9. Preparation of master manufacturing procedures: The manufacturing procedure

includes manufacturing directives, sampling directions, weight sheet, finished and

in-process product specifications. This section is related with the manner of

presentation of manufacturing procedures which helps in facilitating easy

compliance and understanding of processing technicians.

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.

11. Good Manufacturing Practices (GMP) Considerations: This section includes the

following items of GMP that are to be considered while the pilot-plant or scale-up

studies:

i. Equipment qualification

ii. Process validation

iii. Regularly scheduled preventative maintenance

iv. Regular process review and revalidation

v. Relevant written standard operating procedures

vi. The use of competent, technically qualified personnel

vii. Adequate provision for training of personnel

viii. A well-defined technology transfer system

ix. Validated cleaning procedures

x. An orderly arrangement of equipment for easy material flow and prevention

of cross-contamination.

12. Transfer of analytical methods to quality assurance: In research, all analytical

methods must be transferred to the quality assurance department during the

44 Industrial Pharmacy II

scale-up of new product. The quality assurance staff should review the process

and make sure that (a) the proper analytical instrumentation is available and (b)

that personnel are trained to perform the tasks.

PILOT-PLANT SCALE-UP CONSIDERATIONS FOR SOLIDS (TABLETS)

The main responsibility of the pilot-plant scale-up is to make sure that the newly

formulated dosage form developed by product development personnel will prove to be

efficiently, consistently and economically reproducible on large-scale production also.

Pilot-plant design for solids: The design and construction of the pilot-plant scaleup is of such type that will promote maintenance and cleanliness. It should be located

on the ground floor which will help in the expedition of delivery and shipments of

supplies as well as products. Pieces of equipment which are to be used in the pilotplant should be similar to that which will be used during large-scale production. The

measures should be taken to avoid any extraneous and microbial contamination. These

measures will include the following:

i. Fluorescent lighting fixtures should be of ceiling flush type.

ii. Air-conditioned and humidity-controlled area should be there.

iii. The installation of the high-density concrete floor should be there.

iv. The wall in the processing area, as well as packaging area, should be of enamel

cement finish.

 

Summary

42 Industrial Pharmacy II

3. Engineering

4. Maintenance

5. Calibration

6. Material control

7. Inventory

8. Orders

9. Labelling

10. Process and manufacturing activities

11. QA and QC activities

SCALE-UP

It is defined as art for designing of a prototype using the data obtained from the pilotplant process/model. The size of the set-up is bigger than the pilot-plant but smaller

than commercial manufacturing.

Steps in Scale-up

1. Define product economics.

2. Conduct of laboratory studies and scale-up techniques.

3. Identification of key-controlling steps.

4. Conduct large-scale studies.

5. Design, construction and evaluation of pilot-plant results

Objectives of Scale-up

i. To produce physically and chemically stable quality therapeutic and diagnostic

drugs

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

GENERAL CONSIDERATIONS

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

for scale-up:

1. Reporting responsibilities: There should be adequate records and reporting

arrangements to make the transfer of products from laboratory-scale to a commercialscale smooth.

2. Personnel requirement: It is very important for the smooth transfer of products

from laboratory-scale to pilot-plant and then to commercial-scale to have wellqualified staff.

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

Summary 43

4. Review of the formula: A thorough and critical review of each prospect of a

formulation is important.

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.

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.

7. Production rate

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 specific equipment and process

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

vi. The number of batches required for testing

8. Process evaluation: The knowledge of the effect of 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 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.

 

Evolution of Platform Technology in the Pharmaceutical Industry

The platform technology in the pharmaceutical industry evolved gradually. In the 80s

and 90s, the primary focus was on to create and operate the screening platform so that

molecules of sufficient capabilities could be found and finding the right molecule no

longer remains a limitation.

In the last decade, this focus gets shifted. Now the main focus is on reducing the

attrition in clinic by using platforms to improve predictive toxicology. Several

companies developed many preclinical efficacy models, metabolic platforms for

predictive toxicology.

Current Scenario

Nowadays the high running and operating cost of these platforms make companies

collaborate together to develop a platform and then share the platform among

themselves. This leads to an increase in the capability of a company to afford more

expensive tool than it can afford individually.

