International Journal of Industrial

Engineering & Technology (IJIET)

ISSN 2277-4769
Vol. 3, Issue 4, Oct 2013, 15-24
TJPRC Pvt. Ltd.

CRITICAL QUALITY RISK ANALYSIS OF PROCESS PARAMETERS OF FLUID BED

COATING TECHNOLOGY

AMIT KHANDAGADE1, VINITA KALE2 & RAVI SINHA3

1,2
Department of Pharmaceutics, Gurunanak College of Pharmacy, Nagpur, Maharashtra, India
3
Abboott India Ltd, Mumbai, Maharashtra, India

ABSTRACT

The fluidized bed coating (FBC) is a complex process in pharmaceutical formulation engineering since there are a
number of parameters that can affect it. In order to develop a robust pharmaceutical manufacturing process, it is important
to determine all the critical process parameters (CPP) affecting critical quality attribute of the final product. There are
many problems with a fluid bed coating process that produced inconsistent results. Many of the coating parameters
interacted with each other, so conventional one-factor-at-a-time (OFAT) experiments were unable to resolve the issue.

Design of experiments examines all of the variables simultaneously so it enabled us to identify the optimum
values for the factors much more quickly. Main objective of this study is to provide a sophisticated robust and rugged FBC
for the preparation of Ciprofloxacin Pellets with desired quality and performance (i.e. dissolution).

KEYWORDS: Fluid Bed Coating, Optimization, Design of Experiment, Quality Risk Management

INTRODUCTION

Fluid bed processing involves coating, granulation, agglomeration and drying of particulate material. A fluidized
bed is a bed of solid particles with a stream of air or gas passing upward through the particles at a rate great enough to set
them in motion. It is possible to propagate wave motion, which creates the potential for improved mixing. The fluid bed
can be used to coat particles for controlled release or taste masking, dry the wet product, agglomerate particles, improve
flow properties etc. [1]

The three patterns of the fluid-bed processes could be characterized by the position/location of the spray nozzle
i.e. top spray, bottom spray and tangential spray. The most commonly known fluid-bed process for coating in the
pharmaceutical industry is the bottom-spray (Wurster) process. Developed by Dr. Dale Wurster in the late 1950s, the
technique is well recognized for providing excellent coating uniformity and efficiency.

The bottom-spray (Wurster) fluid-bed method is very popular in the pharmaceutical industry for active layering
and for coating to modify or control drug release because it produces a superior film compared with other coating
techniques.

Table 1: Parts of Fluid Bed Coating Machine

Parts of Fluid Bed Coating Machine
1 Nozzle Droplet size and Distribution is controlled
2 ADP Distribute fluidizing air between the inner and outer partitions
3 Plenum Chamber Equalise pressure for more even distribution
4 Cylinder (PG) Particles are actually sucked through the partition gap
5 Candles/ Filter bags For continuous fluidization
6 Expansion chamber For recurring flow of the particles
16 Amit Khandagade, Vinita Kale & Ravi Sinha

Table 2: Process Parameters and Formulation Parameters in Fluid Bed Coating

Parameters
Process Parameters
1 Blower speed
2 Atomization
3 Inlet temperature
4 Spray rate
5 Pump rpm
Formulation Parameters
1 Strength of coating solution
2 Size distribution of substrate
3 Batch size of substrate

Process variables for the Fluid bed coating technology include the liquid addition rate, inlet air temperature,
fluidization blower speed, process air humidity, and the atomization air pressure. It should be noted that atomization air
volume is the key variable, but it often is gauged by atomization air pressure. [2]

Figure 1: Fluid Bed Coating Process

FBC Operation and Operation Parameters

Air enters through the plenum chamber and is evenly distributed to provide uniform fluidization and heat transfer.
Pellets are fluidized by air stream, as the particle moves upward, they are decelerated in the expansion chamber and then
fall outside the wurster column. The returned particles move downward until they are sucked back up to the loop again.
Pellets are actually sucked through the gap, drawn to the centre of the plate, and accelerated inside of the partition (re-enter
the partition column though the partition gap) and repeat the fountain-like cyclic flow. Particles receive coating droplets
during the passage through the spray zone and dried by hot air within the partition column.

