Chemistry Reference
In-Depth Information
6
Setting Speciications
and Investigating
Out-of-Speciication
Results
6.1 IntroductIon
Specifications establish the criteria to which a drug substance or a drug product
should conform to be considered acceptable for its intended use. Setting specifica-
tions requires justifications, and the application of different types of tests under dif-
ferent circumstances, each with their own acceptance criteria.
The most common source of questions on the subject of method validation con-
cerns setting specifications. Specifications that establish tests, procedures, and
acceptance criteria play a major role in assuring the quality of new drug substances
and products at release and during shelf life. But who determines specifications?
How does one find or establish acceptance criteria? In a regulated laboratory, setting
specifications and acceptance criteria is generally left up to the originator. That is,
only the originator (applicant or manufacturer) can determine and justify what is
appropriate for a particular product, test, or procedure for eventual approval (hope-
fully!) by a regulatory agency.
While specifications define a pharmaceutical product's essential characteristics
and establish the criteria for releasing it for further use, during routine use of a vali-
dated analytical method, results will occasionally fall outside the defined specifica-
tions. When results do not meet specifications, an investigation should be triggered so
that corrective action can be taken; and as with many processes in the regulated labo-
ratory, there is a recommended way to carry out an investigation. However, guidance
is available. This chapter discusses the general concepts highlights some specific
guidelines and testing used in the process of setting specifications, and addresses
potential sources and ways to avoid and investigate out-of-specification (OOS) results.
6.2 guIdAnce For settIng specIFIcAtIons
In 2000, the FDA adopted an International Conference on Harmonization (ICH)
guideline on specifications for new drug substances and products [1,2]. This
guideline addresses the process of selecting tests and methods, setting specifica-
tions for the testing of drug substances and dosage forms, and includes several
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