Biomedical Engineering Reference
In-Depth Information
suffi cient for reliable assay, but not so excessive as to bias the results by masking
individual actuation variation. Although the CI size resolution is not stated explic-
itly in this guidance document, for practical reasons a 7- or 8-stage system is needed
to provide fi ve stages having cut-point sizes in the critical range from 0.5 to 5.0
μ
m
aerodynamic diameter if information about the coarse fraction >5
m is to be
obtained as well [
7
]. For post-approval release and stability testing, but not for char-
acterization of the drug product in the initial submission to the regulatory agency,
drug deposition on individual stages may be grouped (so-called stage grouping),
with separate requirements placed on each of the groupings [
8
].
In Europe and Canada, the 2006 jointly approved Guideline on the Pharmaceutical
Quality of Inhalation and Nasal Products also makes reference to the use of a mul-
tistage CI for the measurement of APSD, with the implication that suffi cient stages
will be used to enable fi ne-particle dose <5
μ
m (
FPM
<5.0μm
) aerodynamic diameter
to be obtained, together with the
MMAD
and
GSD
of the
ISM
, if appropriate [
9
,
10
].
Since the statement is also made to the effect that control of the portion of the APSD
>5
μ
m may be necessary depending on the relevance of this fraction for the thera-
peutic index of the drug product, a 7- or 8-stage CI will most likely be used, although
the 5-stage multistage liquid impinger (Apparatus C in the European Pharmacopoeia
monograph 2.9.18 [
11
]) has been used in regulatory submissions. Stage pooling
(grouping) is also permitted, as illustrated by the following example for a generic
pMDI-delivered salbutamol [
12
]:
μ
1. Induction port to represent the oropharyngeal deposition and hence swallowed
dose
2. Pooling 1: Stage 0, 1, and 2 to represent the large nonrespirable particles depos-
ited in upper airway
3. Pooling 2: Stage 3, 4, and 5 to represent the fi ne-particle dose (
FPD
) between 1.1
and 4.5
FPM
1.1-4.5μm
), deposited on bronchi and predictive of the in vivo
bronchodilator effi cacy and of
C
max
(early lung bioavailability)
4. Pooling 3: Stage 6, 7, and fi lter to represent the extrafi ne particles (
EPM
<1.1μm
)
likely to deposit in the alveoli
μ
m (
≡
Acceptance of the AIM concept as a direct substitute for multistage cascade
impaction in regulatory submissions relating to OIP quality control will likely prove to
be a challenging process for industry, requiring much evidence across a wide
range of OIP platforms and abbreviated systems to support its adoption. From
the regulatory perspective, robust demonstrations of the following advantages will
be central in gaining acceptance by meeting the following criteria:
1. Comparable or possibly better precision for AIM systems compared with their
full-resolution counterparts as well as freedom from measurement bias (see
Chap.
10
)
2. Applicability throughout the life cycle of the OIP (see Chap.
6
)
3. Capability of EDA (where proposed as the AIM metric) to provide equivalent or
improved sensitivity to small changes in APSD compared with stage grouping,
leading to better decision making with respect to batch disposition in the QC
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