Critical Quality Risk Analysis of CPPs by QRM

Risk assessment is a valuable science-based process used in Quality Risk Management (QRM) (ICH Q9) that
aided in identifying which material attributes and process parameters potentially had an effect on product Critical Quality
Attributes (CQAs). Risk assessment is typically performed early in the development stage & is repeated as more
information & greater knowledge is obtained. Risk assessment tools i.e. matrix analysis & Failure Mode Effective Analysis
(FMEA) can be concisely used to identify and rank parameters with potential to have an impact on IP/FP CQAs, based on
prior knowledge and initial experimental data. Risk analysis is the estimation of the risk associated with the identified
hazards. It is the qualitative or quantitative process of linking the likelihood of occurrence and severity of harms. The
Critical Quality Risk Analysis of Process Parameters of Fluid Bed Coating Technology 17

ability to detect the harm (detectability) also factors in the estimation of risk. Risk evaluation compares the identified and
analyzed risk against given risk criteria. This list can be refined further through experimentation to determine the
significance of individual variables and potential interactions through a combination of DOEs, mathematical models or
studies that lead to mechanistic understanding to achieve a higher level of process understanding. [3]

The aim of this study was to utilize quality risk management process to increase the process understanding of
fluid bed coating technology. Main objective of this quality risk management (QRM) study is to provide a sophisticated
"robust and rugged" Fluidized Bed Process (FBP) for the coating of pellets with desired quality and performance
(i.e. dissolution).

MATERIALS AND METHOD

Materials

Sugar pellets of size 10# were used as cores for coating. Ciprofloxacin HCl (Zim Laboratories, Nagpur), HPMC
(Colorcon), PVP (Himedia), Ethyl Cellulose (Himedia), Ethanol (China), Titanium Dioxide (Merck) were used in present
study.

Method
Quality Risk Analysis

Recent regulatory guidelines strongly encourage the pharmaceutical industry to apply scientific and risk
management approaches to the development of a product and its manufacturing process. Qualitative Initial Risk-Assesment
from prior knowledge and Quantitative Failure Mode Effective Analysis (FMEA) are used to identify and rank parameters
with potential to have an impact on in Process/Finished Product Critical Quality Attributes (IP/FP CQAs). These Critical
Process Parameters (CPPs) were further refined by DoE that leads to implementation of a control strategy to achieve
consistent finished product quality to prevent possible product failure.

Figure 2: Shows Diagrammatic Representation of Quality Risk Management Process

Risk assessment consists of the identification of hazards and the analysis and evaluation of risks associated with
exposure to those hazards. Quality risk assessments begin with a well-defined problem description or risk question.
18 Amit Khandagade, Vinita Kale & Ravi Sinha

Risk control includes decision making to reduce and/or accept risks. The purpose of risk control is to reduce the
risk to an acceptable level.

Risk Review: The output/results of the risk management process should be reviewed to take into account of new
knowledge and experience.

Depending on prior knowledge and FMEA results, process understanding experiment [Design of Experiments
(DoE)] was developed for FBP and parameters having higher risk priorities were identified in product development. The
effect of each independent CPPs on dependent product quality (e.g. Fines generated, release profile etc.) were analyzed for
establishment of DS to design, analyze, and control manufacturing through timely measurements of critical quality and
performance attributes in-process parameters, which were modeled out with the goal of ensuring product quality. Here, for
establishment of DS for CPPs, Plancket Burman design was used for optimization procedure. [4]

Many authors found that the critical processing factors that most affect coating characteristics were rate of binder
[5] [6]
addition , degree of atomization of the binder liquid , process-air temperature [7], fluidization air velocity [8], and height
[9]
of the spray nozzle from the bed . Each of this process parameter is a very high risk for the development of robust and
rugged fluid bed process (FBP), thus it should be optimized and managed properly in precise manner to reduce its impact
on overall quality of end product[10],[11]. An ideal model for QRM is outlined in above Figure 1.

FMEA

Table 3: Shows FMEA Chart of Process Parameters

Detectability
Occurrence
Severity

RPN
Parameter Failure Mode Failure Effects

Mass/liquid ratio control

Atomization Low or High 3 3 3 27
droplet size
High airflow causes attrition
Blower Low or High 3 3 3 27
and generation of fines
Temperature Low or High Premature Drying 3 3 3 27
Wet quenching,
Spray Rate Low or High 3 2 1 6
agglomeration
Strength of Solution Low or High Blockage of nozzle 2 2 1 4
Batch Size Low or High Affects Fluidization 2 2 1 4
Size Distribution Low or High Affects flow properties 3 1 1 3

Pareto Analysis

Figure 3: Shows Pareto Analysis of Process Parameters

Critical Quality Risk Analysis of Process Parameters of Fluid Bed Coating Technology 19

Design of Experiment

From the above Pareto analysis figure 2, the most three critical process parameters in fluid bed coating were found
to be Blower, Temperature and Atomization. These three parameters were incorporated in three level, Plancket Burman
Factorial design.

