Chapter 1 1 INTRODUCTION Introduction: 1. Introduction to Quality by Design Quality by Design (QbD) refers to a holistic approach towards drug development. Quality by design is a vital part of the modern approach to pharmaceutical quality. Quality by Design (QbD) was first described by Joseph M. Juran, and applied heavily, particularly in the automotive industry. The fundamental premise behind QbD is that quality can be “designed in” to processes through systematic implementation of an optimization strategy to establish a thorough understanding of the response of the system quality to given variables, and the use of control strategies to continuously ensure quality. The FDA has recently begun to advocate the QbD methodology for the pharmaceutical sector.[1] Definition: A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.[2] The overview of QbD is shown in figure 1. FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
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Chapter 11
INTRODUCTION
Introduction:
1. Introduction to Quality by Design
Quality by Design (QbD) refers to a holistic approach towards drug development. Quality by
design is a vital part of the modern approach to pharmaceutical quality. Quality by Design
(QbD) was first described by Joseph M. Juran, and applied heavily, particularly in the
automotive industry. The fundamental premise behind QbD is that quality can be “designed
in” to processes through systematic implementation of an optimization strategy to
establish a thorough understanding of the response of the system quality to given
variables, and the use of control strategies to continuously ensure quality. The FDA has
recently begun to advocate the QbD methodology for the pharmaceutical sector.[1]
Definition:
A systematic approach to development that begins with predefined objectives and emphasizes
product and process understanding and process control, based on sound science and quality
risk management.[2]
The overview of QbD is shown in figure 1.
Fig No 1.1 Overview of Quality by design [1]
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1.1. Regulatory aspects:
In Aug 2009, ICH released a guideline Q8R(2) (Step 4) to guide the industry in the
implementation of quality by design (QbD) in Section 3.2.P.2 (Pharmaceutical
Development) for drug products as defined in the scope of Module 3 of the Common
Technical Document (ICH guideline M4). QbD (ICH Q8(R2)) is defined as “a systematic
approach to development that begins with predefined objectives and emphasizes product
and process understanding and process control, based on sound science and quality risk
management.” This is a more systematic approach to development which include, for
example, incorporation of prior knowledge, results of studies using design of
experiments, use of quality risk management (ICH Q9), and use of knowledge
management (ICH Q10) throughout the lifecycle of the product.[3]
Fig. 1.2 Regulatory Aspects: ICH Q8,Q9, Q10 guidelines [4]
1.2. Principle:
In all cases, the product should be designed to meet patients’ needs and the intended product
performance. Strategies for product development vary from company to company and from
product to product. The approach to, and extent of, development can also vary and should be
outlined in the submission. An applicant might choose either an empirical approach or a more
systematic approach to product development. A more systematic approach to development
also defined as quality by design) can include, for example, incorporation of prior knowledge,
results of studies using design of experiments, use of quality risk management, and use of
knowledge management (see ICH Q10) throughout the lifecycle of the product. Such a
systematic approach can enhance the process to achieve quality and help the regulators to
better understand a company’s strategy. Product and process understanding can be updated
with the knowledge gained over the product lifecycle.
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A greater understanding of the product and its manufacturing process can create a basis for
more flexible regulatory approaches. The degree of regulatory flexibility is predicated on the
level of relevant scientific knowledge provided in the registration application. It is the
knowledge gained and submitted to the authorities, and not the volume of data collected, that
forms the basis for science-and risk-based submissions and regulatory evaluations.
Nevertheless, appropriate data demonstrating that this knowledge is based on sound scientific
principles should be presented with each application.[2]
1.3. Advantages of QbD [1]:
1. It provides a higher level of assurance of drug product quality.
2. It offers cost savings and efficiency for the pharmaceutical industry.
3. It increases the transparency of the sponsor understands the control strategy for the
drug product to obtain approval and ultimately commercialize.
4. It makes the scale-up, validation and commercialization transparent, rational and
predictable.
5. It facilitates innovation for unmet medical needs.
6. It increases efficiency of pharmaceutical manufacturing processes and reduces
manufacturing costs and product rejects.
7. It minimizes or eliminates potential compliance actions, costly penalties, and drug
recalls.
8. It offers opportunities for continual improvement.
9. It provides more efficiency for regulatory oversight:
10. It streamlines post approval manufacturing changes and regulatory processes.
11. It more focused post approval CGMP inspections
12. It enhances opportunities for first cycle approval.
13. It facilitates continuous improvement and reduces the CMC supplement.
14. It enhances the quality of CMC and reduces the CMC review time.
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1.4. Steps in Quality by Design[5]
Fig. 1.3 Steps in Quality by Design
1.5. The Target Product Quality Profile (TPQP): [6]
The quality target product profile (QTPP) is “a prospective summary of the quality
characteristics of a drug product that ideally will be achieved to ensure the desired quality,
taking into account safety and efficacy of the drug product” Target Product Quality Profile
(TPQP) is a tool for setting the strategic foundation for drug development — “planning with
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The TPP can play a central role in the entire drug discovery and development process such
as: effective optimization of a drug candidate, decision-making within an organization,
design of clinical research strategies, and constructive communication with regulatory
authorities. TPP is currently primarily expressed in clinical terms such as clinical
pharmacology, indications and usage, contraindications, warnings, precautions, adverse
reactions, drug abuse and dependence, over dosage, etc. Thus, it is organized according to
key sections in the product’s label. TPP therefore links drug development activities to
specific statements intended for inclusion in the drug’s label. Target Product Quality Profile
(TPQP) is a term that is a natural extension of TPP for product quality. The TPQP of a
generic drug can be readily determined from the reference listed drugs (RLD). Along with
other available information from the scientific literature and possibly the pharmacopeia, the
TPQP can be used to define product specifications to some extent even before the product is
developed.
When ICH Q8 says that pharmaceutical development should include “...identification of
those attributes that are critical to the quality of the drug product, taking into consideration
intended usage and route of administration”, the consideration of the intended usage and
route of administration would be through the TPP.
Many aspects of the TPP constrain or determine the actions of formulation and process
development scientists. These can include the route of administration, dosage form and size,
maximum and minimum doses, pharmaceutical elegance (appearance), and target patient
population (paediatric formulations may require chewable tablets or a suspension). Common
aspects of drug product quality are implicitly in the TPP.[6]
Based on the clinical and pharmacokinetic (PK) characteristics as well as the in vitro
dissolution and physicochemical characteristics of the RLD, a quality target product profile
(QTPP) is defined.
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1.6. Critical Quality Attributes:[2, 5]
A CQA is a physical, chemical, biological, or microbiological property or characteristic that
should be within an appropriate limit, range, or distribution to ensure the desired
product quality. CQAs are generally associated with the drug substance, excipients,
intermediates (in-process materials) and drug product.
CQAs of solid oral dosage forms are typically those aspects affecting product purity,
strength, drug release and stability. CQAs for other delivery systems can additionally include
more product specific aspects, such as aerodynamic properties for inhaled products,
sterility for parenterals, and adhesion properties for transdermal patches.
For drug substances, raw materials and intermediates, the CQAs can additionally
include those properties (e.g., particle size distribution, bulk density) that affect drug product
CQAs.
Potential drug product CQAs derived from the quality target product profile and/or
prior knowledge are used to guide the product and process development. The list of potential
CQAs can be modified when the formulation and manufacturing process are selected and as
product knowledge and process understanding increase. Quality risk management can be
used to prioritize the list of potential CQAs for subsequent evaluation. Relevant CQAs
can be identified by an iterative process of quality risk management and experimentation
that assesses the extent to which their variation can have an impact on the quality of the
drug product.
