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Packaging Development by Design Model for Solid Oral Dosage Form-

Hard Gelatin Capsules

Conference Paper · October 2016

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Shivang Chaudhary
National Institute of Pharmaceutical Education and Research
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 IDENTIFICATION DESIGN OF ANALYSIS OF DEFINING OF DEFINING OF
OF PACK CQAs $TABILITY STUDY STABILITY DATA PACK CONTROLS PACK CONTROLS

Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN

SELECTION & OPTIMIZATION OF CMAs & CPPs OF

Determination of

CQAs BLISTER PACKAGING PROCESS

FOR SOLID ORAL DOSAGE FORM DEVELOPMENT AS PER QbD

B LIDDING FOIL
Quality Risk
Assessment of
MACHINE SPEED E
CMAs &
CPPs
SEALING TEMPERATURE D

FORMING TEMPERATURE C
DoE BASE FILM
& Development A
of Design Space

RISKS

PAT COMPROMISE IN COMPROMISE IN COMPROMISE IN

&Development MECHANICAL STRENGTH PHYSICAL BARRIER CHEMICAL COMPATABILITY
of Feedback
Control system
FAILURE IN BUBBLE TEST, OOT / OOS IN WVTR, OTR, LTR OR OOS IN IMPURITY
VACUUM / PRESSURE DECAY MICROBIAL LOAD TESTS LIMITDURING SHELF LIFE

Implementatn of CHANCES OF DRUG PRODUCT PRODUCT EXPOSURE TO MOISTURE, COMPROMISE IN DRUG

Control INTEGRITY LOSS OXYGEN, LIGHT, MICROORGANISMS PRODUCT SHELF LIFE
Strategy
COMPROMISE IN QUALITY, SAFETY & EFFICACY
© Created & Copyrighted by Shivang Chaudhary © Created & Copyrighted by Shivang Chaudhary.
 IDENTIFICATION DESIGN OF ANALYSIS OF VERIFICATION OF DEFINING OF
OF PACK CQAs $TABILITY STUDY STABILITY DATA PACK CONTROLS PACK CONTROLS

Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN (Contd)
Available Options of Primary Packaging Material

Determination of
A PVC-PVdC 60µ
CQAs
Al 25µ
PVdC 40µ
PVC 250µ

Quality Risk
Assessment of B PVC-PE-PVdC 90µ
CMAs &
CPPs Al 25µ
PVdC 90µ
PE 25µ
PVC 250µ

DoE
& Development C PVC-PCTFE 20µ / 38µ / 76µ
of Design Space

Al 25µ
PVC 250µ
PCTFE Xµ
PAT
&Development
of Feedback
Control system
D Alu-Alu CFF

Al 25µ
Implementatn of OPA 25µ
Control Alu 45µ
Strategy PVC 60µ

© Created & Copyrighted by Shivang Chaudhary.

 IDENTIFICATION DESIGN OF ANALYSIS OF VERIFICATION OF DEFINING OF
OF PACK CQAs $TABILITY STUDY STABILITY DATA PACK CONTROLS PACK CONTROLS

Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN (Contd)
Selection of Primary Packaging Material
Positive Test Pack (For Selection of Packaging material
Negative
Control
Tests PET PVC- PE- PVC - PVC - OPA-Alu- Control (OPA-
(Directly
Determination of
Container PVdC 90µ PCTFE 38µ PCTFE 76µ PVC 60µ Alu-PVC 100µ)
Exposed-OPD)
CQAs Lidding Foil
Material Aluminum Aluminum Aluminum Aluminum Aluminum Aluminum Aluminum
Thickness 25 µ 25 µ 25 µ 25 µ 25 µ 25 µ 25 µ
Base Film
PVC-PE PVC – PVC –
Material OPA- Alu-PVC OPA- Alu-PVC
Quality Risk PVdC PCTFE PCTFE
Assessment of
Open Petri dish
PET PVC: 250 µ OPA: 25 µ OPA: 25 µ
(OPD) PVC: 250 µ PVC: 250 µ
CMAs & Thickness PE: 25 µ
PCTFE: 38µ PCTFE: 76µ
Alu: 45 µ Alu: 45 µ
CPPs PVdC: 90µ PVC: 60 µ PVC: 100 µ
Barrier Properties
++ +++ +++ +++ +++++ +++++
Intrinsic Water Vapor Barrier 2.00 0.31 0.15 0.08 0.00 0.00
Open gm/m2/day gm/m2/day gm/m2/day gm/m2/day gm/m2/day gm/m2/day
DoE Intrinsic Oxygen Barrier ++ +++ ++ ++ ++++ +++++
& Development Light Transmission Barrier + ++ 0 0 +++++ +++++
of Design Space
Processing Parameters
Forming Temperature Induction 110-130°C 130-150°C 130-150°C - -
Sealing Temperature Sealing 170-220°C 150-180°C 150-180°C 150-180°C 150-180°C
Max. Machine Line Speed - 250-450 100-300 100-300 100-200 100-200
(Blister Per Minute) BPM BPM BPM BPM BPM
PAT
&Development
of Feedback
Control system SELECTION CRITERIAS

MECHANICAL PHYSICAL CHEMICAL BIOLOGICAL ECONOMICAL

STRENGTH BARRIER COMPATABILITY SAFETY ACCEPTABLE

Implementatn of -Strong enough to Protection rom Does not react with Extract able/ Leachable Total Cost,
Control withstand handling -moisture -Product Contents Should be Unit Price acceptable
Strategy -should fit in -oxygen /any gas / vapor -Packing Ingredients -biological safe with comparable
packaging line -UV / Visible light -not impart its color odor -nontoxic Advantages
-long life -microorganism taste to drug product
© Created & Copyrighted by Shivang Chaudhary.
 IDENTIFICATION DESIGN OF ANALYSIS OF VERIFICATION OF DEFINING OF
OF PACK CQAs $TABILITY STUDY STABILITY DATA PACK CONTROLS PACK CONTROLS

Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN (Contd)
Comparative Accelerated Stability Study with different Packaging Material – Scale Up Batch

40°±2°C /75±5%RH for 3 Months

Initial
Determination of Specification-CQAs Analysis Positive Test Pack (For Selection of Packaging material for Optimized Negative
Tests
CQAs (Acceptance Criteria)
(0 Days)
Control Finished Product Formulation) Control
(Directly PET PVC- PE- PVC - PVC - OPA-Alu- (OPA-Alu-
Exposed*) Bottle PVdC 90µ PCTFE 38µ PCTFE 76µ PVC 60µ PVC 100µ)
Description Complies Fail Complies Complies Complies Complies Complies Complies
Imp A1: NMT 0.2% 0.07 0.39 0.18 0.15 0.14 0.12 0.11 0.11
Quality Risk
Assessment of Related Imp B2: NMT 0.2% 0.05 0.28 0.14 0.12 0.11 0.11 0.09 0.10
CMAs & Substance
Imp C3: NMT 0.2% 0.09 0.33 0.16 0.14 0.13 0.11 0.11 0.11
(Impurity) /
CPPs HPLC Imp D4: NMT 0.2% 0.04 0.21 0.11 0.08 0.09 0.08 0.07 0.07
Max Unk: NMT 0.2% 0.08 0.36 0.15 0.14 0.13 0.13 0.11 0.10
Total : NMT 1.0% 0.32 1.62 0.75 0.68 0.58 0.65 0.53 0.51
DoE Assay / HPLC 90% to 110% 98.5% 91.7% 96.8% 96.6% 97.4% 97.6% 98.2% 98.3%
& Development
of Design Space Water / KF NMT 15% 12.2 17.9% 14.5 13.9 13.7 13.4 13.2 12.6
Disintegration NMT 30 minutes 9 min 26 min 13 min 11 min 10 min 10 min 9 min 9 min
Not less than 85%
Dissolution (Q) dissolved in 98.1% 85.5% 94.1% 95.2% 97.1% 97% 97.5% 97.7%
PAT 45 minutes
&Development
of Feedback
Control system
1Impurity generated due to oxidation during synthesis of Drug Substance and/or manufacturing of drug product
2Impurity generated due to temperature effect during synthesis and/or storage of drug substance and/or manufacturing and/or storage of drug product
3Impurity generated due to moisture effect during synthesis and/or storage of drug substance and/or manufacturing and/or storage of drug product
4Impurity generated due to light exposure cis- trans during synthesis and/or storage of drug substance and/or manufacturing and/or storage of drug product

