manage the exposure risk for operators when handling vials outside the isolator or BSC. Items are commonly sprayed with disinfectant before being put into an isolator or BSC, but this risks spreading contamination around the working area and so wiping with antiseptic impregnated swabs is preferable. Another problem is that cytotoxic agents present as surface contaminants can be transferred to the gloves (or skin) of workers. For this reason, staff involved in shipping or receiving these products should wear disposable (single-use) gloves and be trained to wash their hands with soap, rather than cleansing with alcohol, after removing the gloves, advised Dr Crauste-Manciet.

During the preparation process, contamination of final products occurs due to leakage or aerosol formation (when needles are withdrawn from over-pressured vials) and due to surface contamination of vials and syringes. It is never possible to reduce contamination to zero but it should be contained by the use of closed system transfer devices, containment of waste, frequent glove changes and improved cleaning processes. The final step is to ensure that health workers are fully educated especially about the risks, gloving and cleansing procedures, concluded Dr Crauste-Manciet.

Contamination of the working environment with cytotoxic agents can be reduced with good housekeeping measures, Paul Sessink (Director, Exposure Control Sweden AB) told the audience. Sources of contamination include spillage during preparation, external contamination of vials and residual drugs in the BSC or isolator. In addition, contamination can occur around the patient (from urine, sweat, blood, vomit or faeces), from spillage during administration and from contaminated waste or laundry. Studies of environmental contamination since 1990 have shown progressively decreasing levels.

The National Institute of Occupational Safety and Health (NIOSH) alert on cytotoxic handling (NIOSH alert: preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings; 2004) had little impact on contamination but the introduction of closed system transfer devices (CSTDs) made a major difference, said Dr Sessink. Whereas during the 1990s contamination was routinely found in many areas of pharmacies and wards, by 2012, in many cases, contamination had fallen to undetectable levels. The introduction of the PhaSeal CSTD had been particularly successful in reducing contamination, he commented. 

When considering the question of acceptable levels of contamination, cyclophosphamide is commonly used as a marker as it is highly toxic, readily penetrates the skin and can be measured accurately. When surface levels are less than 0.1ng/cm2 there is no measurable exposure of workers, which is to say no drug appears in the urine. The current consensus is that a level of cyclophosphamide surface contamination of 0.1ng/cm2 is safe but levels of 10ng/cm2 or more are not acceptable and require immediate action. Intermediate levels call for more frequent monitoring and the introduction of measures to reduce levels to 0.1ng/cm2 or less.  

Cleaning of contaminated surfaces represents a major challenge because there is no unique or proven method. Alcohol is ineffective as a cleansing agent, emphasised Dr Sessink. An effective cleansing procedure would remove or destroy the drugs. A suggested procedure is to use a basic (alkaline) detergent solution of pH greater than 10 and then rinse with water. This should be followed by an acidic detergent solution of pH less than 4, and then a water rinse followed by a final swab with alcohol to disinfect. Although no procedure is 100% effective this approach is likely to be 95% effective, he said. 

Biological monitoring for cytotoxic drugs provides direct proof of uptake of the drug, but the interpretation can be difficult, according to Rudolf Schierl (Institute for Occupational, Social and Environmental Medicine, Munich University, Germany). Internal exposure to a drug is demonstrated by the presence of the drug or its metabolites in the blood or urine. Sensitive assay techniques are available for a number of drugs including cyclophosphamide, ifosfamide, fluorouracil and epirubicin, but timing is critical because most drugs are eliminated in a matter of hours. 

One of the strengths of biological monitoring is that it has an educational effect on the individuals involved. However, it provides no information about the source of drug uptake and there can be difficulties in communicating the results. Moreover, there is no way to interpret the results in terms of personal risk, at present. Dr Schierl concluded that biological monitoring is a powerful tool for quantifying potential uptakes of cytostatic drugs under special circumstances (for example, spillages, accidents, new techniques). As a routine method for risk assessment at workplaces it cannot be recommended at present, but this would change if threshold limit values (TLVs) for safe handling of cytostatic dugs could be established in future.

Reviewing the selection criteria for injectable medicines to be prepared in hospital, Pascal Bonnabry (Director of Pharmacy, Geneva University Hospitals (HUG) and Professor, Section of pharmaceutical sciences, University of Geneva, University of Lausanne, Geneva, Switzerland) said the much had been achieved over the past 15 years. In particular

• risk management tools, such as reporting and investigation of incidents, prospective risk analysis, have been implemented
• risk management measures have been introduced for high-risk drugs
• standardisation of concentrations and labelling have been promoted, especially in high-risk areas (anaesthesiology, intensive care, emergency)
• ready-to-use injectables (prepared in hospital centralised IV additive units (CIVAS)) have been made available, to minimise the opportunities for error.

