Beruflich Dokumente
Kultur Dokumente
Drug Product Science and Technology, Bristol-Myers Squibb, New Brunswick, New Jersey 08901
ABSTRACT: Although significant progress had been made in developing general scale-up rules for an aqueous pan-coating process, there
are often scenarios where small-scale experiments are not found to be truly reflective of what may be observed at the large scale. This
article reviews some of the methods traditionally used for scale-up, identifies the gaps associated with the traditional scale-up rules, and
provides a perspective on a new real-time process monitoring tool that is capable of providing thermodynamic changes taking place in
the microenvironment of the substrate being coated. This tool has been used to ensure increased success during scale-up by maintaining
environmentally equivalent conditions between the processes, especially for systems that are sensitive to small thermodynamic changes.
C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:34123415, 2014
Keywords: coating; scale-up; microenvironment; EEF factor; unit operations; quality by design (QbD); process analytical technology
(PAT); processing; solid dosage form
In absence of droplet size data, as a general rule of thumb, the can be used to quantify the microenvironment experienced by
ratio of spray rate to atomization air flow rate, and atomization the tablets during coating. PyroButtons are data logging de-
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air to pattern air ratio can be kept constant across scales. vices that record T and RH data in real-time. These tablet-sized
It is worthwhile to note that all the scale-up factors dis- devices (16 mm diameter, 6 mm height) were secured at spe-
cussed here are macroscopic factors and do not quantify the cific locations in the equipment (e.g., inlet, exhaust, spray gun
changes experienced by the tablets at the microscopic level as handle, baffles), and also placed in the tablet bed and allowed
they get coated. The fundamental assumption is that changes to tumble freely along with the tablets (Fig. 1). PyroButtons R
to the macroscopic parameters at different scales have sim- that move with the tablets provide information on the ther-
ilar, if not the same, effect on the microenvironment experi- modynamic conditions (microenvironment) experienced by the
enced by the tablets. For example, the exhaust air tempera- tablets during the coating process. There have been a few case
ture is maintained constant across scales during scale-up with studies published recently that show the utility of the informa-
the underlying assumption that by doing so the tablet-bed tion provided by the moving PyroButtons , where correlations
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temperature is maintained constant across scales. Although could be established between the measured microenvironment
this may turn out to be a reasonable assumption at certain and the coated drug products critical quality attributes (CQAs)
process conditions, this cannot be generalized. Recent studies such as appearance, physical, and chemical stability. These case
have clearly shown that the difference between the exhaust studies can be classified into different categories of drug prod-
temperature and tablet-bed temperature is a function of the uct CQAs:
processing conditions, with larger deviation observed between
the two for wetter process conditions. The difference between
the exhaust and the tablet-bed temperature can, in certain 1. Appearance (logo bridging tablet defect): As part of un-
cases, be larger than 10 C depending on the process conditions derstanding this CQA, it was shown via a case study
and also on the exhaust temperature measurement location in that the macroscopic events such as logo bridging coat-
the coater.2,13 The difference between the exhaust RH and the ing defect correlated best to tablet-bed RH when com-
tablet-bed RH (or the RH that the tablets experience) can be pared with the conventionally-measured coating process
higher than 20%.10,14 Such differences between the exhaust air parameters.14 It was shown that a process design space
conditions and the conditions experienced by the tablets high- can be established based on the tablet-bed microenviron-
light the importance of characterizing the conditions at the mi- ment (RH) where no logo bridging was observed (Fig. 2). A
DOI 10.1002/jps.24191 Pandey and Bindra, JOURNAL OF PHARMACEUTICAL SCIENCES 103:34123415, 2014
3414 COMMENTARY
Figure 2. Case study demonstrating a correlation between tablet- Figure 3. Case study showing a correlation between tablet-bed rela-
bed microenvironmental RH to logo bridging coating defect (reproduced tive humidity and a bilayer tablet delamination defect rate when put
with permission from John Wiley and Sons).14 on accelerated stability (40 C/75% RH, 24 h).20
critical tablet-bed RH (30%) was established below which tablet delamination case study, it was observed that when the
no logo bridging was observed. It should be noted that this process was scaled from 24 in. scale coater to 36 in. coater
critical bed RH would be specific to the coating formula- using a constant drying capacity scale-up rule, the resultant
tion, logo design, and tablet core used in that study but tablet-bed microenvironment was drier at the 36 in. scale.20
should be independent of coating scale. The difference The tablet-bed RH was observed to be 37.2% at 24 in. scale and
between the tablet-bed conditions and the exhaust air 28.9% at the 36 in. scale. Given that a drier microenvironment
conditions was found to be a function of the process con- was favorable in terms of delamination/hairline cracks, a mis-
ditions, with more deviation observed at wetter condi- match in microenvironment across scales was not considered
tions. Additionally, the tablet-bed microenvironment was to be an issue. However, it does highlight the limitations of
shown to be a cumulative effect of various process pa- the traditional scale-up rules. In another case study related to
rameters, and therefore can be used as a single param- the chemical stability of a moisture-sensitive drug product, it
eter for control and understanding the coating process was shown that the chemical stability was directly related to
thermodynamics.10 the final moisture content of the coated tablet.21 It was shown
2. Physical stability (bilayer tablet delamination): In this that the traditional scale-up rules, such as keeping constant
case study, it was shown that the delamination tendency EEF value constant across scales, did not result in an equiv-
of a coated bilayer tablet when placed on accelerated sta- alent microenvironment and also resulted in a different drug
bility was related to the microenvironmental conditions product chemical degradation profile due to differences in the
experienced by the tablets during the coating process.20 resultant tablet water content (Table 1).
