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The Pharmaceutical Journal Vol 264 No 7086 p382-3
March 4, 2000 Forum

Joint Pharmaceutical Analysis Group

Health and safety in the laboratory

Safety and environmental aspects of operating a pharmaceutical laboratory were considered at a meeting of the Joint Pharmaceutical Analysis Group in London on December 2, 1999

Providing a general overview of laboratory safety requirements, Dr GERARD LEE (Medicines Control Agency) said that many hazards of the past had been eliminated through improved working practices, the phasing out of hazardous reagents, and new safety legislation. Achieving a safer environment had been helped by professional bodies' codes of practice and guidance documents.
There remained an overriding requirement for employers to ensure a safe working environment and to have in place a management framework to address specific problems. In the past, problems had been created because both employers and employees had made assumptions on health and safety matters. Laboratory safety could only be improved through managing the risks, which involved issues such as handling and processing of materials and waste disposal, as well as the design of the laboratory itself. The employer had to ensure that there was a means of identifying risks which could then be assessed and controlled, together with a procedure for investigating and correcting deficiencies. It was important to investigate and review all accidents that occurred.
The management framework had to include a positive policy on assessing and controlling risks, including a risk reduction programme, safe systems of work and periodic safety audits. A commitment to health and safety was required from the highest level in the organisation, with the duties and responsibilities of all staff being fully understood. Although laboratory safety had improved significantly in the past 30 years, both employers and employees had a continuing duty to promote and improve safety.

Safety in the contract laboratory

Contract laboratories faced particular safety problems because of the wide range of samples handled, said Mr CHRISTOPHER CLARE (Covance Laboratories Ltd, Harrogate). There was usually reasonable safety data for reference materials and samples generated as part of a programme of "in-house" studies. But, where "external" studies were conducted, samples could be received from all over the world, with little control over the quantity or quality of the safety data.
At any one time, a contract laboratory might be conducting many studies, which meant handling large numbers of samples and associated reagents and chemicals. Since a contract laboratory was usually remote from its clients and the site of sample generation, there were problems relating to transport of samples and transfer of safety information. With a high throughput of samples, it was essential to identify the potential hazards associated with each and manage the sample inventory carefully. There was also a need for reliable and safe arrangements to handle large quantities of waste for disposal.
In such circumstances, safety was addressed through effective and accurate labelling and inventory systems and COSHH assessments for every compound and procedure. Where the hazard posed by a sample or reference material was unknown, it had to be treated as being of high hazard.
The relationship between contract laboratory and client was an important aspect of managing safety. Because the laboratory was not part of the client's organisation, it could be treated with suspicion and given limited information. Language and cultural difficulties could also arise. If compounds were still in the early stages of development, safety information might not be available.
Some of these difficulties could be overcome by using pre-study questionnaires to encourage information transfer, by supplying preprinted sample labels to the client and, importantly, by working closely with the client to develop the relationship and encourage trust between the parties.
All contract laboratories needed proper safety training programmes for all employees and full assessments carried out on all samples and procedures in accordance with the Control of Substances Hazardous to Health Regulations 1988 (COSHH). The programme should include health surveillance of staff who handled compounds with unknown risks, including monitoring of the most likely target organs, with respiratory sensitisation, blood count parameters and liver and kidney function tests being carried out annually.

