01 Complete Thesis

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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]

FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH

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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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INTRODUCTION

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

the end in mind.”

Primary components of QTPP are as follows:

1. Description

2. Clinical Pharmacology

3. Indications and Usage

4. Contraindications

5. Warnings

6. Precautions

7. Adverse Reactions

8. Drug Abuse and Dependence

9. Over dosage

10. Dosage and Administration

11. Animal Pharmacology and/or Animal Toxicology Clinical Studies


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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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INTRODUCTION

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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INTRODUCTION

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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INTRODUCTION

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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INTRODUCTION

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.

Sustained release, sustained action, prolonged action, controlled release, extended action,

timed release, depot and repository dosage forms are terms used to identify drug delivery

systems that are designed to achieve a prolonged therapeutic effect by continuously

releasing medication over an extended period of time after administration of single dose

[17]. In the case of orally administered dosage forms, this period is measured in hours and

critically depends on the residence time of the dosage form in the gastrointestinal tract. The

term controlled release has become associated with those systems from which therapeutic

agents may be automatically delivered at predetermined rates over a long period of time [18].

The system attempts to control drug concentrations in the target tissues or cells.

Sustained release systems are any drug delivery system that achieves slow release of drug

over an extended period of time. If the system is successful in maintaining constant drug

levels in the blood or target tissue, it is considered as a controlled-release system. If it is

unsuccessful at this but nevertheless extends the duration of action over that achieved by

conventional delivery, it is considered as a prolonged release system.

In recent years, in association with progress and innovation in the field of pharmaceutical

technology, there has been an increasing effort to develop sustained release dosage forms for

many drugs. The primary objective of this system is to ensure safety and to improve efficacy

of the drugs as well as patient compliance. This is achieved by better control of plasma drug

levels and less frequent dosing. Pharmacokinetic theory suggests that the ultimate method for

reducing the plasma maximum concentration (Cmax) to plasma minimum concentration

(Cmin) ratio is to have zero-order absorption. Once steady state is achieved under these

conditions, drug concentration in plasma is constant as long as absorption persists. Successful

commercialization of an extended release formulation is usually challenging and involves


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consideration of many factors such as physiochemical properties of the drug, physiological

factors, and manufacturing variables.

1.14 Advantages of controlled release dosage forms [19]:

The frequency of drug administration is reduced.

Compliance can be improved.

Drug administration can be made more convenient as well.

The blood level oscillation characteristic of multiple dosing of conventional dosage

forms is reduced.

Better control of drug absorption can be attained, since the high blood level peaks that

may be observed after administration of a dose of a high availability drug can be

reduced.

The characteristic blood level variations due to multiple dosing of conventional

dosage forms can be reduced.

The total amount of drug administered can be reduced, thus:

Maximizing availability with minimum dose;

Minimize or eliminate local side effects;

Minimize or eliminate systemic side effects;

Minimize drug accumulation with chronic dosing.

Safety margin of high potency drugs can be increased and the incidence of both local

and systemic adverse side effects can be reduced in sensitive patients.

Improve efficiency in treatment.

Cure or control condition more promptly;

Improve control of condition i.e., reduce fluctuation in drug level;

Improve bioavailability of some drugs;

Make use of special effects

Economy.

1.15 Disadvantages of controlled release formulations:

Administration of controlled release medication does not permit the prompt

termination of therapy.

Flexibility in adjustment of dosage regimen is limited.


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Controlled release forms are designed for normal population i.e. on the basis of

average drug biologic half-lives.

Economic factors must also be assessed, since more costly process and equipment are

involved in manufacturing of many controlled release dosage forms.

1.16 Physico-chemical factors influencing oral controlled release dosage form [15]:

a. Dose size:

For orally administered systems, there is an upper limit to the bulk size of the dose

to be administered. In general a single dose of 0.5 to 1 gm is considered maximal.

b. Ionization, pKa and aqueous solubility:

The pH partition hypothesis simply states that the unchanged form of a drug species

will be preferentially absorbed through many body tissues therefore it is important to

note the relationship between pKa of the compound and its absorptive environment.

For many compounds the site of maximum absorption will also be the area in which the drug

is least soluble. For conventional dosage forms the drug can generally fully dissolve in the

stomach and then be absorbed in the alkaline pH of the intestine. For dissolution of diffusion

controlled forms, much of the drug will arrive in the small intestine in solid form.

This means that the solubility of the drug is likely to change several orders of

magnitude during its release.

c. Partition coefficient:

The compounds with a relatively high partition coefficient are predominantly lipid soluble

and easily penetrate membranes resulting high bioavailability. Compounds with very low

partition coefficient will have difficulty in penetrating membranes resulting in poor

bioavailability. Furthermore partitioning effects apply equally to diffusion through polymer

membranes.

d. Drug Stability:

Drugs that are unstable in the stomach can be placed in a slowly soluble form or have their

release delayed until they reach the small intestine However, such a strategy would be


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detrimental for drugs that either are unstable in the small intestine or undergo extensive gut

wall metabolism, as pointed out in the decreased bioavailability of some

anticholinergic drugs from controlled /sustained release formulations.

e. Protein Binding:

It is well known that many drugs bind to plasma proteins with a concomitant

influence on the duration of drug action. Since blood proteins are for the most part

recirculated and not eliminated, drug protein binding can serve as a depot for drug

producing a prolonged release profile, especially if a high degree of drug binding occurs.

Levine has shown that quaternary ammonium compounds bind to mucin in the GIT. Drug

bound to mucin may act as depot and act as a sustained release product.

1.17 Biological factors influencing oral sustained release dosage form:

a. Biological Half Life:

Therapeutic compounds with short half-lives are excellent candidates for controlled release

preparations. Drug with very short half-life will require excessively large amounts of drug in

each dosage unit to maintain controlled effects, thus forcing the dosage form itself to become

too large to be administered. Compounds with relatively long half lives, generally greater

than 8 hours are generally not used in controlled release dosage forms since their effect is

already sustained and also GI transit time is 8-12 hrs. Drugs with short half-lives require

frequent dosing in order to minimize fluctuations in blood levels accompanying

conventional oral dosage regimens. Therefore controlled release dosage forms would appear

very desirable for drugs.

b. Absorption:

The characteristics of absorption of a drug can greatly affect its suitability as a

controlled release product. Assuming the transit time of most drugs and devices in

the absorptive regions before release is complete. The absorption rate constant is an apparent

rate constant. It should in actuality be the release rate constant of the drug from dosage form.


