Fig. 2.1: Reporting responsibilities under general considerations

10 Industrial Pharmacy II

scale-up and the pilot-plant should have practical experience in pilot-plant operations.

The level of education and type of education should be matched within the group

because they have to understand each other perspective. The group should have

personnel from different disciplines like engineering, economics, management,

production, etc. The scientists with experience in pilot-plant production as well as

actual production area should be preferred. The number of personnel required depends

upon the number of products being supported and the level of support.

2.1.3 Space Requirements

There are four types of space requirements of a pilot-plant

i. Administrative and information processing

ii. Physical testing area

iii. Standard pilot-plant equipment floor space

iv. Storage area

Administrative and Information Processing

i. Adequate space should be there.

ii. Scientist and technicians should have adequate office and desk space.

iii. There should be proper facilities so that scientists and technicians can do proper

documentation of their activities and observation.

iv. It should be near the work area but away from undue distraction.

Physical Testing Area

i. The space of physical testing area should be adequate so that analysis and physical

testing of samples can be done. It helps in early detection of a production error.

ii. There should be permanent benchtop space for testing equipment (for physical

testing) balances, viscometer, pH meter, etc.

Standard Pilot-Plant Equipment Floor Space

i. The equipment should be in a variety of sizes so as to enable the production of a

product in a different capacity.

ii. There should be discrete pilot-plant space where the equipment need for

manufacturing of all type of dosage forms/formulations can be kept.

iii. There should be space for the cleaning of equipment.

iv. The equipment should be portable so that it can be used when and wherever

possible. This will also help in the storage of equipment in a small storeroom.

v. The production equipment should be of intermediate-size, as well as full-scale

production sized so that the effect of scale-up of research formulations and the

process can be evaluated.

Storage Area

i. There should be two separate areas—one for active ingredients and another one

for excipients so as to avoid intermixing.

ii. Different areas should be provided for in-process materials, products from pilotplant, and materials from scale-up batches.

iii. There should also be the availability of a storage area for packing material.

General Considerations and Pilot-Plant Considerations for Different Dosage Forms 11

2.1.4 Review of the Formula

A thorough and critical review of each prospect of the formulation is important. It is

done to:

i. Understand the purpose of each ingredient and its contribution to the final product

that is manufactured on small-scale laboratory equipment.

ii. Understand the degree and type of stress on the product that can be the result of

scale-up.

 

2.1.5 Raw Materials

One of the main responsibilities of the pilot-plant is to validate and approve the

excipients and active ingredients used in pharmaceutical product's formulation. The

raw materials used in laboratory-scale production may not fit for the large-scale

production batches. There may be several variations in size, shape, density, and

solubility, flow properties, etc. A single supplier may not be able to fulfil the need of

raw material for large-scale production and can leave the manufacturer defenceless.

So, several batches with different alternatives to raw materials (supplied by two or

more suppliers) need to be manufactured. All the data regarding the performance of

this different raw materials (stability, quality tests, etc.) should be well-documented

so that can be thoroughly analysed.

2.1.6 Equipment

On small and laboratory-scale basic equipment has been used during the development

of drug product. So during scale-up alternative manufacturing equipment should be

used. The equipment should be:

i. Economical

ii. Simplest processing

iii. Efficient

iv. Capable of consistently producing products within the set specifications

v. Of optimum size (in accordance with production batch size)

vi. Can be cleaned easily (in case of used for the multiple product manufacturing)

2.1.7 Production Rate

The production rate should be determined by keeping the following things into

consideration

i. Immediate and future market demands and trends

ii. Type and size of equipment that is to be used in production

iii. Proportionality of size of the equipment and its utilization

iv. Product loss data during using a specific equipment and process

v. Clean up time between batches or between multiple product manufacturing

vi. The number of batches required for testing

2.1.8 Process Evaluation

In this step the critical evaluation of process is done and based on the evaluation results,

the process is optimized. The processes that should be evaluated include:

i. Mixing speed and mixing time

ii. Filter size for liquids preparations

12 Industrial Pharmacy II

iii. Screen sizes for solid preparations

iv. Drying time and drying temperature

v. Rate of the addition of solvents, solution of drugs, granulating agents, etc

vi. Order of addition/mixing of components, and their respective adjustments

vii. Heating and cooling rates

The knowledge of the effect of these above mentioned important process parameters

on the finished product and in-process quality is the basis for process validation and

optimization. This is accomplished by monitoring the within the batch variation of

measurable parameters (content uniformity, moisture content and compressibility).