But the question that platform technologies are boon or bane for pharma companies

can only be answered after estimating profit and investment balance. Pharma

companies even small companies can make platform technology their friend by keeping

the following factors in consideration while running or operating a platform:

i. Type of technology required

ii. Prior knowledge about the product

iii. Market demand for technology or drug product

iv. Chance of failure

v. Time limitation

vi. Competitors in the market

vii. Other available platforms and their efficiency

viii. Staff needed for running the platform

ix. Benefit–risk analysis of used resources and result required

Examples of Platform Technologies Used in the Pharmaceutical Industry

i. Immunotherapy platform for treating a range of cancers

ii. Platform technology for targeted drug delivery to the lower gastrointestinal tract

iii. Tumour-targeting technology

iv. Platform technology for speeding discovery and development of marine-inspired

therapeutics

v. Platform technology for developing DNA-based vaccines for infectious disease

vi. Platform technology for developing therapeutic antibodies

vii. Bio-molecular platform to design multiple DNA RNA based therapies for diseases.

SUPAC Guidelines and Platform Technology 39

PRACTICE QUESTIONS

Long Answer Type Questions

1. Explain site changes mentioned under SUPAC guidelines.

 

2. Explain in detail the section that deals with changes in excipient in the drug product

as per SUPAC guidelines.

3. What are SUPAC guidelines? What is the purpose of these guidelines? Explain the

contents of SUPAC guidelines in short.

Short Answer Type Questions

1. Explain evolution and purpose of SUPAC guidelines.

2. Define the following as per SUPAC guidelines

i. Batch ii. Equipment

iii. Drug product iv. Formulation

v. New drug substance vi. Validation

3. Explain different levels of changes under SUPAC guidelines.

4. Describe the type of changes under SUPAC guidelines.

5. What is the platform technology? Explain with an example.

Objective Type Questions

1. SUPAC guidelines deal with

a. Level of changes

b. Filing documentation

c. Recommend chemistry, manufacturing and control tests

d. All of the above

2. The changes that are likely to have significant impact on quality and performance

of formulations are

a. Level 2 b. Level 1

c. Level 3 d. Level 4

3. How many types of changes that SUPAC guidelines deal with

a. 1 b. 4

c. 2 d. 5

4. High permeability and high solubility drugs are if having

a. Dissolution of 75% in 20 min b. Dissolution of 85% in 15 min

c. Dissolution of 70% in 5 min d. Dissolution of 95% in 20 min

5. What does SUPAC stand for?

a. Scale-up and post-approval changes

b. South-western plant authorities

c. Scale-up and pre-approval changes

d. Scale-up and post-accreditation changes

6. Which of the following is a guidance document issued by USFDA regarding

SUPAC to guide industries regarding changes?

a. SUPAC-IR b. SUPAC-MR

c. SUPAC-SS d. All of the above

7. SUPAC guidelines are issued by

a. ICH b. USFDA

c. WHO d. None of the above

40 Industrial Pharmacy II

8. A series of operations and/or actions used to produce a desired result is known as

a. Pilot scale b. Process

c. Operating principles d. Scale-up

9. Change in the excipient (disintegrated) in which of the following percent ranges

comes under level 1, change in composition and component

a. 3% (starch), 2% (other) b. 2% (starch), 3% (other)

c. 3% (starch), 1% (other) d. None of the above

10. A group of technology which acts as a base upon which various other technologies,

process, applications can be developed is known as

a. Information technology b. Platform technology

c. Process d. Scale-up

11. SUPAC task force is established by

a. CDSCO b. CDER

c. WHO d. WTO

12. AADA stands for

a. Antibiotic agents drug approval

b. Antibiotics agonists drug approval

c. Antibiotics application for drug approval

d. Abbreviated antibiotic drug applications

13. Fill in the blanks

a. _______________ are the changes that are unlikely to have any impact, i.e.

detectable in nature or quality or performance of formulations.

b. The ____________ percentage change in filler concentration comes under level 2

of change in composition and control.

c. SUPAC guidelines are guidance document on ____________ issued by __________.

d. Immunotherapy platform for treating a range of cancer is an example of

__________ technology.

14. Mention the changes (as per SUPAC guidelines) to which the following

statements belongs

a. Changes in colour or flavour of the formulation or change in the printing ink.

b. The changes of manufacturing site between facilities in adjacent city block/

campus and other related factor kept constant.

c. Changes in technical grade of an excipient.

d. The changes in which the drug is not meeting dissolution criteria of level 2 changes.

e. Change from non-mechanical or non-automated equipment to an automated

equipment to move ingredients.

