US 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 4 December 2007, the FDA issued a Direct Final Rule for 21 CFR 211 that will make changes to GMP for finished
pharmaceuticals,3 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.
What is a Direct Final Rule?
The usual way for rulemaking by the FDA is a consultative process that involves requesting feedback from industry and other
interested parties. For example, 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." The changes will become effective on 17 April 2008 but the FDA is accepting comments up to 19 February 2008 that must be
made using the Federal eRulemaking Portal as the Agency will no longer accept e-mail comments.
What will Change with 21 CFR 211?
In summary, the changes are updating the US GMP regulations and harmonizing them with the US and international regulations
and guidance and these cover the following topics:
- Plumbing in §211.48(a) to remove the adherence to US 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 covering the following sections of GMP: §211.68, §211.101, §211.103, §211.182, and §211.188.
The major impact on computerized system design and deployment is the last subject: verification by a second individual when
a computerized system is used to automate a process.
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 US 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 there 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 too because you don't want to commit resources to a process that will
fail. However, the GMP regulations were written before the extensive computerization we now have.
The 1978 GMP regulations included §211.68 which outlines the controls required for automated equipment, including computerized
systems, to be used in the manufacture of a drug product.1 In essence these were to assure
- 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 records.