Safety and the pharmacopoeia

Describing revisions made to the European Pharmacopoeia for safety and environmental reasons, Dr JOHN MILLER (European Directorate for the Quality of Medicines, Strasbourg, France) said that monographs for individual active substances, excipients or pharmaceutical formulations were constructed to ensure quality, safety and efficacy. The safety aspects related to the patient, the general population (ie, environmental issues) and also the laboratory analyst.
Monographs that had been revised in the light of concerns for safety of the patient included those for l-tryptophan and glycerol. One l-tryptophan impurity was believed to be responsible for causing eosinophilia-myalgia syndrome, of which there had been 1,600 cases and 38 deaths up to 1991. The monograph had been revised in 1998 to include a gradient liquid chromatographic method to limit the impurity to 10 ppm.
In the case of glycerol, more that 80 children had died in Haiti after receiving a cough syrup containing glycerol contaminated with ethylene glycol. This had resulted from industrial grade glycerol being labelled as United States Pharmacopeia quality. Although the EP monograph would have shown the glycerol to be substandard, it had been strengthened to include a gas chromatographic test for ethylene glycol.
In the light of the bovine spongiform encephalopathy tragedy, many monographs had been revised so that the production section controlled the source of the animal.
Residual solvents had also been considered and changes relating to their identification and control had been incorporated in the EP Supplement 2000. Following a literature review, solvents had now been classified according to their toxicity. Use of the most toxic solvents (eg, benzene and carbon tetrachloride) was to be avoided, while some others were restricted in their use.
Further revisions were designed to reduce risk from toxic reagents and solvents. For example, chloroform was being replaced by dichloromethane for solubility and mobile phases in chromatographic methods. Carbon tetrachloride was being removed for the calibration of refractometers. Other changes included the removal of mercury salts from the analytical methods for the assay of halide salts of organic bases and the assay of penicillins.

Impact of COSHH

Mr STEVE BROOKS (head of safety and environment group, Pfizer Central Research Europe) said that COSHH had improved health and safety standards in the industry. Working practices that had been the norm 10 years ago were no longer acceptable.
New technologies and new ways of working had led to drugs with increased potency, which had led to greatly reduced exposure limits. Because the hazards from compounds in research and development were not fully characterised, the strict application of COSHH principles was needed to ensure operator safety. This had led to new facilities with improved containment, while better employee consultation, communication and training, had resulted in significantly improved employee knowledge of chemical and biological hazards, exposure risks and the necessary control methods. - Contributed.

Radiological safety

Discussing radiological safety for the analyst, Mr MIKE ALLENBY (Amersham Laboratories, Nycomed Amersham) said that exposure from an external hazard could be minimised by four basic principles: using the smallest possible quantity of material; shielding the analyst from radiation; keeping the analyst away from the radiation source (eg, by using remote handling techniques); and minimising the time spent handling the material.
Exposure from an internal hazard could result from ingestion, inhalation, transdermal absorption or absorption through wounds. Inhalation could occur if aerosols were generated or if the material was volatile. In such cases, no radioactive work should be permitted on open benches and working within ventilated enclosures should be a formal requirement. These measures also controlled discharges of radioactive material. Extract ventilation should be filtered to retain radioactive substances and volatile material.
Measuring an individual's radiation dose was a necessary aspect of ensuring staff safety and a requirement of the Ionising Radiation Regulations 1985 (as amended). The use of film badges for measuring personal dose rates was a legal requirement that enabled data to be centrally collated. Although retrospective, the results were nonetheless valuable. Contamination of the working environment was monitored both from static samples and proactively to assess movement of material. Biological tests of the thyroid and urine were carried our periodically as necessary.
Training was important to the control of an analyst's exposure to radioactivity. Training and experience in handling radioactive materials gave the analyst confidence to respect radioactivity and associated hazards without being frightened by them.
On the environmental aspects of handling radioactive materials, Mr Allenby said that all waste disposal was controlled by the Environment Agency. In his own organisation, all liquid waste was piped to a central waste management centre on site where it was collected, stored, decayed and measured before any approval was given for it to be disposed of into the public sewerage system.

Microbiological safety

Speaking on the safety aspects of analytical processes involving micro-organisms, Dr MORAG FERGUSON (National Institute of Biological Standards and Control) said that such organisms were classified into four hazard groups depending on their pathogenicity to man, their level of hazard to laboratory workers, their transmissibility in the community and the availability of effective prophylaxis or treatment for any infection caused. Hazard group 4 contained the most hazardous, such as rabies. Each group had its own standards for containment of the organism in the laboratory. For example, containment level 2 (for group 2 organisms) required specified disinfection procedures, safe storage of biological agents and handling of infected material only in a safety cabinet, isolator or other suitable containment.
Protecting laboratory workers required consideration of the possible routes of infection, such as ingestion, inoculation or inhalation. The primary containment of micro-organisms required a safe system of work based on good laboratory practice and good microbiological practice, backed by good standard operating procedures. Equipment needed to be well designed and appropriate for the purpose, and personal protective clothing was important.
Secondary containment features were good laboratory design and location with appropriate ventilation and security systems. Training was important, as were appropriate procedures for decontamination and waste disposal. The NIBSC had a safety code that all staff had to read and sign.
Another safety issue was transport, not only in the laboratory but also between sites. Each organism had its own problems of packaging, labelling and dealing with spillages.
Viral materials presented particular hazards, especially in vaccine production. Inactivated vaccines were potentially hazardous before inactivation and any tests for residual infectivity could result in the culture of a pathogenic virus. Specific problems included the use of an infectious challenge virus in rabies potency testing and the risk of vaccine associated poliomyelitis from oral polio vaccine.