ANSWERS

1. d 2. c 3. b 4. b 5. a 6. d 7. b 8. b

9. c 10. b 11. b 12. d

13. (a) Level 1, (b) 10, (c) Changes, USFDA, (d) Platform

14. (a) Level 1, change in composition and components,

(b) Level 2, site changes,

(c) Level 2, change in composition and components,

(d) Level 3, change in composition and components,

(e) Level 1, changes in manufacturing.

PLANT

 

a. 

2. Dissolution documentation Case B dissolution profile

3. In vivo bioequivalence None

documentation

Filing Documentation

i. Changes being affected supplement

ii. Annual report (with long-term stability data)

c. Level 3

Definition: This section includes changes in process type, e.g. change from wet

granulation process to direct compression.

SUPAC Guidelines and Platform Technology 37

Test documentation (Table 3.16)

Table 3.16: Test documentation required as per SUPAC guidelines level 3

Sr. No. Type of test documentation Content

1. Chemistry documentation Updated batch records

Notification of change

Application/compendial release requirements

A significant body of information available

One batch with three months accelerated stability data

reported in the supplement; one batch on long-term

stability data reported in an annual report.

A significant body of information not available

Up to three batches with three months accelerated

stability data reported in the supplement; one batch

on long-term stability data reported in an annual

report.

2. Dissolution documentation Case B dissolution

3. In vivo bioequivalence Yes

documentation

Filing Documentation

i. Prior approval supplement with justification

ii. Annual report (long-term stability data)

3.6 INTRODUCTION TO PLATFORM TECHNOLOGY

Platform Technologies

A platform is a group of technology and acts as a base upon which various technologies,

applications, processes can be developed. For example, if we take the example of

computing system, then basic hardware and the operating system act as a platform on

which various programmes and applications can run. It is actually a combination of

hardware and software. There are different types of platforms. But all platforms have

two things in common:

a. They can be used for many candidates (that could be potential products)

b. Their establishment cost is very high and sometimes usage cost is also very high.

Nowadays the pharmaceutical industry uses these platforms to develop new

technology, new drug, new process, etc. Platform technologies are proving to be a

valuable tool in improving efficacy and quality in drug development. A platform is

considered as the most systematic method which helps in taking maximum advantage

from prior knowledge of the product to generate a new molecule. Such platforms

always have a scope of improvement. The data of new molecule which is developed

through the platform can be added to the platform and hence results in an increase in

the robustness of the platform.

But, the major problem in the way of creating and operating platform technology is

its cost. Only a company which runs several active projects can afford a platform.

Small companies with fewer projects cannot afford developing or purchasing a

platform. This is because the cost of running and operating platform technologies can

38 Industrial Pharmacy II

only justified if it helps in making more profit than investment. So, it is access to these

platforms that make big pharmaceutical companies enable to discover more new

medicines than small pharmaceutical companies. The platforms used in pharmaceutical

companies range from vast chemical libraries, huge genetic database and highly efficient

data screening tool to toxicology predicting platforms.

However, there is another point of view also which does not support the idea that

access to platform technology is always beneficial. It sometimes acts as a black hole in

which most of the capital for research gets disappeared.

 Level 1

Definition: This section includes process changes including changes such as operating

speeds and mixing times within application and validation ranges.

Test documentation (Table 3.14)

Table 3.14: Test documentation required as per SUPAC guidelines level 1

Sr. no. Type of test documentation Content

1. Chemistry documentation Not beyond application/compendial release

requirements

2. Dissolution documentation None beyond application/compendial requirements

3. In vivo bioequivalence None

documentation

Filing Documentation

Annual report

b. Level 2

Definition: This section includes process changes including changes such as operating

speeds and mixing times outside application and validation ranges.

Test Documentation (Table 3.15)

Table 3.15: Test documentation required as per SUPAC guidelines level 2

Sr. no. Type of test documentation Content

1. Chemistry documentation Application/compendial release requirements

Stability studies with one batch on long-term stability

data

Updated batch records

 

Table 3.7: Test documentation required as per SUPAC guidelines level 1

Sr. no. Type of test documentation Content

1. Chemistry documentation Not beyond application/compendial release

requirements

2. Dissolution documentation None beyond application/compendial requirements

3. In vivo bioequivalence None

documentation

Filing Documentation

Annual report

b. Level 2

Definition: It consists of changes of manufacturing site between facilities in adjacent

city blocks/site changes within a contiguous campus, or where the standard operating

procedures (SOPs), same equipment, same controls, personnel common (employees

already working on the campus who have suitable experience with the manufacturing

process) and same environmental conditions (e.g. temperature and humidity) are used

and no changes are made to the manufacturing batch records (except for administrative

information and the location of the facility).

