TCS

Classification 1

Introduction
• TCS stands for ‘Topical Classification System”
• TCS is a framework of classifying topical drug products based on qualitative & quantitative
composition & microstructure arrangements of matter to facilitate generic product development.

This helps in the approval of topical drug products without

BCS conducting in vivo studies.

It helps assure product efficacy

TCS TCS is a drug development tool to justify ‘biowaiver’ w.r.t

drug release from the topical dosage form.
TCS Classification 2

BCS & TCS

Solubility Permeability
Of Drug of Drug SUPAC SS Q1,Q2,Q3
Product Product Guidelines Description

Scientific Scientific
Basis of Basis of
BCS TCS
Key Decision Tool:
IVR
Levels of TCS

Qualitative Quantitative Microstructure

Q3 aka IVR
composition of composition of Arrangement of
Q1

Q2
Inactive Inactive Topical
Ingredients Ingredients Semisolid
Products
TCS Classification 3

Q3 (Microstructural Similarity)

• Microstructure similarity: Particle/droplet size measurements - similar

distribution, similar rheological properties and IVR rates.

• Rheology:
• Oscillatory measurements:
Evaluation of linear viscoelastic response;
• Rotational tests:
Shear stress (viscosity) vs. strain rate measurements; Yield stress (σ0)
inversely proportional to spreadability.
TCS Classification 4

IVR & Q3

• The IVR methodology for the evaluation of Q3 similarity is used in TCS

Classification for application of biowaivers.

• Adequately developed and validated, IVR methodology can provide information on

the combined role of several physico-chemical characteristics, including the particle
or droplet size, viscosity and diffusional resistance of the vehicle.

• The IVR reflects the microstructure, arrangement of the matter and the state of
aggregation of the dosage form (Q3)
TCS Classification 5

The TCS Classification System

Ref : VP Shah et al., Int J of Pharmaceutics. 491: 21-25, 2015.

TCS Classification 6

Generic Topical Drug Products

• According to 21 CFR 314.94 the generic topical drug product will need to have the
same excipients, qualitatively (Q1) and quantitatively (Q2) as the Reference Listed
Drug (brand name drug) (RLD).

• If the generic product is not Q1 and Q2 compared to RLD, the applicant must
provide adequate proofs that the differences will not impact the safety and efficacy
profiles of the product.
TCS Classification 7

TCS & Biowaivers

Biowaivers
• TCS Class 1:
q Q1, Q2 and Q3 same à IVR same
• TCS Class 3:
q Q1 and Q2 different, Q3 same à IVR same
q May require additional in vitro studies (e.g., particle size, pH, globule size, rheology)
q Excipient evaluation

Bioequivalence Studies
• TCS Class 2
q Q1,Q2 same but Q3 is different
• TCS Class 4
q Q1, Q2, Q3 all different
In vitro Test for Topical Drug Products (USP) 8

“Product Performance Tests for Topical Drug Products”

• This must have the ability to measure drug release from the finished drug product.

• As per the USP : “It must be reproducible and reliable, and although it is not a measure of
bioavailability, the performance test must be capable of detecting changes in drug release
characteristics from the finished product”

• For topical drug products, 3 types of apparatus may be used:

A] Vertical Diffusion Cell Method:

B] Immersion Cell Apparatus (model A / model B )

C] USP Type IV Apparatus

In vitro Test for Topical Drug Products (USP) 9

A] Vertical Cell Diffusion Method

• A VDC system is used to determine in vitro release of semisolid
(cream, ointment, and gel) preparations.
• Typically, 200–400 mg of a cream, ointment, or gel is spread
evenly over a suitable synthetic inert support membrane. The
membrane, with its application side up, is placed in a vertical
diffusion cell (typically of 15-mm diameter orifice), e.g., a Franz
cell. The release rate experiment is carried out at 32°C ±1°C,
except in the case of vaginal creams for which the temperature
should be 37°C ±1°C.
• Sampling generally is performed over 4–5 hours, and the volume
sampled is replaced with fresh receptor medium. To achieve sink
conditions, the receptor medium must have a high capacity to
dissolve or carry away the drug, and the receptor media should
not exceed 10% of Cs (drug solubility in the releasing matrix) at
the end of the test. The test is
• The test is done with groups of 6 cells. Results from 12 cells,
2 runs of 6 cells, are used to document the release rate.
In vitro Test for Topical Drug Products (USP) 9

B] Immersion Cell Apparatus

In vitro Test for Topical Drug Products (USP) 9

C] USP Type IV Apparatus

Flux/Permeability Co-efficient 10
In vitro Test for Topical Drug Products (USP) 12

“Product Performance Tests for Transdermal Delivery Systems”

• As with topical drug products, a performance test for transdermal drug products
also must have the ability to measure drug release from the finished dosage form,
must be reproducible and reliable, and must be capable of detecting changes in drug
release characteristics from the finished product

• In vitro drug release methods for transdermal patches include

q USP Apparatus 5 (Paddle over Disk Method)
q USP Apparatus 6 (Rotating Cylinder Method)
q USP Apparatus 7 (Reciprocating Holder Method).

