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

 

specific process will consistently produce a product that meets its predetermined

specifications and quality attributes. A validated manufacturing process is one

that has been proven to do what it purports or is represented to do. The proof

of validation is obtained through collection and evaluation of data, preferably beginning

from the process development phase and continuing through the production

phase.

Validation necessarily includes process qualification (the qualification of materials,

equipment, systems, buildings, and personnel), but it also includes the control of the

entire processes for repeated batches or runs.

SUPAC guidelines mainly deal with three factors of changes (Fig. 3.1).

i. Level of changes

ii. Filing documentation

iii. Recommended chemistry, manufacturing and control tests/test documentation

28 Industrial Pharmacy II

3.4 LEVEL OF CHANGES

There are three levels of changes as per the guidance document

a. Level 1

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

in nature on quality or performance of formulations.

b. Level 2

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

or performance of formulations.

c. Level 3

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

quality or performance of formulations.

3.5 TYPE OF CHANGES

There are mainly four types of changes (Fig. 3.2)

i. Change in manufacturing site

ii. Change in composition

iii. Change in manufacturing process

iv. Change in manufacturing equipment

Fig. 3.1: Three factors of changes that SUPAC guidelines deal with

Fig. 3.2: Different components of SUPAC guidelines

SUPAC Guidelines and Platform Technology 29

A. Change in Composition and Components

This section deals with the changes in excipients in the drug product. It does not deal

with the changes in the amount of drug substance in the drug product.

 

F. Equipment

Automated or non-automated, mechanical or non-mechanical equipment used to

produce the drug product, including equipment used to package the drug product.

G. Formulation

A listing of ingredients and composition of the dosage form.

H. Justification

Reports containing scientific data and expert professional judgment to substantiate

decisions.

SUPAC Guidelines and Platform Technology 27

I. New drug substance

Any substance that, when used in the manufacture, processing, or packing of a drug,

causes that drug to be a new drug, but does not include intermediates used in the

synthesis of such substance [21 CFR 310.3(g)].

J. Operating principle

Rules or concepts governing the operation of the system.

K. Pilot-scale

The manufacture of either drug substance or drug product by a procedure fully

representative of and simulating that used for full manufacturing scale.

L. Process

A series of operations and/or actions used to produce a desired result.

M. Ranges

The extent to which or the limits between which acceptable variation exists.

N. Same

Agreeing in kind, amount; unchanged in character or condition.

O. Scale-up

The process of increasing the batch size.

P. Scale-down

The process of decreasing the batch size.

Q. Similar

Having a general likeness.

R. A significant body of information

A significant body of information on the stability of the drug product is likely to exist

after five years of commercial experience for new molecular entities, or three years of

commercial experience for new dosage forms.

S. Validation

Establishing through documented evidence a high degree of assurance that a

 

26 Industrial Pharmacy II

iii. The drug categorization research conducted at the University of Michigan and

the University of Uppsala on the permeability of drug substances; and

iv. The Scale-up and Post Approval Changes (SUPAC) Task Force established by

the Centre for Drug Evaluation and Research (CDER) Chemistry, Manufacturing

and Controls Coordinating Committee to develop guidance on scale-up and other

post-approval changes.

3.3 TERMINOLOGIES USED IN GUIDANCE DOCUMENT

A. Batch

A specific quantity of a drug or other material produced according to a single

manufacturing order during the same cycle of manufacture and intended to have

uniform character and quality, within specified limits [21 CFR 210.3(b)(2)].

B. Contiguous campus

Continuous or unbroken site or a set of buildings in adjacent city blocks.

C. Dissolution testing

Case A Dissolution of Q = 85% in 15 minutes in 900 millilitres (mL) of 0.1 N

hydrochloride (HCl), using the United States Pharmacopeia (USP) <711> Apparatus 1

at 100 revolutions per minute (rpm) or Apparatus 2 at 50 rpm.

Case B Multi-point dissolution profile in the application/compendial medium at

15, 30, 45, 60, and 120 minutes or until an asymptote is reached for the proposed and

currently accepted formulation.

Case C Multi-point dissolution profiles 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 the drug from the drug product is dissolved

or an asymptote is reached. A surfactant may be used with appropriate justification.

D. Drug product

A drug product is a finished dosage form (e.g. tablet, capsule, or solution) that contains

a drug substance, generally, but not necessarily, in association with one or more other

ingredients [21 CFR 314.3(b)]. A solid oral dosage form includes tablets, chewable

tablets, capsules, and soft gelatine capsules.

