U.S. Good Manufacturing Practice (GMP) regulations (21 CFR 211) have existed unchanged since 1978 (1), although in 1996 a
draft amendment was issued but was never implemented (2). However, on December 4, 2007, the FDA issued a Direct Final Rule
for 21 CFR 211 that will make changes to GMP for finished pharmaceuticals (3) effective in April 2008 as well as withdrawing
the draft 1996 amendment (4). This is the first phase in changes that will be made by the FDA to update and harmonize the
GMP regulations over the next few years. In this "Focus on Quality" column, we will look at the overall GMP changes and then
ask the following question: Why has the laboratory not been included in the proposed changes?
R.D. McDowall
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The usual method of rulemaking by the FDA is a consultative process that involves requesting feedback from industry and other
interested parties. For instance, 21 CFR 11 had the following stages before the final regulation became law:
Advance Notice of Proposed Rulemaking (1992)
Draft rule 21 CFR 11 (1994) Final rule 21 CFR 11 and preamble (1997)
During the first two stages, there was consultation and discussion with the industry.
However, with the GMP regulations, the FDA has jumped straight to a Direct Final Rule, omitting the notice and draft stage
because "FDA expects there will be no significant adverse comments on these amendments" (3). The changes will become effective
on April 17, 2008, but the FDA is accepting comments up to February 19, 2008, that must be made using the Federal eRulemaking
Portal because the Agency will no longer accept e-mail comments.
What Will Change with 21 CFR 211?
In summary, the changes are updating the U.S. GMP regulations and harmonizing them with the U.S. and international regulations
and guidance, which cover the following topics:
Plumbing in §211.48(a) to remove the adherence to U.S. EPA regulations.
Aseptic Processing §211.113(b) to bring the regulation into line with existing guidance and industry practice.
Asbestos Filters §211.72.
Verification by a Second Individual is being updated for the following sections of GMP: §211.68, §211.101, §211.103, §211.182,
and §211.188, but interestingly, not §211.194, which covers laboratory results.
While many of you will be waiting with bated breath to learn of the wonders of plumbing, asbestos filters, and aseptic processing,
I am afraid to disappoint you, but I won't be covering these worthy topics. Instead I'll focus on the major impact for spectroscopy
and computerized system design, which is the last subject: verification by a second individual when a computerized system
is used to automate a process or workflow.
Verification by a Second Individual
The four eyes approach is a cornerstone of any quality system (GMP, GLP, or ISO 17025): a first person performs a task and
a second person checks it. In U.S. GMP, there are several references to a second person check or verification, such as container
weights (§211.101), yield calculations (§211.103), cleaning logs (§211.182), batch records (§211.188), and QC analysis for
the laboratory (§211.194). These are all key stages of the pharmaceutical manufacturing process, and the checks are to ensure
that mistakes can be caught and resolved early in the process. Although this is primarily to ensure patient safety and compliance
with the regulations, it is also good business sense as well because you don't want to commit resources to a process that
might fail. However, the GMP regulations were written before the extensive computerization we have now within our laboratories
and organizations.
The 1978 GMP regulations included §211.68 (1), which outlines the controls required for automated equipment — including computerized
systems — that can be used during the manufacture and testing of a drug product. In essence, the controls were to ensure the
following requirements:
- Proper system performance
- Changes to records are made only by authorized personnel
- System inputs and outputs are checked for accuracy
- Data are backed up in an appropriate way to protect the electronic records generated.