Process parameters and material attributes are critical when a realistic change can result in
failure for the product to meet the QTPP or a CQA that is outside an acceptable range.
Process parameters are not critical when there is no trend to failure and there is no evidence
of significant interactions within the proven acceptable range.
CQA has been used by some to describe elements of the TPQP (such as dissolution) while
others have used CQA to describe mechanistic factors (such as particle size and hardness)
that determine product performance. Thus CQA is used to describe both aspects of product
performance and determinants of product performance. The 2004 Q8 draft put CQA and
performance tests into the same pile of physiochemical and biological properties: The
physicochemical and biological properties relevant to the performance or manufacturability
of the drug product should be identified and discussed. These could include formulation
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attributes such as pH, dissolution, particle size distribution, particle shape, polymorphism,
rheological properties, and biological activity or potency, and/or immunological activity. [5]
1.7. Critical Process Parameters:
Critical process parameter is a process parameter whose variability has an impact on a critical
quality attribute and therefore should be monitored or controlled to ensure the process
produces the desired quality.
In this view, every item would be a process parameter. We propose that process parameter be
understood as referring to the input operating parameters (mixing speed, flow rate) and
process state variables (temperature, pressure) of a process or unit operation.[2]
1.8. Risk Assessment [7]:
Low: Broadly acceptable risk. No further investigation is needed
Medium: Risk is acceptable. Further investigation may be needed in order to reduce the risk.
High: Risk is unacceptable. Further investigation is needed to reduce the risk
Overview of typical quality risk management [9]
Fig. 1.4 Quality risk management
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1.9.1. Methods of Risk Assessment:
1.9.1. A. Ishikawa (fishbone) diagram:
It is a very effective tool to capture a brainstormed list of potential process inputs impacting
variation. Mapping the manufacturing process using a process flow diagram (PFD) is helpful
to define the scope of the risk assessment and to identify possible process inputs. API
mapping may include unit operation, chemistry pathways, and an impurities cascade. [8]
Example of Ishikawa (Fish bone) diagram is shown in figure 2:
Figure 1.5 - Ishikawa fishbone diagram
1.9.1. B. FMEA (failure modes and effects analysis): or use of a prioritization matrix
(cause and effect matrix) is helpful in identifying the process inputs that impact on quality
attributes. In some cases, a deeper dive into the driving forces at critical control points in the
manufacturing process can yield a more fundamental understanding of sources of variation.
Before embarking on extensive experimentation, a critical next step is to make sure that
critical measurements are made using ‘‘fit for purpose’’ methodology. A comprehensive risk
assessment should identify those measurements that are suspect. A simple frequency plot of
the data with specification limits will provide an indication of when variation is a potential
problem. [8]
FMEA provides for an evaluation of potential failure modes for processes and their likely
effect on outcomes and/or product performance.
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Steps: [11]
1. Selection of the process
2. Review of the process
3. Brainstorm potential failure modes
4. List of potential effects of each failure mode
5. Assign a severity rating for each effect
6. Assign an occurrence rating for each failure mode
7. Assign a detection rating for each failure mode and effect
8. Calculation of the risk priority number (RPN) for each effect: (RPNs) = O×D×S
9. Prioritize the failure modes for action
10. Taken action to eliminate or reduce the high risk failure modes
11. Improvement index (II): II = (RPN before improvement) / (RPN after improvement)
1.9.1. C. Fault tree analysis
1. Assumes failure of the functionality of a product or process.
2. Identifies all potential root causes of an assumed failure or problem that it is thought
to be important to prevent.
3. Evaluates system or sub system failure one at a time.
4. Can combine multiple causes by identifying casual chains. [8]
1.9.2. Success factors in Risk Management: [1]
Risk management should
1. Create value
2. Be an integral part of organizational processes
3. Be part of decision making
4. Explicitly address uncertainty
5. Be systematic and structured
6. Be based on the best available information
The two primary principles should be considered when implementing quality risk
management: [12]
1. The evaluation of the risk to quality should be based on scientific knowledge and
ultimately link to the protection of the patient; and
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2. The level of effort, formality and documentation of the quality risk management
process should be commensurate with the level of risk.
1.10. Design Space: [5]
ICH Q8 (R1) defines design space as, the multidimensional combination and interaction of
input variables (e.g., material attributes) and process parameters that have been demonstrated
to provide assurance of quality. This definition evolved from early ICH Q8 drafts where
design space was defined as “the established range of process parameters that has been
demonstrated to provide assurance of quality”. The schematic representation of design space
is shown in figure 3:
Fig. No.1.6 Schematic representation of Design Space
Design space is proposed by the applicant and is subject to regulatory assessment and
approval. Because design space is potentially scale and equipment-dependent, the design
space determined at the laboratory scale may not be relevant to the process at the commercial
scale. Therefore, design-space verification at the commercial scale becomes essential unless
it is demonstrated that the design space is scale-independent.
1.10.1. Steps for the Design Space: [8]
Identify the unclassified parameters.
Applying design of experiment on some of unclassified parameters with the other
unclassified parameters fixed.
End is a regulatory situation with some space for the selected parameters but no
flexibility for other parameter.
1.10.2. Implications of Design Space: [13]
Increased process and product understanding.
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Increased assurance to regulators i.e. regulatory flexibility.
In some cases boundaries will be identified that are known to be an edge of failure. In these
situations, it may be important to set boundaries at acceptable tolerance intervals around the
edge of failure to better mitigate the risks near such edges. Application of tolerance interval is
not necessary when the edges of failure are not in play at design space boundaries.
1.11. Control strategy [6]
A planned set of controls, derived from current product and process understanding that
ensures process performance and product quality.
The Control Strategy should establish the necessary controls - based on patient requirements -
to be applied throughout the whole product lifecycle from product and process design
through to final product, including API and Drug Product manufacture, packaging and
distribution.
The controls can include parameters and attributes related to:
Drug substance,
Drug-product materials and components,
Facility and equipment operating conditions,
In-process controls,
Finished-product specifications,
The associated methods and
Frequency of monitoring and control. (ICH Q10)
Specifically, the control strategy may include control of input material attributes (e.g., drug
substance, excipients, and primary packaging materials) based on an understanding of their
impact on process-ability or product quality, Product specifications, Practical controls,
Facility controls, such as utilities, environmental systems and operating conditions, Controls
for unit etc. Implementing Control Strategy will require the application of process models
(multivariate prediction models) that either predicts CQAs or CPPs or a combination of both.
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1.11.1 Developing the control strategy: [1]
Development of a Control Strategy requires a structured process, involving a multi-
disciplinary team of experts, linking pharmaceutical development to the manufacturing
process, and engineering controls of process equipment. The PQLI Control Strategy Team
has proposed a Control Strategy Model that facilitates understanding and that may be used a
cross-functional communication tool. Personnel at all levels should be able to understand the
way control strategy links from CQAs to operational aspects to ensure, for example that:
1. Chemists understand in-process controls are established to keep the process inside the
design
2. Space and seek opportunities for simplification of controls, as knowledge is gained.
3. Engineers know how equipment operating conditions impact product quality.
4. Quality Assurance professionals know where the highest risks are in the process.
Although the primary driver for development of a control strategy will be assurance of
product safety, efficacy and quality, the Control Strategy may also ensure the meeting of
other business objectives such as operator health and safety, protection of the
environment, manufacturability and supplies related issues, efficiency, and profitability.