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c. Metabolism:

Drugs that are significantly metabolized especially in the region of the small intestine can

show decreased bioavailability from slower releasing dosage forms. This is due to saturation

of intestinal wall enzyme systems.

2.3 Technique for preparation of sustained release formulation:

A. Film Coating:

Pharmaceutical coatings are an essential tool to achieve the desired formulation of

pharmaceutical dosage forms.

Coatings are applied to achieve superior property of a dosage form.

Modified drug release

Colour

Texture

Mouth feel and taste masking [21]

When coating composition is applied to a batch of tablets in a coating pan, the tablet surfaces

become covered with a tacky polymeric film. Before the tablet surface dries, the applied

coating changes from a sticky liquid to tacky semisolid, and eventually to a nonsticky dry

Surface pans. The entire coating process is conducted in a series of mechanically operated

acorn-shaped coating pans of galvanized iron stainless steel or copper. The smaller pans are

used for experimental, developmental, and pilot plant operations, the larger pans for

industrial production.

Basic principles involved in tablet coating:

1. Tablet coating is the application of coating composition to moving bed of tablets with

concurrent use of heated air to facilitate evaporation of solvent.

2. Solution in which influences the release pattern as little as possible and does

not markedly change the appearance.

3. Modified release with specific requirement and release mechanism adapted to

body function in the digestive tract.

4. Colour coating which provides insulation.

5. To incorporate another drug or formula adjuvant in the coating to avoid

chemical incompatibilities or to provide sequential drug release.


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6. To improve the pharmaceutical elegance by use of special colours and contrasting

printing.

Primary components involved in tablet coating

1. Tablet properties

2. Coating process

3. Coating equipments

4. Parameters of the coating process

5. Facility and ancillary equipments

6. Automation in coating processes.

Coating Process Design & Control [21]

In most coating methods, the coating solutions are sprayed onto the tablets as the tablets are

being agitated in a pan, fluid bed, etc. As the solution is being sprayed, a thin film is formed

that adheres directly to each tablet. The coating may be formed by a single application or may

be built up in layers through the use of multiple spraying cycles.

Rotating coating pans are often used in the pharmaceutical industry. Uncoated tablets are

placed in the pan, which is typically tilted at an angle from the horizontal, and the liquid

coating solution is introduced into the pan while the tablets are tumbling. The liquid portion

of the coating solution is then evaporated by passing air over the surface of the tumbling

tablets. In contrast, a fluid bed coater operates by passing air through a bed of tablets at a

velocity sufficient to support and separate the tablets as individual units. Once separated, the

tablets are sprayed with the coating composition.

The coating process is usually a batch driven task consisting of the following phases:

Batch identification and Recipe selection (film or sugar coating)

Loading/Dispensing (accurate dosing of all required raw materials)

Warming

Spraying (application and rolling are carried out simultaneously)

Drying

Cooling

Unloading


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Coating equipment

A modern tablet coating system combines several components:

A coating pan

A spraying system

An air handling unit

A dust collector

Advantages of tablet coating [21]

1. Tablet coatings must be stable and strong enough to survive the handling of the tablet,

must not make tablets stick together during the coating process, and must follow the fine

contours of embossed characters or logos on tablets.

2. Coatings can also facilitate printing on tablets, if required. Coatings are necessary for

tablets that have an unpleasant taste, and a smoother finish makes large tablets easier to

swallow.

Disadvantages of tablet coating [21]

1) Disadvantages of sugar coating such as relatively high cost, long coating time and high

bulk have led to the use of other coating materials.

2) However the process of coating is tedious and time-consuming and it requires the expertise

of highly skilled technician. The process is tedious and time-consuming and it requires the

expertise of highly skilled technician.

Sustained release can also be achieved by following mechanisms:

Embedding the drug in slowly dissolving or erodible matrix (monolith).

In such systems the drug is homogeneously dispersed throughout a rate controlling medium

and employs waxes such as bees wax, carnauba wax, hydrogenated castor oil etc. Dissolution

of drug is controlled by controlling the rate of penetration of dissolution fluid into the matrix

by altering the porosity of tablet, decreasing its wet ability or by itself getting dissolved at

slower rate. The drug release is often followed by first order kinetics from such matrices. A

major disadvantage of matrix system is that drug release rate continuously decreases with

time due to increased diffusional distance and decreased surface area at the penetrating


Chapter 122

INTRODUCTION

solvent front. Consequently, to achieve zero order release, it is necessary to select geometry

that compensates the increase in diffusional distance with the corresponding increase in

surface areas for the dissolution.

To achieve zero order drug release a novel approach is proposed by incorporating non-

uniform drug distribution in a matrix material, encapsulation or coating with slowly

dissolving or erodible substances (Reservoir devices).[22]

These systems generally employ coating of drug particles or granules with slowly dissolving

materials. Time required for the dissolution of the coat is a function of thickness of coat and

its aqueous solubility. One can obtain controlled action by employing a wide spectrum of

coated particles of varying coat thickness. Coating can be achieved by one of the several

micro encapsulation techniques with slowly dissolving materials like cellulose. [23]

Diffusion controlled release system

Matrix diffusion controlled systems [21, 24]

In these systems the dug is dispersed in an insoluble matrix of rigid non-swellable

hydrophobic materials or swellable hydrophilic substances. For rigid matrix insoluble plastics

such as PVC and fatty materials like bees wax, stearic acid etc. are used. While for the

swellable matrix hydrophilic gums of natural origin (tragacanth, guar gum), semi synthetic

(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.


Chapter 223

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


Chapter 224

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).


Chapter 325

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


Chapter 426

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


Chapter 527

MATERIALS AND EQUIPMENTS

MATERIALS AND EQUIPMENTS

Drugs and excipients

Drugs/ excipients Provided by

Venlafaxine Hydrochloride Cipla Pharmaceuticals, Mumbai

Eudragit RLPO, RSPO Evonik Degussa,

Microcrystalline cellulose Loba Chemie, Mumbai

Lactose Loba Chemie, Mumbai

Talc Loba Chemie, Mumbai

Magnesium Stearate Loba Chemie, Mumbai

Acetone Loba Chemie, Mumbai

Isopropyl alcohol Loba Chemie, Mumbai

Table no. 5.1: List of drugs and excipients

Equipments

Instrument/Apparatus Make and model

Planetary mixer Gem pharma machineries

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


Chapter 628

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


Chapter 629


Sr. No.


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.

9. Volume of distribution

7.5 ± 3.7 L/kg [venlafaxine]5.7 ± 1.8 L/kg [O-desmethylvenlafaxine(active metabolite)]

10. Contraindications

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


Chapter 630


Sr. No.