Research has shown that the reconstitution and dilution of drugs are highly error-prone steps, and so Professor Bonnabry has looked for ways to avoid these by providing ready-to-use products wherever possible. One important step here was the development of a risk assessment matrix for injections used in intensive care and the emergency department. This made it possible to identify the highest-risk products in use in the hospital and determine what should be provided in a ready-to-use form from the pharmacy. Currently 15 products are prepared in-house and this corresponds to 30,000 doses per year. 

 The regulations governing the manufacture or preparation of injectable medicines in the UK allow for several categories, Julian Smith (All Wales Quality Assurance Pharmacist, St Mary’s Pharmaceutical Unit, Cardiff & Vale University Health Board, Cardiff, UK) told the audience. There are a number of different categories of unlicensed medicines. These include:

• medicines imported into the UK that are licensed abroad but not licensed in the UK 
• medicines imported into the UK that are not licensed abroad or in the UK
• medicines that are licensed in the UK, but not used for their licensed indication (off label)
• medicines prepared as ‘specials’ by licensed manufacturers but do not hold marketing authorisations 
• dispensed medicines.

The preparation of ‘specials’ in the UK is regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). Dispensing activities are controlled by the General Pharmaceutical Council . A ‘specials’ manufacturer must hold a ‘specials’ manufacturing licence issued by the MHRA and the manufacturing facility must be licensed by the MHRA. The specification of products to be supplied should be agreed between the purchaser (pharmacist) and the prescriber.

Generally, it is agreed that medicines required for patients with special needs can be supplied as either ‘specials’ (from a licensed manufacturer) or as extemporaneously dispensed (so-called ‘Section 10’) preparations. The essential distinction between these two types of preparation is based on risk. Extemporaneous (Section 10) preparations are generally considered to present a higher risk of harming patients than products prepared as ‘specials’ in a licensed unit. However, extemporaneously dispensed preparations are generally more readily available and can be provided to patients in a shorter time frame. Section 10 products are made under the supervision of a pharmacist, are prepared on demand (in small quantities), undergo limited testing and have a short shelf-life. ‘Specials’ are prepared under licensed conditions; undergo stability assessment, have a longer validated shelf-lives and can be prepared in large batches.

Many commercial ‘specials’ companies now exist in the UK and are used by hospitals and community pharmacies. The risk of preparation errors then rests with the commercial supplier.

Outsourced preparation of injectable drugs in nine compounding units run by Baxter Pharmacy Services now accounts for approximately one million doses per year, according to Bryan Horrocks (Director of Quality Assurance for Compounding in Europe, Baxter UK). The product range includes chemotherapy (cytotoxics and monoclonal antibodies), parenteral nutrition, anti-infectives and analgesics, and these are packed in intravenous bags, syringes and infusors. All products are prepared aseptically in dedicated units. These units are able to offer a number of services including preparation of dose-banded, off-the-shelf, cytotoxic drugs, multi-dose ‘stock’ bags, patient-specific items, and fully-outsourced hospital pharmacy aseptic services. Products can be delivered in four hours. Same-day, multiple deliveries are also possible. Customised solutions, such as in-hospital distribution hubs or direct ward deliveries, are also possible. 

There are some important risks and challenges associated with the use of outsourcing. There can be loss of local expertise and consequent loss of capacity to deal with emergencies. New ways of working are required with skills in supplier management and communications. The service is more structured with formal documentation and specification of service levels leading to a better understanding of the true cost of the service. One major benefit of outsourcing is that capacity constraints in the hospital are reduced – time is liberated for clinical activities for both pharmacists and nurses. In addition, safety and quality of service are improved with reduced risks of medication errors and reduced patient waiting times. Finally, there are economic benefits as a result of reduced wastage, reduced stock-holding and increased patient throughput. 

GERPAC (Groupe d’Evaluation et de Recherche sur la Protection en Atmosphère Contrôlée) was formed in 1998 by a group of hospital pharmacists, university teachers and researchers. The group’s main area of interest is the preparation of pharmaceuticals in controlled environments such as isolators and controlled-atmosphere rooms. It promotes research and development in all aspects of pharmaceutical aseptic preparation and manufacturing. See www.gerpac.eu 

Author

Laurence A Goldberg FRPharmS
Editorial Consultant, HPE