A higher tablet-bed RH led to a higher tendency of the Based on these case studies, it is believed that a good match
bilayer tablet to show defects along the bilayer tablet in- of microenvironment across scales is essential to enable suc-
terface, as shown in Figure 3. Interestingly, this study cessful scale up, where the drug product CQAs can be repro-
showed that the bilayer tablets exhibited a memory of duced across scales. Often the traditional scale-up rules may
the coating process conditions even when they were dried work well-enough and provide good starting points, and a mi-
to a similar LOD (loss on drying) at the end of the coating croenvironmental level of scrutiny may not be required for a
process and no physical differences (appearance) could be drug product that is robust to the thermodynamic conditions
observed at the end of the coating run. experienced during the coating process. However, maintaining
3. Chemical stability (degradation profile of a moisture- the same thermodynamic environment (T and RH) that tablets
sensitive drug product): This case study showed a cor- experience across scales would undoubtedly ensure a better
relation between the degradation (hydrolysis) rate of a scale-up outcome in terms of drug product CQAs, and is critical
drug product on stability to the microenvironment expe-
rienced by the tablets during the coating process.21 The
water activity of the coated tablets at the end of the coat- Table 1. Scale-Up of Process Using EEF Rule Versus Constant
ing run was found to be linked to the tablet-bed microen- Microenvironment Rule
vironmental conditions. Scale Coated Tablet Average
(Pan diameter) EEF Water Activity Tablet-Bed RH%
These studies demonstrated that monitoring the microen-
15 in. 2.78 0.28 30
vironment during the coating process provides a deeper un- 24 in. 2.77 0.35 40
derstanding and better control of the coating process and its 24 in. 3.22 0.28 30
effects on the drug product CQAs. Some of these case studies
also included scale-up experiments. For example, in the bilayer Adapted from Kestur et al.21
Pandey and Bindra, JOURNAL OF PHARMACEUTICAL SCIENCES 103:34123415, 2014 DOI 10.1002/jps.24191
COMMENTARY 3415
for sensitive drug products, and likely for functional coating 8. Porter SC. 2012. Coating of pharmaceutical dosage forms. In Rem-
scenarios. ington the science and practice of pharmacy; Allen LVea, Ed. 22nd ed.
An assurance of successful scale-up and good reproducibility London: Pharmaceutical Press, pp 977987.
of CQAs across scales would allow for more experimentation at 9. Porter S, Sackett G, Liu L. 2009. Chapter 33Development, opti-
mization, and scale-up of process parameters: Pan coating. In Develop-
a small-scale in order to identify the critical process parameters
ing solid oral dosage forms; Qiu Y, Chen Y, Zhang GGZ, Liu L, Porter
for a given drug product and establish a process design space,
WR, Eds. San Diego: Academic Press, pp 761805.
which can be then scaled-up based on matching the tablet-bed 10. Pandey P, Bindra DS, Felton LA. 2014. Influence of process pa-
microenvironment. rameters on tablet bed microenvironmental factors during pan coating.
AAPS PharmSciTech 15(2):296305.
11. Chen W, Chang S-H, Kiang S, Early W, Paruchuri S, Desai D. 2008.
CONCLUSIONS
The measurement of spray quality for pan coating processes. J Pharm
PyroButton data loggers are an effective PAT tool which can
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Innov 3:314.
provide a meaningful thermodynamic signature of the coating 12. Wang J, Hemenway J, Chen W, Desai D, Varia S, et al. 2012.
process that can be correlated to drug product CQAs. Addition- An evaluation of process parameters to improve coating efficiency
of an active tablet film-coating process. Int J Pharm 427:163
ally, such measurements allow for establishing a new method-
169.
ology of scaling up the coating process thermodynamics at a
13. Wobker MS, Mehrotra A, Carter B. 2010. Use of commercial data
higher level of scrutiny, where the microenvironment experi- loggers to develop process understanding in pharmaceutical unit oper-
enced by the tablets is maintained across scales in order to ations. J Pharm Innov 5(4):169180.
achieve good reproducibility of CQAs. 14. Pandey P, Ji J, Subramanian G, Gour S, Bindra DS. 2014.
Understanding the thermodynamic micro-environment inside a pan
coater using a data logging device. Drug Dev Ind Pharm 40(4):542
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DOI 10.1002/jps.24191 Pandey and Bindra, JOURNAL OF PHARMACEUTICAL SCIENCES 103:34123415, 2014