"Intravenous pharmaceuticals: stability in practice" was the topic for a meeting at the Royal Pharmaceutical Society's headquarters, London, on June 24. Held to review advances in intravenous therapy, the meeting was organised jointly by the Joint Pharmaceutical Analysis Group, the National CIVAS Group and the Society's Hospital Pharmacists Group
Speaking on ensuring the stability of intravenous pharmaceuticals used in high technology home care, Professor GRAHAM SEWELL (University of Bath) said that home care combined the therapeutic need for infusion with ambulatory care, thus freeing hospital beds. A hospital survey had shown that most patients treated at home were receiving cytotoxics, antibiotics or parenteral nutrition.
Miniaturisation of delivery devices had improved ambulatory care, but drug stability and compatibility were still issues. Preparation could be by a nurse on the ward, a carer in the home or a hospital pharmacy, either as a dispensed item or a "special". Aseptic dispensing in United Kingdom hospitals was probably the most regulated in the world and long shelf lives were needed to reduce nurse/ carer intervention and hence sepsis rates.
Stability trials should reflect storage, transport and in-use conditions using the actual device. It was important to know whether toxic products were formed. Infusion devices should be characterised for their physicochemical properties. However, the real issues were whether preparation was performed under a microbiologically controlled or uncontrolled environment, whether trained, validated staff or untrained staff were used and whether there was process and documentation monitoring or not.
The risks associated with the IV route had to be appreciated by all, including the regulators, who needed to understand the clinical issues. The current seven-day limit on aseptically prepared products under validated conditions was unhelpful.
Pharmacy-operated aseptic services
Describing the hospital and academic response to the challenge of IV therapy, Professor MIKE ALLWOOD (Derby university) said that the conflict between increasing demand for newer, safer and more convenient IV therapy and cost containment pressures was enormous. Saying no was not an acceptable option, but these developments in therapy meant that the gap between the manufacturer and patient needs was growing.
The pharmacy-operated aseptic service helped bridge the gap, both for hospitalised and home patients. Fundamental requirements to operate such a service included maintenance of sterility, extended shelf lives and drug delivery systems appropriate to the patient's therapeutic need. Staff protection was also crucial, particularly for cytotoxic drugs. The needs of the service were therefore appropriate products and information, particularly on long term stability.
Unfortunately, products on the market did not always allow patients' needs to be met. For example, the removal from the market of buffered benzylpenicillin, which had been comparatively stable when reconstituted, had left only the unstable unbuffered product. The stability of the same drug from different manufacturers might vary; and this problem was increased with the increasing proliferation of delivery systems. The research challenge was therefore to maximise shelf life, assess container risk, avoid physical incompatibilities and assess the effects of administration on stability.
There were conflicting commercial interests between the drug manufacturer, the device supplier and home care companies. Licensing considerations could make the problem worse and the compounding unit was left in the middle trying to meet the clinical needs of the patient, with little communication from the other interested parties.
Shelf life
Speaking on the European Medicines Evaluation Agency guidance note on the "Maximum shelf life for sterile products for human use after first opening or following reconstitution", Dr LINDA ANDERSON (Medicines Control Agency) said that the guidance note had first been discussed by the Committee for Proprietary Medicinal Products quality working party in June, 1995. It had not been until three years later, in July, 1998, that the single page note had come into operation. The guidance note had probably caused more correspondence than any other single guideline from the EMEA.
As the traditional MCA stance was that injections should be used within 24 hours of reconstitution, she had been surprised by the criticism of this stance when addressing a meeting in June, 1996. The first draft of the guidance notes issued later that month had sought to restrict immediate use to three hours, a proposal opposed by the MCA. The MCA's first priority was to maintain the status quo, but it was also aware from the June meeting that this caused confusion in hospital practice and effectively blocked manufacturers from supplying stability data, which would be of use to hospital pharmacists. This first draft had resulted in an enormous post bag to the EMEA. A second draft issued in June, 1997, had allowed 24 hours in a refrigerator and excluded radiopharmaceuticals and extemporaneously prepared products. However, there was still concern about the impact on hospital practice. The final draft, which had come into operation in July, 1998, clearly recognised that shelf life could be extended beyond 24 hours when reconstitution took place under validated conditions and allowed the manufacturers to provide stability information beyond 24 hours.
