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Developing A Quality by Design Approach To Model Tablet Dissolution Testing: An Industrial Case Study
Developing A Quality by Design Approach To Model Tablet Dissolution Testing: An Industrial Case Study
RESEARCH ARTICLE
1. Introduction There has been a growing interest in the use of QbD tools for
understanding and prediction of drug release from tablets.
The concept of Quality by Design (QbD) was first introduced in
Hernandez et al. (2016) used NIR to predict in real time dissol-
1992 by Dr Joseph M. Juran (Juran 1992). The US Food and
ution of tablet exposed to different levels mechanical strength.
Drug Administration (FDA) encourages risk-based approaches
Yekpe et al. (2015) demonstrated that dissolution can be pre-
and the adoption of QbD principles within pharmaceutical indus-
dicted based on disintegrant distribution with NIR Chemical
try (Yu et al. 2014). QbD proposes that quality should be built
Imaging Technology. Basalious et al. (2011) applied QbD for
into initial product design rather than assessed at the end of tab- pharmaceutical development of felodipine solid mixture contain-
let manufacture (ICH Q8, R2 2009). Furthermore, the goal of QbD ing hydrophilic carriers and/or polymeric surfactants, for easier
is to ensure finished product quality, improve tablet manufactur- development of controlled-release tablets of felodipine. Dumarey
ing and curtail product costs. Thus, with the QbD initiative, rou- et al. (2015) studied the influence of granule and compression
tine quality control testing, such as dissolution testing (DT) variability introduced by a design of experiments on the entire
performed after tablet manufacturing, could be discontinued if dissolution profile with a multivariate tool. Cui et al. (2012) used a
influential parameters are controlled (Rathore et al. 2009). single time point to study and predict the drug release as a func-
DT aims at verifying active pharmaceutical ingredient (API) dis- tion of API physical properties.
solution in simulated gastrointestinal fluid (Dressman and Kramer Ultimately, if influential parameters are identified and con-
2005; Le Hir et al. 2009). Such pharmaceutical control testing has trolled a priori, efficient applications of QbD principles and risk-
now been applied for more than 30 years and is recognized as a assessment tools could reduce and perhaps eliminate the need
gold standard for in vivo dissolution correlation (Buri 1983; for tests such as “tablet DT” (ICH Q8, R2 2009; ICH Q9 2011a, ICH
Juenemann et al. 2011). Moreover, this control test is routinely Q10 2011b). Such evolution would be highly beneficial to the
employed by the pharmaceutical industry and regulatory agencies pharmaceutical industry in terms of process understanding, envir-
to improve monitoring of batch-to-batch reproducibility in manu- onmental impacts, and time to market.
facturing processes (Dressman and Kramer 2005). However, the The following methodology was adopted: after identifying
test consumes much time, material, equipment, and human drug product dissolution as a Critical Quality Attribute (CQA),
resources. The present work evaluates the possibility of modeling quality risk assessment ascertained potentially critical material and
DT for solid oral dosage products based on QbD principles and process parameters that may impact dissolution. Experiments
proposes a novel approach to ensure conformity with ICH were designed to further identify crucial process parameters and
guidelines. elucidate their impact on product dissolution profiles.
CONTACT Nicolas Abatzoglou Nicolas.Abatzoglou@USherbrooke.ca Department of Chemical & Biotechnological Engineering, Universite de Sherbrooke, 2500
boul. Universite, Sherbrooke, Quebec, J1K2R1, Canada
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 647
Table 1. Failure Mode and Effects Analysis (FMEA) of parameters impacting the
dissolution tests – quantifying their Occurrence (O), Impact (I), and Detectability
(D).
Parameters I O D RPN Comments
Tablet 5 2 1 10 Tablets with inadequate hardness
compression will present unacceptable dis-
integration/dissolution profiles.
While its impact is important,
its presence is easily detect-
able and corrected by adjust-
ing compression setting.
Coating 5 2 1 10 Tablet coating is critical and
could have a very high impact
on dissolution profiles.
Inhomogeneous and/or under-
coated tablets can often easily
be detected.
API particle size 5 1 2 10 Particle size has a very important Figure 2. Ibuprofen PSD obtained from three suppliers: A – blue, B – red, and
impact on dissolution testing C – green.
as stated by the
Noyes–Whitney equation.
Ibuprofen physical– 5 1 2 10 Ibuprofen Physical–Chemical be rejected which indicates that the average particle sizes for the
chemical properties Properties have a significant three powders are statistically equal.
effect on dissolution. As this
study is for an existing prod-
uct, these parameters are not Factor 3: crystal identification. The third factor of this initial ibu-
included into the DoE. profen study was crystal identification with X-Ray Diffraction
Ibuprofen 5 2 1 10 Drug concentration has an (XRD). The purpose of this part of this article was to determine if
concentration important impact on dissol- the crystalline structure of the three ibuprofen powders is the
ution testing as stated by the
Noyes–Whitney equation.
same. As ibuprofen structure is crystalline, it was expected to
However, the ability to detect obtain sharp narrow diffraction peaks for the three powders.
a problem of drug concentra- The crystal identification was realized with an X’pert Pro MRD
tion is easily to detect during diffractometer from PANanalytical. The results are presented in
routine QC assay testing.