Test documentation (Table 3.8)

Table 3.8: Test documentation required as per SUPAC guidelines level 2

Sr. no. Type of test documentation Content

1. Chemistry documentation Location of new site

Updated batch records

Not beyond application/compendial release requirements

Annual report (with one batch on long-term stability data)

2. Dissolution documentation Not beyond application/compendial release requirements

3. In vivo bioequivalence None

documentation

SUPAC Guidelines and Platform Technology 33

Filing Documentation

i. Changes being affected supplement

ii. Annual report (with long-term stability data)

c. Level 3

Definition: It consists of changes in manufacturing site to a totally different campus

(one that is not on the same original contiguous site or where the facilities are not in

adjacent city blocks), or where the standard operating procedures (SOPs), same

equipment, same controls, personnel common (employees already working on the

campus who have suitable experience with the manufacturing process) and same

environmental conditions (e.g. temperature and humidity) are used and no changes

are made to the manufacturing batch records (except for administrative information

and the location of the facility).

Test documentation (Table 3.9)

Table 3.9: Test documentation required as per SUPAC guidelines level 3

 

Sr. no. Type of test documentation Content

1. Chemistry documentation Location of new site

Updated batch records

Application/compendial release requirements

A significant body of information available

One batch with three months accelerated stability data

reported in the supplement; one batch on long-term

stability data reported in an annual report.

A significant body of information not available

Up to three batches with three months accelerated

stability data reported in the supplement; one batch

on long-term stability data reported in an annual

report.

2. Dissolution documentation Case B: Low permeability, high solubility drugs

3. In vivo bioequivalence None

documentation

Filing Documentation

i. Changes being affected supplement

ii. Annual report (with long-term stability data)

C. Changes in Batch Sizes (Scale-up/Scale-down)

This section includes change after approval in the size of batch from pilot/pivotal

scale bio batch material to smaller or larger production batches call for additional

information's admission in the application. The batch scale-down below 10,000 dosage

unit is not covered by this document. The validation of all scale-up changes should be

done properly and should be inspected by authorised agency personnel, where needed.

a. Level 1

Definition: It includes change in batch size, up to and including a factor of 10 times

the size of the pilot/bio batch, where

34 Industrial Pharmacy II

1. The equipment used to produce the test batch is of the same operating and design

principles;

2. The batch is manufactured in compliance with CGMPs; and

3. The same standard operating procedures (SOPs) and controls, as well as the same

manufacturing and formulation procedures, are on the full-scale production batch

and are used on the test batch.

Test documentation (Table 3.10)

Table 3.10: Test documentation required as per SUPAC guidelines level 1

Sr. no. Type of test documentation Content

1. Chemistry documentation Application/compendial release requirements

Notification of changes

Submission of updated batch records

Annual report

2. Dissolution documentation None beyond application/compendia requirements

3. In vivo bioequivalence None

documentation

Filing Documentation

Annual report (with long-term stability data)

b. Level 2

Definition: It includes change in batch size, beyond the factor of 10 times the size of

the pilot/bio batch, where

1. The equipment used to produce the test batch is of the same operating and design

principles;

2. The batch is manufactured in compliance with CGMPs; and

3. The same standard operating procedures (SOPs) and controls, as well as the same

manufacturing and formulation procedures, are on the full-scale production batch

and are used on the test batch.

Test documentation (Table 3.11)

Table 3.11: Test documentation required as per SUPAC guidelines level 2

Sr. no. Type of test documentation Content

1. Chemistry documentation Application/compendial release requirements

Notification of changes

 

Other Beyond 0.2

Film coat Beyond 2

Test documentation (Table 3.6)

Table 3.6: Test documentation required as per SUPAC guidelines level 1

Sr. no. Type of test documentation Content

1. Chemistry documentation Application/compendial release requirements, batch

records, if

A significant body of information available

One batch with three months accelerated stability data

reported in the supplement; one batch on long-term

stability data reported in an annual report.