The conclusions from the development of the annex were that consultation was important, views were listened to, misunderstandings had to be clarified at the earliest opportunity and meetings between regulators, industry and hospital pharmacists could provide an important forum .
Quality of medical devices
Moving from medicines to devices, Mr JOHN ANDREWS (Lloyds Register) described the role of the notified body in assuring their quality. Directive 93/42/EEC required all medical devices for human use to be "CE"-marked by June, 1998. Medical devices covered a whole range of products including instruments, apparatus, appliances and materials. Active implantable devices and in vitro diagnostic agents were the subject of their own directives.
The role of the notified body depended upon the class of the device. A simple Class 1 device would be the subject of self certification following registration with the competent authority (the Medical Devices Agency). If a Class 1 device was used for measurement or was sterilised, the notified body had to be involved in that part of the process. Higher classifications required notified body involvement.
The manufacturer had to ensure that the device met the essential requirements, followed the appropriate conformity route, raised an EC declaration of conformity and then affixed the CE mark. The notified body ensured that everything had been performed correctly, including the classification of the device. The manufacturer could choose any notified body in the EU but the notified body had to be approved by the competent authority. The conformity assessment procedure would vary according to the class of product and might involve type examination, a full quality assurance system, with or without a design dossier, or product quality assurance. EN29000, the general quality standard, was supplemented by EN46000 which was specific to the manufacture of medical devices. The manufacturer needed to perform a risk assessment and set up a post-marketing vigilance system. Mr Andrews also discussed the drug-device interface and the roles of the MCA and notified bodies in this interface.
Evaluation of packaging
The practical considerations for the analysis of extractables from pharmaceutical containers were addressed by Mr JEREMY COOK (Covance). The main emphasis had come from the US Food and Drug Administration, which had issued draft guidance on the documentation required in drug applications for container/closure systems.
The packaging should protect and be compatible with the dosage form and be composed of materials that were considered safe with the product and route of administration. Importance was placed on protection from light, solvent loss or leakage, microbial contamination and water vapour. The product should not interact with the packaging and any extractives should be determined and their toxicological effects evaluated. The performance of the container to deliver the dosage form should also be assessed.
The safety evaluation consisted of exhaustively extracting the packaging components using solvents and characterising any extracted components using, for instance, gas or liquid chromatography linked to mass spectrometry (GC/MS or LC/MS). Their toxicity could then be evaluated either via a literature search or by experimentation.
When rubber closures were investigated, problems sometimes arose because the manufacturers could not access the original formula. However, despite obtaining numerous components when butyl rubber (for example) was vigorously extracted using organic solvents, nothing was obtained when it was extracted with aqueous formulations.
Once packaging had been approved for use, control of production had to be assured by batch release procedures. These had to be validated and a specification developed by analysing representative samples from a manufacturing campaign. Typical methods would rely on organic extraction followed by gas chromatography coupled with flame ionisation detection (GC/FID), as opposed to MS used during the development stages.
Discussing the industrial challenge in developing IV products, Dr ELSPETH GRAY (Abbott Laboratories) said that, while researchers approached stability challenges from a scientific basis, potential commercial and regulatory constraints also had to be considered, particularly the ability to comply with global regulatory standards to avoid costly repeat studies.
In 1995, Abbott had wanted to introduce vancomycin to the European market. Its chemical division had manufactured a bulk drug which was marketed in the United States as a "standard purity" pharmacopoeial quality product. At the time, however, the innovator and pharmacopoeias had been introducing a "high purity" product and so it had been important to meet this new standard. Commercially it had also been essential to match the innovator product by having a minimum shelf life of 18 months at room temperature and excellent appearance.