This provides data that helps in identifying and accessing where the process is

performing as intended and where problem areas may be found.

2.1.9 Preparation of Master Manufacturing Procedures

The manufacturing procedure includes manufacturing directives, sampling directions,

weight sheet, finished and in-process product specifications (Fig. 2.2). This section is

related with the manner of presentation of manufacturing procedures which helps in

facilitating easy compliance and understanding of processing technicians.

The weight sheet should clearly categorize the chemicals which are required in the

batch, their order and quantities in which they will be used. The names and identifying

numbers for the ingredient should be used on batch records. These names and

identifying number should be in correspondence with those on the bulk material

containers. The process directions should be explicit as well as precise.

Various specifications (like addition rates, mixing times, mixing speeds, heating

and cooling rates and temperatures, the actual times, temperature and speeds, the

time and the manner in which finished and in-process samples are to be taken, handled

and stored) should be mentioned in the batch record directions. The manufacturing

procedure should only be written by actual operator.

Fig. 2.2: Different aspects included in manufacturing procedure

General Considerations and Pilot-Plant Considerations for Different Dosage Forms 13

2.1.10 Product Stability and Uniformity

Each pilot-plant batch should be studied for stability. The physical as well as chemical

stability studies should be performed on pilot-plant batches. The stability studies of

finished packages should be carried out.

2.1.11 Good Manufacturing Practices (GMP) Considerations

 

1. a 2. a 3. a 4. a 5. d 6. c 7. 1(d), 2(c), 3(a), 4(b)

8. a. money, material, machine

b. prototype, pilot-plant

c. laboratory

d. scale-up

e. calibration, QA QC activities, labelling.

General Considerations and Pilot-Plant Considerations for Different Dosage Forms 9

2.1 GENERAL CONSIDERATIONS (Fig. 2.3)

General consideration includes the following points to be kept in mind while planning

for scale-up.

2.1.1 Reporting Responsibilities (Fig. 2.1)

There should be adequate records and reporting arrangements to make the transfer of

products from laboratory-scale to a commercial-scale smooth. The transfer is a

multidisciplinary approach as it includes pilot-plant group and other groups like R&D,

processing, engineering, quality assurance, regulatory, marketing, etc. There should

be good communication and relationship between pilot-plant groups and other groups.

R&D group should be with separate staffing. Production department can be under

formulator and formulator can provide support even after the transition of production

has been completed.

2.1.2 Personnel Requirement

It is very important for the smooth transfer of products (from laboratory-scale to pilotplant and then to commercial-scale) to have well-qualified staff. They should have

good knowledge about pharmacy and pharmaceutical industry. Those employed for

9

General Considerations and

Pilot-Plant Considerations for

Different Dosage Forms

2

 

ii. To review the processing equipment used in the manufacturing of a product

iii. To check compliance with guidelines for production and process control

iv. To conduct evaluation and validation of process

v. To identify the critical characteristics of the process

vi. To provide master manufacturing formula

1.3.4 Relation between Pilot-Plant and Scale-up (Figs 1.2 and 1.3)

Fig. 1.2: Relations between pilot-plant and scale-up

Introduction to Pilot-Plant and Scale-up 7

PRACTICE QUESTIONS

Long Answer Type Questions

1. Define pilot-plant. Explain pilot-plant operations and need for conducting pilotplant studies.

2. Explain scale-up process. What are the steps in conducting scale-up studies?

Short Answer Type Questions

1. What is pilot-plant? Explain the reasons for conducting pilot -plant studies.

2. Define scale-up and elaborate the need for scale-up.

3. Describe the relation between pilot-plant and scale-up.

4. What are the objectives of establishing pilot-plant?

Objective Type Questions

1. Which of the following is/are reason for conducting pilot-plant studies?

a. Evaluation of results b. Determination of waste products

c. Decision making d. All of the above

2. The manufacture of either drug or drug product by a procedure fully representative

of and stimulating that used for full manufacturing scale is known as

a. Pilot-plant b. Validation

c. Scale-up d. Commercial production

3. Which of the following is one of three key objectives of designing pilot-plant?

a. Clinical supply manufacture b. Profit making

c. Marketing d. None of the above

4. The plant size of set up is bigger than pilot-plant but smaller than commercial

manufacturing is known as

a. Scale-up b. Clinical trial batch

c. Trial batch d. None of the above

5. Which of the following provides base for commercial-scale production?

a. Pilot-plant b. Scale-up

c. Trial batch d. All of the above

Fig. 1.3: Different steps followed in the development process of the product from laboratory-scale to

