The value of increased sterility assurance in compounding is ensured patient safety, and the need to have robust bio-decontamination processes, rapid transfer protocols and an ergonomic aseptic processing environment is becoming increasingly important
Mark Oldcorne BSc (Hons) Pharm
Principal Pharmacist, Quality Assurance,
Betsi Cadwaladr University Health Board, UK
Email: [email protected]
The overarching concern of the hospital aseptic services pharmacist is patient safety, with the two greatest areas of potential risk being the bio-contamination of medications and prescription errors. Yet the modern hospital pharmacy faces many challenges. Increasingly rigorous regulations, requirements for individualised patient prescriptions, the need to develop batch production to improve efficiency and changes in the types of therapeutic prescribed are all creating added pressure on the pharmacy environment. Reviewing traditional working practices and implementing process improvements that help to make pharmacies more efficient and effective have become essential.
Tightening regulatory environment
For patient safety, it is crucial that pharmaceutical compounding take place under strict aseptic conditions. There are clear regulatory expectations for the total particulate and microbiological control levels in aseptic preparation environments. Risks of bio-contamination are increased where sterile medicinal products or ingredients are opened and exposed for compounding.
In the UK, hospital pharmacy aseptic processing units may operate under a Manufacturing Licence – Specials (MLS), enforced by the Medicines and Healthcare products Regulatory Agency (MHRA). This allows compounding and storage of medicinal products for extended periods, typically up to 90 days for aseptic products. As products can be stored, process efficiencies can be achieved by producing large batches of standardised products.
Regulatory requirements for MLS units are becoming increasingly rigorous, with the aim of bringing the pharmacy environment in line with the EU Good Manufacturing Process – GMP Annex 1 requirements for pharmaceutical manufacturing. This creates challenges for many hospital pharmacies as equipment becomes older and funding limited but substantial investment may be required to update or renew.
Other units operate under Section 10 of the Medicines Act. In these cases, audits are carried out by a regional quality assurance pharmacist. Section 10 units are restricted to storing compounded products with a maximum expiry of seven days, in effect limiting units to on-demand processing. The reduced ability to pre-process batches of product means more individualised processes are required. This, in turn, creates a higher potential risk for contamination or error, and greater process inefficiencies. Where batches can be produced, final sample testing can confirm compounding is correct. With individualised prescriptions, there is a reliance on accurate compounding paperwork, with no prospective chemical or microbiological assay.
Units therefore need to weigh up the challenges of meeting Annex 1 requirements against the potential safety and efficiency benefits of working under MLS licence.
Bio-contamination control and monitoring
People are the greatest source of contamination during the aseptic processing of medications or sterility tests. Reducing direct personnel intrusions into the processing zone has significant benefits to bio-contamination control. Isolators are therefore routinely used for compounding in all but a few UK hospital pharmacies, providing product, environment and personnel protection. However, practices vary across Europe.
Bio-contamination control traditionally relies on manual cleaning with alcohol spray. However this ‘spray and wipe’ technique is inconsistent, being open to operator variance and verifying any meaningful log reductions in bioburden across the entire environment is problematic. Most significantly, alcohol spray is not sporicidal. Although the alcohol itself may be free from spores as a result of irradiation, it will not kill bacterial spores present on the surfaces of products undergoing sanitisation. The technique cannot therefore reliably deliver Annex 1 compliance.
GMP Annex 1 specifies that EU Grade A/ISO 5 critical zones of isolators have a microbiological control requirement of less than one colony forming unit (CFU). Less than one CFU is effectively zero-detected bio-contamination events, meaning that the detection of bio-contamination (one or more than one CFU) is significant and needs appropriate investigation. The time and cost of the required investigations creates added pressure and has implications for process inefficiencies.
A major challenge to maintaining an aseptic processing environment occurs when transferring materials in and out of the isolator environment. Gassing has been used as an effective agent to kill bacterial spores during the transfer process and for the sanitisation of isolators. Traditional gassing methods are slow – batch processing taking up to six hours. Where time constraints dictate or large batch processing is not an option, gassing may be by-passed for ‘spray and wipe’ techniques, with subsequent implications for bio-contamination control.
Operator strain can also be a key cause of contamination and error, due to the need for repetitive movements and consequent fatigue or repetitive strain injury (upper limb disorders). This can lead to the risk of positive tests and subsequent time-consuming investigations.
Developments in therapeutics
As pharmacists, we play an important role in policing patient prescriptions to ensure they are clinically correct, dosed accurately and compatible with other patient medications. UK studies have shown that errors in the preparation of intravenous drugs on wards can occur in up to a 50% of cases.(1) Many manipulations that could be carried out on the ward are undertaken in the pharmacy by preference in order to ensure safety and accuracy.
With products such as total parenteral nutrition and centralised intravenous additive service traditionally compounded in the pharmacy, efficiencies can be achieved through batch processing. However, developments in personalised or stratified medicine have led to an increased need for the compounding of medications in the pharmacy to meet specific patient requirements. Cytotoxic drugs, such as those used for oncology medications, are compounded to meet the needs of the individual, with a patient’s weight or body surface area often being a key consideration. Products often need to be prepared for immediate use.
As well as maintaining the aseptic technique required for sterile compounding, practitioners must take extra care when working with cytotoxic compounds. It is vital that the drugs that can be toxic to healthcare workers be prepared safely. This often requires dedicated aseptic environments.