• In general, it has been found that Apparatus 5, a modified paddle method, is simpler
and is applicable for most types, sizes, and shapes of TDDS.
In vitro Test for Topical Drug Products (USP) 13

“Product Performance Tests for Transdermal Delivery Systems”

Apparatus 5 : Paddle over Disk
In vitro Test for Topical Drug Products (USP) 14

“Product Performance Tests for Transdermal Delivery Systems”

Apparatus 6 : Rotating Cylinder Method
In vitro Test for Topical Drug Products (USP) 15

“Product Performance Tests for Transdermal Delivery Systems” USP <724>

Apparatus 7 : Reciprocating Holder
Draize’s Test 16

Introduction
• The Draize’s test is an acute toxicity test developed in 1944 by the
US-FDA toxicologist John H. Draize & Jacob M.Spines.

• The procedure involves applying 0.5mL or 0.5g of a test

substance to the eye or skin of a restrained, conscious animal, and
then leaving it for set amount of time before rinsing it out and
recording its effects

• The animals are observed for up to 14 days for signs of erythema

and edema in the skin test, and redness, swelling, discharge,
ulceration, hemorrhaging, cloudiness, or blindness in the tested
eye.

• Although thought of as a ‘gold standard’ of sorts, this test has

been widely criticized for its cruelty & allegedy being unscientific
Draize’s Test 16

Procedure
1.Select 6 female white albino rabbits in the weight range of 2-3 kg body weight were employed in the
present study. The animals utilized must be nulliparous and non-pregnant.

2. Keep animals individually with proper animal husbandry techniques.

3. The rabbits must be acclimated for a minimum period of 5 days in the controlled environment
(temperature: 20±3 °C; relative humidity: 50±20% and light: 12 h light/dark cycle) and ad libitum
water and standard rabbit pellet food.

4. Distribute the animals in 2 groups – test & control

5. Clipping the fuzz on skin surface to an area of about 6 cm2 on both sides of the dorsal surface of the
trunk of the animals, about 24 h before the analysis. Take care to prevent scraping of the skin . Select
only healthy animals with intact skin.
Draize’s Test 17

Procedure
6. Apply the test material to the clipped skin area on the left side of animals and the areas were covered
with a gauze patch that was held in place with non-irritating tape. The right untreated side is to be
reserved as a control area. The patch is to be loosely held in contact with the skin by means of an
appropriate semi-occlusive dressing. Restrainer (neck collar) may be used to avoid the ingestion of the
test substance from the application site.

7. Examine the skin reaction subjectively score within 1 hour of patch removal . Continued the same
procedure at 1, 2 ,3, 7 and 14 days.
Cell line testing for skin irritation 18

Introduction
• In vitro systems such as culturing primary human cells

In vitro (Cell line) Testing

are becoming increasingly important for decision
making in the drug development pipeline.
2D Cell Cultures

• Use of cell-lines:
q Reduces number of animal studies 3D Cell Cultures
q Reduces associated costs
q Alleviates ethical concerns of animal testing
Histocultures
• 2 Main end-points are studied:
q Cell-viability
q Release of inflammatory mediators Human Skin
Equivalents
Cell line testing for skin irritation 19

Summary of techniques

•Conventional
keratinocyte/fibroblast
cultures 2D Cell Culture
•3T3 Fibroblast Cell line

•Scaffold based methods

•Non-Scaffold Methods
•Microfabricated/Bioprinted 3D Cell Culture
Systems

•Culturing of skin tissue on

on a growth media Histoculture
•Episkin
•Epiderm FT
•SkinEthic RHE
Human Skin
•TESTSKIN
•Skin2
Equivalents
Cell line testing for skin irritation 19

EpiDerm Skin Irritation Test

The EpiDerm Skin Irritation Test was developed and designed to predict skin irritation potential of neat test
substances in the context of identification and classification of skin irritation hazard according to the EU
classification system (R 38 or no label) and the UN GHS system. The EpiDerm Skin Irritation Test allows for the
discrimination between irritants of category 2 and non-irritants

https://www.mattek.com/application/skin-irritation-test-oecd-439/
Cell line testing for skin irritation 19

EpiDerm Skin Irritation Test Protocol

https://www.mattek.com/application/skin-irritation-test-oecd-439/
Stability Protocol of Semisolids 20

Sample Protocol
q Batch Selection
• Data from stability studies should be provided on at least three primary batches of the drug
product.
• The primary batches should be of the same formulation and packaged in the same container
closure system as proposed for marketing.
• The manufacturing process used for primary batches should simulate that to be applied to
production batches and should provide product of the same quality and meeting the same
specification as that intended for marketing.
• A minimum of 2 of 3 batches should be at least pilot scale batches and the 3rd one can be smaller,
if justified.
Stability Protocol of Semisolids 21

Sampling Protocol
q Containers & Storage Conditions
• Containers must be stored in various orientations during study in order to determine effect of
orientation. Data should be presented separately for each orientation.
• If a product should be used within three months after removal of the protective packaging
(according to the nstructions for use), the product should be removed from the protective
packaging three months before the end of the shelf life, and tested at the end of the shelf life.
Stability Protocol of Semisolids 22

Sampling Protocol
q Sampling Plan
• Long Term Studies
Year 1 0 months 3 months 6 months 9 months 12 months

Year 2 12+6 months 12+ 12 months

Year 3 onwards 12+12+12

months

• Intermediate studies( if there is significant change in accelerated testing)

Year 1 0 months --------- 6 months 9 months 12

months
Stability Protocol of Semisolids 23

Sampling Protocol
q Sampling Plan
• Accelerated Testing
Year 1 0 months 3 months 6 months -------- --------

q Tests to be carried out

Drug Content Rheology

pH Microbial Load
Drug Release Water Loss
Consistency Physical Appearance