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


Chapter 631


Sr. No. Property Description

3. Product Form Powder4. Targeted Drug

Release AreaTime controlled release, pH independent

5. CAS number 33434 – 24 – 16. Chemical/IUPAC

namePoly(ethyl acrylate-co-methyl methacrylate-co trimethylammonioethyl methacrylate chloride) 1:2:0.2

7. INCI name Acrylates / Ammonium Methacrylate Copolymer8. Monographs Ph. Eur.: Ammonio Methacrylate Copolymer,

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)


Chapter 632


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

faint amine-like odour.2. Chemical structure

3. Product Form Powder4. Targeted Drug

Release AreaTime controlled release, pH independent

5. CAS number 33434 – 24 – 16. Chemical/IUPAC

namePoly(ethyl acrylate-co-methyl methacrylate-co trimethylammonioethyl methacrylate chloride) 1:2:0.1

7. INCI name Acrylates / Ammonium Methacrylate Copolymer8. Monographs Ph. Eur.: Ammonio Methacrylate Copolymer,

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)


Chapter 633


PROFILE OF OTHER EXCIPIENTS

Lactose Monohydrate [53]

Sr. No.


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]


Chapter 634


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]


Chapter 635


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.


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.


Chapter 636


Magnesium stearate [56]

Sr. No. Property Description1. Synonyms Stearic acid magnesium salt, Magnesium octadecanoate.

2. Molecular Weight 125

3. Description Magnesium stearate is a fine, white, precipitated, milled,

impalpable powder of low bulk density, having a faint,

characterstic odour and taste. The powder is greasy to

touch and readily adheres to skin.

4. Pharmaceutical

UsesMagnesium stearate is widely used in cosmetics,

foods and pharmaceutical formulations. It is primarily

used as lubricant in capsule and tablet manufacturing at

concentration between 0.25-5.0% w/w.

5. SolubilityPractically insoluble in ethanol, ethanol (95%), ether and

water, slightly soluble in warm benzene and warm

ethanol (95%).


Chapter 737

EXPERIMENTAL WORK

7.1. Analysis of drug

7.1.a. Analysis of Venlafaxine hydrochloride:

The drug sample was used without further purification. Characterization of drug was done by

physicochemical methods.

7.1.b. Organoleptic properties and description

The sample of Venlafaxine hydrochloride was studied for organoleptic characters like

appearance, color, and odor.

7.1.c. Melting point

The melting point was determined using melting point apparatus.

7.1.d. Solubility

The solubility of Venlafaxine hydrochloride was determined by adding excess amount of

drug in the solvent at 370C. Solubility was determined by taking supernatant and analyzing it

on U.V Spectrophotometer (Jasco).

7.1.e. U.V. Spectroscopy [30]

A standard stock solution of Venlafaxine hydrochloride was prepared by dissolving

accurately weighed 10 mg of Venlafaxine hydrochloride in quantity of 10 ml of water, then

appropriate dilutions were prepared and λmax was determined.

Procedure-

Detection wavelength-

Prepare 10 µg/ml solution by following method,

Dissolve 10mg Venlafaxine hydrochloride in 10ml distilled water. Dilute 1ml of this solution

to 10ml with distilled water (SOLUTION A i.e. 100 µg/ml). From this solution further

dilutions are made as 2-14 µg/ml are carried out. Measure the absorbance of above solution

and find out the detection wavelength.


Chapter 738

EXPERIMENTAL WORK

7.1.e.1. Linearity and range-

Dilute aliquots of each A to 10ml with Distilled Water so as to get solutions of concentration

2, 4, 6, 8, 10, 12, 14µg/ml and measure the absorbance of each of above dilution at detection

wavelength.

Find out the equation of line and regression coefficient (R2) from linearity graph.

7.1.e.2. Precision-

Prepare 6 replicates of SOLUTION of 12 µg/ml and measure the absorbance of each. Find

out standard deviation and average. Find out %RSD as follows,

(S.D/AVG)* 100

It must be less than 2

7.1.f. Assay: (BP) [69]

Procedure: Dissolve 0.25 g in a mixture of 5 ml of 0.01 M hydrochloric acid and 50 ml of

ethanol (96%). Carry out a potentiometric titration using 0.1 M sodium hydroxide. Read the

volume added between 2 points of inflexion. Carry out a blank titration.

1ml of 0.1M NaOH is equivalent to 31.39 mg C17H28ClNO2.

7.1.g. Infra-red spectroscopy:

The IR spectrum of the pure drug was obtained to prove the chemical identity of the drug.

The drug was powdered and intimately mixed with dry powdered potassium bromide. IR

spectrum was recorded by scanning in the wavelength region of 400 to 4000 cm−1 in a FTIR

Spectrophotometer (model 460 Plus, Jasco, Japan).

7.2. Excipient compatibility studies:

A compatibility study of drug with excipients is an early risk reduction strategy which

precludes the use of excipients which may interact with the drug substance.

Drug was triturated with individual excipients in 1:1 ratio. The samples were stored for 4

weeks and analyzed by IR spectroscopy.


Chapter 739

EXPERIMENTAL WORK

7.3. Dissolution study of marketed Venlafaxine Tablets:[70]

Venlafaxine sustained release matrix tablets are available in market. A dissolution study of

marketed tablets (Ventab XR 37.5) was carried out for 24 hrs. A USP dissolution type II

apparatus was used. Speed was adjusted at 50 rpm. Deaerated water was used as a dissolution

medium.

7.4. Quality by Design Protocols

7.4.a. Quality target product profile (QTPP) for Venlafaxine Hydrochloride sustained

release tablet:



taking into account safety and efficacy of the drug product.”

The QTPP is an essential element of a QbD approach and forms the basis of design of the

generic product. For ANDAs, the target should be defined early in development based on the

properties of the drug substance (DS), characterization of the RLD product and consideration

of the RLD label and intended patient population. The QTPP includes all product attributes

that are needed to ensure equivalent safety and efficacy to the RLD. 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) was defined for

Venlafaxine Hydrochloride Tablets. It included following parameters:

Dosage form and type

Route of administration

Potency

Appearance

Identification

Assay

Impurities

Content Uniformity


Chapter 740

EXPERIMENTAL WORK

Dissolution

Hardness, Friability

Pharmacokinetics

% Coating Defects

Coating colour uniformity

7.4.b. Critical quality attributes:

Critical Quality attributes indicate the attributes which were classified as drug product critical

quality attributes (CQAs). CQAs are those that have the potential to be impacted by the

formulation and/or process variables and, therefore, were investigated and discussed in detail

in subsequent formulation and process development studies.

