In the twenty-first century, everyone operating in pharmaceutical QA/QC should be familiar with Laboratory Information Management Systems (LIMS). In pharmaceutical manufacturing particularly, they are ubiquitous. In R&D, the picture is more complex but they are nevertheless commonplace. The LIMS arena has experienced some headline changes recently and a keen awareness of the implications of these could prove invaluable in assessing both the system and the vendor.

These can be summarised as follows:

• The Use of Internet Technologies
• Compliance with 21 CFR part 11

Both issues are business pressures; the former is, of course, optional and offers process improvements and efficiencies, while the latter is mandatory.
For many pharmaceutical laboratories, the choice is now whether to upgrade or replace legacy LIMS, and also whether to harmonise on a single vendor. There is a bewildering choice of LIMS and LIMS vendors. In addition, many other software systems are capable of implementing functionality traditionally viewed as being within LIMS. For example, standalone systems exist for instrument integration and information archival. Many Enterprise Resource Planning (ERP) systems include functionality for storage of specifications and analytical results, together with support for sample tracking and disposition. Therefore, evaluation of potential vendors is complex and it could be anticipated that recent technological and regulatory changes will further complicate matters.
Internet technology is fashionable and fast moving but, to their credit, LIMS customers are on the whole demanding web-based tools for sound business reasons. The key driver is now delivery of the LIMS application via a browser on the desktop machine.

This architecture allows simpler and cheaper maintenance of client machines. It permits users of LIMS to access and interact with the system without the need for installation and maintenance of any software, assuming they already have an Internet browser. But perhaps most importantly for LIMS in pharmaceutical applications, it offers a high degree of assurance that the software (as implemented and validated) will remain unaltered and secure. This is due to the fact that all critical components can be installed on central server machines with access physically controlled.

The FDA Electronic Records and Electronic Signatures Final Rule (21 CFR Part 11, or 'Part 11', or even 'the Rule'), in force now since 20th August 1997, brought about a sea of change in laboratory compliance for several reasons.

Computer System Validation

The Rule mandates Computer System Validation. The recent FDA draft Guidance for Industry on the Part 11 rule focuses almost exclusively on validation. The responsibility of the end user to define system requirements is made starkly clear in this document:

"Without first establishing end user needs and intended uses, we believe it is virtually impossible to confirm that the system can consistently meet them."

Nevertheless, the vendor has a key role to play in not only in the selection, but also in the compliant deployment of complex mission-critical software. Many pharmaceutical companies choose to use the GAMP guideline for validation. Under this approach, LIMS is typically classified as Category 4 - Configurable Software Package. For such systems, GAMP specifies that a vendor audit is required to assess the quality of software development techniques.

To qualify as a validated system the vendor has to be able to demonstrate systematic, high quality software specification, development and testing methodologies, together with documentary evidence that they have been followed. Vendors that offer LIMS to the pharmaceutical market will have undergone many such audits. For the end user to document information on design, testing and traceability is neither necessary nor desirable in cases where this has already been done to a high standard by the vendor, provided evidence of this is available.

Confirmation that the vendor works to sound and well-documented standards is essential for two practical reasons. Firstly, it is necessary for compliance. Post-hoc testing of software that was not produced to pre-approved specifications will not meet the FDA definition of validation. Secondly, such post-hoc acceptance testing of software means companies run the genuine risk of investing large amounts of effort only to detect an unacceptable level of critical defects.

An additional advantage of purchasing from a vendor who adopts sound software testing procedures is that the vendor may market some of this collateral for use in end user acceptance testing (Performance Qualification). Automated test suites are particularly useful in this context.

For all these reasons, the optimum strategy for a pharmaceutical LIMS customer is to attempt to ensure, prior to their purchase decision, that the vendor will pass the software supplier audit.

Of course, regulatory compliance required software validation prior to Part 11's introduction, although Part 11 enforcement and guidance has increased its profile. Part 11 has, however, pushed the boundaries of what the pharmaceutical laboratory must achieve in other respects.

Technical Compliance

A second area of impact is technical compliance with the Rule. Part 11 compliance includes procedural controls and training, in addition to software controls. In light of this, potential LIMS users should be wary of vendors who claim their LIMS is compliant. Nevertheless, technical compliance of the software is critical. The rule specifies many individual controls regarding both electronic records and electronic signatures and these are well documented and discussed elsewhere. In evaluating software, technical compliance should be assured prior to purchase. There is no simple route to achieving this assurance. In fact, it necessitates the evaluation of the software against a checklist derived from the Rule and the confirmation of technical compliance with all the relevant controls. Of course, the chosen vendor must participate in this. Indeed, the vendor may be willing to undertake the whole process. However, reassurance will only be provided by involving someone who understands the Rule and is independent of the vendor, whether an internal validation specialist or an external consultant.

The publication of the draft FDA Guidance for Industry [1] was followed in October 2001 by a Comments document from the PhRMA. This document details some of the issues which are delaying Part 11 compliance, and proposes a phased approach to full compliance based on feasibility, cost and risk. Manufacturing LIMS and QA systems are positioned second in terms of perceived risk or benefit to public health, second only to manufacturing batch records. In addition, although by no means trivial, the technical controls necessary for compliance as applied to LIMS records should have been added by vendors, considering the fact that the rule has been in force since August 1997. Therefore, by the PhRMA criteria and taking risk and feasibility into account, Part 11 compliance in the Manufacturing LIMS arena should by now have been achieved or else have extremely high priority status.

Electronic Record Management

There is a third area impacting on LIMS and highlighted by Part 11, which is electronic record retention. There are occasions when an instrument is linked directly to a LIMS terminal and the first analytical record manifestation written to durable media is a LIMS record. This is rare, however. Almost as infrequent are cases where a paper record is the primary analytical record, which is then transcribed into the LIMS. The typical scenario is where the primary record is an electronic record produced by an instrument. Prior to Part 11 this record would be printed on paper and transcribed into the LIMS, or else result information would be parsed electronically into the LIMS. Neither approach is compliant with the Rule, which mandates the retention of the entire electronic record (or else an "accurate and complete" copy) for the record retention period specified by the predicate rule. This area is made more complex by the wide variety of electronic records (often in proprietary format) that are also subject to the Rule. Proprietary record formats that can only be rendered human-readable by a specific software package (and specific version and operating system and hardware platform) will not satisfy the requirement for electronic record keeping over a lengthy and indefinite period.

This is an area outside the conventional scope of LIMS, but nonetheless intimately connected with core LIMS functionality for analytical record management, and therefore vital for Part 11 compliance. It is essential that LIMS vendors with pharmaceutical customers are aware of issues concerning long term archival and have plans to address them. One approach is to develop software functionality for archival/electronic record management that integrates with the LIMS.

In Summary

To summarise, this has been a brief overview of recent factors affecting the LIMS arena. Its intention is to provide a useful background for those seeking to acquire or upgrade their LIMS application. There are also critical success factors in a LIMS selection and implementation that remain unaffected by recent technological and regulatory changes. Recent changes do not alter the fact that, as with any major software project, the failure rate is much higher than the rate of success and those 'people' issues outweigh the technological. So in vendor evaluation, it cannot be overstated that availability of experienced and qualified people, who understand the business as well as the technology and the software, may well be the single most important success factor.

References

Author Biography

* An edited version of this article appeared in the Feb/March 2002 edition of Pharmaceutical Formulation & Quality magazine.