E. Drug substance

An active ingredient that is intended to furnish pharmacological activity or other direct

effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to

affect the structure of any function of the human body, but does not include

intermediates used in the synthesis of such ingredient [21 CFR 314.3(b)].

 

Short Answer Type Questions

1. Explain the following with respect to general “considerations”

a. Reporting responsibilities

b. Space requirements

c. Review of the formula

d. Process evaluation

2. Explain preparing of master manufacturing procedures.

3. What are the types of oral liquids?

4. Explain different steps in liquid manufacturing process.

5. What is the importance of documentation during pilot-plant scale-up process?

Objective Type Questions

1. Which of the following items of GMP are to be considered under general

consideration?

a. Reporting responsibilities b. Space requirements

c. Equipment d. All of the above

24 Industrial Pharmacy II

2. Which of the following items of GMP are to be considered under GMP

consideration?

a. Validation b. Equipment qualification

c. Training d. All of the above

3. Storage area and physical testing area requirements comes under which of the

following general considerations?

a. Equipment b. Production rate

c. Space requirements d. None of the above

4. Product loss data during using a specific equipment and process comes order

which of the following general considerations?

a. Process evaluation b. Raw material

c. Production rate d. Transfer of analytical methods to QA

 

5. Which of the following should be considered during blending process in pilotPlant considerations for solids dosage form?

a. Mixing speeds b. Dry granulation

c. Characteristics of ingredient d. Binding agent amount

6. A liquid dosage form of two liquids that usually do not mix together but miscible

with the help of other substance is known as

a. Suspension b. Solution

c. Emulsion d. Tablet

7. Trial batches are:

a. Prepared after R&D b. 70% of size of exhibit batch

c. a and b both d. Also called NDA batch

8. The batches which have approximately 10% of production-scale batch are known

as

a. Pre-exhibit batch b. Exhibit batch

c. Scale-up batch d. None of the above

9. Arrange the following in order

1. Trial batch 2. Exhibit batch

3. Full-scale batch 4. Validation batch

5. Pre-exhibit batch

a. 1, 2, 3, 4, 5 b. 4, 2, 5, 3, 1

c. 1, 5, 2, 4, 3 d. None of the above

10. Match the following

Name of equipment Scale-up considerations

a. Hot air oven i. Capping

b. Dryer ii. Surface temperature

c. High speed tablet process iii. Depth of granulation on trays

d. Transfer pumps iv. Type of material

e. Fluidised bed coating column v. Viscosity of product

ANSWERS

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

8. b 9. c 10. a (ii), b (iii), c (i), d (v), e (iv)

SUPAC Guidelines and Platform Technology 25

SUPAC GUIDELINES

 

All the processes regarding concerned drug are performed on these three batches.

After checking the results the average of results from these batches is taken and data

will be compiled. This process results in formation of various documents like SOPs for

machines, record books, etc. After validation batches, the large-scale production of

the product will be done.

For implementing efficient documentation practices, here is a suggestion which

mentions the areas required for GMP document implementation. These below

mentioned areas provide only guidance and should not be treated as maximum criteria

for documentation. Any other document not on the list will be included if helps in

improving the quality of products.

i. Design and development reports

ii. Distribution records

iii. Operational procedures/techniques/methods, out of specifications (OOS), out

of trend (OOT),

Fig. 2.5: Stepwise flow of products from small-scale batches to full-scale batches

General Considerations and Pilot-Plant Considerations for Different Dosage Forms 23

iv. User requirement specifications and utilities like water systems, HVAC, AHU,

etc.

v. Dossiers and Drug Master Files for regulated markets

vi. Man, materials, machines, methods, maintenance, manufacturing operations and

controls

vii. Cleaning and calibration records and reports

viii. Containers and closures analysis report, contamination and change control,

ix. Monitoring, master formula, manuals (quality, safety and environment), medical

records

x. Engineering control and practices

xi. Environment control

xii. New products and substances

xiii. Technology transfer

xiv. Training

xv. SOPs, supplier qualification, specifications and standard test procedures

xvi. Site master file (quality assurance)

xvii. Stability studies reports, quality risk management report

xviii.Validation reports, qualification reports, analytical method transfer reports

xix. Notices, circulars, amendments, complaints details, entry–exit details, trend

analysis report

xx. Safety practices, sanitation, storage, self-inspection, standardization,

xxi. Documents mentioning roles and responsibilities of personnel working at the

facility with their qualification and other details.