Registration stability studies had been initiated to cover the shelf life of the finished product and reconstitution and compatibility with recommended infusion solutions. However, the first experimental batches had shown unexpectedly poor stability, limiting shelf-life.They had also shown minor discolouration. While this was acceptable according to the global regulatory standards applied to this product at the time, Abbott had perceived it as comparing unfavourably with the innovator product.
Investigations had been instituted which had discovered trace quantities of the metal chelator EDTA in samples of the innovator's product. This led the company to investigate iron levels which, while low, were higher in the Abbott product than the innovator's.
Since the manufacture of the initial high purity batches, the bulk drug manufacturers had undertaken considerable process development which had improved bulk drug stability. This refined product had therefore been used to assess the impact of various formulation factors. Under accelerated conditions, none had had any significant effect on vancomycin stability, which closely matched that of the innovator, but EDTA had not had an effect on colour.
As the addition of EDTA was not favoured it had been decided to impose tight colour stability controls which had led to a stable product meeting both commercial and regulatory criteria.
Some of the legal aspects of pharmaceutical production and preparation were discussed by two of the speakers at the meeting, both of whom were solicitors.
Describing the main aspects of health and safety legislation, Mr RICHARD BRETTON (partner, Osborne Clarke) said that the Health and Safety at Work Act 1974 laid down the employer's duties to the employee, covering working environments, systems of work, information, instruction, training and supervision. Employers also had to provide safety information on the substances they supplied.
The Management of Health and Safety at Work Regulations 1992 required a risk assessment to be undertaken which identified hazards, assessed risk and identified control measures and priorities.
The Control of Substances Hazardous to Health Regulations 1999 covered prevention or control of exposure to specific hazardous chemicals. The normal control measure hierarchy was to eliminate their use; if this was not possible they should be isolated and their use reduced or controlled. Protection was a last resort. The control measures had to be maintained and tested, and exposure monitored. Health surveillance was also required. For toxic pharmaceuticals the problems included the lack of availability of maximum exposure limits (MELs) and occupational exposure standards (OESs), so in-house standards had to be developed. The Association of the British Pharmaceutical Industry issued helpful guidelines. Current discussions between the Health and Safety Executive and the Medicines Control Agency over cytotoxic preparations illustrated the problem of meeting all official regulations, some of which seemed contradictory.
The disposal of toxic pharmaceuticals was covered by the Environmental Protection Act 1990, which laid down a duty of care. It classified waste and placed a responsibility on the person disposing of the waste to decide if various licences were required or if consent were required from the Environment Agency, local authority or regional water company. Waste disposal should form part of the hazard risk assessment.
Discussing other legal issues affecting intravenous products, Dr PETER HARROWING (legal adviser, United Bristol Healthcare NHS trust) said that Medicines Act 1968 problems could arise from breaches of the licensing and labelling provisions or the supply of medicines not of the quality demanded. Storage of prefilled syringes and disposal of waste materials could cause complications under the Misuse of Drugs Act. Breaches of both these Acts were criminal offences - and the criminal law was being used increasingly where errors led to death.
The Consumer Protection Act 1987 laid down strict liability offences. The supplier was liable for damage caused by a defective product. Contract law covered breach of contract and damages for loss. It also covered the product's fitness for purpose, as did the Sale of Goods Act.
Negligence was the greatest risk area. Legislation laid down a duty of care which, if a breach caused injury, would result in damages. Tort was a breach of legal duty that could affect health workers if there was misrepresentation, particularly in holding out special skills. Acting beyond one's competence or lack of training could lead to a failure of the system and the risk of damages.
"Specials" were a complicated area. Liability depended upon factors such as who provided the formula and the role of the prescriber and manufacturer, not only under the Medicines Act, but also under contract law, the Sale of Goods Act and tort.
In this legal minefield the best defence was trained, knowledgeable staff, safe systems of work, adherence to standard operating procedures and good record keeping.