On the other hand, if CQAs include Dosage form and type, route of administration, potency,

appearance, identification which are unlikely to be impacted by formulation and/or process

variables were not discussed in detail in the pharmaceutical development report. However,

these CQAs are still target elements of the QTPP and are ensured through a good

pharmaceutical quality system and the control strategy.

7.4.c Risk assessment for Drug substance attributes:[9]

According to ICH Q9 Quality Risk Management, it is important to note that “it is neither

always appropriate nor always necessary to use a formal risk management process (using

recognized tools and/or internal procedures e.g., standard operating procedures). The use of

informal risk management processes (using empirical tools and/or internal procedures) can

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.


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


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]


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


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:


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.


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.


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


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.


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.


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


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


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


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


Chapter 854


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


Chapter 855


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.


Chapter 856


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)


Chapter 857


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


Chapter 858


8.4. Quality by Design Protocols

8.4.a. Quality target product profile (QTPP) for Venlafaxine Hydrochloride sustained

release tablet



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

Route of administration

Oral - Ease of administration

Potency 37.5 mg Assay Efficacy Appearance Round, convex tablets - Patient complianceIdentification Venlafaxine tablets IR, UV spectra Efficacy Assay 98-102 % w/w of

label claim- Efficacy

Impurities Minimal impurities Individual : NMT 0.2%Total : NMT 0.5%

Efficacy

Dissolution Equivalent to or better than RLD

- Therapeutic effect

Hardness Sufficient 5kP Stability during transport and shelf life

Friability Minimum NMT 1 % Stability during transport and shelf life

Pharmacokinetics PK parameters AUC and C max fall within BE limits

C max = 150ng/ml Bioequivalence

% Coating Defects Good performance and minimal defects

< 5% Efficacy and patient compliance

Coating colour uniformity

Uniform color Uniform color Efficacy and patient compliance

Table No.8.3 Quality Target Product Profile

8.4.b. Critical quality attributes:

Quality attributes of Venlafaxine Hydrochloride tablets and indicates which attributes were

classified as drug product critical quality attributes (CQAs). For this product Dissolution,

Assay, No. of defective tablets, tablet surface roughness, coating process efficiency were

identified as the CQAs that have the potential to be impacted by the formulation and/or


Chapter 859


process variables and, therefore, will be investigated and discussed in detail in subsequent

formulation and process development studies.

On the other hand, if CQAs include Dosage form and type, route of administration, potency,

appearance, identification, coating color uniformity, which were unlikely to be impacted by

formulation and/or process variables will not be discussed in detail in the pharmaceutical

development report. However, these CQAs were still target elements of the QTPP and were

ensured through a good pharmaceutical quality system and the control strategy.

Various Attributes affecting tablet properties

(++high effect, + moderate effect, - low effect)

Quality Attributes

Effect of API on product qualitySalt form Particle

sizeSolubility Purity Residual

solventMoisture

Appearance - - - - - -Identification - - - - - -Microbiology + - - - - +Dissolution + ++ ++ - +Hardness - - - - - -

Assay - - - - - -Flow - ++ - - - -Taste ++ - ++ - - -

Degradation - - - - - -Impurities - - - ++ ++ ++

Table No.8.4: API Attributes

It can be seen from table no. 8.4 that quality attributes that are affected by API attributes are dissolution, flow, taste, and impurity profile.

Quality AttributesEffect of Excipient on product quality

Lactose (Diluent)

Magnesium Stearate

(Lubricant)

Talc (Glidant)

Eudragit RLPO/ RSPO (Polymer)

Appearance + + - +Identification - - - -Microbiology - - - -Dissolution - - - ++Hardness - - - -

Assay - - - -Flow + + ++ -Taste - - - -

Degradation - - - -Impurities - - - -

Table No.8.5 Excipient Attributes


Chapter 860


It can be seen from table no. 8.5 that quality attributes affected by excipient attributes are dissolution, and flow.

Quality Attributes Effect of coating material parameters on product qualitySolution Viscosity Amount of coating

solutionType of solvent

% CPE ++ ++ -No. of Defective

Tablets+ ++ ++

Tablet Moisture - + ++Surface Roughness + - -

Dissolution - ++ -Moisture - - ++

Table No.8.6: Coating Material Attributes

It can be seen from table no. 8.6 that all quality attributes affected by coating material attributes.

Quality Attributes Effect of process parameters on product qualityMixing Granulation Lubrication Compression

Appearance + - - -Identification - - - -Dissolution - - ++ ++Hardness - ++ + ++

Assay ++ - - -Flow - ++ - -Taste - - - -

Degradation - - - -Impurities - - - -

Table No.8.7: Tablet Compression Process Parameters

Dissolution, assay, hardness and flow are affected by tabletting process parameters.

Quality Attributes Effect of coating process parameters on product quality

Pan Speed Pan load Spray Pressure

Temperature

CPE - ++ - -No. of Defective Tablets ++ ++ ++ +

Tablet Moisture - - - +Surface Roughness + - + -

Dissolution - - - -Table No.8.8: Coating Process Parameters

No. of defective tablets, Coating process efficiency are affected by coating process parameters.


Chapter 861


Variables and Process ParametersCQAs API

AttributesExcipient Attributes

Tabletting process

Coating Process

Appearance Low Low High HighIdentification Low Low Low LowDissolution High High High HighHardness Low High High Low

Assay High Low High LowFlow Low High High LowTaste High Moderate Low High

Degradation Low Low Low LowImpurities Low Low Low Low

% CPE Low Low Low HighNo. of Defective

TabletsLow Low Low High

Tablet Moisture Low Low Low HighSurface Roughness Low Low Low High

Table No.8.9: Identification of CQAs using Initial Risk Assessment

Sr. No. CQAs Critical Process parameters

1 Dissolution Coating Polymer/s, Ratio 2 Hardness Process of tabletting (Direct

compression/Granulation)3 Friability 4 No. of defective tablets Process variables:

Temperature, Pan load,Pan Speed, Atomization Pressure

5 Coated Tablet Roughness 6 Coating Process Efficiency

Table No.8.10: Critical Quality Attributes

8.4.c Risk assessment for Drug substance attributes:

Failure Mode and effects:

(S- Severity ranking, O- Probability of Occurrence, D- Probability of detection, RPN- Risk priority number)

Sr. No.