Blood product safety

The safety aspects of handling blood products were determined not only by legislation but also by specific National Blood Authority regulations and policies and in-house departmental procedures, Ms MARGARET PATTMAN (bioproducts laboratory, NBA) said. Handling blood products required particular precautions because laboratory staff could come into contact with blood-borne viruses such as hepatitis B and C and HIV.
The NBA's comprehensive training programme included induction training, followed by repeat training if necessary and regular refresher training. The management of safety was based on restricted access to laboratory areas, appropriate use of personal protective equipment and procedures for dealing with spillages, accidents and waste disposal. Laboratory areas handling HIV positive samples adopted strict procedures using safety cabinets and robotic handling.
Accidents were recorded, and some would be reportable under the Reporting of Injuries, Diseases and Dangerous Occurrences Regulations 1995. Needlestick injuries and blood splashes were dealt with by immediate first aid treatment and referral of the member of staff to the occupational health department for hepatitis immunisation. It was important also to act on any "near misses" that occurred, so as to avoid any future problems arising.

Cytotoxic drug safety

The occupational health risks associated with sampling and handling cytotoxic drugs were irritancy, teratogenicity, mutagenicity and carcinogenicity, Professor GRAHAM SEWELL (department of pharmacy and pharmacology, University of Bath) told the meeting. Cytotoxic drugs were presented in a range of parenteral, oral and topical forms, each offering its own problems. These problems often started with the final container presented for analysis. Research had shown that up to 10 per cent of prefilled syringes were contaminated on the outside with the cytotoxic drug. Even vials received from the manufacturer could be contaminated on the outside.
For safe handling of cytotoxic drugs, one had to consider the potential routes of exposure. The main route was through the skin, but it could occur in other ways. Exposure of the eye to cytotoxic drugs could cause problems for those who wore hydrophobic contact lenses, which could absorb the drug and cause it to be slowly released into the eye.
In the hospital service, quality control laboratory staff were at risk of exposure, as well as cytotoxic preparation staff. Pathology department staff and others, such as porters, should be aware when they handled cytotoxic drugs and should know the appropriate precautions to be taken, particularly in the event of accidental spillage.
Factors affecting the risk from cytotoxic drugs included frequency of use and the irreversible nature of their adverse effects. The drugs were also odourless and hard to detect.
The principles laid down by COSHH were paramount. The risk should be assessed and avoided if possible. If it could not be avoided then it should be controlled. Training was important, as was ensuring safe working practices. Negative pressure isolators should be used when reconstituting drugs (as opposed to open laminar flow cabinets) coupled with the use of "closed systems" and the correct protective clothing. Staff should be aware that some drugs could vaporise, and aerosolised drugs could pass through HEPA filters.
Because of the large numbers of doses prepared by staff, a pragmatic risk-benefit analysis was needed in handling cytotoxic drugs. This would involve appropriate staff rotation with the exclusion of vulnerable staff, such as women who had become pregnant, and occupational exposure monitoring where possible. Careful consideration had be given to the design of protective clothing and the materials used. In any risk-benefit analysis there was a conflict between the protection of the finished product and the protection of the operator.
Health surveillance techniques included urine mutagenicity tests, cytogenetic testing and direct assay for cytotoxic drugs in blood and urine. However, these techniques lacked sensitivity and selectivity and their prognostic significance was unknown. Their use could cause to unnecessary anxiety and might even lead to complacency.