PRACTICE QUESTIONS

Long Answer Type Questions

1. Describe pilot-plant scale-up consideration for solids in detail.

2. Describe pilot-plant scale-up considerations for semisolids and oral-liquids in detail.

3. Explain general consideration under pilot-plant studies.

 

1. Trial batches

2. Pre-exhibit batches

3. Exhibit batches

4. Validation batches

Trial Batches

These are the batches with small batch size. These batches are prepared after R&D

division work. In these batches, the stability and dissolution of product are checked.

These batches provide products for animal studies and clinical trials.

Table 2.10: Parameters of equipment used are to be considered during pilot-plant scale-up of

semisolids

Name of equipment Parameters to be considered

Mixing equipment Should efficiently move the semisolid mass from outside walls to the

centre and from bottom to top of the container

Motors Should handle the product at its most viscous stage

Transfer pumps Should be able to move any type of viscous material. It should not apply

excessive shear during the transfer process and also should not

incorporating air.

The following factors should be considered while choosing size and

type of pump

• Viscosity of product

• Required pumping rate

• Product compatibility with pump surface

• Required pumping pressure

22 Industrial Pharmacy II

Pre-Exhibit Batches

It has 70% of the size of the exhibit batch. In this batch, complete process documentation

is done. The fully validated analytical methodology is used at this stage. It helps in

detecting any problem that may arise during the manufacturing of exhibit batch.

Exhibit Batch

It is demonstration batch having main purpose of getting approval in the market from

a regulatory agency. It has 10% of the production scale batch. It contains all

manufacturing documentation, specifications, stability data reports, etc. It is

manufactured under GMP compliance. It is also called NDA or ANDA, bioequivalence,

regulatory reference or stability tested batch.

Validation Batch

The production of validation batches started after the regulatory agency of concerned

country approved the drug. The validation batches are divided into three parts:

i. Batch 1

ii. Batch 2

iii. Batch 3

 

iii. Compression

iv. Ejection of tablet from the cavity

At the pilot-plant scale-up the compression characteristics of a tablet can only be

determined if trials run at tablet press speed same to that of speed in normal

production.

8. Tablet coating: At laboratory-scale the tablet coating is done in conventional coating

pans. There are many changes in the coating technology due to new developments

of safety and environment regulations, new polymeric materials, coating types, etc.

Nowadays, the place of conventional sugar coating pan has taken by perforated

pans and fluidised bed coating columns. The development of new polymeric

materials gives way to aqueous sugar coating and aqueous film coating (Table 2.7).

Table 2.6: Scale-up considerations during compression

Name of equipment Scale-up considerations

High-speed tablet press Sticking to the punch surface

Tablet hardness

Capping

Weight variations

Interaction of press with granules is appropriate or not

Speed of press

Filling of die cavities

Feed frame efficacy

Press rotation

Size of compression rollers

Ejection of tablets (should be free from sticking)

Table 2.5: Scale-up considerations during particle size reduction

Name of equipment Scale-up consideration

Oscillating granulator Lubricants and glidants should be added at the size reduction

Hammer mill stage during scale-up

Mechanical sieving device

Screening device

18 Industrial Pharmacy II

2.3 PILOT-PLANT SCALE-UP CONSIDERATIONS FOR ORAL LIQUIDS

Oral liquids can be defined as homogenous liquid preparations, mainly contain an

emulsion, a suspension or a solution (Fig. 2.4) having one or more active ingredients

in an appropriate base, i.e. liquid. They are for oral administration. These preparations

are used either as such or after dilution. The main substances added in these preparations are emulsifying agents, suspending agents, sweetening agents, flavouring agents,

stabilizing agents, thickening agents, etc. During pilot-plant scale-up each and every

material and equipment is tested in the same amount and with same characteristics as

to be used at large-scale production. This is a pourable dosage form which displays

Newtonian or Pseudoplastic flow behaviour. This dosage form remains conforms to

its container.

Steps in Liquid Manufacturing Process

1. Planning of material requirements: In this step the calculation for material required

to manufacture a product is done. It consists of majorly three functions.

i. Taking inventory of components or material needed and on hand

ii. Identification of the needed components and materials

iii. Scheduling the production or purchase of needed materials and components

Fig. 2.4: Different types of oral liquids

Table 2.7: Scale-up considerations during tablet coating

Name of equipment Scale-up considerations

Perforated pans Type of materials (polymeric)

Fluidised bed coating columns Nature of material (hydrophilic or hydrophobic)

Size of tablet

Safety and environmental guidelines

Batch size

Temperature and humidity required

Hardness of tablets

General Considerations and Pilot-Plant Considerations for Different Dosage Forms 19

2. Liquid preparation: It is done by suspending, dissolving or emulsifying active

ingredients and excipients as per master manufacturing formula which is prepared

in compliance with guidelines.