Failure Mode

Failure Effect

S Failure Cause O Control Measure

D RPN

1. Receiving incorrect material

Contamination, cross contamination in raw material

8 Incorrect check during receiving of raw material

2 Approved Vendor

1 16

2. Improper mixing

Non uniformity

7 Mistake in sieve no.

3 Proper checking, follow BMR

1 21


Chapter 862


Sr. No.

Failure Mode

Failure Effect

S Failure Cause O Control Measure

D RPN

3. Mixing time Improper mixing

6 Equipment problem, time not followed as per BMR

2 Follow BMR 1 12

4. Mixing speed Improper mixing

6 Equipment problem, speed not followed as per BMR

2 Follow BMR 1 12

5. Mixing load Improper mixing

5 Load excess or less than equipment capacity

2 Follow BMR 1 10

6. Compression Non uniform release of dose

7 Improper compression force

2 Follow BMR 1 14

7. Compression Non uniform release of dose

6 Unspecified diameter and thickness

2 Follow BMR for die and punch specification

1 12

8. Compression Weight variation

6 Flow property of granules

7 Improve flow properties

1 42

9. Coating Poor film formation

8 Lack of experience

6 Change the solution

5 240

10. Spraying Developm-ent of droplets

6 Lack of experience

5 Adjustment of spray gun

3 90

11. Coating Poor film formation

8 Pan load 6 Adjustment of pan load

1 48

12. Coating Breakage, picking, sticking, color variation

8 Pan speed 5 Adjustment of pan speed

4 160

13. Coating Twinning, picking and sticking

8 Atomization pressure

7 Adjustment of atomization pressure

1 56

Table no. 8.11 Failure mode, effect, cause, measure with RPN calculation

Severity Ranking

When severity ranking is 8, it states loss of primary function. Thus this ranking is given to:


Chapter 863


Receiving incorrect raw material: Loss of primary function i.e. effect of active

ingredient

Coating (improper spraying, poor film formation and defects) Loss of primary

function i.e. sustained release over long time.

When severity ranking is 7, it states highly reduced level of performance. Thus this ranking is

given to:

Improper mixing (mistake in sieve number): It will affect uniformity of blend and

flow.

Improper compression force: It will affect hardness and thickness resulting in

improper release.

When severity ranking is 6, it states reduced level of performance. Thus this ranking is given

to:

Improper mixing (Mixing time, mixing speed): It will affect uniformity of blend.

Compression (Weight variation): The batch may fail due to more tablets falling

outside the limits.

Improper spraying (Development of droplets): There may be delay due to improper

spray pattern.

When severity ranking is 5, it states slightly reduced level of performance. Thus this ranking

is given to:

Improper mixing (Improper mixing load): There may be some problem with capacity

of mixing equipment, and result in delay in manufacturing time.

Occurrence Ranking

When occurrence ranking is 7, it states repeated failure. Thus this ranking is given to:

Improper compression due to variable flow property. This may affect weight

variation. Thus IPQC checks should include weight variation testing.

Improper coating due to variable atomization pressure. This may happen due to

variability in pump pressure. Thus IPQC checks should include atomization pressure

testing at frequent time points.


Chapter 864


When occurrence ranking is 6 and 5, it states occasional failure. Thus this ranking is given to:

Improper coating due to poor film formation. This depends on operator’s skill and

knowledge about parameters like solution properties, spray pattern and pan speed.

Thus failure is occasional.

When occurrence ranking is 3 and 2, it states relatively few failures. Thus this ranking is

given to:

Incorrect check during receiving of raw material

Mistake in sieve no.

Improper time and speed

Load excess or less than equipment capacity

Improper compression force, unspecified diameter and thickness

All of the above types of failures depend on following BMR. Thus these types of failures are

relatively few.

Detection Ranking

When detection ranking is 5, it states detection on preproduction system components. Thus

this ranking is given to:

Poor film formation due to different coating solution: Changes in coating solution can

be detected before starting of coating process.

When detection ranking is 4, it states moderate detection. Thus this ranking is given to:

Various coating defects: These types of failures are detectable on early prototype

system elements.

When detection ranking is 3, it states good detection. Thus this ranking is given to:

Poor film formation: These types of failures show good detection at simulation and

modelling in early stage.

When detection ranking is 1, it states certain to detect, i.e. proven detection methods available

in concept stage. Thus this ranking is given to:


Chapter 865


Receiving incorrect material

Improper mixing

Compression

Coating

Different proven analytical methods are available for detection of these types of failure.

8.5. Formulation development:

Initial risk assessment is done and CQAs were identified. Focusing on coating process, a

formulation fulfilling all requirements of hardness, friability, size and shape is developed.

8.5.a. Preparation of tablets:

8.5 a.2. Selection of process for preparation of tablets:

Flow properties of powder blend

Batch 1 2 3 4 5 6 7 8 9

Housner’s Ratio

1.332 1.466 1.394 1.461 1.461 1.394 1.428 1.62 1.032

Carr’s index

25 31.7 28.2 31.57 31.57 28.2 30 38.46 35

Table no. 8.12 Flow properties of powder blend

Flow properties of granules

Batch 1 2 3 4 5 6 7 8 9

Housner’s Ratio

1.09 1.09 1.1 1.09 1.1 1.095 1.1 1.09 1.15

Carr’s index

8.69 8.69 9.09 8.33 9.09 8.69 9.09 8.69 13.04

Table no. 8.13 Flow properties of granules

In case of dry blend, out of various batches batch no. 9 shows excellent housner’s ratio, but

Carr’s index was very poor. This may be due to In case of batch 1, Carr’s index and

Housner’s ratio was only passable. This may be due to a high difference in bulk and tapped

density. On the other hand, in case of granules all batches show good to excellent Housner’s


Chapter 866


ratio and Carr’s index, since interparticle interactions lessen due to granulation technique.

Overall dry blend flow properties were not satisfactory; hence granulation was used as a

tabletting method.

8.6. Evaluation of preliminary batches

Hardness of all batches was found to be within limits. Thickness was measured with the help

of vernier calipers. All batches pass test for uniformity of weight. Friability results were

much below the limit, i.e. 1%, for all batches.

Batch 1 2 3 4 5 6 7 8 9

Hardness 5 5 5 5.5 5 5.5 5 5 5.5

Thickness2.44± 0.03

2.44± 0.05

2.44± 0.06

2.44± 0.04

2.44± 0.05

2.44± 0.04

2.44± 0.03

2.44± 0.03

2.44± 0.03

Uniformity of weight

Passes

Passes Passes Passes Passes Passes Passes Passes Passes

Friability Test

0.15 0.26 0.15 0.13 0.18 0.12 0.16 0.12 0.22

Table no.8.14: Results of evaluation of preliminary batches

Assay was done for selected batch and was found to be 99.92%

8.7. Coating Process Development:

CQAs were identified and risk assessment was done using FMEA.