Recent years have also seen a boom in high-cost antibody-based therapeutics and active biological products that have short shelf lives. These protein-based medicines also require careful handling to avoid their denaturation. Although these can be compounded on the ward, their high value means that they are more usually made up in the pharmacy to reduce the risk of errors or wastage. The changes in therapeutic type and the way in which they are administered have created the need to handle smaller individualised ‘batches’ in the aseptic processing environment. Consequently, more frequent set-up and clean-down of isolators is required, slowing production processes.
The need to have robust bio-decontamination processes, rapid transfer protocols and an ergonomic aseptic processing environment is becoming ever more important.
Greater efficiency and effectiveness
Advances in rapid gassing technology offer significant process improvements, supporting fast transfer protocols, reduced downtime and improved sterility assurance. Within the NHS there have been a limited number of hydrogen peroxide vapour (HPV) rapid gassing systems implemented with substantial benefits.
HPV – produced by vaporising aqueous hydrogen peroxide – has been validated to demonstrate a 6-log reduction of bioburden within the cleanroom enclosure (Figure 1). A 6-log reduction provides a 99.9999% reduction in bioburden on critical surfaces. Most importantly, HPV is sporicidal and proven to be effective against a wide range of environmentally associated nosocomial pathogens, including meticillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile, vancomycin‑resistant enterococci, Klebsiella, Acinetobacter and other Gram-negative bacteria.
There are a number of proprietary HPV systems available, such as that from Bioquell, which offer technology ensuring a uniform distribution of HPV throughout an enclosure.
Vaporised hydrogen peroxide molecules are only delivered to surfaces at saturation point. An even microcoating (2–6μm) of the active agent on all surfaces triggers the rapid onset of bio-decontamination. Controlled removal converts the hydrogen peroxide to water vapour and oxygen leaving the surface completely free from HPV residue. As the process is not ‘wet’, it can be as safely applied to a variety of materials including electrical equipment.
This gaseous vapour phase decontamination process can be achieved in a rapid 20-minute cycle (depending on target area, size, load type and starting environmental conditions) and has been recognised as a method of achieving surface sterilisation by international regulators. GMP Annex 1 can be routinely achieved, both reducing risks to patient safety and unnecessary investigations into bio-decontamination deviations.
Data from finger dabs, the main indicator of bio-contamination failures during transfer, have demonstrated a significant reduction in contamination events since using HPV technology. Using alcohol decontamination methods, a failure rate of 3-4% is not uncommon, with HPV this has been reduced to <0.1%. With every individual finger plate with a single CFU requiring investigation, even a small number of incidences have considerable time implications. Reducing the number of these investigations consequently reduces the resource required for data analysis paperwork and quality risk management. It also reduces the cost implications associated with destroying expensive batches of product unnecessarily.
An ideal hospital aseptic department would be designed for sterility assurance incorporating an HPV gassing component as the only way of consistently achieving GMP Annex 1 compliance with confidence. As well as reducing costly bio-contamination investigations, compliance enables efficiencies through the ability to batch process and store product.
The flexibility to handle a range of product types and batch sizes (for example, from 1ml to 5l containers with concomitant pump systems) with rapid gas transfers is also a key requirement. Fully optimised cycle times can then be achieved, leading to reduced downtime and improved process efficiency.
An ergonomic aseptic processing environment would reduce the risks of operator strain and error. While a modular system would allow isolator units dedicated to different applications to be integrated, for instance, negative airflow for operator protection and positive airflow for when product protection is required.
New systems coming onto the market (such as the Bioquell QUBE) promise to address these requirements. Combining unique modular isolator technology with fully integrated HPV technology offers the possibility of a complete aseptic processing solution for hospital pharmacies, and ensures compliance with the bio-contamination levels required by regulatory bodies.
Insightful solutions are required for the efficient handling of individualised prescriptions. Currently, each individual patient prescription is transferred into the processing environment separately along with an associated worksheet. Systems should offer the potential to further speed the process by transferring multiple prescriptions in a single gas transfer. By maintaining separation of prescriptions using a track and trace ‘cage’ system, it could be possible that four patient prescriptions can be sterilised in an approximate 20-minute cycle (Figure 2). A workstation would therefore facilitate the processing of individual patient prescriptions as well as batches.
The pharmacy of the future
When investing in new technologies for process improvements in the pharmacy environment, it is important to look to the future. The promise of further developments in personalised medicine and the potential application of gene therapy will require further adaptation of pharmacy processes. The flexibility of modular multi-functional units is required, which can be integrated easily into existing processes to meet new challenges. It is critical to work alongside solution providers who are able to understand the process requirements both now and in the future.
Introducing new systems and processes into the pharmacy environment can require validation; this can be alleviated considerably by working with a single manufacturer that can support the complete validation process and offer proven validation rationales developed across different scales of process. The degree of penetration of HPV into the packaging systems used in the hospital pharmacy also needs to be validated. Independent studies are underway to determine the clinical implications of such penetration.
The initial cost outlay and resource implications of revising processes can be a point of contention. However, it is important to consider the potential time and cost savings of a system with improved sterility assurance. Reduced time spent investigating environmental deviations offers considerable efficiencies.
Coming back to the overarching concern of the pharmacist, what is the value of increased sterility assurance – the answer is, ensured patient safety.
- Taxis K, Barber N. Ethnographic study of incidence and severity of intravenous drug errors. BMJ 2003;326(7391):684.