Module 1

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BUILDING FORMULA AND PRODUCTION PROCESS

ADMINISTRATION OF SOLID MEDICINE
MODULE 1: TABLET
Copyright @SEN Pharma. All rights reserved

Overview of tablets
Agenda 01 - Concepts and standards
- Excipients, process
Document search and preformulation

02 - Search and analyze reference documents
- Pre-formulation tests
Formula formulation, screening & optimization

03 - Develop formula, select excipients + production process
- Screening and optimizing formulas
Research on stability and technology transfer

04 - Research on stability and ways to shorten time
- Issues that need attention when transferring technology
Workshop: Case study + Trouble shooting

05 - Case study analysis, group discussion
- How to solve problems in experiments

1. Overview of tablets
Important background knowledge for formulation

1. What are tablets?
QT Stamping tablets
Active Finished product
4
How to make tablets?
1. Die Filling – Metering

2. Compaction, including: -
Compression (Reducing the volume of granules)
- Consolidation (Forming a link)

- Decompression.
3. Tablet Ejection.

How to make tablets?

1. What happened when pressing the tablets?

What is the role of excipients?
Diluent
01 Shaping tablets, affecting almost all properties of tablets.
Ex: MCC, lactose
Fall apart
Binder: Sticky Slippery

02 Increase adhesion ÿ hardness
For example: PVP K30, corn starch, HPC-L
Disintegrant:
03 Rapid expansion helps disintegrate tablets
For example: Sodium croscarmellose, sodium starch glycolate, crospovidone
Padded Other TDs
Lubricating
04 excipients: Glidant, lubricant, anti-adherent
Eg: Mg stearate.
Other excipients: Increase
05 permeability, aid dissolution, stabilize tablets, color, taste...

For example: SLS, Tween, citric acid, sodium carbonate, sucrose, sorbitol

Mix active ingredients with excipients and press tablets?
Granulation
Powder Granules

How to make granules?

Pressure
POWDER GRANULE
Moist + sticky TD
Grind dry seeds Grind wet seeds

Granulation process

2. Collect documents + Preformulation

Collect enough information to save time for formulatio

Generic product development
Ingredient Finished product meets TC
Formula
Active
Excipients
Process
Packaging

Research stages
Pre-formula Recipe screening Upgrade lot size
first 2 3 4 5 6
Collect documents Starting formula Stability
ROLE
1. What are the difficulties? (DHT, Impurities, Measurement...)
2. Correct selection of materials and processes 3. Quickly
find the cause and solution when encountering problems
ÿ “Right first time”: NC, POS time

2.1. Collect documents Find

information about APIs and finished products

ÿ Standards
ÿ Standards
ÿ Physicochemical properties
ÿ Generic drugs
• Sensory, allotropy, HH
• API characteristics
• Solubility, PS, BCS Class
• Formula and process
• Chemical reactions, incompatibility
•
Physical and
• Mechanical
mechanical properties • Packaging, shelf life, stability
properties ÿ Stability - storage
ÿ Other finished products
ÿ Safety
ÿ Excipients
Active Finished product

Information about active ingredients?
Standard Physical and chemical TC Stability Security

ÿ Sensory ÿ Sensory, HH form ÿ Expiry date ÿ Risk of exposure
ÿ Qualitative ÿ Solubility, PS, BCS Class ÿ Packaging & storage conditions ÿ PPE
ÿ Quantification, moisture ÿ Mechanical properties ÿ Decomposition, impurities ÿ Impact on the environment

content ÿ Impurities ÿ Chemical interactions & incompatibilities. ÿ Change in criteria

References
Standard Physical and chemical TC Stability Security

ÿ Mobile ÿ Patents, Articles ÿ Patents, articles ÿ MSDS
ÿ COAs ÿ SPC, assess. report ÿ ÿ Production ÿ SPC
ÿ Pro.Spec Drugbank, Wikipedia… ÿ DD, documents ÿ SPC, assess. ÿ Assess. report
COA, Prod. pec report ÿ Mobile, COA, Prod. pec

