Quality assurance and quality control of medicines

Quality assurance and quality control of medicines

Hospital manufacturing units

The manufacture of medicines is a complex operation and must conform to GMP requirements of the MHRA. These require a system of QA designed to build quality into each product at all stages of its manufacture. To this end, pharmaceutical QA services work closely with production staff and provide a series of checks, tests and controls throughout the manufacturing process as follows:

·      pharmaceutical quality systems

·      pharmaceutical risk management

·      microbiological and chemical testing, where appropriate, of ingredients, labels and packaging components, in-process samples and finished products

·      checking and approval of all standard operating procedures and production documents

·      environmental monitoring in clean and aseptic areas, validating processes, equipment and procedures

·      change control

·      corrective and preventive actions

·      product quality reviews

·      the performance of sterilisers

·      pharmaceutical development work, including formulation development, stability studies and manufacturing and analytical method development and validation

·      planned quality auditing at regular intervals

·      liaison with the MHRA.

Each manufacturing unit is required to be licensed under the Medicines Act, holding a manufacturer’s specials licence. A requirement of the licence is that there must be a named production manager and named quality controller for the release for use of all products manufactured in the unit. This is a key role for QA pharmacists and other appropriately qualified and experienced QA staff. Before releasing each batch for use, the quality controller has to satisfy him- or herself that GMP, as laid down in MHRA guidance, has been complied with, that all manufacturing and QC processes have been validated, that all checks and tests have been carried out and are satisfactory, that all documen-tation is satisfactory and that all other factors which affect product quality are satisfactory. This requires QC staff who are fully trained and competent in the quality, safety and efficacy requirements for pharmaceutical products.

Purchased medicines

Hospital pharmacists purchase medicines either through a system of contracts or through local purchasing arrangements with suppliers (see Chapter 3). QA pharmacists have an important role in advising procurement staff on the quality and suitability of commercially manufactured pharmaceutical prod-ucts purchased through the contracting system or purchased locally. Regional pharmaceutical QA services carry out work in assessing samples of products prior to contract awards. This includes medication error potential analysis, involving risk assessment of each product for its potential to lead to medica-tion errors in use. It can also include laboratory testing for compliance with standards, and for bioequivalence where appropriate, and assessment of the packaging and labelling for correctness.

Holders of manufacturers’ specials licences prepare unlicensed medicines or they may be imported from outside the UK. These products are frequently required for individual hospital patients with special needs when no suitable licensed equivalent is available.

Unlicensed medicines are not subject to the same controls as licensed medicines, and so special care needs to be taken during their purchase and use. The MHRA and regional QA pharmacists have issued guidance on these issues. QA pharmacists have a key role in assessing and approving suppliers of specials, in evaluating and, if necessary, testing the products themselves before use. They can also make an important contribution in training and advising pharmacists and other users on risks associated with unlicensed medicines and the standards and controls to be applied.

Quality assurance of pharmacy services

Owing to their detailed knowledge and experience of the application of the principles of QA and GMP to manufacturing and aseptic dispensing activities, QA staff have developed their services in the past few years to encompass other areas of pharmacy services. A particular area is in extem-poraneous dispensing activities. These carry a high risk to the patient if mistakes are made. The risk of error can be reduced or eliminated by the application of appropriate QA and QC systems. QA pharmacists have, in some hospitals, introduced systems such as QC of dispensing ingredients, independent QC checking of documentation and testing and releasing of extemporaneously dispensed products. Further developments have included issuing guidance on standards, facilities and procedures for dispensing operations and the introduction of internal and external audit schemes. It is hoped that the application of quality systems to dispensing processes and other high-risk areas of pharmacy practice will become universal through-out pharmacy services in the near future.

Quality assurance of aseptic services

Aseptic preparation units in hospital pharmacies prepare a large range of injectable and other sterile products for individual patient use, including addi-tives to infusion solutions, total parenteral nutrition (intravenous feeding) solutions, prefilled syringes and cytotoxic drug injections (see Chapter 6). Many of these products have a narrow therapeutic range and carry a very high risk to the patient if they are not made up correctly or if they become contam-inated with microorganisms. There are many reports in the literature describe ing errors when injections have been made up by nursing or medical staff on the ward. In order to minimise risks to patients, whenever possible these high-risk products should be prepared under pharmacy control in appropriate facilities where risk of contamination risks is known to be reduced. This approach was confirmed by the Audit Commission’s advice in A Spoonful of Sugar.