5. Development of a Control Strategy for a product will therefore be a structured activity
involving a multidisciplinary team of experts. This team may include representatives
from formulation development, drug substance development, process development,
analytical development, QC, QA, Regulatory Affairs, manufacturing, engineering, and
specialists in Process Analytical Technology (PAT) and chemo-metrics. A Control
Strategy and a product release strategy are not the same, but demonstration of adherence
to the Control Strategy would support the product or batch release strategy.
1.12. Tools of Quality by Design
1.12.1 Design of Experiments (DOE) [14, 37]
Design of experiments (DOE) is a structured and organized method to determine the
relationship among factors that influence outputs of a process.
Application of DOE in QbD helps in gaining maximum information from a minimum number
of experiments. When DOE is applied to a pharmaceutical process, factors are the raw
material attributes (e.g., particle size) and process parameters (e.g., speed and time), while
outputs are the critical quality attributes such as blend uniformity, tablet hardness, thickness,
and friability. As each unit operation has many input and output variables as well as process
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parameters, it is impossible to experimentally investigate all of them. Scientists have to use
prior knowledge and risk management to identify the key input and output variables and
process parameters to be investigated by DOE. DOE results can help identify optimal
conditions, the critical factors that most influence CQAs and those who do not, as well as
details such as the existence of interactions and synergies between factors.
DOE provides an enhanced knowledge of product performance over a wider range of
material attributes, processing options and process parameters. This proves a higher degree of
process understanding. Scientific understanding is important to provide a design space, which
is an important part of quality by design, and can be gained by formal design of experiments.
Types of Designs:
Factorial design: In a factorial design the influences of all experimental variables,
factors, and interaction effects on the response or responses are investigated. If the
combinations of k factors are investigated at two levels, a factorial design will consist of 2k
experiments.
Fractional factorial design: To investigate the effects of k variables in a full factorial design,
2k experiments are needed. Then, the main effects as well as all interaction effects can be
estimated. To investigate seven experimental variables, 128 experiment will be needed; for
10 variables, 1024 experiments have to be performed; with 15 variables, 32,768 experiments
will be necessary. It is obvious that the limit for the number of experiments it is possible to
perform will easily be exceeded, when the number of variables increases. In most
investigations it is reasonable to assume that the influence of the interactions of third order or
higher are very small or negligible and can then be excluded from the polynomial model.
This means that 128 experiments are too many to estimate the mean value, seven main effects
and 21 second order interaction effects, all together 29 parameters. To achieve this, exactly
29 experiments are enough. To determine main effects, it is sufficient to perform less no of
experiments. Depending on the size of fraction, and number of variables, a lesser no. of
experiments are possible using fractional factorial design.
Optimization:
Two strategies can be applied: Simplex optimization and response surface methodology.
Simplex optimization: A simplex is a geometric figure with (k+1) corners where k is equal to
the number of variables in a k dimensional experimental domain. When the number of
variables is equal to two the simplex is a triangle.
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Response surface methodology: Response surfaces are used to determine an optimum. In
addition, it is a good way to graphically illustrate the relation between different experimental
variables and the responses. To be able to determine an optimum it is necessary that the
polynomial function contains quadratic terms.
Central composite design: A full central composite design consists of the following parts:
A full factorial or fractional factorial design. Experiment at centre. Experiments where points are situated on the axis in a coordinate system and are axial
points.
Mixture designs: In mixture experiment, it is not the actual amount of a single ingredient that
matters, but rather its proportion in relation to other ingredients. The sum of all the
ingredients is a constant total T, which is equal to 100% or 1. The constant total T represents
a constraint on mixture experiments that implies independence between all mixture factors.
1.12.2. Process Analytical Technology (PAT): [15]
PAT has been defined as “A system for designing, analysing, and controlling manufacturing
through measurements, during processing of critical quality and performance attributes of
raw and in-process materials and processes, with the goal of ensuring final product quality”.
The goal of PAT is to “enhance understanding and control the manufacturing process, which
is consistent with our current drug quality system: quality cannot be tested into products; it
should be built-in or should be by design.” The design space is defined by the key and critical
process parameters identified from process characterization studies and their acceptable
ranges. These parameters are the primary focus of on-, in- or at-line PAT applications. In
principle, real-time PAT assessments could provide the basis for continuous feedback and
result in improved process robustness. NIR act as a tool for PAT and useful in the RTRT
(Real Time Release Testing) as it monitors the particle size, blend uniformity, granulation,
content uniformity, polymorphism, dissolution and monitoring the process online, at the line
and offline, thus it reduces the release testing of the product.
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1.13. Introduction to sustained release:
The basic goal of therapy is to achieve a steady state blood level that is therapeutically
effective and non-toxic for an extended period of time. The design of proper dosage regimens
is an important element in accomplishing this goal. Sustained release (SR) dosage forms
continue to draw attention in the search for improved compliance and decrease the incidence
of adverse drug reactions [16]. A sustained release system includes any delivery system that
achieves slow release of the drug over an extended period of time.
(HPMC, Xanthan gums, CMC), or synthetic (polyacrylamides) can be used.
Reservoir Devices
In these systems an inner core of drug is surrounded by a water insoluble polymeric
membrane. The polymer can be applied by coating or microencapsulation techniques.
Commonly used polymers are HPC, Ethyl cellulose and polyvinyl acetate. The drug release
mechanism across the membrane involves its partitioning into the membrane with subsequent
release into the surrounding fluid by diffusion.
Dissolution and Diffusion controlled Release system
In such system, the drug core is enclosed in partially soluble coating. Pores are formed due to
dissolution of parts of the membrane which can permit entry of dissolution fluid into the core
and hence drug dissolution and allow diffusion of dissolved drug out of the system.
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LITERATURE SURVEY
Sr. No.
Author/Organisation
Title Conclusion/ Description
Quality By Design
1.
International Conference On Harmonisation(ICH) [2]
Pharmaceutical Development Q8R(2)
Describes in detail basic principles of Quality by Design
2. Sandipan Roy [25]
Quality by design: A holistic concept of building quality in pharmaceuticals
Gives the details of role of OGD to integrate QbD into its ANDA drug filing by using a question based review.
3.CMC IM Working Group [26]
Pharmaceutical Development: Case study: ACE tablets
Case study explaining each step of Quality by design approach used for ACE tablets along with in vivo testing
Sustained Release Formulation
4.Dinanath Gaikwad et al [22]
Formulation and Evaluation of Sustained Release Tablet of Aceclofenac by Film Coating
SR tablets were prepared by using HPMC E5 LV. Diffusion disso controlled prolonged and gradual release was obtained.
5.Bhavani Boddeda et al [27]
Formulation and evaluation of glipizide sustained release tablets
Of 2 hydrophobic polymers and 2 hydrophilic gum resins, Olibanum was found to exchibit better SR characteristics
Venlafaxine Hydrochloride
6.Shital Bhavin Butani [28]
Development and Optimization of Venlafaxine Hydrochloride Sustained Release Triple Layer Tablets Adopting Quality by Design Approach
Triple layer tablets were developed by varying amount of important variables and using quality by design approach. Xanthan gum as well as polyethylene oxide was used to formulate matrix tablets with comparable drug release to Effexor®XR 150 mg capsules.