Figure 4. Peak position and intensity for the three ibuprofen pow-
Storage humidity 5 2 1 10 Storage Humidity has a signifi-
cant effect on physical and ders were compared using the internal library of the apparatus;
chemical properties of exci- the comparison shows that the three powders are identical.
pients and API contained in However, peak intensity for the three powders presents slight dif-
tablet. Thus, storage Humidity ference for some peak positions. This difference is explained by a
could impact API dissolution.
phenomenon called preferred orientation, defined as the non-ran-
dom distribution of the crystallites within a sample, and is the
likely cause of intensity variations in XRD powder diffractograms.
Thus, no polymorph of ibuprofen and no amorphous phase have
In the following sections, ibuprofen powders from supplier A, B, C been found on XRD spectra; consequently, the crystalline structure
will be referred to accordingly. of the three ibuprofen samples is the same.
Factor 1: particle size distribution. Particle size (PS) and particle Factor 4: Ibuprofen concentration. According to the FMEA, the
size distribution (PSD) are important variables in pharmaceutical impact of API concentration on dissolution testing is high (Smith
industry. Indeed, API and excipients PSD can affect final formula- 2015). It was decided to test tablets containing 90, 100, and 110%
tion (dissolution, appearance, and stability). Ibuprofen A, B, and C of ibuprofen claim in the tablets. Batches of 90 and 110% ibupro-
PS were measured via a light scattering method using a fen have the same formulation as regular ibuprofen tablets, but
Mastersizer 2000, Malvern instrument. The results are presented in excipient percentage within each formulation was modified in
Figure 2. They illustrate that the volumetric PS of all three pow- order to reach either 90 or 110% of API claim. Dissolution profiles
ders is unimodal, similar in shape with a relatively low proportion of 90% and 100% ibuprofen as well as those of 110 and 100%
of fines (mean particle size below 10 microns). ibuprofen were compared in order to estimate if the dissolution
profiles of the two formulated batches are similar.
Factor 2: particle shape. The shape and surface morphology of The dissolution testing was performed on six tablets of each
the particles were examined with a FEG-SEM S-4700, Hitachi batch, using USP apparatus 2 (Distek Inc., North Brunswick, NJ) in
instrument. The micrograph of the three powders (Figure 3) indi- 900 ml of dissolution media (phosphate buffer at pH 7.2) at
cates that particles for the three suppliers have similar shapes. 37 ± 0.5 C with UV detector as required in USP at 221 nm. Section
Moreover, the typical range of PS is confirmed: a wide range of 2.5 contains technical details concerning the dissolution test.
mean particle sizes (from 12 to 188 microns) can be seen for all Each dissolution profile was compared with dissolution profiles
three powders. Eight images were acquired for each of the three of 100% API Tablets. For all three cases, dissolution profiles show
powders. For each image, 10 particles were measured: ibuprofen that more than 85% of the drug is dissolved within 15 min, which
A, B and C present average particle sizes of 88.1(12.3), 82.4(8.7), indicates that the products dissolve rapidly. Indeed, in 6 min more
and 83.4(18.5) mm, respectively (values in parenthesis represent than 85% of ibuprofen is dissolved for all three batches.
standard deviation). An ANOVA was done to test the null hypoth- Coefficients of variation for the three batches were not more than
esis that the average particle sizes for the three powders are stat- 1% between 10 and 60 min indicating good data repeatability.
istically equal. With a p values of 0.68, the null hypothesis cannot USP dissolution testing specifications require that at least 85% of
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 649
of commercial product family. The tablets obtained after this step Table 4. Dissolution models under study.
have been coated. Model Equation
Zero-order (Costa and Sousa Lobo 2001) %disso ¼ kt (1)
First-order (Polli et al. 1997) %disso ¼ 1 ekt (2)
2.4. Tablet properties Higuchi (1963) %disso ¼ kt1=2 (3)
Korsmeyer–Peppas (Korsmeyer et al. 1983) %disso ¼ ktn (4)
Tablet properties (weight uniformity, length, thickness, and hard- 3
Hixson–Crowell (Hixson and Crowell 1931) %disso ¼ ð1 ktÞ b (5)
ness) were measured in randomly selected tablets from each Weibull (Dokoumetzidis et al. 2006) %disso ¼ 1 ðe ðatÞ
) (6)
batch. Five (5) tablets were tested for weight uniformity, length,
thickness, and hardness. Tablet weight uniformity was established
by AT460 Delta Range electronic balance (Mettler Toledo,
Columbus, OH). Length and thickness were quantified with a CD-
6" CX digital caliper (Mitutoyo, Aurora, IL). Hardness was analyzed
with a Type HT500 tablet hardness tester (Key International, Inc.,
New-York, NY). Relative standard deviation (RSD) values were cal-
culated for each batch.