In 2007 the NPSA published patient safety alert 20 Promoting Safer Use of Injectable Medicines, which included a number of actions for healthcare organisations, including risk-assessing injectable medicine procedures and con-trols in all clinical areas, and developing an action plan to minimise high risks. As a result, there has continued to be a large increase in the activity of pharmacy aseptic units, with high-risk aseptic preparation activities trans-ferring to pharmacy control. Guidance on standards for aseptic services is given in the fourth edition of Quality Assurance of Aseptic Preparation Services. This describes standards for facilities, procedures and controls to be applied, and also includes useful guidance on the risks associated with aseptic prepa-ration, and the management of these risks.

A priority for pharmaceutical QA services is to work closely with these aseptic units to ensure the safety and quality of the products prepared. QA staff are routinely involved in assisting in the design of facilities, and in monitoring them using a series of regular environmental and personnel moni-toring techniques (see later in this chapter). They are involved in training aseptic unit staff and regularly issue advice and guidance on all aspects of QA in aseptic preparation. They are also involved in quality audit processes. In licensed units, the QA officer is named as the quality controller and has responsibility for releasing all products for use.

The continuing direct involvement of QA personnel with aseptic prepara-tion activities is a key future role for the QA service.

Quality audit

Quality audit is a systematic and independent examination to deter-mine whether quality activities and related results comply with planned arrangements and whether these arrangements are implemented effectively and are suitable to achieve objectives.

QA pharmacists have been involved for many years in the application of audits to license manufacturing units and other pharmacy technical services such as radiopharmacy. In the 1990s aseptic dispensing in unlicensed units was the subject of two NHS Executive Letters, EL(96)95 and EL(97)52. The former required hospitals to carry out an internal audit exercise and the latter set in place an ongoing system of external audits carried out by regional QA specialists every 12–18 months. These audits are reported directly to the chief executives of NHS trusts and to the commissioners of these services, with areas requiring action highlighted. The NHS Pharmaceutical Quality Assurance Committee has issued guidance on the training of auditors to undertake these audits.

The audit system in pharmacy services is now firmly established as a key component of the NHS clinical governance agenda. Audit aims to improve quality continuously, and to assist in the identification and management of risks and in learning from errors and near-misses.

Advisory services and research and development

Advisory services

The QA specialists’ knowledge of quality systems, pharmaceutical QA, audit and QC is utilised widely for advising pharmacists, other healthcare profes-sionals, health authorities, hospital trusts and primary care trusts.

Research and development

The pharmaceutical QA specialist has a key role in catalysing innovation and ensuring its uptake, as described in the 2008 government White Paper. As clinical practice changes there is a constant need for the development of new formulations and for determining their shelf-lives. R&D activity is therefore mainly focused around formulation and pharmaceutical development pro-jects and stability studies, although much other R&D work around analytical method development and validation, method transfer, bioavailability and compatibility with packaging components is carried out. R&D activities undertaken in NHS QA services are co-coordinated through the R&D sub-committee of the NHS Pharmaceutical QA Committee.

There is a particularly heavy demand for R&D activities associated with aseptic preparation of medicines, often involving complex mixtures of drug substances and drug-packaging component interaction.

QA personnel are increasingly involved in clinical research and good clinical practice, in particular in providing qualified person support to clinical trials and the releasing for use of investigational medicinal products. In 2009 the NHS Pharmaceutical Quality Assurance Committee issued guidance on pharmacy clinical trial activities.

Dedicated laboratory and controlled temperature and humidity storage facilities for both real-time and accelerated stability studies are usually avail-able in the larger laboratories and regional QA centres.

Testing piped medical gas installations

Standards for medical gas installations in hospitals are laid down in a health technical memorandum (HTM02-01). This covers the design, installation, validation, verification and maintenance of pipeline systems. Medical gases are classified as medicinal products under the Medicines Act, and the quality controller has responsibility for the QC of the medical gases supplied by the pipeline system. A register of quality controllers who are authorised to release medical gas pipeline installations for patient use is maintained by the NHS Pharmaceutical QA Committee.

QA personnel are regularly required to visit operating theatres, wards and other clinical areas where medical gas pipelines are used, to carry out testing of the identity, quality and purity of the gases prior to them being taken into use. The tests involve using portable equipment including paramagnetic oxygen analysers, infrared gas analysers, particle filter test units and chemical reagent tubes. A permit-to-work system is used for recording details of work performed.