Table 4: Three Level Plancket Burman Factorial Design

Plancket Burman Factorial Design well suited to the goal of optimization. The software developed a 12 run which
included 8 combinations of the factors plus four center points used to estimate pure error. A common blend was used to
coat 12 batches in a fluid bed coater with a Wurster insert.

Figure 4: Shows Steps of Coating

Optimization of Batch Size

Fluidization is affected by the quantity of particles which are introduced into the coating chamber, at least 50% of
the volume external to the partition or the wurster tube must be occupied by particles to be coated. This makes it possible
to have a sufficient quantity of particles inside the partition to accumulate the maximum coating solution droplets and to
avoid thereafter the phenomenon of premature drying or depositing on the walls of partition. To calculate the load of
particles to be introduced, it is enough to calculate the external total volume of the partition, to multiply it by the density of
the particles in bulk which gives the total capacity in Kg as described in the equation:

Where r1 and r2 are, respectively, the chamber radius and partition radius, L is the length of partition, pis bulk
density of pellets. [12]

Optimization of Coating Solution

Strength of coating solution plays an important role in nozzle blockade; Upon increasing the strength of coating
solution, the nozzle of Wurster column get blocked due to higher viscosity hence it should not be highly concentrated as
well as very much diluted. So it is important to optimize the strength of coating solution [11]. Different concentrations of
Coating solutions were used to coat the pellets and efficiency of coating is observed. [13]

Optimization of Spray Rate

Spray rate was determined by the drying capacity of the equipment which is directly proportional to cross-
sectional area of the air distribution plate rather than by the increase in batch size. At a given atomization pressure and air
20 Amit Khandagade, Vinita Kale & Ravi Sinha

flow volume, change in liquid spray rate directly affects droplet size which in turn impacts particle agglomeration and may
[14]
cause lumping. Pellets were fluidized and allowed to coat at different spray rate (rpm) and results were monitored.

Evaluation of Pellets [15]

Content Uniformity

Ciprofloxacin Hydrochloride was estimated by using UV-Spectrophotometer at 271nm. Formulation quantity

equivalent to 25 mg of Ciprofloxacin Hydrochloride was taken for assay and dissolved in 10 ml of water, sonicated and
1ml sample was withdrawn and volume was made upto 10ml. From this 1ml solution was taken and volume was made
upto 10ml. After filtration drug content was analyzed spectrophotometrically at about 271nm. Each sample was assayed to
triplicate (n=3).

Microscopic Study

Pellets size formed after each coating is observed under electronic microscope. Motic is used to study the pellets.
Their radius, area and perimeter were observed.

In-Vitro Drug Release Study

The drug release study for the prepared pellets was carried out using USP XII Dissolution Test Apparatus-I
(Electrolab) basket method in 900 ml 0.1N HCl maintained at 370.50C, at 50 rpm for first 2 Hours and 6.8 pH buffer for
next 6 hours. Accurately weighed pellets were placed in each flask of dissolution apparatus. Samples were withdrawn
using graduated pipette. The samples were filtered through whatman filter paper. The fresh dissolution medium replaced
every time with same amount of sample. The collected samples were suitably diluted and absorbance was measured
spectrophotometrically at 271 nm. The percentage of Ciprofloxacin HCl released at various time intervals was calculated
and plotted against time. The results indicated for each dissolution studies are the average of three determinations.

RESULTS AND DISCUSSIONS

Table 5: Shows Optimization of Batch Size
Pellets Coating Material Batch Size Efficiency
Sugar Pellets HPMC 2%
348.50gm Maximum
(10 no.) PVP 0.4%

Variation in batch size changes the quality of final product. The more batch size varies the more quality issues
that will arise in the coating process.

Table 6: Shows Optimization of Strength of Coating Solution

Process Parameters Trial 1 Trial 2 Trial 3 Trial 4
HPMC 5% HPMC 4% HPMC 3% HPMC 2%
Coating Formula
PVP 0.4% PVP 0.4% PVP 0.4% PVP 0.4%
Load 150 gm 150gm 150gm 150gm
PG (mm) 18 18 18 18
Coating level (% w/w) 2 2 2 2
Nozzle get Nozzle get Nozzle get Uniform
Observation
Blocked Blocked Blocked Coating

Strength of coating solution is important parameter in fluid bed coating technology. Upon increasing the strength
of coating solution, the nozzle of wurster column gets blocked due to higher viscosity. 2% HPMC solution was found to be
ideal for coating.
Critical Quality Risk Analysis of Process Parameters of Fluid Bed Coating Technology 21