commercial-scale

8 Industrial Pharmacy II

6. Arrange the following in accordance with the development process

1. Pilot-plant

2. Laboratory-scale

3. Scale-up

4. Commercial-scale

a. 1, 2, 3, 4 b. 3, 1, 2, 4

c. 2, 1, 3, 4 d. 4, 3, 2, 1

7. Match the following

Content Terminology

1. Batch size is larger than pilot-plant but smaller a. Quality assurance

than commercial-scale.

2. Releasing and testing of finished products. b. Pilot-plant

3. Testing of products in-between processes. c. Quality control

4. When a lab-scale formula is transferred before d. Scale-up

commercial batch production

8. Fill in the blanks

a. A plant can be defined as a place where Ms like ____________, _____________,

method, man and ___________ are brought together for manufacturing process.

b. Scale-up is defined as art of designing of ___________ using the data obtained

from _____________ process/model.

c. Pilot-plant is larger than ____________ scale.

d. Pilot-plant provides base for ____________.

e. Validation, training, engineering, maintenance, ____________, material control,

___________, orders, ____________ are operations of pilot-plant studies.

ANSWERS

 

Introduction to Pilot-Plant and Scale-up 3

Starting up a new production unit is tricky but it would become risky if unforeseen

difficulties would not be identified. At the initial stage of development the product is

manufactured at laboratory-scale. It is many folds smaller than that of commercial

scale. So, this is not an intelligent idea to directly transfer product from laboratory

scale to commercial stage due to possibility of birth of many problems, e.g. corrosion,

high cost on material, low yield, less profit, etc. So, to detect and avoid the unforeseen

problems pilot-plant is used.

Pilot-plant can be defined as “the manufacture of either drug or drug product by a

procedure fully representative of and stimulating that used for full manufacturing

scale.” Pilot-plant is a part of the pharmaceutical industry where a lab-scale formula is

transformed into a viable product by development of liable and practical procedure of

manufacture.

1.2.1 Reasons for Conducting Pilot-Plant Studies

i. Evaluation of results: The pilot-plant helps in evaluating the results of laboratory

studies so that process and product corrections can be made accordingly.

ii. Determination of qualitative and quantitative details of product: In pilot-plant

small quantities can be produced which enables sensory microbiological

evaluations, limited marketing testing by providing small samples to

potential customers and determination of shelf life as well as storage stability

studies.

iii. Determination of waste products: By pilot-plant studies the possible salable byproducts can be determined. It also helps in determination of methods by which

waste management can be done in future.

iv. Decision making: By pilot-plant studies enough data can be collected which help

in making decision either to start a full-scale production or not. In case of positive

results the designing or modifying of plant can be done.

v. Need to make supplies: Pilot-plant provides supplies for several studies like bench

studies, animal studies and clinical studies. These studies are essential to

determine product characters, purity, toxicology, pharmacokinetics, ADME,

efficacy of product.

1.2.2 Objectives of Pilot-Plant

i. To attempt the procedure on a model of a proposed plant before spending

substantial whole of cash on a production unit.

ii. To examine of the procedure to decide its capacity to withstand batch scale and

process alteration.

iii. To validate and evaluate for process and supplies.

iv. To detect unforeseen problems during commercialised production.

v. To make master manufacturing formula

vi. To identify the critical control points of a process

vii. To avoid scale-up problems

A Pilot-plant design should support the three key objectives

a. Formulation and process development

b. Clinical supply manufacture

c. Technology evaluation, scale and transfer

4 Industrial Pharmacy II

These three objectives can be achieved by the following attributes

a. Compliance with CGMP.

b. A highly trained and flexible staff with experience of concerned field

c. Equipment that can support multiple dosage forms development.

d. Equipment at multiple scales based on similar operating principles to those

in production.

