Instrument integration in pharmaceutical QA labs

Pharmaceutical companies are under relentless pressure to bring more drugs to market, more quickly, at a lower cost.

Thereafter, once a drug is released, increasing focus is placed on ensuring that production costs are minimised to ensure maximum return. Quality assurance laboratories provide the final verification of product quality (hence safety and efficacy) for the manufactured and distributed drug.

As such, they are the highest area of risk in terms of regulatory scrutiny, and the impact of mistakes could be catastrophic in terms of a product recall or regulatory action.

Typically, the types of analyses performed are similar (defined by regulation) for similar dosage forms and do not change regularly for any given product.

The most commonly utilised analytical techniques are HPLC (high performance liquid chromatography), UV-Vis (ultraviolet visible spectroscopy) and automated dissolution equipment.

The instruments perform analysis of samples and results are processed, stored and distributed by laboratory information management systems (Lims).

There is also limited application of scientific data management systems (SDMS) primarily for compliance purposes.

Electronic laboratory notebooks (ELN) have begun to emerge.

Surprisingly, most laboratories deal manually with data flows between the analytical instruments and these types of systems.

Automating the data flow can have significant benefits both within the laboratory and the wider organisation.

This document considers the detailed rationale behind this type automation, ie, integrating analytical instruments with Lims, SDMS and ELN.

What is instrument integration? (Much more than connectivity).

Instrument integration can be split easily into three categories: basic, standard and advanced.

In the basic category, connectivity is provided between the instrument in question and the target system (Lims, ELN or SDMS) for limited data such as raw results and data.

No application intelligence exists, nor is there any attempt to optimise or automate the analytical testing process that produces the results.

Some Lims, ELN and SDMS provide this limited level of integration natively.

In the standard category, the integration is bi-directional in that analysis requirements are downloaded to the instrument and instrumental results are processed, transformed and enhanced prior to storage in the target system.

In this way, the manual operations which the analysts performs in order to achieve the correct final results for reporting are automated and optimised to the appropriate level.

In advanced instrument integration, specialised algorithms and processes are applied to support specific applications like content uniformity, automated dissolution profiles and handling of unknown compounds by chromatography.

As you will see, increasingly significant benefits for automation exist as you move up the continuum from manual systems, through basic, standard and advanced instrument integration.

This document not only considers potential benefits in detail but also describes how to ensure that the resulting solution is effective.

Important business drivers.

The requirement to provide 'bullet-proof' drug quality is critical to the industry.

We can start with helicopter views of the impact of failing to do so.

In the past four years, the FDA has levied extensive fines to a number of major pharmaceutical companies for failing to perform to GMP requirements.

For example, Schering Plough signed a consent decree in May 2002 at a cost of $500 million following 13 inspections since 1998 where the FDA found significant violations of CGMP regulations related to facilities, manufacturing, quality assurance and laboratories Wyeth-Ayerst Laboratories signed a consent decree in October 2000 at a cost of $30 million because of failing to comply with CGMP regulations related to quality control.

Abbott Laboratories paid a $100 million fine in November 1999 for failing to comply with regulations related to process validation, process and production control.

In addition to these potential costs, the company can also receive significant negative effects from product recalls or from adverse events should the quality of the product be found not to meet standards.

The quality assurance and quality control laboratories are the final step in the production process which verifies whether the finished drug meets the specifications approved by the FDA when the drug was made available for sale commercially.

Let us now illustrate how instrument integration can eliminate potential errors and facilitate a 'bullet proof' quality system.

Benefits of instrument integration. Quality.

Compliance.

Reduced laboratory costs.

Standardisation quality.

Reduced errors.

Pharmaceutical companies are required by regulation to have extensive reviews of all quality related laboratory data.

Transcription errors generated in transferring the raw data to the calculated results, or from the laboratory notebook to the Lims are a major source of potential error.

It is essential that pharmaceutical companies adopt methods of reducing transcription errors.

The use of reliable instrument interfacing with Lims systems provides a significant route to reducing errors introduced through human mistake.

It is a generally accepted statistic that there is a 3% error in each level of transcription, which reduces to 0.5% with checking.

By removing the need for transcription, this source of error is eliminated. The full benefits may be somewhat less easy to quantify, for example reduced errors in reporting results also adds to the cost/benefit analysis.

The recall of a product batch could cost $150k per recall let alone any damage to a company image if the recall becomes common knowledge.

There is a strong message emerging from drug discovery companies and that is that they need to protect their existing investments in IT, while upgrading it to meet today's challenges.

In the late 1980s a Price Waterhouse Cooper report stated that as much as 80% of the information held by pharmaceutical companies was unstructured and not easily searchable.

Data from laboratory instrumentation would almost certainly have contributed to this figure.

Analytical lab managers struggling with the issue of data integration may well find that, irrespective of the particular Lims or analytical instrumentation they have available, instrument integration will take them along the path of fully functional data integration and management, without having to abandon existing tools.

Compliance. As of 20 Feb 2003, the FDA announced that it has completed the first steps of its broad initiative to improve regulation of pharmaceutical manufacturing.

