Chemistry Reference
In-Depth Information
TABLE 11 . 9 . Minimum Guideline from the ICH Q1A(R2) for Room-Temperature Product
Minimum Time Period Covered
by Data at Submission
Study
Storage Condition
Long term
a
25
±
2
°
C/60
±
5% RH or
30
±
2
°
C/65
±
5% RH
12 months
Intermediate
b
30
±
2
°
C/65
±
5% RH 6 months
Accelerated 40
±
2
°
C/75
±
5% RH 6 months
a
It is up to the applicant to decide whether long-term stability studies are performed at 25
±
2
C/60
±
5% RH or
°
30
±
2
C/65
±
5% RH.
°
b
If 30
±
2
C/65
±
5% RH is the long-term condition, there is no intermediate condition.
°
the way to a coated solid dosage form, are all known risk factors for promoting physical
phase transformations and chemical instability.
Stability is examined in two different manners:
first by meeting at least the minimum
regulatory requirement needed to launch a drug and then by examining the root causes of
degradation, if any. From a scienti
c/engineering perspective, it is important to deter-
mine what affects the stability of the drug in order to design a drug product process
around these factors. Regulatory requirements for stability need to be done in the
intended primary commercial package. ICH guidance [48] governs the expectations of
pivotal stability studies. The minimum required for submission is shown in Table 11.9;
real-time data are needed for shelf life dating over 2 years.
The QbD approach incorporates studies that increase our overall understanding of
stability and allow identi
cation of the critical parameters for stability. These studies (see
Table 11.10 for details on design and testing) include the following:
1. The end-to-end (E2E) stability study justi
es the independent shelf lives of the
SDD and tablets.
2. The temperature and relative humidity (
(T/RH) stability study allows for mecha-
nistic understanding of factors responsible for chemical instability of tablet.
3. Physical stability studies and solid-state experimental investigations assess
physical stability of SDD and tablets under the proposed storage conditions
and shelf life.
T
T/RH stability study was to develop a drug product chemical
stability model that correlates the formation of epimer, the primary degradant of
telaprevir, with the parameters that impact its formation, namely, surface pH of the
excipient (traced to residual impurity from excipient), moisture content of the tablet,
storage temperature, and time.
Tablets were equilibrated at varying RH (typically ranging from 10 to 60%RH, with
corresponding tablet moisture contents of 0.4
The purpose of the
T
3.4%), and then hand-sealed in foil
pouches to ensure constant moisture content. These tablets were then placed on stability
at storage conditions of 25, 30, and 40
-
C for up to 12 months. Multiple studies were
conducted, using excipient having varying levels of impurity. Figure 11.11 shows %
°