QA staff are also involved in advising on suitable procedures for the handling, storage and control of medical gases.

Training pharmacy staff

QA staff are regularly involved in the provision of training on a wide range of QA issues to preregistration pharmacists and to other pharmacy personnel.

Defective medicines

Great care is taken to ensure that all medicines used in hospitals are of a suitable quality. However, occasionally defects are identified in medicinal products: this requires rapid and reliable action to determine the severity of the defect and its implications to the patient and to other patients who may be receiving treatment from the affected batch.

Defects may be reported by patients themselves, or by any healthcare professional. They may be relatively minor in nature, for example chipped tablets, or potentially very serious, for example suspected contamination of an intravenous injection. Systems are in place in all hospitals to communicate rapidly the details of the defect, and if appropriate to take the sample to the regional QA department for investigation.

In the laboratory, rapid response procedures are then initiated to investi-gate the defect, carry out laboratory testing if necessary, and to communicate the outcome of the investigation as appropriate. Serious defects are reported directly to the Defective Medicines Reporting Centre at the MHRA and, if it is considered necessary, a formal drug alert is sent to regional QA services to be communicated throughout the NHS. In serious cases the affected batches are withdrawn from use.

Laboratory services

QC laboratory facilities can be divided into two specialist areas: pharma-ceutical chemistry and microbiology.

Pharmaceutical chemistry facilities comprise areas for classical ‘wet’ chemical methods of analysis and gravimetric analysis, along with laboratory areas for a range of physical testing methods such as melting point, hardness, friability, disintegration and dissolution testing. Wet analysis includes aque-ous and non-aqueous volumetric analysis (although burettes have now largely been replaced by computer-controlled autotitrator systems). Other chemistry laboratory areas are dedicated to instrumental methods of analysis, such as spectrophotometry (ultraviolet–visible, Fourier transform infrared and atomic absorption), polarimetry, refractometry, subvisual liquid particle counting and chromotography (thin-layer, gas and high-performance liquid chromatography). The use of high-performance liquid chromatography in pharmaceutical analysis has grown enormously over recent years owing to the ability of this technique to separate and quantify mixtures of components in aqueous formulations. It is also utilised very heavily in pharmaceutical development and in stability studies since it can separate and quantify active drugs and degradation products produced on storage. Liquid chromatogra-phy–mass spectrometry is also used, for example for analysing cytotoxic drug residues, and a number of other techniques are under development for the analysis of monoclonal antibodies and other drugs of biological origin.

Analytical methods used in the laboratories are primarily pharmacopoeial, taken from the British Pharmacopoeia or European Pharmacopoeia or from other international pharmacopoeias as appropriate. However, in many cases no suitable official monograph exists, so in-house specifications are devel-oped and validated. The frequent changes in and development of new clinical treatments require the formulation and QC testing of new products and the ongoing development of new product specifications and analytical methods. This presents a variety of interesting challenges to laboratory staff, requiring a high level of scientific knowledge and the ability to apply it to new problems.

Samples entering the laboratory are many and varied, ranging from phar-macopoeial raw materials, in-process samples and finished products from hospital manufacturing units to samples of unlicensed medicines. These may have been purchased by hospitals from commercial holders of manu-facturers’ specials licences or may have been imported from anywhere in the world to meet a specific patient’s need. Samples may also be of any licensed medicinal product being assessed for its suitability for purchase, or may be the subject of a defective medicines report, referred to the laboratory for investi-gation. In many cases (such as in the case of suspected defective medicines) the analysis and assessment of the product are required urgently. It is therefore essential that suitable laboratory resources and expertise are available to deal with these when required.

A key area of work of the laboratories is R&D, covering a range of activities including investigational medicinal products, new product formu-lation and pharmaceutical development, analytical method development and validation, and stability studies. In many laboratories this work runs alongside other QC work with the same staff carrying out QC testing and R&D activities, but in some larger regional laboratories a separate R&D section with its own dedicated laboratories is in place. These dedicated R&D laboratories are mainly equipped with chromatographic equipment, especially high-specification computer-controlled high-performance liquid chromatography equipment utilising mass spectrometer, diode array, fluor-imetric, refractive index and other detectors, along with gradient elution programmers and autoinjectors allowing the equipment to be utilised 24 hours a day. Data generated are analysed by sophisticated data-handling software systems.