7.Rahul Thorat et al [29]
Formulation development and evaluation of Venlafaxine HCl sustained Release matrix tablet
Optimum concentration of Carbopol 971P and Ethyl cellulose based formulations was found to provide the desired release (95.47%) with a reduced frequency of administration.
8. Sundaraganapathy R. Development and The method was validated with
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LITERATURE SURVEY
Sr. No.
Author/Organisation
Title Conclusion/ Description
[30]
validation of UV spectrophotomericMethod for the determination of VenlafaxineHydrocholoride in bulk and solid dosage forms
respect to linearity, precision, accuracy, selectivity and sensitivity according to ICH guideline anddefinition.
Coating
9.Susanne Tobiska, Peter Kleinebudde [31]
Coating uniformity and coating efficiency in a Bohle Lab-Coater using oval tablets
Pan speed has a big influence on the quality of the film tablets the mass variance of the tablets, disintegration and dissolution behaviour
10.Daniela Brock et al [32]
Evaluation of critical process parameters for inter-tablet coating uniformity of active-coated GITS using Terahertz Pulsed Imaging
Coating uniformity was assessed by calculating the coefficient of variation (CV) of coating thickness, and the CV of API content measured by high performance liquid chromatography (HPLC).
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NEED OF WORK
Need of work: [57]
Currently, most of the pharmaceutical products in the market are of good quality. End product quality for them is not an issue. However, there is a huge scope for improvement at ‘Development and manufacturing’ level.
The improvement may be in terms of:
Minimisation of batch failures and reworks. Minimisation of long cycle times. Transforming traditional ‘Frozen process’ into a flexible process. Implying newer technologies to generate opportunities for improvement.
In current state, the problem is uncontrolled variability, which may be in terms of variability in quality of raw material, or manufacturing processes.
Fig. 3.1 Difference between current manufacturing process and Quality by Design
Objective:
Primary objective:
To study and implement Quality by Design Approach for formulation development and process optimization.
Secondary objective:
1. Formulation development of sustained release tablet by film coating using Quality by Design approach
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PLAN OF WORK
PLAN OF WORK
Sr. No. WORK TO BE DONE
1. Literature survey
2. Selection of drug
3. Selection and Procurement of Excipients and Polymers
4. Study of Quality Target Product profile for formulation
5. Study of Critical Quality attributes of formulation and coating process
6. Marketed product dissolution study
7. Study of components of drug product
1. Drug
2. Polymers
3. Drug excipient compatibility studies
8. Initial risk assessment for tablet formulation using FMEA
9. Tablet Formulation development
10. Coating process development
1. Coating formula development
2. Release optimization
3. Optimization of coating process parameters
11. Study quality attributes of final batch
12. Updated risk assessment for coating process
13. Conclude design space and control strategy for
1. Raw material attributes
2. Tablet compression
3. Coating
14. Stability Studies
15. Conclusion
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Tablet compression machine Rimek minipress II, 12station
R and D coater R and D coater, Ideal Cures
UV Visible Spectrophotometer JASCO V-530
FT-IR Spectrometer JASCO 460 plus
Tablet Dissolution Test Apparatus Electrolab
Friability tester Electrolab
Stability chamber (Thermo lab, TH 200S).
Table no. 5.2: List of equipments
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DRUG AND EXCIPIENT PROFILE
DRUG AND EXCIPIENTS PROFILE
DRUG PROFILE
Venlafaxine Hydrochloride [43, 44, 45]
Sr. No.
Property Description
1. Chemical Structure
Venlafaxine is structurally and pharmacologically related to the atypical opioid analgesic tramadol, and more distantly to the newly released opioid tapentadol, but not to any of the conventional antidepressant drugs, including tricyclic antidepressants, SSRIs, MAOIs, or RIMAs.
2. Chemical Name (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a [a- (dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride.
3. Empirical formula
C17H27NO2.HCl
4. Appearance It is a white to off-white crystalline solid.5. Melting point 215-217 °C6. Water solubility 572 mg/ml (Hydrochloride salt)7. Mode of action Venlafaxine is usually categorized as a serotonin-
norepinephrine reuptake inhibitor (SNRI), but it has been referred to as a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It works by blocking the transporter "reuptake" proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin and norepinephrine. Additionally, in high doses it weakly inhibits the reuptake of dopamine, with recent evidence showing that the norepinephrine transporter also transports some dopamine as well, since dopamine is inactivated by norepinephrine reuptake in the frontal cortex. The frontal cortex largely lacks dopamine transporters, therefore venlafaxine can increase dopamine neurotransmission in this part of the brain. Venlafaxine interacts with opioid receptors (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) as well as the alpha2-adrenergic receptor.
8. Pharmacokinetics Venlafaxine is well absorbed, with at least 92% of an oral dose being absorbed into systemic circulation. It is extensively
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 629
DRUG AND EXCIPIENT PROFILE
Sr. No.
Property Description
metabolized in the liver via the CYP2D6 isoenzyme to desvenlafaxine (O-desmethylvenlafaxine), which is just as potent a SNRI as the parent compound.Steady-state concentrations of venlafaxine and its metabolite are attained in the blood within 3 days. Therapeutic effects are usually achieved within 3 to 4 weeks. The primary route of excretion of venlafaxine and its metabolites is via the kidneys.The half-life of venlafaxine is relatively short, so patients are directed to adhere to a strict medication routine, avoiding missing a dose.
Paediatric age group Allergic to the inactive ingredients, like gelatin, cellulose,
ethylcellulose, iron oxide, titanium dioxide and hypromellose.
Monoamine oxidase inhibitor (MAOI), as it can cause potentially fatal serotonin syndrome
Glaucoma Pregnant women
11. Drug interactions St John's wort.Lowers seizure threshold with bupropion and tramadol positive phencyclidine (PCP) results caused by large doses of Venlafaxine.
12. Side effects Skin rash or hives; difficulty breathing; swelling of your face, lips, tongue, or throat.Mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights; easy bruising; high levels of serotonin in the body - agitation, hallucinations, fever, fast heart rate, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, fainting;low levels of sodium in the body - headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady; orsevere nervous system reaction - very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, feeling like you might pass out.
13. Dose A.Usual Adult Dose for Depression(a) Immediate release:
Initial dose: 37.5 mg orally twice a day or 25 mg orally 3 times a dayMaintenance dose: May increase in daily increments of up to 75 mg at intervals of no less than 4 daysMaximum dose: (moderately depressed outpatients): 225
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 630
DRUG AND EXCIPIENT PROFILE
Sr. No.
Property Description
mg/dayMaximum dose (severely depressed inpatients): 375 mg/dayDaily dosage may be divided in 2 or 3 doses/day
(b) Extended release:Initial dose: 75 mg orally once dailyMaintenance dose: May increase in daily increments of up to 75 mg at intervals of no less than 4 daysMaximum dose (moderately depressed outpatients): 225 mg/dayMaximum dose (severely depressed inpatients): 375 mg/dayB. Usual Adult Dose for Anxiety:Extended release:Initial dose: 75 mg orally once dailyMaintenance dose: May increase in daily increments of 75 mg at intervals of no less than 4 daysMaximum dose: 225 mg/dayC. Usual Adult Dose for Panic Disorder:Extended-release:Initial dose: 37.5 mg once a dayMaintenance dose: May increase dose in daily increments of 75 mg at intervals of no less than 7 daysMaximum dose: 225 mg/day
PROFILES OF THE POLYMER [46, 47]
Eudragit RLPO
EUDRAGIT® RL PO
EUDRAGIT® RL PO is a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups. The ammonium groups are present as salts and make the polymers permeable.
