In an increasingly competitive industrial environment, UKpharmaceutical companies are introducing new strategies andtechnologies to improve the efficiency of analytical laboratories insupport of R&D and production. Joseph Chamberlain reports from aone-day symposium organised by the Joint Pharmaceutical Analysis Groupat the Royal Pharmaceutical Society’s London headquarters on 16 October2008
In an increasingly competitive industrial environment, UK pharmaceutical companies are introducing new strategies and technologies to improve the efficiency of analytical laboratories in support of R&D and production. Joseph Chamberlain reports from a one-day symposium organised by the Joint Pharmaceutical Analysis Group at the Royal Pharmaceutical Society’s London headquarters on 16 October 2008
The quality control (QC) laboratory, in both the R&D and operations environments, is a key element of the supply chain and has a significant impact on lead times, affecting speed of drug development and overall site manufacturing performance.
As the UK pharmaceutical industry faces ever-increasing competition from abroad, the enhancement of laboratory productivity to improve the product-process development cycle and manufacturing efficiency has become even more crucial for the long-term viability of UK-based sites.
This symposium reviewed advances in laboratory efficiency which, both individually and collectively, are designed to achieve these outcomes, through the adoption of process-based improvement tools, automation and integrated data handling within the laboratory.
Improved efficiency in the testing laboratory may often be thought to lie in the implementation of new technology or in the application of automation. However, the first two speakers in the symposium emphasised that greater thought about working practices could bring about dramatic improvements.
Improving a QC laboratory
“A place for everything and everything in its place” was one of the themes of a presentation by Duncan Handysides, of Sanofi-Aventis, describing operational improvement in a high-volume solid-dose QC laboratory.The QC function at the company’s Fawdon site comprises 41 staff covering intermediates, finished product and raw materials testing, raw materials sampling, stability, packaging inspection, technical support, and reference standards. It also has a dedicated process improvement officer.
A management initiative, dubbed the Fawdon Focus, is an improvement programme using a common approach of learning by doing. Being a team approach, it can only succeed with everyone’s involvement.
Mr Handysides first demonstrated how basic good housekeeping — reagents labelled appropriately and stored in labelled locations, for example — was a simple but effective route to improved efficiency.
The second theme was to address the seven areas of potential waste:
- idle time
- operator movements
- poor quality
The success of the project was demonstrated by experience with an immediate-release product. A major challenge was in lead-time adherence. A multidisciplinary team was selected, which assessed current trends and set targets and goals.
The target was to reduce the lead time and minimise the work in progress. Sustainable, robust methodology was required to achieve improvements in quality, cost and delivery. The results of the campaign were more than satisfactory.
The original target had been to reduce lead time from nine days to five, but the actual achievement was reduction to one day.
Lean manufacturing or lean production (often known simply as “lean”) is the practice of a theory of production that considers that expending resources for any means other than the creation of value for the presumed customer is wasteful and a target for elimination.
For several years lean methodology has been used in routine manufacturing industries such as the automotive industry, said Kanny Claire in his description of how the analytical laboratory of the drug delivery systems division of 3M pioneered lean implementation in an R&D environment.
As well as taking advantage of advances in technology, the move was thought necessary to maintain market competitiveness, cheaper and quicker products, to improve quality and to promote growth.
To initiate the process, the stakeholders needed to be committed to a well-defined vision, which in its turn was developed from workshops focusing on key areas requiring improvement.
The initial output from these workshops in analytical R&D was an improved testing process, with reduced time required for routine testing. Non-project activities were managed within technical functions, with a new group created to prioritise, co-ordinate and resource non-project activities. Work scheduling, allocating and tracking were improved.
A training schedule was introduced with cycling times that reduced the time for training new recruits.
Other planned R&D workshops are expected to improve clarity of roles and availability of support or information to enable documents to be approved quickly. Improvements will be expected in automation of data transfer between electronic systems, and reduced time spent on monitoring and cleaning.
Standards would be maintained when introducing new facilities such as an electronic system for managing inventory.
Further application of lean thinking is planned across R&D in the future as the 3M organisation aims to be the favoured provider for drug delivery solutions across the pharmaceutical industry, concluded Mr Claire.
Rapid microbiological methods
Process analytical technology could revolutionise the control of the quality of pharmaceutical manufacturing processes, said Paul Newby, of GlaxoSmithKline. It achieves real-time or rapid feedback controls, focusing on
- prevention of poor quality, at-line, on-line and in-line measurement of performance attributes
- greater insight and understanding of processes
- the potential for significant reduction in production (and development) cycle times
- reduced regulatory concerns
- the feasibility of remote inspection strategies
However, said Dr Newby, the pharmaceutical industry is conservative, as are microbiologists. Pasteur and Koch would recognise the procedures for microbiological testing in today’s laboratories. Because assays typically require several days of incubation, conventional microbiological methods cannot deliver real-time data. The problem is to replace 19th century thinking with 21st century capabilities.
The first phase of this exercise comprised technology evaluation and development of the implementation strategy, with the focus on post-regulatory approved non-sterile products as a reasonably economical model for evaluation, considering the high costs of regulatory licensing.
For rapid microbiological technologies GSK has identified adenosine triphosphate bioluminescence and solid phase laser cytometry as viable methods. The second phase was to establish the new technologies with the regulators, and useful contacts have been made with the US Food and Drug Administration and the European authorities.
Thus, claimed Dr Newby, GSK has been instrumental in implementing new technology in manufacturing processes by providing an effective blueprint or framework offering guidance on implementation and defining specific acceptance criteria for biological systems.