As a result of the wide variety of samples submitted for QC testing, along with the involvement in R&D activities, laboratory staff obtain a large breadth of experience in pharmaceutical analysis. As well as pharmacists, other laboratory staff are trained to graduate or higher level in chemistry, microbiology or an associated science. Opportunities exist for continuing professional development and many QC laboratory staff have undertaken external courses such as the MSc in Pharmaceutical Technology and Quality Assurance, run jointly by the NHS and Leeds University.

Pharmaceutical microbiology facilities comprise areas for carrying out a wide range of microbiological tests on pharmaceuticals and raw materials, such as total viable counts, incubation and reading of settle plates (and media from other environmental and personnel-monitoring techniques such as active air sampling, surface testing or finger dabs), organism identification, preservative efficacy testing and microbiological stability studies. There are also dedicated areas for carrying out endotoxin testing (using automated systems involving Limulus amoebocyte lysate) and dedicated aseptic facilities for sterility testing.

The quantity of work passing through the pharmaceutical microbiology laboratory has increased significantly over recent years, reflecting the large increase in activity of hospital pharmacy aseptic preparation and dispensing units and the publication of standards laying down high levels of monitor-ing. Each aseptic unit is required to undertake a programme of sessional, daily, weekly and quarterly validation and monitoring tests, resulting in large numbers of settle plates and other microbiological media, along with samples of finished products for sterility testing or endotoxin testing. Microbiology laboratory facilities have therefore increased in size and capacity in response to this increasing demand.

A key element of the work of the pharmaceutical microbiologist is the interpretation of the significance of the results obtained from the various tests performed and their effect on the quality and safety of aseptically prepared and manufactured products. This requires a constant awareness of trends in results for each aseptic unit, and the ability to react quickly and issue advice and guidance to the pharmacist supervising aseptic preparation if problems are found. Modern Laboratory Information Management Systems (LIMS), utilising bar-coding and direct data entry by laboratory staff, coupled with automatic trend analysis and electronic reporting to the aseptic or manufacturing unit, facilitate these processes.

The standard of laboratory work performed is of prime importance in all hospital QC laboratories. QA and other pharmacists, in making critically important decisions regarding release of batches of medicines for use in patients, rely upon all results generated, and so it is essential that all results are valid. Pharmaceutical quality systems are in place to ensure this is the case, including systems for staff training, supervision and checking, method validation, calibration, traceability of standards, documentation, internal QC procedures and participation in interlaboratory testing schemes. The Pharmassure scheme has run successfully in this regard for many years, with a large number of hospital QC laboratories participating. Many laborato-ries follow an ISO 9000 quality system model. Some laboratories are accredited by the UK Accreditation Service (UKAS) for compliance with ISO IEC 17025 standards. All laboratories associated with licensed manufacturing operations are subject to regular risk-based inspection by MHRA inspectors. The small number of laboratories associated with hos-pital units producing CE-marked medical devices are also subject to noti-fied body inspection.

Environmental monitoring services

Specialist QC staff are involved in the monitoring of hospital pharmacy clean and aseptic environments used for the manufacture and aseptic dispensing of medicines, along with other hospital clean areas such as ultraclean ventilation systems in operating theatres, clean isolation rooms in bone marrow units and hospital sterilising and disinfecting units. Portable monitoring equipment consisting of a range of physical and microbiological equipment is used.

Physical testing has several components: first, airborne subvisual particle counting, using laser-equipped particle counters capable of counting particles as small as 0.3 mm. A second aspect is air velocity measurements using an-emometers for calculating the rate of air exchange in clean rooms and for ensuring that devices such as laminar air flow cabinets and pharmaceutical isolators are operating within the required parameters. Air pressure differen-tial monitoring between different categories of clean rooms is undertaken using portable manometers. Filter integrity testing is carried out using dis-persed oil particle generators and photometric detection equipment to ensure that high-efficiency particulate air filters and their housings are not leaking. Finally, operator protection testing is carried out using potassium iodide discus equipment.

Microbiological monitoring comprises settle plate testing, active air sam-pling, surface swabbing, finger dabs and other techniques designed to monitor levels of environmental microorganisms in the clean aseptic area and to demonstrate whether acceptable levels are exceeded.

Owing to the specialised nature of this work, and the high cost of some of the test equipment, these services are often organised on a regional or group of hospitals basis.