A discussion about regulations would be incomplete without including 21 CFR Part 11 regulations of electronic records and electronic signatures. In 1991, industry and FDA representatives met to determine
how to accommodate paperless record systems under 21 CFR Parts 210 and 211. Specifically, industry requested FDA's official position on substituting 21 CFR Part 211, section 186 "full signature, handwritten" with an electronic signature (12). In response, FDA publshed its progress
report Electronic Identification/Signature Working Group in 1992 (13). The report identified seven key issues: legal acceptance, regulatory acceptance, enforcement integrity, validation
and reliability, security, standards, and freedom of information. The final regulation was published in 1997, and although
the regulation is now 10 years old, discussions and issues still revolve around most of these points. Former FDA Commissioner
David Kessler is believed to have said that he was surprised by the number of experts he found when he searched the topic
of Part 11 on the Internet, especially because FDA was still trying to address and develop a better understanding of the implementation
and enforcement of the regulation. Even more interesting in hindsight is how the initial request for FDA to address a specific
section of 21 CFR Part 211 has now evolved and encompassed all other aspects of the GMPs.
Even now, some uncertainty about Part 11 regulations remains. A contributing factor to this confusion may be the fact that
earlier FDA guidelines on the regulation were revoked in 2003 (14) and replaced by a single guideline (15) with the intention
of adding other guidelines later. FDA's reasoning behind withdrawing these guidelines (Fed. Register, Docket 00D-1540 in Feb. 2003) was "to avoid loss of time spent by industry in their efforts to review and comment on Part
11 issues that may no longer be representative of FDA's approach under the new GMP initiative." Since then, no additional
guidelines have been issued, but FDA is working on a Part 11 amendment (16).
Perspective on the industry's approach
While FDA published its official regulations and guidelines, the industry also was actively addressing computer validation.
In the late 1980s to the early 1990s, the Pharmaceutical Manufacturers Association (PMA, now Pharmaceutical Research and Manufacturers
of America, PhRMA) Computer System Validation Committee (CSVC) led by Ken Chapman was the industry's main forum to discuss
computer-validation issues. One series of discussions about system-development life cycle (SDLC) methodology resulted in the
selection of the waterfall life cycle model (see Figure 1). In the mid 1990s, a variation of this waterfall model, the V model,
became more popular (see Figure 2) and is still the model of choice. Looking back, there is no significant change in the computer
validation SDLC. This is rather surprising because in some cases, using other methodologies might be advantageous (e.g., rapid prototyping methodology, which involves configuring how software should operate first, then documenting the final configuration
and functional operation, followed by the software's operational verification).
Figure 1. "Waterfall" life cycle method.