Record makers

If there's one number that the drugs industry fears more than any other, it's 483.

Pharmaceutical companies and their regulatory departments live in fear of having a 483 non-compliance notice slapped on their manufacturing operations by the all-powerful US Food and Drug Administration (FDA). Failing to comply completely with cGMP (current good manufacturing practice) requirements can mean the total shut-down of a plant until identified problems are rectified, with inevitable loss of profits and shareholder confidence.

Every extension to cGMP rules provides further potential non-compliance pitfalls. The regulation currently exercising the talents of the pharma industry's regulatory specialists is the snappily-entitled 21 CFR Part 11 regarding electronic records. First published in August 1997, it establishes the criteria by which electronic records and signatures are considered to be equivalent to their paper-based cousins.

Compliance with these rules is becoming increasingly important as electronic submissions of data for drug licensing are now encouraged by the FDA. It will accept all types of licensing application by 2002, and new drug applications have been accepted in wholly electronic format since February 1999. Most submissions now have at least some electronic component, and about 15 per cent are totally electronic.

The regulations affect every stage of pharmaceutical manufacturing, from lab analysis through to process operation. Manufacturing has generated mountains of paperwork. This paper audit trail is gradually turning into an electronic one. 21 CFR Part 11 will allow the mountain to shrink, but creates a whole set of new problems.

Time machines

All data have to be kept for at least ten years after a licensing application is submitted, so early analytical data must be accessible for at least 25 years after it was originally generated. With the wide range of proprietary operating systems today's machines use, it is unlikely that controllers or spectrometers a quarter of a century from now will be able to regenerate the original spectra or batch records from ancient data. The FDA has changed its wording to accommodate this sort of eventuality, replacing the word 'true' with 'accurate and complete' in the description of the electronic records that is required. This clearly establishes the fact that obsolete equipment need not be maintained to generate 'true' data.

It has been deemed sufficient to save the data in a format that means no information is lost, as long as it cannot be altered once saved. XML, or extensible markup language, is becoming the industry standard for such data storage. The files are ASCII-based, retaining the 'knowledge' in the data, and allow any data structure to be accurately represented. It is publicly-available, and the data are human-readable and self-describing.

One company that has been addressing the problem of saving compliant spectral data is Thermo LabSystems. Its eRecordManager package is designed for the storage and cross-referencing of data from different analytical devices. Unlike some systems, which produce merely an image of a spectrum, it gives access to XY data pairs so the spectrum can be regenerated from scratch. This means that if an FDA inspector wants the data to be expanded to reveal, say, the precise position of a chromatogram's baseline, it can be done. This would be near-impossible in a pictorial record such as a PDF file, as expanding the picture would blur the lines.

eRecordManager archives the original raw data from the instrument software and the normalised representation in XML. Both 2D and 3D representations of data structures can be visualised on a PC. Manufacturing, too, generates large amounts of data that need to be preserved for FDA inspection, and solutions providers have been looking at how they can integrate the needs of 21 CFR Part 11 into their software offerings. Honeywell POMS claims to be the only solutions provider to offer complete compliance, which it attributes to close work with former FDA employees who have helped the company interpret what the FDA wants when amendments are published.

All of Honeywell POMS' MES and CMS software is now fully compliant. Each data entry, for example, can be recorded to a historical log file, and into a relational database such as Oracle or SQL Server. It can then generate the required 'accurate and complete' copies of these data in both electronic and human-readable formats. The password-protected write-only historical log file captures users' actions as data. Intellution, part of Emerson Process Management, introduced a consulting service in August designed to help drugs manufacturers achieve compliance. Gaps in technology and processes are identified by Intellution staff, and specific recommendations provided to eliminate them.

The consulting service complements its compliant software applications, including iWorkInstruction, a compliant version of its batch control application iBatch, which enables operator actions to be captured accurately and securely. Records are stored as XML for easy integration into data repositories.