8.7.a. Coating Formula Development


Chapter 867


8.7a.1. Selection of solvents based on viscosity and drying time:

Solvent Ratio Viscosity (cp) Water: Ethanol 1:9 1.0501

Water: IPA 1:9 2.1986 Water: Acetone 1:9 0.417 IPA: Acetone 4:6 0.8483

Table no.: 8.15: Viscosities of solvents

Water: Acetone (1:9) and IPA: Acetone (4:6) was found to have lower (0.417 and 0.8483 cp

respectively) viscosities.

They were further checked for drying time. The drying time for water acetone combination

was high because of presence of moisture; it was lesser in case of acetone-IPA mixture, since

both are volatile liquids. In order to ensure high speed of coating, IPA: Acetone combination

was selected for further studies.

8.7.a.2. Selection of Plasticizer based on stickiness and folding endurance

Film prepared by using polyethylene glycol (PEG) was sticky, so PEG was not selected for

further studies. Triethyl citrate gave non sticky film, but folding endurance was less.

Increasing concentrations of TEC were tried; of 0.6% concentration gave folding endurance

around 210. As concentration of plasticizer increases, folding endurance increases since

plasticizer is responsible for decreasing tackiness of film. This concentration was selected for

further studies.

Sr. No. Plasticizer Folding endurance Stickiness1. PEG: 0.2% - Sticky2. TEC:0.2% 47±3 Non sticky3. 0.4% 98±5 Non sticky4. 0.6% 210±6 Non sticky

Table no. 8.16 Effect of plasticizers: Stickiness and folding endurance

8.7.a.3. Effect of fillers on film roughness:

These fillers gave rough films and folding endurance was less When film was casted, the

fillers settled at the bottom of Petri plates, giving uneven surfaces. Apart from this, taking

into consideration the difficulty in spraying a suspension and constant stirring to be provided

at laboratory scale, fillers were not added in coating formula.


Chapter 868


Fillers Folding Endurance Roughness Stickiness MCC 55 Very Rough Nonsticky Talc 46 Rough Nonsticky

Lactose 50 Rough Nonsticky

Table no. 8.17 Effect of fillers: Folding endurance, roughness, stickiness

8.7.a.4. Selection of ratio of sustained release polymer:

Polymers in selected ratios were used to coat tablets. Dissolution study was then carried out.

The ratio which gives a release profile similar to marketed formulation was selected for

further studies.

Time (hrs)

RSPO:RLPO(1:1)

RSPO:RLPO(1:2)

RSPO:RLPO(2:1)

2 18.54 17.44 6.864 56.69 45.68 38.736 78.71 78.87 65.048 92.03 92.81 75.3610 92.92 94.36 89.9212 93.39 95.25 92.3814 94.43 95.92 93.6616 96.15 97.79 94.8118 98.45 98.95 97.0220 99.17 99.69 97.9222 99.16 99.69 99.2224 99.17 99.67 99.22

Fig no. 8.18: % Release for various polymer ratios


Chapter 869


Fig. No. 8.10: Comparative Dissolution Study of various polymer ratio coatings

Tablets coated with Eudragit RLPO alone shows complete release in 8 hrs, hence this coating

type was not selected for comparison. Tablets coated Eudragit RSPO alone shows only

29.9% release in 8 hrs, hence this type of coating also was not considered for comparison.

Eudragit RSPO polymer is a water impermeable polymer; Eudragit RLPO is water permeable

polymer. When drug is very soluble in given medium, it is desirable to use water

impermeable polymer in higher proportion. When its concentration is less than or equal to

that of Eudragit RLPO, Venlafaxine (being highly water soluble), shows higher release.

Depending on drug release, ratio of Eudragit RSPO: RLPO (2:1) is selected for further

studies.

8.7.a.5. Selection of % weight gain:

Coating thicknesses 7.5% and 10% show release similar to that of 5%, but lesser amount of

drug is released as thickness increases. This may be due to fact that the amount of Eudragit

RSPO (responsible for impermeability to water) increases with increasing coating thickness,

2 times more than Eudragit RLPO (water permeable polymer).


Chapter 870


Time (Hrs)

5% 7.50% 10% Time (Hrs)

5% 7.50% 10%

2 6.86 3.56 0 14 93.66 76.41 62.144 38.73 21.87 8.92 16 94.81 76.02 63.716 65.04 41.37 22.56 18 97.02 80.15 65.468 75.36 55.36 38.05 20 97.92 84.52 71.8610 89.92 69.44 49.98 22 99.22 85.61 74.1112 92.38 75.22 60.84 24 99.22 86.31 75.84

Table no. 8.19: % release at various coating thickness

Fig No. 8.11: Dissolution Study at various percentages of wt gain

8.7.c. Optimization of process parameters

8.7.c.2. Evaluation results of preliminary batches

Batch No. 1 2 3 4 5 6 7

Polymer

amount

1 1 1 2 2 3 4

Pan load 50 50 200 200 200 200 200

Temperature 300 c 400 c 400 c 600 c 600 c 600 c 600 c


Chapter 871


Batch No. 1 2 3 4 5 6 7

Pan speed 30 30 30 40 50 30 40

Pressure 5 5 5 5 15 10 10

Process

efficiency

9.31% 10.55% 23.51

%

29.55% 30.51% 26.15% 35.42%

Picking and

sticking

10 8 4 2 - 2 1

Breakage 5 - - - 1 - -

Edge

erosion

- - - - - - -

Peeling - - - - - - -

Colour

variation

4 2 - - - - 1

Twinning 1 2 2 - - 1 -

Orange peel

effect

3 2 2 - - 1 -

Table no.8.20: Evaluation results of preliminary batches

In some batches, pan load, temperature and pan speed were low. Hence the problems due to

sticking and picking are high. For batches where pan load was less, problems like tablet to

tablet colour variation were high, as pan load increased, no. of such defects decreased. If pan

speed is too low, defects like twinning, colour variation increase. Problems like peeling, edge

erosion were not observed in batches.

8.7.c.3. Effect of temperature on quality of coating:

Temperature Concentration Load Pan speed Defects

300c

3 50 40

12

400c 8

600c 3


Chapter 872


Table no. 8.21: Effect of temperature on no. of defects

At lower temperature, the sprayed solution takes longer time to dry, making tablets stick to

each other. At higher temperature, curing process is faster as compared to lower temperature.