Finished product
Standard Generic Drugs Other Finished Products Excipients
1. Reference pharmacopoeia: Targets Quality level

UP, BP, P, JP, DDV Qualitative (+)
https:// www.drugfuture.com/ standard Quantitative 90.0 - 110.0% (95.0 - 105.0%)
Uniformity HL/
Obtain
Evenly distributed units
Environment: 900ml HCl 0.1

2. Self-build – Analytical R&D (ARD)
Solubility Stirring paddle – 50 rpm
YC: ÿ 80% in 30 minutes
ÿ General treatise, ICH, FDA Impurity A ÿ 3.0%
ÿ Patent, Research article Related impurities Any impurity ÿ 0.2%

Total impurities (not including impurity A) ÿ 2.0%
Other requirements In vitro test f2 ÿ 50

Note: DHT test method (FDA)
https:// www.accessdata.fda.gov

How to find generic drugs?

Information/notes Address
https://www.drugs.com/
Orange book - FDA https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm
https://go.drugbank.com/
Categories Original brand name drug https://
dav.gov.vn/ Pharmacircle (fee applicable) https://www.pharmacircle.com/info/
Google and Wikipedia
ÿ Keywords: API name, original brand name, brand name, innovator, originator
Note: Generic drug names may vary between countries

Information from generic drugs?

1 Pharmaceutical substance 2 Properties 3 Excipients 4 Process
• Size • Sensory. Pellet • TD type • Production process
• HH form, allotropy • structure • Volume, thickness. • TD amount • Equipment
Manufacturer • Hardness, disintegration, DHT
• Packaging, expiration date

Where to find information?

1 Pharmaceutical substance 2 Properties 3 Excipients 4 Process
• Patents, articles • Drugs.com • EMC, MHRA • Patents, articles

• Assessment report • Patents, articles • ANSM • Assessment report
• Distributor, SPC • Google • Dailymed
• Pharmacircle

Where to find information?
Website name Address

EMC (UK) https://www.medicines.org.uk/emc/
MHRA (UK) https://products.mhra.gov.uk/

ANSM (France) https://base-donnees-publique.medicaments.gouv.fr
Dailymed (USA) https://dailymed.nlm.nih.gov/dailymed/
TGA (Australia) https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI

?OpenForm&t=pi&q=atorvastatin

1. Collect documents
• Handbook of Pharmaceutical excipients (book) •

Pharmacopoeia
• Producer
• FDA (https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm)
• https://www.pharmaexcipients.com/

How to read patents

How to analyze articles
1. Title
2. Abstract
3. Method
4. Results & Discussion
5. Conclusion
FIGURE & TABLE

2.2. Preformulation
Tests that need to be conducted
before formulating

2.2. Preformulation
Generic drug analysis Pre-formulation test
Lipitor 10 mg film-coated tablets – Pfizer

Targets Characteristic
Ellipse, white. One side has the word PD 155, the other side
Sensory –
has the number 10 printed.
size
Dimensions: 9.8 x 5.2 mm.
KLV (mg) 200
Hardness (N) 40 - 80
Disintegration
(minutes) 5 - 6 Solubility According to Pharmacopoeia or FDA, with pH 1.2; 4.5; 6.8 (if testing BE)

2.2. Preformulation
KIÿM TRA PROCEED MEANING
Sensory Color, smell, taste, shape
Fluidity Sensory, measuring machine Choose the appropriate preparation method

Hygroscopicity Sensory (test) Conditions for preserving energy and rice; risk of mortar and pestle sticking.
API
Size NL Mastersizer 3000 Effects: solubility, compressibility
Compression resistance,
Physicochemical properties Support formula development and troubleshooting
solubility, stress test, T0 nc, TH
form, pH Quantification, impurities

API – excipient incompatibility Choose appropriate excipients
DSC (less common)

2.2. Preformulation
ÿ Capacity size

2.2. Preformulation
ÿ Capacity size

2.2. Preformulation

2.2. Preformulation
ÿ Incompatibility of active ingredients - excipients
ÿ How to do: Mix physically at 1:1 ratio, save LHCT sample.
Mix 2, 3, 4 Mixing ratio no Edema conditions

ingredients??? must be 1:1??? fit ???