Sr. No. Property Description1. Physical properties: It is a solid substance in form of white powder with a
faint amine-like odour.2. Chemical structure
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Type A USP/NF: Ammonio Methacrylate Copolymer, Type A - NF JPE: Aminoalkyl Methacrylate Copolymer RS
9. Drug Master File # 124210. Weight average molar
massapprox. 32,000 g/mol
11. Alkali Value 28,1 mg KOH/ g polymer12. Glass Transition
Temperature (Tg)63°C (+/- 5°C)
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 632
DRUG AND EXCIPIENT PROFILE
Eudragit RSPO
EUDRAGIT® RS PO is a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups. The ammonium groups are present as salts and make the polymers permeable.
Sr. No. Property Description1. Physical properties: It is a solid substance in form of white powder with a
Type A USP/NF: Ammonio Methacrylate Copolymer, Type A - NF JPE: Aminoalkyl Methacrylate Copolymer RS
9. Drug Master File # 124210. Weight average molar
massapprox. 32,000 g/mol
11. Alkali Value 28,1 mg KOH/ g polymer12. Glass Transition
Temperature (Tg)63°C (+/- 5°C)
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 633
DRUG AND EXCIPIENT PROFILE
PROFILE OF OTHER EXCIPIENTS
Lactose Monohydrate [53]
Sr. No.
Property Description
1. Chamical Structure
2. CAS No. 10039-26-63. Chemical Name: LACTOSE, MONOHYDRATE4. CBNumber: CB86854185. Molecular Formula: C12H24O12
6. Formula Weight: 360.317. MOL File: 10039-26-6.mol8. Melting point ~215 °C (dec.)9. Solubility : H2O: 0.5 M at 20 °C, clear,
colorless
Microcrystalline cellulose: [52]
Sr. No. Property Description1. Chemical
formula(C6H10O5)n
2. Chemical structure
3. CAS No. 94700-07-94. Uses Microcrystalline cellulose is a term for refined wood pulp
and is used as a texturizer, an anti-caking agent, a fat substitute, an emulsifier, an extender, and a bulking agent in food production.The most common form is used in vitamin supplements or tablets. It is also used in plaque assays for counting viruses, as an alternative to carboxymethylcellulose.[2]Approved within the European Union as a thickener, stabilizer or emulsifiers microcrystalline cellulose was granted the E number E460(ii) with basic cellulose given the number E460(i)[3]
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 634
DRUG AND EXCIPIENT PROFILE
Sr. No. Property Description5. Density 1.76 g/cm3
6. pH 5-7.5
Polyvinylpyrrolidone [48, 49]
Polyvinylpyrrolidone (PVP), also commonly called polyvidone or povidone, is a water-soluble polymer made from the monomer N-vinylpyrrolidone.
Sr. No. Property Description1. Chemical structure
2. Molecular formula (C6H9NO)n3. Molar mass 2.500 – 2.500.000 g·mol−14. Appearance White to light yellow, hygroscopic, amorphous powder5. Density 1.2 g/cm36. Melting point 150 to 180 °C (302 to 356 °F; 423 to 453 K) (glass
temperature)7. Uses PVP was used as a plasma volume expander for trauma
victims after the 1950s.It is used as a binder in many pharmaceutical tablets;[2] it simply passes through the body when taken orally. However, autopsies have found that crospovidone (PVPP) contributes to pulmonary vascular injury in substance abusers who have injected pharmaceutical tablets intended for oral consumption.[3] The long-term effects of crospovidone or povidone within the lung are unknown. PVP added to iodine forms a complex called povidone-iodine that possesses disinfectant properties.[4] This complex is used in various products like solutions, ointment, pessaries, liquid soaps and surgical scrubs. It is known under the trade names Betadine and Pyodine among a plethora of others.
It is used in pleurodesis (fusion of the pleura because of incessant pleural effusions). For this purpose, povidone iodine is equally effective and safe as talc, and may be preferred because of easy availability and low cost.[5]
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 635
DRUG AND EXCIPIENT PROFILE
Talc [50, 51]
Talc is a common metamorphic mineral in metamorphic belts which contain ultramafic rocks, such as soapstone (a high-talc rock), and within whiteschist and blueschist metamorphic terranes. USP grade talc is used as an inert filler in tablets and as a lubricant / glidant in tablet coatings. Pharmaceutical grade talcs are also widely used in medicated foot powders, creams, lotions, ointments and as a release agent in tablet molds.
Sr. No.
Property Description
1. Synonyms Talcum powder.2. Chemical Name Hydrated magnesium silicate3. CAS No. 14807-96-6 4. Empirical formula Mg3Si4O10(OH)2 5. Category Silicate mineral6. Specific gravity 2.5–2.8
7. colour white to grey
8. Applications: In medicine talc is used as a pleurodesis agent to prevent
recurrent pleural effusion or pneumothorax. In the European
Union the additive number is E553b. Talc finds use as a
cosmetic (talcum powder), as a lubricant, and as a filler in
pharmacueticals and cosmetic manufacturing. . Because of
talc’s crystalline platy structure and softness, talc is used as a
lubricant or glidant in the manufacturing of pharmaceutical
tablets. It is also commonly used as an in ingredient in enteric
(time release) tablet coating formulations. Talc has been
shown to improve direct compression of tablet formulation
disintegration properties and can be used in combination with
magnesium stearate to restore disintegration and dissolution
properties caused by the addition of magnesium stearate as a
lubricant. Smaller particle size talcs have also been shown to
improve lubricant efficiency. USP grade talc is often found in
medicated foot powders.
9. Solubility: Talc is not soluble in water, but it is slightly soluble in dilute
mineral acids.
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
also be considered acceptable. Appropriate use of quality risk management can facilitate but
does not obviate industry’s obligation to comply with regulatory requirements and does not
replace appropriate communications between industry and regulators.”
The two primary principles considered when implementing quality risk management:
• The evaluation of the risk to quality should be based on scientific knowledge and ultimately
link to the protection of the patient; and
• The level of effort, formality and documentation of the quality risk management process
should be commensurate with the level of risk.
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 741
EXPERIMENTAL WORK
Based upon the physicochemical and biological properties of the drug substance, the initial
risk assessment of drug substance attributes on drug product CQAs was done.
Risk assessment using FMEA: FMEA provides for an evaluation of potential failure modes
for processes and their likely effect on outcomes and/or product performance.