A significant body of information not available

Up to three batches with three months accelerated

stability data reported in the supplement; one batch on

long-term stability data reported in an annual report.

2. Dissolution documentation Case A: High permeability, high solubility drugs

If Dissolution of 85% in 15 minutes in 900 ml of

0.1 N HCl.

Case B: Low permeability, high solubility

Case C: High permeability, low solubility drugs.

3. In vivo bioequivalence Full bioequivalence study. The bioequivalence study may

documentation be waived only if an acceptable in vivo and in vitro

correlation has been verified.

32 Industrial Pharmacy II

Filing Documentation

i. Prior approval supplement (all information including accelerated stability data)

ii. Annual report (that includes long-term stability data and all other information)

B. Site Changes

This section consists of changes in the location of the manufacturing site either of the

manufacturer or contract manufacturing facilities. This section does not include scaleup changes. The site should be in accordance with CGMP guidelines.

a. Level 1

Definition: Level 1 changes consist of site changes within a single facility where the

standard operating procedures (SOPs), same equipment, same controls, personnel

common (employees already working on the campus who have suitable experience

with the manufacturing process) and same environmental conditions (e.g. temperature

and humidity) are used and no changes are made to the manufacturing batch records

(except for administrative information and the location of the facility).

Test documentation (Table 3.7)

 

Case B: Low permeability, high solubility drugs if multipoint dissolution profile should be performed in the

application/compendial medium at 15, 30, 45, 60 and

120 minutes or until an asymptote is reached.

Case C: High permeability, low solubility drugs if multipoint dissolution profiles should be performed in water,

0.1 N HCl, and USP buffer media at pH 4.5, 6.5, and 7.5

(five separate profiles) for the proposed and currently

accepted formulations. Adequate sampling should be

performed at 15, 30, 45, 60, and 120 minutes until either

90% of drug from the drug product is dissolved or an

asymptote is reached.

3. In vivo bioequivalence None (if the drug product does not belong to any of the

documentation above-mentioned cases, then refer to level 3 changes)

Filing Documentation

i. Prior approval supplement (all information including accelerated stability data)

ii. Annual report (that includes long-term stability data and all other information)

Note: The test and filing documentation of level 2 depends upon three factors:

Solubility, permeability and therapeutic range of drug product.

SUPAC Guidelines and Platform Technology 31

c. Level 3

Definition: These are the changes that are likely to have a significant impact on the

quality or performance of formulations.

Examples:

i. Change in the technical grade of an excipients

ii. All changes in which drug is not meeting dissolution criteria of level 2 changes.

iii. Changes in the excipients as per the following per cent ranges (based on an

assumption that the drug substance in the formulation is 100% of as mentioned

on label/potency) are given in Table 3.5.

Table 3.5: Change in excipients (in %) as per SUPAC guidelines level 3

Name of excipients Percentage excipient of total target dosage form

weight (± n %)

Filler Beyond 10

Disintegrant

Starch Beyond 6

Other Beyond 2

Binder Beyond 1

Lubricant

Calcium or magnesium stearate Beyond 0.5

Other Beyond 2

Glidant

Talc Beyond 2

 

a. Level 1

Definition: These are the changes that are unlikely to have any impact, i.e. detectable

in nature on the quality or performance of formulations.

Examples:

i. Change in colour or flavour of the formulation or change in the printing ink

ii. Changes in the excipients as per the following per cent ranges (based on

assumption that the drug substance in the formulation is 100% of as mentioned

on label/potency and the total additive change should not be more than 5%) are

given in Table 3.1.

Test documentation (Table 3.2)

Filing Documentation

Annual report (that includes long-term stability data and all other information)

b. Level 2

Definition: These are the changes that could have a significant impact on the quality

or performance of formulations.

Examples:

i. Change in the technical grade of an excipient

Table 3.1: Change in excipients (in %) as per SUPAC guidelines considered as level 1

Name of excipients Percentage excipient of total target dosage form weight (± n %)

Filler 5

Disintegrant

Starch 3

Other 1

Binder 0.5

Lubricant

Calcium or magnesium sterate 0.25

Other 1

Glidant

Talc 1

Other 0.1

Film coat 1

Table 3.2: Test documentation required as per SUPAC guidelines level 1

Sr. no. Type of test documentation Content

1. Chemistry documentation Application/compendial release

requirements and stability testing

2. Dissolution documentation None beyond application/compendial

requirements