ÿ OPA/Al/PVC
ÿ PVC/PVDC, PVC/PE/PVDC ÿ HDPE, LDPE, PET plastic

ÿ OPA/Al/PVC
ÿ Al/PE/Paper
ÿ Glass
Blister Press BOTTLE Blister Tear

Build a starting formula

Select excipients, process and CT construction

Which excipient to choose?
01 Generic medicine
Research documents (patent, article)

02
03 Practical experience according to the properties of medicinal substances
04 Price and raw materials available at the factory

Excipients tablets
Excipient filler Adhesive excipients (0.5-3%)

MCC, lactose, starch, (pregelatinized starch) Gelatin, Povidone K30, K90, HPMC E5; E6;
mannitol, dicalcium phosphate, tricalcium 15, Starch, pregelatinized starch,
phosphate, maltodextrin, saccharose, HPC-L
D D
Tablets
Disintegrants (2-5%)
Starch, sodium starch glycolate, sodium
R T Plain excipients (0.25-3%)
Mg stearate, calcium stearate, stearic acid,

croscarmellose, crospovidone, L-HPC sodium stearyl fumarate, hydrogentated castor
Internal decay - external decay oil, glycerin benhenate, PG 6000, talc…

Compare disintegrants
ÿ Disintegration method ÿ Affects pH

Excipient filler

Excipient filler

Other excipients
TT Excipients to increase permeation and aid dissolution: SLS, Tween 20, Tween 80, docusate Na...
pH adjusters: citric acid, fumaric acid (acidifier), CaCO3 , NaHCO3 ,

pH
Na2CO3 , MgO, Ca(OH)2 (alkalizer)
O2 Antioxidants: BHA, BHT, vitamin C, EDTA…
M Color excipients: dye, lake, iron oxide...
Flavoring excipients : saccharin, sucrose, aspartame...

Choose production process?
01 Research documents (patent, article)
02 Properties of active ingredients
03 Available equipment
04 Economy and convenience

QTSX tablets

Formula construction
Follow the 4 guided steps, from choosing tablet

weight to the ratio of excipients

CT screening
From the starting formula to the final formula, going

through the steps of adjusting the formula and production
process.
Choose the right solution to save research time

Adjust the formula
01 Type of excipients, granulation solvent, level 1 packaging
02 Ratio of excipients used, amount of rubbing solvent
03 Production process and machine parameters
04 Weight of pellets or mortar and pestle
05 sources of active ingredients

Formula optimization
Theory and practice

Concept
Formula Process
optimization optimization

Optimize formula & QTSX

Meaning
Understand clearly the ÿ Save time and costs ÿ Limit

influence of ingredients incidents
and parameters on product quality
Determine safety ranges of

formulas and process
parameters



Theory Reality at the company

There are many designs Difficulty in fully
depending on the number implementing testing
of risk factors

Ideas for practical application
Survey variables Appropriate evaluation

and ranges are based and analysis of TK
on experience and data data, preformulation
and initial research
Be careful in
experimenting and
analyzing results
Copyright ® HCAC
Copyright @SEN Ltd. All
Pharma. Co. All rights
rights reserved.
reserved
STABILITY STUDY

The role of stability testing
Screening of stable formulations
01 Screen the formula through its resistance to

moisture, heat, and light
Choose packaging and storage conditions
02 When the active ingredient is sensitive to moisture and

atmospheric oxygen, consider suitable moisture-resistant packaging
Predict product lifespan
03 Based on the stability results, preliminarily Mandatory requirement to prove HD

calculate the trend of indicators over time,
for example: content, impurities, solubility...
04 New product: Initial stable data
Update data over time until expiration date