Steps: [11]
1. Selection of the process
2. Review of the process
3. Brainstorm potential failure modes
4. List of potential effects of each failure mode
5. Assign a severity rating for each effect
6. Assign an occurrence rating for each failure mode
7. Assign a detection rating for each failure mode and effect
8. Calculation of the risk priority number (RPN) for each effect: (RPNs) = O×D×S
9. Prioritize the failure modes for action
10. Taken action to eliminate or reduce the high risk failure modes
11. Improvement index (II): II = (RPN before improvement) / (RPN after improvement)
Score scale for frequency of occurrence
Failure Probability of failure Occurrence RankingVery High: (Failure is almost inviolable)
≥ 1 in 2 101 in 3 9
High: (Repeated failure) 1 in 8 81 in 20 7
Moderate: (Occasional failure) 1 in 80 61 in 400 51 in 2000 4
Low: (Relatively few failure) 1 in 15000 31 in 150000 2
Remote: (Failure is unlikely) 1 in 1500000 1Table No.7.1 Score scale for frequency of occurrence
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 742
EXPERIMENTAL WORK
Score scale for probability of detection
Detection Criteria Detection Ranking
Impossible to detect No known techniques available 10Remote detection Only unreliable technique available 9Very slight detection Providing durability tests on products with system
components installed8
Slight detection On product with prototypes with system components installed
7
Low detection On similar system components 6Medium Detection On preproduction system components 5Moderate detection On early prototype system elements 4Good detection Simulation and modeling in early stage 3High chance of detection Proven analysis available in early design stage 2Certain to detect Proven detection methods available in concept
stage1
Table No.7.2 Score scale for probability of detection
Score scale for severity
Severity Effect Severity RankingHazardous without warning
Without warning, people can get severely wounded
10
Hazardous with warning May cause hazards, with warning 9Very high Loss of primary function 8High Highly reduced level of performance 7Moderate Reduced level of performance 6Low Slightly reduced level of performance 5Very low Defect noticed by most of the customers 4Minor device Defect noticed by average customers 3Very minor Defect noticed by discriminating
customers2
None Almost no effect 1Table No.7.3 Score scale for severity
7.5. Formulation development:
Initial risk assessment was done and CQAs were identified. Focusing on coating process, a
formulation fulfilling all requirements of hardness, friability, size and shape was developed.
7.5.a. Preparation of tablets:
7.5.a.1. Selection of excipients:[49]
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 743
EXPERIMENTAL WORK
Various excipients were selected for good tabletting purpose. Lactose monohydrate was used
as filler. Microcrystalline starch cellulose was also used as filler, having additional binding
properties. PVP was used as binder (added later in the formula, when process was finalized).
Talc and Magnesium stearate which are hydrophobic in nature were used as glidant and
lubricant respectively.
Sr. No. Excipient Name % of Tablet Wt Weight in mg
1. Lactose monohydrate -(q.s.) qs
2. Microcrystalline Cellulose 5% 10
3. PVP(solution) 2.5% 5
4. Magnesium Stearate 1.5% 3
5. Talc 2% 4
Table No. 7.4 Formula for core tablets
7.5.a.2. Selection of process for preparation of tablets: [71]
Tablet formulations were prepared by both direct compression and wet granulation technique.
Required quantities of drug and excipients were mixed thoroughly. Tablet blend was checked
for flow properties.
The granules were also prepared by same formula, and checked for flow properties.
(Lubricant: L, Glidant: G)
Batch 1 2 3 4 5 6 7 8 9
L 1.5 1 1 1.5 0.5 1 0.5 1.5 0.5
G 2.5 2.5 2 3 2.5 3 3 2 2
Table No. 7.5 Overview of levels of lubricant and glidant at different levels
The tablets were compressed using 8mm concave punches on a Rimek Mini Press-II tablet
compression machine.
7.6. Evaluation of preliminary batches: [68]
a) Hardness
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 744
EXPERIMENTAL WORK
The hardness was tested using Monsanto tester. “Hardness factor”, the average of the three
determinations, was determined.
b) Thickness
Thickness of the tablets was measured using vernier calipers.
c) Uniformity of weight
Twenty tablets were weighed individually. Average weight was calculated from the total
weight of all tablets. The individual weights were compared with the average weight. The
percentage difference in the weight variation should be within the acceptable limits
(7.5%). The percent deviation was calculated using the following formula.
% Deviation = Individual weight – Average weight x 100
Average weight
Not more than two of the individual weights deviate from the average weight by more than
7.5% and none deviates by more than twice that percentage.
d) Friability Test
Roche Friabilator was used to measure the friability of the tablets. Ten tablets were weighed
collectively and placed in the chamber of the Friabilator. It was rotated at a rate of 25 rpm. In
the Friabilator, the tablets were exposed to rolling, resulting from free fall of tablets within
the chamber of the Friabilator. After 100 rotations (4 minutes), the tablets were taken
out from the Friabilator and intact tablets were again weighed collectively. Permitted
friability limit was 1.0%. The percent friability was determined using the following formula.
(W1 – W2)
Friability = x 100
W1
Where, W1 = weight of the tablets before test, W2 = weight of the tablets after test
7.7. Coating Process Development:
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 745
EXPERIMENTAL WORK
CQAs were identified and risk assessment was done using FMEA.
7.7.a. Coating Formula Development
7.7a.1. Selection of solvents based on viscosity and drying time: [59]
Sr. No. Solvent Ratio
1. Water: Ethanol 1:9
2. Water: IPA 1:9
3. Water: Acetone 1:9
4. IPA: Acetone 4:6
Table No. 7.6: Solvent combinations and their ratios
Various solvents as described above were selected in varying ratios. The viscosities were
measured using Ostwald’s viscometer. Selected ratios were further checked for drying time.
A ratio, in which drying time was lowest, was selected.
7.7.a.2. Selection of Plasticizer based on stickiness and folding endurance [58, 72]
Polyethylene glycol and triethyl citrate were chosen as plasticizers. Initial trials were taken at
a concentration of 0.2% of each. Further trials were taken with 0.4% and 0.6% concentration
of previously chosen plasticizer.
7.7.a.3. Effect of fillers on film roughness:
Fillers are said to increase film adherence and bulk. Their effect on roughness and folding
endurance was checked. Fillers like lactose, talc, microcrystalline starch were used for study.
7.7.a.4. Selection of ratio of sustained release polymer: [73]
The objective of this work was to prepare sustained release tablet of Venlafaxine
hydrochloride. The work thus involves use of Eudragit polymer for the SR formulation.
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 746
EXPERIMENTAL WORK
An initial coating using Eudragit RLPO and RSPO alone was done. Eudragit RSPO was used
in combination to Eudragit RLPO, which is a water impermeable polymer.
Various ratios of polymer were selected, as shown in table below and depending on which
ratio gives proper dissolution, a ratio was selected. Percentage weight gain was kept constant
(5%) initially.
In vitro Dissolution study:
In-vitro drug release study of the samples was carried out using USP – type II dissolution
apparatus (Peddle type). The dissolution medium, 900 ml of deaerated water, was placed
into the dissolution flask maintaining the temperature of 37 0.5 0C and rpm of 50.
Tablets were placed in each basket of the dissolution apparatus. The apparatus was allowed to
run for 24 hours. Samples measuring 5 ml were withdrawn after every 1 hour up to 24 hours
manually and samples were filtered. The fresh dissolution medium was replaced every
time with the same quantity of the sample withdrawn. Collected samples were analyzed
at 225 nm using water as blank. Percentage drug release was calculated.
Sr. No. Eudragit RLPO Eudragit RSPO
1. 1 -
2. - 1
3. 1 2
4. 1 1
5. 2 1
Table No.7.7 Selection of ratio of sustained release polymer
7.7.a.5. Selection of % weight gain: [73]
Selected polymer ratio was used for this study. Coating at 7.5% and 10 % weight gain was
also achieved. Dissolution study (24 hrs) was carried out, and results were compared.
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 747
EXPERIMENTAL WORK
The value of % weight gain which gives complete and more sustained release over 24 hours
was selected.
7.7.b. Preparation of coating solution:
Accurately weighed quantities of polymers were dissolved in solvents. Selected amount of
triethyl citrate was added. Sunset yellow color was added. The resulting solution was stirred
for 15 min on a magnetic stirrer to ensure complete dissolution of polymer. It was then
filtered using Whatmann filter paper to remove undissolved particles of color, if any.