Table 5. Means and standard deviations associated with k, a, and b values for the 13 lots to pH 6.4. 6.8, and 7.2.
k Constant (1st order) a Parameter (Weibull) b Parameter (Weibull)
1 1
pH value Average (min ) Standard-deviation (min ) Average (min) Standard-deviation (min) Average (adimensional) Standard-deviation (adimensional)
6.4 0.13 0.03 1.33 0.27 0.30 0.05
6.8 0.22 0.05 0.78 0.13 0.20 0.04
7.2 0.40 0.12 16.58 34.88 1.51 0.95
Regarding ICH Q8/Q9/Q10 (R2) which explains the role of mod- between formulation and manufacturing process variables and
els in QbD (ICH Q8/Q9/Q10 (R2) 2011c), the models presented in BCS Class II API DT to improve our fundamental knowledge of dis-
this article are categorized as high-impact models. solution testing (DT).
An interesting finding is that the last tested factor, coating Risk analysis, identification of critical formulation/process varia-
weight, had no effect on drug dissolution. This can be explained bles, understanding the effects of these critical variables and inter-
by the fact that the tablets under study were film-coated and actions on key product quality attributes are essential steps to
principally composed of very soluble excipients that dissolved rap- achieve enhanced product and process awareness and offer
idly upon wetting, thus not interfering in tablet disintegration or opportunities to develop control strategies while ensuring final
API dissolution. product quality. Indeed, as DT results at 60 min were all similar, it
According to QbD principles, a specific method is required to was not possible to model dissolution with operating conditions
specify the design space (ICH Q8, R2 2009). Design space gener- specified by USP. Preliminary results have shown that modeling at
ation begins with CQA identification, risk assessment, DoE, model DT time of 10 min can be performed allowing us to understand
building, and design space visualization (Yu 2008; Little, 2013). and predict DT. In these situations, opportunities exist to develop
According to ICH Q8 (R2), a design space can be described in
more flexible regulatory approaches, for example, to facilitate real-
terms of ranges of material attributes and process parameters, or
time quality control, leading to reduction of end-product release
through more complex mathematical relationships (ICH Q8, R2
testing.
2009).
This case study exemplified the application of QbD principles
Thus, the relationship between the process inputs (material
and tools to drug product and process development. It demon-
attributes and process parameters) and the critical quality attrib-
strated that DoE effects/response surface analysis represents a
utes can be described thanks to the design space. Inside the
design space, product quality is assured. powerful tool to investigate the effects of selected factors (API PS,
The design space is proposed by the applicant and is subject tablet hardness, and coating weight) on response–dissolution per-
to regulatory assessment and approval. Therefore, in order to be centages, showing product and process robustness. The following
approved, the model underlying the design space requires fulfill- points comprise the main new information brought forward by
ing specifications. our study:
The design space is this article can be explained mathematic- The two parameters impacting dissolution kinetics at
ally through the equation describing relationships between quality 10 min are API PS and tablet hardness. They can easily be
attributes and process parameters and/or Material Attributes: controlled during and after the manufacturing process
Y(Dissolution percentage at a specific time) ¼ F(API PS and tablet with standard equipment such as an online laser-granul-
hardness). ometer and hardness tester, this information is highly use-
Moreover, according to the results of the current study, the ful for formulation improvement.
edge of failure of the design space is beyond the selected limits Models can be used to predict DT if appropriate validation
for this modified control strategy. The selected limits for this was to be performed.
modified control strategy are presented in Table 8. This QbD approach demonstrates product and process
Thus, the edge of failure of the design space was beyond the robustness.
limits selected. As stated in ICH Q8, R2 and confirmed in The QbD concept can completely eliminate the need of dissol-
“Questions and Answers on Design Space Verification” published ution testing or eventually either decreases required dissolution
on 24 October 2013 (FDA and EMEA 2013), the determination or testing time as the finale dissolution percentage can be predicted
demonstration of edge of failure is not an essential part of the knowing the first minute dissolution percentage the first minutes’
definition of design space; the edge of failure of this design space dissolution percentage. Thus, dissolution test can be reduced, or
was found to be outside the selected parameters studied. even eliminated, if confirmed by a validation procedure.
Moreover, our study proves that the examined manufacturing pro- In conclusion, the methodology presented in this article (FMEA,
cess was robust. DoE, and Design space definition) could be replicated and per-
For the formulation under study, which has a relatively simple formed in other dosage forms like controlled release tablets, emul-
dissolution behavior, the first order model worked satisfactorily. sions, suspensions, etc.
However, more complex formulation where drug release depends
on amount of other ingredients like controlled-release polymers
and pH modifiers might be determined by other models (Costa Disclosure statement
and Sousa Lobo 2001). In this case, the advantages and disadvan-
tages of model dependent and model independent methods The author declares that she has no relevant or material financial
should be examined to predict dissolution. Once the ability to interests that relate to the research described in this paper.
predict dissolution with a model is well demonstrated, meeting
the remaining requirement for implantation in pharmaceutical
control quality strategy like method validation based on current References
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