 

1.2.3 Pilot-Plant Operations

A pilot-plant operation includes series of operational aspects. These are as follows:

1. Validation includes the following of all utility systems, process equipments, control

systems so that pilot-plant can be fully validated and ensure compliance with CGMP

i. DQ (Design Qualification)

ii. IQ (Installation Qualification)

iii. OQ (Operational Qualification)

iv. PQ (Performance Qualification)

2. Training should be given in four areas

i. Compliance with CGMP and other quality systems

ii. Environmental and safety responsibilities

iii. Compliance with SOPs

iv. Technical knowledge and skills

3. Engineering support is required for

i. Design, commissioning, and validation of pilot-plant facility

ii. Co-ordination, direction and scheduling of ongoing operations at the pilotplant facility

4. Maintenance is required

i. To compliance with CGMP norms

ii. To ensure integrity of data and reliability of equipment

5. Calibration of equipment/instrument is required

i. To compliance with CGMP norms

ii. To ensure the integrity of data generated during the development process

6. Material control with computer-based system

7. Inventory should be maintained by computer-based inventory system

8. Orders should be placed through computer-based system and first-in first-out

criteria is followed.

9. Labelling should be done in compliance with regulatory guidelines

10. Process and manufacturing activities includes

i. Formulation and process development

ii. Clinical supply manufacture

iii. Technology evaluation, scale and transfer

11. QA and QC activities

QA activity involves

i. Auditing pilot-plant, component suppliers.

ii. Reviewing validation and engineering documentation

iii. Reviewing, approving and maintaining batch records for clinical supplies

iv. Sampling and release of raw materials and clinical supplies

v. Maintaining and approval of SOPs

Introduction to Pilot-Plant and Scale-up 5

QC activities include

i. Releasing and testing (physical, chemical and microbiological testing) of

finished products.

ii. Testing for validation as well as revalidation programs.

iii. QC in-process testing during each stage (drug development, pilot-plant, scaleup and technology transfer)

 

Pilot-Plant Scale-up Techniques

2 Industrial Pharmacy II

The pharmaceutical industry is growing with high speed in the last few years. New

drugs, as well as generic drugs, have been coming in the market. Research and development sector is also growing with good growth rate. Researchers are encouraged to

use the latest processes and technologies. In short, Cona, the pharmaceutical industry,

has witnessed significant innovations and inventions coming day by day. A huge sum

of money is invested in the pharmaceutical production to this much loss unit. According to a recent study, developing a new prescription medicine which gains market

approval is estimated to cost drug makers nearly $2 billion. One cannot afford loss

after setting up a commercial production unit.

So to avoid this loss, a replica of the main design has been set up but at a smallscale. This is known as pilot-plant and the data obtained from this pilot-plant is used

in establishing a commercial plant is known as scale-up. If we go with the dictionary

meaning then the pilot-plant is a “small factory that is built as a model to test systems

and processes before building other similar factories” and scale-up is “to increase the

size, amount, or importance of something, usually an organization or process.” In the

pharmaceutical industry pilot-plant scale-up techniques have different considerations

for different dosage forms.

1.1 PLANT

A plant can be defined as a place where 5Ms like money, material, method, man and

machines are brought together for the manufacturing of products. A plant contains all

assets of business like land, money, equipment, employees, etc. In the pharmaceutical

industry a plant is used as a synonym for manufacturing plant where drug/medical

devices/cosmetics manufacturing is going on. Various guidelines by regulatory authorities have to be followed by the manufacturer before setting up a manufacturing

plant in the pharmaceutical industry. There are several types of manufacturing plants

in the pharma industry like API manufacturing plant, formulation manufacturing plant,

contract manufacturing plant, etc.

1.2 PILOT-PLANT

There is a saying that “commits your blunders on a small-scale and make up your

profits on a large-scale.”