7.7.c. Optimization of process parameters
7.7.c.1. Selection of process parameters:
Initially, solid content was varied between 1%- 4%. Initial trial batches were taken by
changing different process parameters like:
Temperature
Pan load
Pan Speed
Atomization pressure etc.
Study
No.
Polymer
Amount
(% w/v)
Pan Load
(No. of
tablets)
Temperature
(0 c)
Pan speed
(RPM)
Atomization
pressure
(lb/in2)
1. 1 50 tabs 300 c 30 5 lb/in2
2. 1 50 tabs 400 c 30 5 lb/in2
3. 1 200 tabs 400 c 30 5 lb/in2
4. 2 200 tabs 600 c 40 5 lb/in2
5. 2 200 tabs 600 c 50 15 lb/in2
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 748
EXPERIMENTAL WORK
6. 3 200 tabs 600 c 30 10 lb/in2
7. 4 200 tabs 600 c 40 10 lb/in2
Table No.7.8 Process parameters and polymer amount for preliminary batches
7.7.c.2. Evaluation of preliminary batches [74]
1. Percentage of weight gain: It is percentage the difference between weights of tablets
before and after coating.
% Wt gain = [(Final wt – Initial Weight)/Initial Weight] X 100
2. Coating Process Efficiency (CPE): CPE actual percent weight gain relative to the
theoretical percent. Coating process efficiency was determined by the following equation.
CPE = (%wga/%wgt) ×100%
where wgt is the theoretical percent weight gain and wga is the actual percent weight
gain.
3. Tablet Surface roughness: It is not considered as individual defect, but overall surface
texture of the batch. Specialized tablet surface roughness equipments are available, but
for laboratory purpose, it is ranked as 1: Very smooth, 2: Slightly rough, 3: Very rough
4. Picking and sticking: The tablets show coating material pulled from the tablet surface
and/or coating material deposited on the surface.
5. Breakage: Tablets are broken during coating run.
6. Edge erosion: The edges of the tablets are worn away or damaged during the coating run.
7. Peeling: The coating peels away from the tablet surface.
8. Tablet to tablet colour variation: The colour of tablets is uneven within the batch.
9. Twinning: Two or more tablets are stuck together.
10. Orange peel roughness: The entire surface of the tablet appears rough, like a surface of an
orange.
11. Colour variation: The colour of individual tablets is uneven or non-uniform.
7.7.c.3. Effect of temperature on quality of coating:[35]
For this study, three batches were coated with temperatures 300c, 400c and 600c whereas
concentration, load and pan speed were kept constant.
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 749
EXPERIMENTAL WORK
Temperatur
e
Concentration
(% w/v)
Load
(No. of tablets)
Pan speed
(RPM)
300c
3 50 40400c
600c
Table No. 7.9 Effect of temperature on quality of coating
7.7.c.4. Effect of pan load on Coating process efficiency:
LoadConcentration
(% w/v)
Temperature
(0c)
Pan speed
(RPM)
50
3 600c 40200
300
415
Table No.7.10 Effect of pan load on coating process efficiency
7.7.c.5. Effect of Solid content, pan speed and atomization pressure on Process
efficiency, defects, and tablet roughness.
Based on risk assessment using FMEA and initial trials, process parameters like solid
content, pan speed, atomization pressure which were identified as CQAs were varied.
Goal of present study was to select levels of above stated parameters and to study their
interactions.
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 750
EXPERIMENTAL WORK
Levels of parameters were set referring to those in initial studies. Experiment was designed
by Box-Behnken design using Stat-Ease Design Expert Software.
Independent variables -1 0 +1
Solid Content (%) 3 4.5 6
Pan Speed 40 55 70
Atomization Pressure 5 10 15
Dependant variables Process efficiency, no. of defects, and
tablet roughness.
Table No.7.11 Overview of Independent and dependent variables in the design of
experiments
Temperature and Pan load were kept constant.
Design layout
Sr. no.
Concentration
(% w/v)
Pan Speed (RPM)
Atomization Pressure (lb/in2)
1. 3 40 10
2. 3 55 5
3. 3 55 15
4. 3 70 10
5. 4.5 40 5
6. 4.5 40 15
7. 4.5 55 10
8. 4.5 55 10
9. 4.5 55 10
10. 4.5 55 10
11. 4.5 70 5
12. 4.5 70 15
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 751
EXPERIMENTAL WORK
Sr. no.
Concentration
(% w/v)
Pan Speed (RPM)
Atomization Pressure (lb/in2)
13. 6 40 10
14. 6 55 15
15. 6 55 5
16. 6 70 10
Table No.7.12 Design layout Box-Behnken Design
7.8. Updated risk assessment of formulation and process variables:[9,11]
Acceptable ranges for the high risk formulation variables have been established and were
included in the control strategy. Based on the results of the formulation development studies,
risk assessment of the formulation and process variables was updated.
7.9. Defining Design Space: [2, 60]
ICH Q8 (R1) defines design space as, the multidimensional combination and interaction of
input variables (e.g., material attributes) and process parameters that have been demonstrated
to provide assurance of quality.
This definition evolved from early ICH Q8 drafts where design space was defined as “the
established range of process parameters that has been demonstrated to provide assurance of
quality”. The Design Space is linked to criticality through the results of risk assessment,
which determines the associated CQAs and process parameters. It describes the multivariate
functional relationships between CQAs and the process parameters that impact them. The
Design Space also contains the proven acceptable ranges (PAR) for process parameters and
acceptable values for their associated CQAs.
By combining the results of all performed studies final design space were defined as per
quality target product profile.
7.10. Defining control strategy:[2]
The control strategy for Venlafaxine hydrochloride SR Tablets was built upon the outcome of
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 752
EXPERIMENTAL WORK
extensive product and process understanding studies. These studies investigated the material
attributes and process parameters that were deemed high risk to the CQAs of the drug product
during the initial risk assessment. Through these systematic studies, the CMAs and CPPs
were identified and the acceptable operating ranges were established. All variables ranked as
high risk in the initial risk assessment were included in the control strategy because the
conclusion of the experiments was dependent on the range(s) studied and the complex
multivariate relationship between variables. Thus, the control strategy is an integrated
overview of how quality is assured based on current process and product knowledge.
Controls can include parameters and attributes related to:
Drug substance
Excipients
Facility and equipment operating conditions
In-process controls
Finished product specifications
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 853
RESULTS AND DISCUSSION
8.1. Analysis of drug:
8.1.a. Analysis of Venlafaxine hydrochloride:
The drug sample was used without further purification. Characterization of drug was done by
physicochemical methods.
8.1.b. Organoleptic properties and description:
Appearance: Amorphous powder
Color: White
Odor: Odorless
8.1.c. Melting point:
The melting point was determined by open capillary method. It was found to be 2150c,
within given range of the reported results.
8.1.d. Solubility:
Venlafaxine is soluble in water, ethanol, methanol, acetone and isopropyl alcohol.
8.1.e. U.V. Spectroscopy:
Procedure-
Maximum absorption wavelength was found at 225 nm.
8.1.e.1. Linearity and range:
Solution was found to be linear over given range.
R² Linearity Equation
0.995 y = 0.024x + 0.004
Table No. 8.1: R2 value and linearity equation
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 854
RESULTS AND DISCUSSION
0 2 4 6 8 10 12 14 160
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
f(x) = 0.0237571428571429 x + 0.00417142857142863R² = 0.997847987307748
Fig. No. 8.1 Linearity of Venlafaxine
8.1.e.2. Precision:
System Precision: % RSD was found to be 0.0006%.