3. Filling and packing: Based on the characteristics of the liquid prepared

(photosensitive, volatile, microbial property, etc.), the container-closure system for

packaging is chosen. Labelling of the container will be done as per labelling

guidelines followed in the company.

4. Quality assurance: Qualitative and quantitative tests like identification, microbial

testing, stability testing, etc, for liquid preparation and packaging material, will be

done in accordance with validated analytical tests and with validated equipment.

This will be done to check whether the product is prepared and packed as per

specifications or not.

Critical aspects of liquid manufacturing (Table 2.8)

Formulation aspects of oral liquids (Table 2.9)

Contd.

 

Table 2.9: Formulation consideration of different dosage forms of oral liquids

Sr. No. Dosage form Formulation aspects (purpose) Considerations (agents)

1. Solution Protecting the API Buffers, antioxidants, preservatives

Maintaining the appearance Colorings, stabilizers, antimicrobial

preservatives, co-solvents

Taste/smell masking Sweeteners, flavourings

Table 2.8: Parameters to be considered while scale-up with respect to the different dosage forms

Sr. No. Dosage form Parameters to be considered

1. Solution Tank size (diameter), impeller type, impeller diameter, the rotational

speed of the impeller, number of impellers, number of baffles, the

mixing capability of impeller, clearance between impeller blades and

wall of the mixing tank, height of the filled volume in the tank,

filteration equipment (should not remove active or adjuvant

ingredients), transfer system, passivation of SS (prereacting the SS

with acetic acid or nitric acid solution to remove the surface alkalinity

of the SS)

2. Emulsion Addition and dispersion of suspending agents (lab-scale—sprinkling

method and production-scale—vibrating feed system), hydration/

wetting of suspending agent, time and temperature required for

hydration of suspending agent, mixing speeds (high speed leads to

air entrapment), selection of the equipment according to batch size,

versator (to avoid air entrapment), mesh size (the one which is chosen

must be capable of removing the unwanted foreign particulates but

should not filter out any of the active ingredients. Such a sieve can

only be selected based on production batch size trials.)

3. Suspension Temperature, mixing equipment, homogenizing equipment, in process

or final product filters, screens, pumps and filling equipment, phase

volumes, phase viscosities, phase densities

20 Industrial Pharmacy II

2.4 PILOT-PLANT SCALE-UP CONSIDERATIONS FOR SEMISOLIDS

Semisolid dosage forms are composed of mainly two phases, i.e. oil and water. One of

the phases is a continuous or external phase and the other one is dispersed or internal

phase. The active pharmaceutical ingredient is mainly dissolved in one phase and if it

is insoluble in one or both phases, then a third phase is introduced. This is known as a

three-phase system.

Various factors affect the physical property of the semisolid dosage form. Some of

them are as follows:

i. Size of dispersed particle

ii. The interfacial tension between the phases

iii. The partition coefficient of an active ingredient in between the phases

iv. Rheology of product

v. The viscosity of both phases

vi. Nature of the third phase (if introduced)

These all factors mentioned above determined the release as well as other

characteristics of drugs. The following parameters of equipment used are to be

considered during pilot-plant scale-up of semisolids (Table 2.10).

The other considerations for processes (during the manufacturing of semisolid

dosage form) are:

i. Mixing speed

ii. Addition of active ingredients

iii. Product transfer

iv. Working temperature range

v. Shear during handling and transferring of product

vi. Working temperature range

vii. Component homogenization

Table 2.9: Formulation consideration of different dosage forms of oral liquids (Contd.)

Sr. No. Dosage form Formulation aspects (purpose) Considerations (agents)

2. Suspension Protecting the API Buffers, antioxidants, preservatives,

 

iii. Depth of granulation on the trays

iv. Surface temperature of oven, etc.

Because each product has specified airflow and air temperature for the drying

process. If the granulation bed has high depth or high density then the drying will

be inefficient. So, at scale-up stage fluidised bed dryer is the best alternative for

circulating hot air oven (Table 2.4).

6. Particle size reduction: Particle size distribution affects many compression factors

like flowability, tablet weight uniformity, content uniformity, the hardness of tablet,

the color of the tablet, compressibility and hence ultimately the quality of tablet.