GSK continues co-developing product and process applications for novel technologies and existing rapid techniques within their product and R&D portfolios.
Laboratory automation is in demand to support ongoing initiatives such as quality by design and parametric release. Automation will be increasingly used in early product development, but current technologies are too slow and have too high a validation burden.
The traditional view of laboratory automation for solid dose formulations is that it is limited to the later phases of drug development. There are two main reasons for this view, said Jon Faulkes, of AstraZeneca. Large numbers of samples are only produced in late phase stability programmes (and release), and the validation burden for current technology is high and only justifiable for compounds later in development and, therefore, less likely to be wasteful on failure of the project.
The first step in pharmaceutical analysis is often extraction of the analyte from the test sample. As testing requirements evolve, a generic extraction technology is needed to meet such new testing requirements. AstraZeneca has collaborated with industrial partners in two areas to develop such a generic extraction technology.
A collaboration with Covaris is based on adaptive acoustics. In this technology, acoustic energy is applied to a sample, causing bubbles to form; when the energy is removed the bubble collapses and an intense, localised jet of solute is created. This jet travels over a very short distance but at a very high velocity. It is a simple but effective extraction process.
A collaboration with RTS Life Sciences uses a sample extraction technology based on BioPrep’s Big Prep DNA lyophilisation system. The technology needs to be able to extract the analyte from immediate release, extended release and encapsulated formulations.
In addition, as the system would be used on early-phase formulations, the technology needs to be forgiving of formulation variants that are sub-optimal, such as hard tablets or tablets with a high moisture content.
The results from both systems showed that extraction times could be significantly faster than both the manual process and the timings achieved in current automated systems.
In addition, the true parallel processing capability demonstrated by the RTS system would lead to significant efficiency gains. The Covaris adaptive acoustic system has potential but may be limited by applicability for all solid dose formations and the solubility of the active ingredient.
Although some issues are yet to be solved, the future of this technology platform is encouraging and future systems, based on the same extraction technology, will have an increased throughput, claimed Mr Faulkes.
GSK’s chemical development facility provides specifications, synthetic routes, methods, and active ingredient for clinical trials and production, and generates and submits documents for regulatory approval.It has more synthetic chemists than analysts and because high performance liquid chromatography (HPLC) support was varied, time-consuming and expensive, a walk-up generic HPLC station was started to handle simple problems for chemists.
Rising workload and constrained resources in analytical chromatography, however, continued to raise pertinent questions, said Bill Young, of GSK.
- Does the analyst need to do even the sophisticated measurements?
- Is it possible to improve the management and use of an increasingly large number of methods and columns?
- Does each new project really need bespoke methods?
- Can time and costs associated with analytical chromatography be better managed?
Recognising that 80 per cent of the demand was met by 20 per cent of the chromatographic set-ups, a reduced set of methods and columns could be identified for use by chemists for reaction monitoring and impurities analysis.
The main principles to be borne in mind are that instruments must be available when the customer needs them and user-friendly, while also being under control. The instrument has for be fit for purpose with appropriate blanks and test mixtures.
Thought needed to be given to analytical modules, spares and consumables, and to computer hardware and software. A tiered set of walk-up systems was eventually developed to allow the chemists to drive their work forward.
Analysts are used when specials are needed, or when the work is done under good laboratory practice or good manufacturing practice. The chemist enters nine pieces of information and submits the sample under suitably defined conditions and receives an e-mail containing the results of that measurement.
This instrument system manages a multilevel queue of samples to run and has automated start up and shutdown procedures. For access to the data in the laboratory, the chemist can easily access the report in PDF format at the instrument.
More recently, a data viewing system was added to allow for greater ease of data access and data sharing. Today, there are more than 60 instruments worldwide across eight sites, and 200,000 samples were processed by this set of instruments in 2007.
To support these, a large effort towards standardisation was started several years ago and continues today.
It had been hard work to get here, but it was a good place to be, concluded Mr Young.
Electronic laboratory notebooks
Considering the impact computers have had on every aspect of life and the considerable advantages which are evident, it may be considered surprising how little inroads electronic notebooks (ELN) have made into the analytical laboratory, said John Trigg, of phaseFour Informatics Ltd.
Organisations that have implemented ELN claim to be making time savings in the order of 10–15 per cent, with an improvement in operational efficiency of about 20 per cent.
Improvements in personal productivity have also been claimed and anecdotal evidence points to additional, non-quantifiable benefits, such as
- more time in the laboratory
- easier write-ups
- improved protection of intellectual property
- a searchable archive
- increased efficiency and improved data quality
- smooth transitions when people leave the company
- use in informal meetings
The barriers, however, are not in the technology, but may be found in legal, patent and regulatory considerations. There are also matters of long-term data preservation, electronic records management, user acceptance and, inevitably, costs.
The legal barriers may be coming down. For example, it is now accepted in the US that electronic records should be admissible as evidence in interferences before the Board of Patent Appeals and Interferences to the same extent that electronic records are admissible under the Federal Rules of Evidence. The weight given any particular record necessarily must be determined on a case-by-case basis.
Long-term data preservation has several problems related to the file format, physical life of the electronic media, and future availability of current hardware and software.
Nevertheless, Mr Trigg suggested that there are no basic business reasons for continuing to use a paper laboratory notebook.
ELN may be the last piece to be added to the laboratory’s systems portfolio, but it may also be the start of a new era of integration and collaboration. As can be seen in social networking systems such as Facebook, the focus has shifted from applications to content.
Breaking the paradigm of an application-centric approach is a key requirement. The advent of ELN can be the catalyst for a new era of collaboration in science, concluded Mr Trigg.
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