Defining a batch and a lot for excipients produced by continuous manufacturing.
It was recognized that the definitions for a batch [21 CFR 210.3(b)(2)] or a lot [21 CFR 210.3(b)(10)] applicable to the manufacture of drug products can be applied in principle to the manufacture of excipients.
According to current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, a batch means a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified
limits, and is produced according to a single manufacturing order during the same cycle of manufacture [21 CFR 210.3(b)(2)]. Furthermore, a lot means a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits;
or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of
time or quantity in a manner that ensures its having uniform character and quality within specified limits [21 CFR 210.3(b)(10)].
Workshop participants determined that continuous flow processes can be compliant with the CGMP definitions of batches and
lots. It was felt that for continuous flow processes used to manufacture excipients, a batch or lot can be defined by an agreement
between the excipient supplier or excipient manufacturer and drug product manufacturer.
Testing excipient batches.
The CGMP regulations for finished pharmaceuticals [21 CFR 211.84(d)(1) and 21 CFR 211.84(d)(2)] require that before using an excipient in the manufacture of a drug product, the drug-product manufacturer
must perform at least one test to verify the excipient's identity and must demonstrate that the excipient conforms to appropriate
written specifications for purity, strength, and quality. The CGMP regulations also specify that in lieu of such testing by
the drug-product manufacturer for purity, strength, and quality, a report of analysis may be accepted from the supplier of
a component (i.e., excipient), provided that at least one specific identity test is conducted on such component by the drug-product
manufacturer and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate
validation of the supplier's test results at appropriate intervals.
CGMP regulations for component identity testing, 21 CFR 211.84(d)(1), is intended to ensure that a component is what it purports to be on the container labeling. CGMP regulations
in 21 CFR 211.84(d)(2) are intended to provide sufficient flexibility to minimize, reduce, or avoid duplicative or repetitive testing
of excipient attribute(s) when the drug-product manufacturer establishes the reliability of the excipient supplier's (or excipient
Current industry practice for excipient manufacturers is to use in-process testing and manufacturing process controls to ensure
batch uniformity. Such practices also are intended to ensure compendial compliance, and as such, not all compendial tests
are routinely performed by the excipient manufacturer. The CoA received by the drug-product manufacturer for an excipient
batch may not report compendial test result(s) but will state that "if tested will meet pharmacopeial requirements." When
such a statement is based on process controls, the survey reported that the current practice is for the drug product manufacturer
to perform the compendial test(s).
There are numerous scenarios where compendial tests are performed on a bulk excipient after all manufacturing processes are
complete, but before final package filling. Where an in-process or bulk excipient test result is traceable to the finished
excipient material, such a test result can be reported on the CoA.
The determination of "critical" or "noncritical" attribute(s) of an excipient should be determined by the drug product manufacturer,
depending on the excipient's use in a drug product with respect to its dose, dosage form, route of administration, and manufacturing
process(es). When a drug-product manufacturer wants certain tests performed on its supply of an excipient, the manufacturer
may need to set up a contract with the excipient manufacturer or supplier. In any case, as stated above, the CoA generated
for each batch of excipient should indicate the compendial (or otherwise specified) tests performed, as well as those tests