Statistical Implications of the CGMPs: A 30-Year Retrospective - Pharmaceutical Technology

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Statistical Implications of the CGMPs: A 30-Year Retrospective
This article looks at the current good manufacturing practice regulations from a statistical perspective while addressing their requirements and implications and inviting the industry to assess its past performance in meeting the regulations.

Pharmaceutical Technology

The term representative sample is carefully defined in Section 210 (21) as "a sample ... of units that are drawn based on rational criteria such as random sampling...." Note the use of rational criteria. Sampling is the physical act of selecting the units and the validity of the sample, and its representativeness is directly related to the physical actions used to select it. Once a sample has been taken, it is impossible to determine whether it is actually representative of the lot. Documentation and standard operating procedures (SOPs) are key to compliance.

Although simple random sampling (in which every unit has an equal chance of being selected) is preferred from a theoretical consideration, it is often very difficult or impossible to obtain because of physical limitations. Other statistically valid sampling techniques include systematic sampling with or without a random start and cluster sampling. Nonstatistical sampling includes a judgment sample selected by an "expert" to be representative or a convenience sample taken because it is easy to obtain (also called a grab sample).

Our task is to examine the rational criteria to "assure that the sample accurately portrays the material being sampled," as stated in Section 210 (21), and to observe the act of sampling by the operator. Only by actual observation of the physical act of sampling can we determine validity—reading an SOP is insufficient.

Notice that the objective of the sampling inspection and the acceptance criteria is to make a decision to accept or reject. This must be documented and communicated to management. Sampling is not a substitute for process control and improvement.

The words sampling and representative samples are used in the following sections: 211.80(a); 211.84(a) and (b); 211.110(a); 211.122(a); 211.134(b); 211.160(b)(1), (2), and (3); 211.165(c); and 211.186(b) (9). Sampling plans are statistical descriptions of the procedures used to sample units, including the physical activities to select the units.

Section 211.84 notes that "The number of containers to be sampled ... shall be based upon appropriate criteria such as statistical criteria for component variability, confidence levels and degree of precision desired, the past quality history of the supplier...." Section 211.165(d) goes further by stating, "The statistical quality control criteria shall include appropriate acceptance levels and/or appropriate rejection levels."

Sampling plans have historically been either Military Standard 105E for attribute sampling or Military Standard 414 for variables. These documents describe a set of sampling plans that have been used in the industry since 1942. In fact, we find this quote in an article by Olson and Lee in 1966 (5):

For practical purposes the need to design a sampling plan has been eliminated by a series of government sponsored sampling plans, two of which are MIL STD 105D for attribute single, double, and multiple sampling plans; and MIL STD 414 for variables sampling plans. These books have gained acceptance throughout most of the United States industry in a manner much like the USP and NF. Government contracts for the purchase of pharmaceuticals usually refer to one or both of these books. The obvious advantage of selecting plans from either of these books is communicability and acceptance throughout industry. Hence, there is little or no advantage to specially designed sampling plans.

However, Military Standard 105E was discontinued by the US government in February of 1995. No reason was given, but cost may have been a factor as the government tried to downsize. Thus, technically Military Standard 105E is not available any more. However, a variation of it is available from ANSI/ASQ as Z1.4 (3) for 105E and Z1.9 (6) for 414.

Other statistical issues in CGMPs

The CGMPs also directly discuss or are related to process control, setting specifications, stability testing method validation, and out-of-specifications.


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