Stability test conditions
Temperate (21/45)
Hot and
dry (30/35)
Mediterranean and subtropical (25/60)

Hot and
humid (30/65
or 30/75)

Testing conditions in Vietnam
TYPE OF STUDY CONDITIONS TRACK TIME FRAME ROLE
Simulate the process

Temperature: 30oC ± 2oC , 0, 3, 6, 9, 12, 18, 24, of drugs being circulated
Long term conditions
RH: 75% ± 5% 36, (48, 60) (month) and preserved on the
market
Accelerate results.
Temperature: 40oC ± 2oC Simulate harsh
Accelerated aging 0, 1, 3, 6 (months)
RH: 75% ± 5% conditions in storage
onion
temperature ÿ 50oC
Maximum savings in
Stress 0, 1, 2, 4, 6, 8 (weeks) formula screening
RH: not specified time

Evaluation criteria
Why is it necessary
to track mandatory
indicators in
NC DOD?
REQUIRED TARGETS INTERNAL REFERENCE CRITERIA
• Appearance, color •
• Moisture •
Disintegration – Solubility •
Color
Quantitation •
measurement • Pellet hardness
Related impurities

Device
ROOM
STABLE CABINET/DRYING CABINET
STABILITY

How to speed up QT C?
Perform testing under more severe conditions

UPGRADE LOT SIZE AND

TECHNOLOGY TRANSFER

Device differences
01 Understanding the differences in equipment between experimental batches and
technology batches is an important factor for success
Process differences
SCALE-UP & 02 Differences in equipment cause the process at some stages of the experimental
batch to be different from the technological batch
TECHNOLOGY
Key to success
TRASFER 03 Practical experience on points to note during the technology transfer process
Critical factor
04 Important factors to check during the technology transfer process

1. Equipment between experimental batch and technological batch
Stage Experiment Industry
Make green rice
Press tablets

Stage Experiment Industry
Film cover
Blister

What can be done to

minimize the impact of
equipment differences?
The device operating mechanism is different. For example, the process of Consider operating parameters to obtain the same bulk
MUSCLE repairing dry beans product, for example:
CHECKING • Experimental batch: grinding mortar and pestle + rubbing by hand • Measure particle size distribution ÿ adjust
• Technology block: high-speed blades grind seeds through the mesh grinding speed
Consider adjustments when upgrading batch sizes,

Device performance for the same period is different. For example, wet
BRAND for example in wet stuffing:
granulation with the same amount of solvent
POWER • Amount of solvent
• Stuffing machine > Stuffing by hand
• Stuffing time

2. Process between experimental batch and technological batch
Differentiating factors Process differences For example
• Experimental batch: grinding by hand using a mortar

Other parameter types and pestle without parameters
completely different • Technology plot: grinding blade speed, sieve size
Different
equipment
Different shipping parameters • Mixing time and mixing speed are different between
onion the experimental batch and the technological batch
Request of There are new steps to complete

• Clean up, record records, liquidate
GMP full

3. Key to success
Control semi-finished products and end-points

WORKSHOP 01
Discussion groups
- Develop formula and process for Olmesartan 20 mg tablets
- Solutions for case studies
AGENDA
Recipe review
02 - Analyze proposed formulas and processes
- Documents and important patents for Olmesartan tablets
Case study
03 - Discuss and come up with solutions for Olmesartan tablets
- Solution for Paracetamol and Para + DPH tablets
Final exam + survey + Summary

04 - Final exam and participate in course survey
- Summary of the curriculum

BACKGROUND ISSUE - SOLUTION
- API: Olmesartan Medoxomil 20 mg Hardness when stamping: 6 - 8 kP

Disintegration: 2-4 min
- PS: D90 = 6 µm
- Generic KLV: 218 mg, 9 mm punch Solubility: 73-82% (required >80%)
- Viable KLV 204 mg, punch 8 mm
Pellet ingredients % mg/tablet
Olmesartan Medoxomil 10.50 21.00