Optimization of Spray Rate

Table 7: Shows Optimization of Spray Rate

Parameters Trial 1 Trial 2 Trial 3 Trial 4 Trial 5
Blower 30 30 30 30 30
Temperature 45 45 45 45 45
Atomization 0.8 0.8 0.8 0.8 0.8
Spray rate 5 4 3 2 1
Pellets Pellets Pellets Pellets
Ideal for
Observation adhere to the adhere to the adhere to the adhere to the
coating
wall of FBP wall of FBP wall of FBP wall of FBP
Parameters Trial 6 Trial 7 Trial 8 Trial 9 Trial 10
Blower 40 40 40 40 40
Temperature 60 60 60 60 60
Atomization 1.2 1.2 1.2 1.2 1.2
Spray rate 5 4 3 2 1
Pellets Pellets Pellets Pellets
Ideal for
Observation adhere to the adhere to the adhere to the adhere to the
coating
wall of FBP wall of FBP wall of FBP wall of FBP

Figure 5: Microscopic Image of Wet Quenching

When an atomized coating solution successfully collides with pellets, it wets their surfaces. Depending on the
conditions inside the bed, wetted particles may collide and form liquid bridges between them or they can be dried resulting
in a layered growth. If there is excessive wetting, many pellets will form bridges between them, thus joining together to
form large wet clumps which will lead to the defluidization of the bed in a phenomenon known as wet quenching. In the
case of moderately wetted particles, a number of pellets will remain joined together when their liquid bridges are dried.

Table 8: Shows Optimized Formula for Coating

Agglomerative Colour Base Coating Ethyl Cellulose

Process Parameters Base Coating
Coating Coating with Drug Coating
HPMC 2% HPMC 2%
HPMC 2% HPMC 2%
Coating Formula PVP 0.4% PVP 0.4% EC 2%
PVP 0.4% PVP 0.4%
EY q.s. Drug 2%
Load 150 gm 140gm 130gm 120gm 100gm
PG (mm) 18 18 18 18 18
Coating level (% w/w) 2 6 2 Till dose achieved 2

Evaluation of Pellets

Drug Content: Drug content of pellet formulation (FC8) was found to be 99.140.6425. So the drug content was
found to be within limits.
22 Amit Khandagade, Vinita Kale & Ravi Sinha

In Vitro Drug Release

The different formulations prepared by changing the process variables were subjected to in-vitro drug release
studies. All the formulations were filled into hard gelatine capsules and in vitro drug release study was carried out in USP
dissolution apparatus basket type USP XXII (Electrolab) at 50rpm. From table, it was observed that 92.97% of drug
released in 8 Hrs from formulation FC8.

Figure 6: Comparative In-Vitro Release Profile of Coated Pellets w. r. t. Marketed Formulation

Contour Plot

Figure 7: Shows Contour Plot for Atomization at Low Level and High Level

A contour plot is a graphic representation of the relationships among three numeric variables in two dimensions.
The Blower and temperature effects can be examined graphically by looking at contour plots at various level of
atomization time point 1 with atomization at its low level as seen in Figure 7. This plot shows that a higher percentage
of the product is released when temperature is high, blower is low and atomization air volume is low.

Multi-Vari Chart for Drug Release (%DR) with Respect to Temperature, Blower and Atomized Air

Figure 8: Shows Multi Vari Chart for Drug Release

Critical Quality Risk Analysis of Process Parameters of Fluid Bed Coating Technology 23

From the above multi vari chart it was found that maximum dissolution was found at 60C, 30Hz Blower and 0.8
Atomization.

Optimized Parameters

From all above observations and results, the optimized process parameters were found to be:

Table 9: Shows Optimized Process Parameters

Parameters Optimized
Blower 30
Inlet Temperature 60
Product Bed Temp (High) 55
Product Bed Temp (Low) 50
P.Pump (rpm) 1 rpm
Atm. Air 0.8

CONCLUSIONS

Fluid bed processor offer unique opportunity to develop and produce coated controlled release products.
However, various process parameters easily can alter the performance of a product and hence should be examined
thoroughly. The interactions of various process parameters presents a great challenge in optimizing the coating process,
hence it is important to investigate and understand these variables to ensure a reproducible performance of controlled
release products.

From the result of this QRM study for Ciprofloxacin drug formulation with Control Strategy engendered by
Three level, Plancket Burman Design: It has been proved that QRM, along with DoE can be a systematic process for the
assessment, control, communication, and review of any process-related risks to the quality of the drug product. In FBP,
there are so many factors which may affect final product. In this study all these parameters were identified and optimized.

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