21CFR Part 11 is the comprehensive piece of legislation outlining controls necessary for the pharmaceutical industry to use electronic records and according to the Society for Life Science Professionals, "Without careful interpretation, this can lead to over engineered solutions, introducing excessive QA burdens for validation without adding any benefit to the process or ultimate result".

Instrument integration however is a routine solution, and several systems have a proven track record of success in the pharmaceutical industry.

Once implemented, the automated approach to collecting analytical data does not permit any actions to be missed out, so ensuring adherence to laboratory procedures.

Reduced laboratory costs.

Based on real conditions from a working pharmaceutical laboratory, it can be estimated that to set up a run of 50 samples, entering all the sample details would take on average 15 minutes.

To report assay and impurities for the run, typing all the results into the Lims, checking the data transcription, calculating and checking the calculation and then reporting out the results would take one working day, bearing in mind that with an integrated instrument/Lims system that there is no double sample details entry, no data transcription, no manual calculation and therefore no information checking required, it is becoming very obvious that there are considerable time savings to be made.

Working on an estimated average analyst salary of $35/hr, without even considering lab overheads, it is apparent that there are also considerable financial savings to be made.

The greatest benefits will be seen in routine/high volume environments.

Whilst the actual saving generated will depend on the specific working practices of the individual lab and the volumes of samples analysed, there is not surprisingly a roughly linear relationship between the volume of results generated and time saved.

Lab automation is not a new phenomenon, but the concept of linking all automateable functions, is still not widely implemented.

This is in spite of the competitive advantages and bottom line gains that can be achieved through effective interfacing of instrumentation to Lims.

Instrument interfacing can be used to create a high degree of standardisation across a company.

The benefits of this are increasingly being recognised and can be readily implemented on a global scale potentially reducing operational expenditure across the company.

Since linking instruments to Lims can be implemented across remote sites, global roll out of procedures, control, reporting, training etc can be achieved from instrument to instrument and set up exactly to company specifications, lab to lab.

An additional benefit is that the integrated approach will promote corporate consistency and culture.

In addition, there is the potential for reduced training times across the company, as the same look and feel can be generated for all combinations of instrumentation and Lims. The instrument set-up and results reporting can be rolled out globally, requiring only one basic global training package. Standardisation in the way data are collected, treated and stored results in an increase in lab productivity.

Results are valuable to a company, as a form of intellectual capital, and the ability to retrieve this capital can allow organisations to respond effectively to changes in the business environment.

Conversely if rapid, accurate retrieval is not available, then time, effort and money may be wasted in redoing experiments and potentially losing competitive advantage.

This retrieval of relevant information can only be achieved if the linking system is flexible enough to handle all elements of the process.

There is thus a strong case for linking systems to 'mke the data productive'. Return on investment.

So how do you measure ROI? The direct cost savings are one area to consider, but probably the most overwhelming factor is that of compliance.

The cost of compliance is critical based on the estimated cost of delay to market of a fair to good drug being $1.5M to $5M per day.

The ability of a system to speed up the process of compliance in an auditable manner must therefore contribute to a tangible financial advantage.

Requirements for an integrated instrument/Lims system. The benefits of instrument integration can only be fully achieved if the integrating system results in the automatic operation being completely matched to all of the systems and protocols that the laboratory needs to run.

Selection of the method and software is more straightforward if those making the decision are fully aware of all the data and information flow requirements of the laboratory and those of the Lims.

The article 'What to ask, What to tell' (Lims/Letter, Volume VI, Issue III, September 2000) highlights that it is essential to have a complete understanding of the data and information flow requirements of the laboratory.

Several technologies will play a part in the decision making process including computer processors and storage, data acquisition and instrument control, a database engine, data communications network, procedural programming languages, report writers and formats and the system user interface.

The instrument integration software must be able to interface any instrument with any Lims, ELN or SDMS and be transferable in the event of either side of the interface being modified.

In this respect the architecture of flexible, configurable central software with interchangeable drivers has many advantages.

It allows any system to be linked to any other system and tailored to the lab's specific requirements.

One of the areas most commonly overlooked in the detail of the decision making process is that of the instrument interface, including analytical control, sample handling, data collection and treatment, automatic decision making based on results and reporting.

It is in this area that it is critical to be aware of all the requirements and seek input from a team of stakeholders including analysts, project managers, lab managers and software experts.

Given the potential for complexity, it is a strong advantage to collaborate with a vendor who has practical experience of how a laboratory operates and can understand what the specific needs of a given laboratory are.

Summary.

The majority of companies, for whom there would be a benefit, have not yet linked their analytical instruments to their Lims or ELN system.

This may seem surprising considering the demonstrable improvements that can be made in quality, compliance and efficiency.

It may be due to the lack (until recent times) of suitable products, combined with traditional heavy reliance on paper systems with pharmaceutical quality assurance.

The overriding element is the internal intelligence of the instrument integration software.

To handle every situation that might occur, the software needs to be of comparable sophistication to the Lims, the client/server chromatography data system (CDS) or instrument data analysis suite.

At the same time the users need something that is simple to use and flexible enough to meet their needs.

The benefits are clear.

Just make sure that you get a system that matches your detailed laboratory requirements.