2

Introduction to Pilot-Plant and

Scale-up

1

 

12.4.1 NABL Vision 187

12.4.2 NABL Mission 187

12.4.3 Achievements of NABL (As per the Official Website of NABL) 188

12.4.4 Scope of NABL Accreditation 188

12.4.5 Benefits of Accreditation 189

Long Answer Type Questions 190

Short Answer Type Questions 190

Objective Type Questions 190

Summary 193

xvi Industrial Pharmacy II

UNIT 5: Indian Regulatory Requirements

13. Central and State Drug Regulatory Authority of India 206

13.1 Drug Regulatory Authority 206

13.2 Central Drug Standard Control Organisation (CDSCO) 208

13.3 State Licensing Authorities (SLA) 212

Long Answer Type Questions 213

Short Answer Type Questions 213

Objective Type Questions 213

14. CTD and New Drug Approval Process in India 215

14.1 Common Technical Document 215

14.2 Certificate of Pharmaceutical Product (COPP) 217

14.3 New Drug Approval in India 218

Requirements for New Drug Approval 220

Long Answer Type Questions 221

Short Answer Type Questions 221

Objective Type Questions 222

Summary 224

Index 229

1. Introduction to Pilot-Plant and Scale-up

2. General Considerations and Pilot-Plant Considerations

for Different Dosage Forms

3. SUPAC Guidelines and Platform Technology

Summary

1

 

2.5 Documentation 21

Long Answer Type Questions 23

Short Answer Type Questions 23

Objective Type Questions 23

UNIT 1: Pilot-Plant Scale-up Techniques

xii Industrial Pharmacy II

3. SUPAC Guidelines and Platform Technology 25

3.1 Purpose of Guidance 25

3.2 Evolution of SUPAC Guidance 25

3.3 Terminologies used in Guidance Document 26

3.4 Level of Changes 28

3.5 Type of Changes 28

3.6 Introduction to Platform Technology 37

Long Answer Type Questions 39

Short Answer Type Questions 39

Objective Type Questions 39

Summary 41

UNIT 2: Technology Development and Transfer

4. Technology Development and Transfer 50

4.1 Technology 50

4.2 Technology Development 50

4.3 Technology Transfer 50

4.4 Technology Transfer in Pharmaceutical Sciences 51

4.4.1 Reasons for Technology Transfer 54

4.4.2 Types of Technology Transfer 55

4.4.3 Methods of Technology Transfer 56

Long Answer Type Questions 57

Short Answer Type Questions 57

Objective Type Questions 57

5. WHO Guidelines for Transfer of Technology 60

5.1 Introduction 60

5.2 Transfer of Technology (TOT) as per WHO 60

5.3 Scope of WHO Guidelines for TOT 62

5.4 Terminologies Source 62

5.5 Organisation and Management 66

5.6 Quality Risk Management 68

5.7 QRM Application in Pharmaceuticals 72

5.8 Transfer from R&D to Production (Process, Packaging and Cleaning)

and Granularity of TT Process (API, Excipients, Finished Products,

Packaging Material) 74

5.9 Analytical Method Transfer 79

5.10 Premises and Equipment 81

5.11 Documentation 84

5.12 Qualification and Validation 84

Long Answer Type Questions 85

Short Answer Type Questions 85

Objective Type Questions 85

Contents xiii

6. Regulation of Transfer of Technology 87

6.1 Authorities and Agencies Involved in TOT 87

6.2 Problems Faced During Commercialisation 89

6.3 Case Studies of Technology Transfer 90

6.4 TOT Agencies in India 91

6.4.1 APCTT 91

6.4.2 NRDC 93

 

