Chemistry Reference
In-Depth Information
Consider the need for
verifying chiral identity in
drug substance release
and/or acceptance
testing.
Chiral identity, assay
and impurity procedures
are not needed.
Is the new
drug substance
chiral
1
?
No
Ye s
and racemic
Ye s
and one enantiomer
Needed for durg substance specification:
2
- chiral identity
3
- chrial assay
4
- enantiomeric impurity
5
Needed for durg product specification:
6
- chiral assay
4
- enantiomeric impurity
5
FIgure 6.2
Establishing identity, assay, and enantiomeric impurity procedures for chiral
new drug substances and new drug products containing chiral drug substances.
1
Chiral sub-
stances of natural origin are not addressed in this guideline.
2
As with other impurities arising
in and from raw materials used in drug substance synthesis, control of chiral quality could be
established alternatively by applying limits to appropriate starting materials or intermediates
when justified from developmental studies. This essentially will be the case when there are
multiple chiral centers (e.g., three or more), or when control at a step prior to production of
the final drug substance is desirable.
3
A chiral assay or an enantiomeric impurity procedure
may be acceptable in lieu of a chiral identity procedure.
4
An achiral assay combined with a
method for controlling the opposite enantiomer is acceptable in lieu of a chiral assay.
5
The
level of the opposite enantiomer of the drug substance may be derived from chiral assay data
or from a separate procedure.
6
6Stereospecific testing of drug product may not be necessary if
racemization has been demonstrated to be insignificant during drug product manufacture and
during storage of the finished dosage form.
establish inspection and enforcement policies and procedures. FDA good guidance
practices state that official procedures should be followed when communicating new
or different regulatory expectations that are not readily apparent from current regu-
lations to a broad public audience [16]. However, similar to the recently published
FDA guidance on method validation [17,18], guidelines on OOS investigations first
appeared in draft, not final form [14]. Draft guidance represents the FDA's current
thinking on a particular topic and opens it up for public comment [19]. By issuing
draft guidance, the FDA can update guidelines based on advances in technology and
knowledge, changes in regulatory requirements, and policy mandates.
The FDA's OOS guidance applies to active pharmaceutical ingredients, excipi-
ents, and other components and the testing of finished products to the extent that
current good manufacturing practices apply. It discusses how to investigate suspect,
or OOS results, including responsibilities, the laboratory phase of the investigation,
