The director of quality control walked up to my cubicle at G.D. Searle in Skokie, Illinois, and said, "FDA has just published
a revision to the Current Good Manufacturing Practice regulations, and I would like for you to review it for the statistical
implications." It was February 1976, I had been with the company less than two months, and so started my 30-year career of
applied statistics in the service of the current good manufacturing practice (CGMP) regulations. That internal memo later
became a formal presentation at the 20th annual Quality Clinic (1) and I have primarily pursued the same goal ever since.
The 30th anniversary issue of Pharmaceutical Technology now prompts the same question and a related question: How have we, the pharmaceutical industry, done in responding to the
statistical implications?
The first set of regulations for finished pharmaceuticals was published in 1963 by the Food and Drug Administration, (FDA)
on the basis of standards developed by the industry and by the Pharmaceutical Manufacturers Association in 1961. These regulations
were amended in 1965, revised in 1971, amended again February 13, 1976 (2), and published in the Federal Register as 21 CFR 210 and 211.
SamplingA reading of 21 CFR 210 and 211 finds statistical topics expressed both explicitly and implicitly. The most frequently occurring topics are representative
samples, sampling, and sampling plans. Section 210 (20) finds
Acceptance criteria means the product specifications and acceptance/rejection criteria, such as acceptable quality level and
unacceptable quality level, with associated sampling plan, that are necessary for making a decision to accept or reject a
lot or batch.
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Note that there are three parts to the acceptance criteria: the specifications, the acceptable quality level (AQL) (3), and
the unacceptable quality level. The unacceptable quality level is usually known as the limiting quality (LQ). (Note that the
definition of AQL changed in the 2003 version of ANSI/ASQ Z1.4 to be the acceptable quality limit.) The acceptable quality limit (AQL) is the percent of defects or defectives that is the worst tolerable process average.
The probability of rejection at the AQL is the "producer's risk." A typical sampling plan will reject 5% or less of the lots
with a defect level at or less than the AQL. The LQ is the percent of defects or defectives that is unacceptable. The probability
of acceptance is the "consumer's risk." A typical sampling plan will accept 5% (or 10%) or more of the lots with this defect
level or greater. The implication is that we should look for all three parts anywhere the term acceptance criteria appears.
Most standard operating procedures and manufacturing instructions give the specifications and the AQL, but few provide the
LQ. Historically, sampling plans were indexed primarily by the AQL with little note of the LQ values. With FDA's new emphasis
on risk and risk management, however, the LQ or consumer's risk takes on new importance for compliance.
Manufacturers typically interpret the regulations to mean that they must set their internal product specifications requirements
tighter than the regulatory compendial requirements. As stated in USP, "Confusion of compendial standards with release tests and with statistical sampling plans occasionally occurs" (4). Compendial
standards define what constitutes an acceptable article and describe test procedures that demonstrate that the article is
in compliance. These standards apply at any time in the life of the article from production to consumption. The manufacture's
release specifications, and compliance with good manufacturing practices generally, are developed and followed to ensure the
article will indeed comply with compendial standards until its expiration date, when stored as directed.