Intraday Precision: % RSD was found to be 1.22%.
Interday Precision: % RSD was found to be 1.299%.
8.1.f. Assay: (BP)
% purity of Venlafaxine was found to be 100.208 % w/w.
8.1.g. Infra-red spectroscopy:
Fig. No.8.2: Infrared Spectrum for Venlafaxine Hydrochloride
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 855
RESULTS AND DISCUSSION
Functional Group Range Observations
Hydoxyl 3300-3400 cm-1 3321.42 cm-1
Benzyl 1500-1600 cm-1 1514.12 cm-1
Aliphatic CH 2800-3000 cm-1 2943.37 cm-1
C-O-C 1000-1200 cm-1 1039.63 cm-1
Table No.8.2 IR Functional Group ranges and observations
Functional groups like hydroxyl, benzyl, aliphatic CH, ether and their ranges were observed
Fig. No.8.3: IR Spectrum of Eudragit RLPO
Fig. No.8.4: IR spectrum of Eudragit RSPO
8.2. Excipient compatibility studies:
IR spectra of drug with excipients showed characteristic peaks for the drugs. This shows that
there is no interaction of the drug with excipients.
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 856
RESULTS AND DISCUSSION
Fig. No.8.5: Overlay spectra of pure drug(black) with a mixture of drug and Lactose
Fig. No. 8.6 Overlay spectra of pure drug with a mixture of drug and Microcrystalline
Cellulose(black)
Fig. No. 8.7: Overlay spectra of pure drug with a mixture of drug and Talc(black)
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 857
RESULTS AND DISCUSSION
Fig. No. 8.8 Overlay spectra of pure drug with a mixture of drug and Magnesium
Stearate(black)
8.3. Dissolution study of marketed Venlafaxine Tablets:
Dissolution study was carried out for tablets Ventab XL (37.5 mg), manufactured by Intas
Pharmaceuticals. Manufacturing date was June 2014, and expiry date was May 2017.
Tablets showed 21.84% release in 2 hrs, 58.40% in 6 hrs, 70.34% in 8 hrs, 90.34% in10 hrs,
92% release in 12 hrs, and 99.66% release in 24 hrs. This gave a reference profile for
developing sustained release tablets by film coating approach.
-1 4 9 14 19 240
102030405060708090
100
% Release
% Release
Time in hrs
%Release
Fig. No. 8.9: Dissolution study of marketed tablets
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 858
RESULTS AND DISCUSSION
8.4. Quality by Design Protocols
8.4.a. Quality target product profile (QTPP) for Venlafaxine Hydrochloride sustained
release tablet
The quality target product profile (QTPP) is “a prospective summary of the quality
characteristics of a drug product that ideally will be achieved to ensure the desired quality,
taking into account safety and efficacy of the drug product.”
QTPP TPP TPQP Justification Dosage form and type Sustained release film
coated tablet. Sustained release over 24 hrs
Sustained release over 24 hrs, ease of administration
Fig No. 8.16: a Graphical Representation of design space
b. Control Space
In above given red area covers extreme variable points, known as points of failure. Here, concentration ranges from 0 to 8%, and pan speed ranges from 10-90 RPM.
The yellow area is knowledge space, which gives results according to quadratic model in DOE.
The green area is covered by ranges tested in DOE, also called as design space, the movement in which is not considered as a change in process.
Fig b represents solution given by Design expert, which known as Control Space.
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 884
RESULTS AND DISCUSSION
All six plots show design space where X1= Concentration, X2= Speed and Pressure= 5, 10, 15 respectively for both a and b.
Check date of retesting.4. Raw material dispensing Approved Vendor
Check labeling properly. 5. Weighing Ensure balance is in proper position
Weigh in controlled environment 6. Sifting Pass ingredients through #24 sieve 7. Blending Mortar Pestle rotate between 30-100 times 8. Granulation Ensure proper drying (500c)
Granules pass through #18 and are retained on #20 9. Lubrication Pass Through #44 mesh size 10. Compression Punch- 8mm, concave, Compression force – 5 kg/cm2
Single Punch Used IPQC Checks: Hardness, Weight variation
11. Coating Ensure that Spray Pattern is properEnsure tablet load and temperature is proper
12. Dissolution Apparatus - USP type II Paddle ApparatusSpeed – 50 RPMMedium – 900ml Deaerated WaterTemperature – 370cAnalysis on UV spectrophotometer - 225 nm
Table no. 8.27 Control strategy
Scale up for processes: Checklist
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 885
RESULTS AND DISCUSSION
Following points should be considered when the process is to be applied and optimized at pilot/ production scale.
Process Parameter College level experiments
Pilot scale/ Production
Batch size ≤ 20 g 50 kg/ 150 kgSifting Equipment Sieves Vibratory sifterBlending Equipment Mortar Pestle BlenderGranulation Equipment Mortar pestle, sieve Blender/ Fluidized bed granulatorLubrication End point Speed alone Speed and timeCompression
No. of stations 12 27-60
Speed 10 RPM Upto 60 RPMCoating Pan brim volume 250ml-1L 4.6- 900 L
Pan speed 40-70 RPM 8-20 RPMAchievable Process efficiency
55% More than 90 %
Table no. 8.28 Parameters to be considered for scale up
Following PAT tools can be applied to manufacturing processes for controlling without destruction of formulation due to sampling and testing. [39, 40]
Process Parameter PATDispensing Raw material characterization NIR and Raman SpectroscopyBlending Blend uniformity NIRGranulation Particle size distribution Laser light diffractionCompression Tablet identification Acoustic resonance spectrscopy
Thickness At line checkmasterContent uniformity NIR and Raman SpectroscopyWater content and hardness Diffuse reflectance-NIR
Coating Thickness Terahertz pulsed imagingComposition of coating polymers NIR
Dissolution Time Predicted from measured variables like content uniformity and hardness
Table no. 8.29 PAT tools
Stability Studies:
Samples kept under Accelerated stability conditions were evaluated for hardness, friability, weight variation, drug content and dissolution study. No significant reduction in the content of the active drug was observed over a period of one month.
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 886
RESULTS AND DISCUSSION
Sr. No. Parameter Before Stability After Stability1. Weight Variation Complies Complies
2. Friability Complies Complies
3. Hardness Complies Complies
4. Assay 99.95% 99.55%
Table no. 8.30 Stability studies
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
SUMMARY AND CONCLUSION 87
SUMMARY
Quality by design (QbD) was defined as a systematic approach to development that
begins with predefined objectives and emphasizes product and process understanding
and process control, based on sound science and quality risk management.
Current process is quality by testing, suffering from process variability by a small
change in processing parameters. Hence it was understood that if we want to reduce
the variability, we have to increase the process understanding, by applying QbD.
Venlafaxine is an antidepressant drug mostly used for treatment of major anxiety
disorder, and social anxiety disorder. For treatment of patients, it is desirable to have
single daily dose preparations. Sustained release tablets are available in market, but
prepared by matrix tablet approach.
Objective of the study was to study in brief and apply QbD approach to formulation
development of a sustained release film coated tablet having similar release profile as
that of marketed product.
Quality target product profile was defined for tablets, and parameters including
parameters like Dosage form and type, route of administration, potency, appearance,