FDA/GLP Regulations
COST EFFECTIVE IMPLEMENTATION
Food and Drug Administration regulation 21 CFR Part 11 defines significant and wide-ranging requirements for auto-mated systems used in laboratories (and in other regulated settings). Compliance with the regulation is both mandated and an appropriate representation of good management prac-tices. Unless carefully planned, however, Part 11 compliance can be a cumbersome and expensive—though necessary—
process. With appropriate planning strategies, however, labo-ratory Part 11 compliance can be a smooth, seamless, and cost-effective process.
The modern investigatory, quality control, preclinical, or other laboratory generally requires a highly automated envi-ronment. Computer models may be used for preliminary screening; separation technologies are software-driven, and preliminary and preclinical testing involves computer reci-pes, LIMS networks, and statistical analysis programs. In such an environment compliance with Part 11 and related GLP requirements is not only good science, it is also good business. In a budget-conscious world, however, the business pressures on laboratory management require consideration of cost-effective criteria The well-managed laboratory must comply with the spirit and letter of the regulatory require-ments and with extraregulatory concerns related to health and safety, but raising the bar above that which is both re-quired and safety-necessitated adds expense, which ulti-mately may drive drug and biologic prices beyond
affordabil-ity for patients in need. Good management, then, calls for cost-effective compliance.
There are four specific strategies for cost-effective compli-ance with Part 11 in laboratory environments. These strate-gies include: (1) adopting a multitier validation standard; (2) conducting inexpensive internal compliance audits to identify and focus on key areas of weakness; (3) adopting existing audit strategies to building an internal audit trail; and (4) building compliance into the system selection and adaptation process.
The multitier validation strategy is discussed in depth in the chapter on system validation. In short, all too many com-panies establish the most stringent of validation standards and apply them uniformly to all systems regardless of actual risk. Adopting a multilevel validation and Part 11 compliance protocol and calling for more rigid controls in high-risk envi-ronments is appropriate, accepted, and cost-controlling.
That multitier approach can be effectively married with a strategy of utilization of internal preaudits to identify key deficiencies and areas of real risk. Rather than adopting a pol-icy of implementing controls across the board, the preaudit allows cost-neutral continuation of existing controls where no real problems are found, and allocation of energy and funds to those areas in greatest need of compliance and control.
Third, one of the most expensive changes dictated by Part 11 refers to audit trails. If an electronic audit trail was not designed into an existing LIMS, for example, adding such a trail or replacing the LIMS with a compliant alternative may be a very expensive strategy. Alternately, it is often pos-sible to utilize internal audit procedures, including careful SOPs requiring and assuring the use of a manual audit trail document, to achieve the same level of interim control at a fraction of the expense. Cost is not an excuse for noncompli-ance, but at the same time compliance does not require choos-ing the most expensive alternatives.
Finally, clearly reviewing the Part 11 (and other GLP) requirements in preparation for a request for proposal and selection of a new LIMS or other laboratory system can result
in cost-efficient building of compliance requirements into an initial system. Again, the audit trail requirement serves as an effective example; building in a secure audit file is a rela-tively inexpensive addition to the development of a LIMS (or equivalent) file management system. Adding such a feature on after design is a much more expensive process. Maximum cost efficiency can be achieved by using the Part 11 require-ments as a part of the selection or design template in pur-chasing any new automated laboratory components.
With these four strategies compliance with Part 11 can be cost-effectively integrated into the management of any au-tomated laboratory, and while primary consideration must be paid to compliance with requirements and to adding safety controls as necessary beyond those requirements, cost-effec-tiveness can appropriately be utilized as a third-level crite-rion in laboratory system selection, design, and management.
SUMMARY
The requirements of 21 CFR Part 11 apply well beyond the laboratory environment, but do stand as supplemental to and interpretative of the GLP in automated laboratory environ-ments. Compliance requires an understanding of the key ele-ments of the Part 11 document, and the formulation of a strategy that assures safety, regulatory acceptance, and cost-effective management.
As the Part 11 requirements are subject to interpreta-tion through field review they will no doubt be modified. Ad-ditional changes will result from technological innovation and from the integration of innovative requirements (dual signature approvals, e.g.) into norms of system design, but the intent of Part 11 is critical and permanent.
In a modern laboratory the general guidelines encom-passed in good laboratory practices require careful interpre-tation when applied to a laboratory that relies heavily on au-tomated documentation, data files, and electronic signatures;
21 CFR part 11 provides that interpretation.