WHAT CAUSES UNSUFFICIENT SOLUTION?
Lactose DC 29.50 60.00
MCC 112 50.00 100.00
L-HPC 1.00 2.00
Crospovidon XL10 4.00 8.00
Sodium lauryl sulfate 3.00 6.00

Aerosil 0.50 1.00
Magnesium stearate 1.50 3.00
Film coating mixture 2.00 4.00
Total 100.00 200.00

BACKGROUND ISSUE - SOLUTION
Moisture content: 1.95%

- API: Paracetamol 500 mg
- Grind wet seeds with starch and PVP Hardness when pressing tablets: 45 - 55 N, tablets easily separate layers
- Desired KLV 560 mg Disintegration: 1p30-2p
Pellet ingredients % mg/tablet CAUSES OF UNSUFFICIENT HARDNESS AND SOLUTIONS

Paracetamol 89.3 500.0
Corn starch (dry mix) 2.8 15.60
Corn starch (cook starch) 2.0 11.0

PVP K30 3.0 16.8
odium starch glycolate (mixed 11.0
2.0
outside)
Magnesium 1.0 5.6
stearate is pure qs
Total 100.0 560.0

THANK YOU See

you in the next course!

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Machine Translated by Google

BUILDING FORMULA AND PRODUCTION PROCESS

Copyright @SEN Pharma. All rights reserved

Document search and preformulation

Formula formulation, screening & optimization

Research on stability and technology transfer

Workshop: Case study + Trouble shooting

Copyright @SEN Pharma. All rights reserved

Copyright @SEN Pharma. All rights reserved

1. What are tablets?

Active Finished product

How to make tablets?

1. Die Filling – Metering

Compression (Reducing the volume of granules)

- Consolidation (Forming a link)

Copyright @SEN Pharma. All rights reserved

How to make tablets?

Copyright @SEN Pharma. All rights reserved

1. What happened when pressing the tablets?

Copyright @SEN Pharma. All rights reserved

What is the role of excipients?

Binder: Sticky Slippery

Other excipients: Increase

05 permeability, aid dissolution, stabilize tablets, color, taste...

Copyright @SEN Pharma. All rights reserved

Mix active ingredients with excipients and press tablets?

Copyright @SEN Pharma. All rights reserved

How to make granules?

Grind dry seeds Grind wet seeds

Copyright @SEN Pharma. All rights reserved

Copyright @SEN Pharma. All rights reserved

2. Collect documents + Preformulation

Copyright @SEN Pharma. All rights reserved

Generic product development

Ingredient Finished product meets TC

Copyright @SEN Pharma. All rights reserved

Pre-formula Recipe screening Upgrade lot size

Collect documents Starting formula Stability

Copyright @SEN Pharma. All rights reserved

2.1. Collect documents Find

Copyright @SEN Pharma. All rights reserved

Active Finished product

Copyright @SEN Pharma. All rights reserved

Information about active ingredients?

Standard Physical and chemical TC Stability Security

ÿ Quantification, moisture ÿ Mechanical properties ÿ Decomposition, impurities ÿ Impact on the environment

Copyright @SEN Pharma. All rights reserved

Standard Physical and chemical TC Stability Security

ÿ COAs ÿ SPC, assess. report ÿ ÿ Production ÿ SPC

ÿ Pro.Spec Drugbank, Wikipedia… ÿ DD, documents ÿ SPC, assess. ÿ Assess. report

COA, Prod. pec report ÿ Mobile, COA, Prod. pec

Copyright @SEN Pharma. All rights reserved

Standard Generic Drugs Other Finished Products Excipients

1. Reference pharmacopoeia: Targets Quality level

Environment: 900ml HCl 0.1

ÿ Patent, Research article Related impurities Any impurity ÿ 0.2%

Other requirements In vitro test f2 ÿ 50

Copyright @SEN Pharma. All rights reserved

How to find generic drugs?

Copyright @SEN Pharma. All rights reserved

Information from generic drugs?

1 Pharmaceutical substance 2 Properties 3 Excipients 4 Process