8.7.c.4. Effect of pan load on Coating process efficiency:

Load Concentration Temperature Pan speed %CPE

50

3 600c 40

14.76%

200 35.51%

300 52.21%

415 -

Table no. 8.22: Effect of pan load on coating process efficiency

Coating efficiency was shown to be affected by pan load. As pan load increases, the spray

falls on tablet bed, instead of falling on pan surface. This decreases wastage of spray solution,

resulting in greater weight gain, thus increasing overall process efficiency.


Chapter 873


8.7.c.5. Effect of Solid content, pan speed and atomization pressure on Process

efficiency, defects, and tablet roughness.

Coated tablets were evaluated for Process efficiency, defects, and tablet roughness.

Sr. no.

Concentration Pan Speed

Atomization Pressure

Process efficiency

Defects Roughness

1. 3 40 10 13.26 4 1

2. 3 55 5 15.03 2 1

3. 3 55 15 19.66 2 1

4. 3 70 10 21.13 2 1

5. 4.5 40 5 8 4 3

6. 4.5 40 15 11 2 2

7. 4.5 55 10 13.04 4 2

8. 4.5 70 5 12.88 3 2

9. 4.5 70 15 12.48 2 2

10. 6 40 10 8.75 5 3

11. 6 55 15 7.15 2 2

12. 6 55 5 11.56 5 3

13. 6 70 10 9.31 4 2

Table no. 8.23: Results of optimization batches


Chapter 874


Response I- Coating process efficiency

Design-Expert® SoftwareFactor Coding: ActualCPE

Design points above predicted valueDesign points below predicted value21.13

7.15

X1 = A: ConcentrationX2 = B: Speed

Actual FactorC: Pressure = 10

40

46

52

58

64

70

3 3.6

4.2 4.8

5.4 6

5

10

15

20

25

CP

E

A: Concentration

B: Speed



7.15

X1 = B: SpeedX2 = C: Pressure

Actual FactorA: Concentration = 4.5

5

7

9

11

13

15

40

46

52

58

64

70

5

10

15

20

25

CP

E

B: SpeedC: Pressure



7.15

X1 = A: ConcentrationX2 = C: Pressure

Actual FactorB: Speed = 55

5

7

9

11

13

15

3 3.6

4.2 4.8

5.4 6

5

10

15

20

25

CP

E

A: Concentration

C: Pressure


Chapter 875


Fig. No. 8.12 3D Surface plot showing effect of Independent Parameters on CPE

Coating Process Efficiency = 13.04-4.03875 * A+ 1.84875 * B +0.3525* C -1.8275* AB -2.26 * AC -0.85 * BC+ 1.16625 * A2 -1.09375 * B2 -0.85625 * C2

Equation states that Concentration has negative effect on process efficiency; Pan Speed has a

positive, whereas atomization pressure has a positive effect on process efficiency. Effect of

concentration was the most significant.

As concentration increases, solution solid content increases. For given batch size (50

tablets), loss of coating solution on coating pan increases. Hence, relative % weight gain

decreases, resulting in lower coating process efficiency.

As pan speed increases, it improves distribution of coating solution onto tablet bed.

Sussane Tobiska et al (Coating uniformity and coating efficiency in a Bohle Lab-Coater

using oval tablets, Europian journal of pharmaceutics and biopharmaceutics, 2003) show that

with increasing pan speed less polymer has to be applied to coating, that is efficiency of

given process increases.[31]

As Atomization Pressure increases, droplet velocity increases and droplet size decreases,

drying time decreases and efficiency increases.

J. Wang et al (International Journal of Pharmaceutics 427, 2012) stated a direct relationship

between atomization pressure (i. e. pattern air flow rate) and coating process efficiency.


Chapter 876


Response II- Defects

Design-Expert® SoftwareFactor Coding: ActualDefect

Design points above predicted valueDesign points below predicted value5

2



40

46

52

58

64

70

3

3.6

4.2

4.8

5.4

6

2

3

4

5

6

De

fe

ct

A: ConcentrationB: Speed


5

2



5

7

9

11

13

15

3

3.6

4.2

4.8

5.4

6

2

3

4

5

6

De

fe

ct

A: Concentration

C: Pressure



2



5 7

9 11

13 15

40

46

52

58

64

70

1

2

3

4

5

6

De

fe

ct

B: Speed

C: Pressure


Chapter 877


Fig. 8.13: 3D Surface plot showing effect of Independent Parameters on No. of defects

Defect = 4+ 0.75 * A -0.5 * B -0.75 * C + 0.25 * AB -0.75 * AC + 0.25 * BC -0.125 * A2 -0.125* B2 -1.125 * C2

Equation states that Concentration has positive effect on coating defects; Pan Speed and

atomization pressure have a negative effect on coating defects. Concentration and

atomization Pressure have opposite effects of same magnitude.

High content of solid and low atomization pressure result in larger droplet size, which

takes more time to dry, and may result in increased no. of defects.

High solid concentration increases viscosity of solution; pan speed is also low, this takes

longer time to dry, resulting in wetting of surface, and problems like sticking-picking, tablet

color variation, spray drying ( logo filling) etc.

Colorcon film coating troubleshooting chart provides solutions to these problems; like

increasing pan speed, atomization pressure, decreasing solution viscosity.


Chapter 878


Response III- Surface Roughness

Design-Expert® SoftwareFactor Coding: ActualRoughness


1



40 46 52 58 64 70

3 3.6

4.2 4.8

5.4 6

0.5

1

1.5

2

2.5

3

Ro

ug

hn

es

s

A: ConcentrationB: Speed



1



5

7

9

11

13

15

40

46

52

58

64

70

0.5

1

1.5

2

2.5

3

Ro

ug

hn

es

s

B: Speed

C: Pressure



1



5

7

9

11

13

15

3

3.6

4.2

4.8

5.4

6

0.5

1

1.5

2

2.5

3

Ro

ug

hn

es

s

A: Concentration

C: Pressure


Chapter 879


Fig. 8.14: Surface plot showing effect of Independent Parameters on S roughness

Roughness = 1.75 + 0.75 * A-0.25* B -0.25 * C -0.25 * AB -0.25 * AC + 0.25 * BC -0.25 * A2

0.25 * B2+0.25 * C2

Equation states that Concentration has positive effect on surface roughness; Pan Speed has a

negative, whereas atomization pressure also has negative effect on Surface Roughness. Effect

of concentration is more than other variables.