6.4.3 TIFAC (Technology Information Forecasting and

Assessment Council) 95

6.4.4 BCIL (Biotech Consortium India Limited) 97

6.4.5 TBSE (Technology Bureau for Small Enterprises)/SIDBI

(Small Industries Development Bank of India) 98

6.5 TOT Related Documentation 99

6.5.1 Confidentiality Agreements 99

6.5.2 Licensing 100

6.5.3 MoU 102

6.5.4 Legal Issues 103

Long Answer Type Questions 104

Short Answer Type Questions 104

Objective Type Questions 104

Summary 107

UNIT 3: Regulatory Affairs and Regulatory Requirements for Drug Approval

7. Regulatory Affairs and its Role 114

7.1 Introduction 114

7.2 Historical Overview of Regulatory Affairs 115

7.3 Regulatory Authorities 116

7.4 Role of Regulatory Affairs Department 117

7.5 Responsibility of Regulatory Affairs Professionals 119

Long Answer Type Questions 120

Short Answer Type Questions 120

Objective Type Questions 120

8. Drug Development and Non-Clinical Studies 122

8.1 Drug Development Teams 122

8.2 Non-clinical Drug Development 124

8.3 Toxicology 126

8.4 Drug Metabolism 126

Long Answer Type Questions 128

Short Answer Type Questions 128

Objective Type Questions 128

xiv Industrial Pharmacy II

9. INDA and NDA 130

9.1 General Considerations of Investigational New Drug (IND)

Application 130

9.2 Investigator’s Brochure (IB) 131

9.3 New Drug Application (NDA) 132

9.4 Clinical Research/BE (Bioequivalence) Studies 134

9.5 Biostatistics in Pharmaceutical Product Development 136

9.6 Data Presentation for FDA Submissions 138

9.7 Management of Clinical Studies 139

Long Answer Type Questions 139

Short Answer Type Questions 140

Objective Type Questions 140

Summary 142

UNIT 4: Quality Management Systems

10. Quality and Related Concepts 150

10.1 Concept of Quality 150

10.2 Quality Control 155

10.3 Quality Assurance 156

10.4 Comparison Between Quality Control and Quality Assurance 156

Long Answer Type Questions 157

Short Answer Type Questions 157

Objective Type Questions 157

11. Total Quality Management and Other Quality Management

Systems 159

11.1 Total Quality Management (TQM) 159

11.1.1 Origin of TQM 159

11.1.2 Characteristics of TQM 159

11.1.3 Principles of TQM 160

11.1.4 Key Elements of TQM 160

11.1.5 Main Objective of TQM: Continuous Improvement 161

11.1.6 Importance of TQM in the Pharmaceutical Industry 163

 

FDA submissions, management of clinical studies.

UNIT 4 08 Hours

Quality management systems: Quality management & certifications: Concept of quality, total quality

management, quality by design (QbD), six sigma concept, out of specifications (OOS), change control,

introduction to ISO 9000 series of quality systems standards, ISO 14000, NABL, GLP

UNIT 5 07 Hours

Indian regulatory requirements: Central Drug Standard Control Organization (CDSCO) and State

Licensing Authority: Organization, Responsibilities, Certificate of Pharmaceutical Product (COPP),

Regulatory requirements and approval procedures for new drugs.

Recommended Books: Latest Editions

1. Regulatory Affairs from Wikipedia, the free encyclopedia modified on 7th April available at http,

//en.wikipedia.org/wiki/Regulatory_ Affairs.

2. International Regulatory Affairs Updates, 2005. available at http://www.iraup.com/about.php

3. Douglas J Pisano and David S. Mantus. Text book of FDA Regulatory Affairs A Guide for Prescription

Drugs, Medical Devices, and Biologics, Second Edition.

4. Regulatory Affairs brought by learning plus, inc. available at http.//www.cgmp.com/ra.htm.

Contents

Preface vii

1. Introduction to Pilot-Plant and Scale-up 2

1.1 Plant 2

1.2 Pilot-Plant 2

1.2.1 Reasons for Conducting Pilot-Plant Studies 3

1.2.2 Objectives of Pilot-Plant 3

1.2.3 Pilot-Plant Operations 4

1.3 Scale-up 5

1.3.1 Need of Scale-up 5

1.3.2 Steps in Scale-up 5

1.3.3 Objectives of Scale-up 6

1.3.4 Relation between Pilot-Plant and Scale-up 6

Long Answer Type Questions 7

Short Answer Type Questions 7

Objective Type Questions 7

2. General Considerations and Pilot-Plant Considerations for

Different Dosage Forms 9

2.1 General Considerations 9

2.1.1 Reporting Responsibilities 9

2.1.2 Personnel Requirement 9

2.1.3 Space Requirements 10

2.1.4 Review of the Formula 11

2.1.5 Raw Materials 11

2.1.6 Equipment 11

2.1.7 Production Rate 11

2.1.8 Process Evaluation 11

2.1.9 Preparation of Master Manufacturing Procedures 12

2.1.10 Product Stability and Uniformity 13

2.1.11 Good Manufacturing Practices (GMP) Considerations 13

2.1.12 Transfer of Analytical Methods to Quality Assurance 13

2.2 Pilot-Plant Scale-up Considerations for Solids (Tablets) 13

2.3 Pilot-Plant Scale-up Considerations for Oral Liquids 18

2.4 Pilot-Plant Scale-up Considerations for Semisolids 20