The particle size distribution of granulation is determined by using multiple stacked

sieves of decreasing mesh openings. The particle size reduction of dried granulation

can be done by using screening device, oscillating granulator, hammer mill, sieving

device, etc.

Table 2.4: Scale-up considerations during drying

Name of equipment Scale-up consideration

Hot air oven Airflow

Air temperature

Surface temperature

Fluidised bed dryer Air flow rate

Inlet air temperature

Optimum load

The humidity of air entering

Tray dryer Airflow

Air temperature

Depth of granulation on trays

Monitoring of drying by use of moisture and temperature probes

Monitoring of drying times at specific temperature and specific air

flow rates for a particular product

Table 2.3: Scale-up considerations during addition of binders

Problems can be faced during scale-up Solutions to the respective problem

Binding agents may impart viscosity to the This can be avoided by adding all binding agents

granulating solution which makes transfer in the dry powder prior to granulation.

of fluid difficult.

General Considerations and Pilot-Plant Considerations for Different Dosage Forms 17

At laboratory-scale, the lubricants and glidants are usually added to the final

blend but at scale-up, they are added during sizing operation. This is done to avoid

agglomeration of some additives like magnesium stearate if added to the final blend

in large quantities in the blender (Table 2.5).

7. Compression: The ultimate critical step in the tablet formulation is compressing.

The success of tablet formulation depends on whether it can be compressed on a

high-speed tablet press. The tablet press performs the following functions during

compression (Table 2.6).

i. Filling of empty die

ii. Precompression (optional)

 

2. Blending: The powder which is to be used for formulation should be well blended

to ensure efficient drug distribution. Inadequate/improper blending can cause a

discrete portion of batch either of low or of high potency. So, it is essential to ensure

that all ingredients are thoroughly blended with no lumps and agglomerates. In

Fig. 2.3: Different aspects of general considerations

General Considerations and Pilot-Plant Considerations for Different Dosage Forms 15

any blending operation, both operations, i.e. segregation and mixing occur side by

side. Screening and milling techniques are used for making this procedure more

reproducible and reliable (Table 2.1).

Table 2.1: Scale-up considerations during blending

Equipment used Scale-up considerations

V-blender The following should be of primary consideration

Double cone blender during blending:

Ribbon blender • Time of blending

Slant cone blender • Blender loading

Bin blender • Size of blender

Orbiting screw blender's horizontal • Mixing times

and vertical high intensity mixers • Mixing speeds

• Material characteristics

• Bulk density of raw material

• Particle abrasion (in case of use of high shear

mixers with spiral screws and blades)

3. Granulation: Granulation is the most important step in tablet formation or

sometimes in encapsulation. Good granulation will ensure good flow property of

the material, increase the apparent density of powder, affect particle size distribution,

and ensure uniform dispersion of active pharmaceutical ingredient (Table 2.2).

Specialised Granulation Procedures

a. Slugging (dry granulation): This is used for the dry powder that has poor flow

properties and hence cannot be directly compressed. A tablet press having pressure

of about 15 tons is used for slugging. The slugs have a diameter of 3/4th of inch to

1 inch depending upon the difficulty of compressing the powder. The size of slug

decreases with increasing difficulty in compressing. Less size increases pressure

per unit area for slugging. In case of excessive amount, the material should be

screened and recycled through slugging operation.

b. Dry compaction: In this process the powder is passed between two rollers having

pressure of up to 10 tons per linear inch. This process is generally opted for the

material of very low density, e.g. aluminium hydroxide.

Table 2.2: Scale-up considerations during granulation

Equipment used Scale-up considerations

Sigma blade mixers Type of granulation

Heavy-duty planetary mixer Dry granulation

Fluidized bed dryer Wet granulation

Multifunctional processors (capable of Characteristics of ingredient used like

performing all functions required to prepare hydrophobic or hydrophilic in nature,

finished granulation like dry blending, wet thermolabile or thermostable, solubility, etc.

granulation, drying, sizing, etc.)

16 Industrial Pharmacy II

4. Binders: The binders have important place in tablet production. Binders are used

to make powders more compressible so that tablets can be made which are more

resistant to breakage while handling (Table 2.3).

5. Drying: After granulation drying is an essential step. Circulating hot air oven (heated

by steam or electricity) is the most conventional method used for drying. But during

scale-up certain factors regarding hot air oven needs to be considered like:

i. Airflow

ii. Air temperature