Sanjay Patel et al (formulation, process parameters optimization and evaluation of delayed

release tablets of rabeprazole sodium, International journal of pharmacy and pharmaceutical

sciences, 2010) also stated that higher solid content and lower atomization pressure increase

surface roughness. [32]

Optimization Studies:

The results of experiments were entered in the software and numerical optimization solutions

were obtained. These experiments were repeated as per the given solutions and evaluated.

Independent variables were set to ‘in range’ a value, i.e. experimental ranges. Goal for

coating process efficiency was set to ‘maximize’ value. Goal for defects was set to

‘minimize’ value. Goal for coating process efficiency was set to ‘minimize’ value.

Three solutions were selected according to desirability and experimental conditions.

Predicted and observed values were compared. (C: concentration, S: Speed, A: Atomization

Pressure, CPE: Coating process efficiency, RE: Residual error)

PredictedSolution

No.C S A CPE Defect Roughness Desirability

1 3.000 63.228 14.193 21.130 2.000 1 0.99246 3.000 70.000 9.101 20.483 2.169 1 0.95665 3.506 63.014 14.588 18.113 2.000 1 0.871

Observed Solution

No.CPE RE Defect RE Roughness RE

1 20.982± 0.13 0.148 1 - 1 -46 19.845± 0.58 0.638 2 - 1 -


Chapter 880


65 18.187± 0.64 0.074 2 - 1 -

Table no. 8.24: Predicted vs observed values for optimization

8.8. Updated risk assessment of formulation and process variables:

Steps Failure mode RPN I RPN II Risk priority IndexReceiving Receiving incorrect material 16 8 2Mixing Improper mixing 21 7 3

Mixing time 12 6 2Mixing speed 12 5 2.4Mixing load 10 10 1

Compression Compression 14 14 1Compression 12 12 1Compression 42 12 3.5

Spraying Coating 240 80 3Spraying 90 90 1Coating 48 32 1.5Coating 160 32 5Coating 56 24 2.33

Table no.8.25: Updated risk assessment

Fig No. 8.15: FMEA analysis of manufacturing process


Chapter 881


8.9. Defining Design Space:

Design Space for Materials and process parameters

Formulation

Attributes

Design space Response

Drug Fine powder

Assay -98-102 %

Volume- 37.5 mg

Assay

Dissolution

Polymer level Eudragit RSPO: Eudragit RLPO ratio

2:1

Dissolution

Talcum level 2- 2.5% Physical Characteristic

Mg.St. Level 1-1.5% Physical Characteristic, flow

Mixing Mixing frequency: 30-100 times, so

that %RSD is lowest.

Blend uniformity

Compression Weight of tab – 200mg ± 5 %

Hardness – 5Kg/cm2 ± 0.5 5Kg/cm2

Assay, Content Uniformity,

Dissolution Time

Coating process

parameters

Concentration: 3-6

Pan speed: 40-70

Atomization Pressure: 5-15

Coating process efficiency,

Defects, Surface roughness

Table no. 8.26: Design Space


Chapter 882


Graphical Representation of Design space for coating process


Chapter 883


a

Design-Expert® SoftwareFactor Coding: ActualOverlay Plot

CPEDefectRoughness

Design Points



3 3.6 4.2 4.8 5.4 6

40

46

52

58

64

70Overlay Plot

X1: A: ConcentrationX2: B: Speed

Defect: 5Roughness: 3


CPEDefectRoughness

Design Points



3 3.6 4.2 4.8 5.4 6

40

46

52

58

64

70Overlay Plot


Roughness: 1 4


CPEDefectRoughness

Design Points



3 3.6 4.2 4.8 5.4 6

40

46

52

58

64

70Overlay Plot


CPE: 7.15

b

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.


Chapter 884


All six plots show design space where X1= Concentration, X2= Speed and Pressure= 5, 10, 15 respectively for both a and b.

8.10. Defining control strategy:

Sr. No. Attributes/ Steps Control Measures

1. Drug Pass through #24 mesh sizeAssay 98 -102 %

2. Excipients Pass through #24 mesh size3. Coating polymer Check labeling properly.

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


Chapter 885


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.


Chapter 886


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


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,

identification, assay, impurities, content uniformity, dissolution, hardness, friability,

pharmacokinetics, coating defects and coating colour uniformity.

Critical quality attributes were defined using initial risk assessment. Risk assessment

was applied also using failure modes effects analysis (FMEA).

Analysis of drug for organoleptic properties, melting point and solubility was done.

Identification was done and interaction with excipients was checked using infrared

spectroscopy.

Selection of tabletting process was done based on flow properties. Granulation was

finalized as tabletting method. Hardness, dimensions, friability and assay were found

to be within limit for core tablet.

For coating, both formula and processing parameters were studied in depth to

understand process better. It included selection of solvents based on viscosity and

drying time, selection of plasticizer based on stickiness and folding endurance, effect

of fillers on film roughness, selection of ratio of sustained release polymer, selection

of % weight gain, effect of temperature on quality of coating, effect of pan load on

coating process efficiency and effect of solid content, pan speed and atomization

pressure on process efficiency, defects, and tablet roughness by application of DOE.


SUMMARY AND CONCLUSION 88

Risk was updated and risk priority number was calculated for every process step and

design space was defined. Control strategy was given to maintain process robustness.

Accelerated stability studies confirmed that product was stable over given time

period.

CONCLUSION

Film coated tablets gave complete and sustained release over 24 hours. Application of initial

risk assessment and FMEA tool helped easy identification of critical quality attributes.

Design of experiments was also useful in designing of proper experiments. Temperature and

pan load had large influence on quality and efficiency of coating process. Further ANOVA

and statistical test showed that concentration of polymer, pan speed; pan load also had an

effect on coating process efficiency, no. of defective tablets and tablet surface roughness.

Taking the results into consideration, a design space and control strategy was defined. In this

way, quality by design approach was successfully applied to sustained release film coated

tablet formulation.

Further study can be extended at pilot and production scale, also using PAT tools like NIR

spectroscopy, Raman spectroscopy, prediction using chemometrics etc.


REFERENCES 89

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PUBLICATIONS 96

1. Title: “Formulation and evaluation of sustained release film coated tablets using quality

by design (QbD) approach”

Journal: Indian Journal of pharmaceutical sciences

Status: Communicated

2. Title: “Design & Development of Transdermal Drug Delivery System For Arthritis”

Journal: Inventi Journals Pvt. Ltd.

Status: Communicated


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