Implementatn of
Control
Strategy Here , Drug Substance is susceptible to oxidation, temperature, moisture & light. Thus, with respect to comparative impurities generated in different
packs upon storage, OPA-Alu-PVC (Alu Alu CFF) Blister Pack was selected as primary pack for packaging of Exhibit-Submission Batch.

© Created & Copyrighted by Shivang Chaudhary.

 IDENTIFICATION DESIGN OF ANALYSIS OF VERIFICATION OF DEFINING OF
OF PACK CQAs $TABILITY STUDY STABILITY DATA PACK CONTROLS PACK CONTROLS

Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN (Contd)
Accelerated Stability Study with Finalized Primary Pack : Alu-Alu CFF– Exhibit Batch

Specification-CQAs Initial Analysis 40°±2°C /75±5%RH up to 6 Months: in PVC-PCTFE 38µ Pack

Tests
(Acceptance Criteria) (0 Days) 1 Month 2 Months 3 Months 6 Months
Determination of Description Complies Complies Complies Complies Complies
CQAs Imp A1: NMT 0.2% 0.07 0.09 0.10 0.12 0.13
Related Substance Imp B2: NMT 0.2% 0.05 0.06 0.08 0.10 0.12
(Impurity) / HPLC Imp C3: NMT 0.2% 0.09 0.11 0.12 0.13 0.15
Imp D4: NMT 0.2% 0.03 0.05 0.06 0.07 0.1
Max Unknown: NMT 0.2% 0.08 0.10 0.11 0.12 0.14
Quality Risk Total : NMT 1.0% 0.34 0.43 0.48 0.56 0.65
Assessment of
CMAs & Assay / HPLC 90% to 110% 98.7% 98.4% 97.9% 98.2% 97%
CPPs Water / KF NMT 15% 12.2 12.7 13.1 13.4 13.9
Disintegration NMT 30 minutes 9 min 9 min 10 min 10 min 11 min
Not less than 85% (Q) 98.1% 97% 96.7% 95.6%
Dissolution dissolved in 45 minutes 97.5%

DoE
& Development
of Design Space

PAT
&Development
of Feedback
Control system

Implementatn of
Control
Strategy

© Created & Copyrighted by Shivang Chaudhary.

 IDENTIFICATION DESIGN OF ANALYSIS OF VERIFICATION OF DEFINING OF
OF PACK CQAs $TABILITY STUDY STABILITY DATA PACK CONTROLS PACK CONTROLS

Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN (Contd)
Implementation of Controls for Packaging of– Commercial Batches

Ranges studied at Actual data Proposed range for

CPAs / CPPs PURPOSE of Control
LAB scale for EXHIBIT batches COMMERCIAL batch
Lidding Foil
Determination of
Material Aluminum Aluminum Aluminum To ensure batch to batch
CQAs consistency in shelf life of drug
Thickness 25 µ 25 µ 25 µ product during transportation,
storage or routine-use
Base Film
Material PVC-PCTFE PVC-PCTFE PVC-PCTFE To ensure batch to batch
Quality Risk
Assessment of
consistency in shelf life of drug
PVC: 250 µ PVC: 250 µ PVC: 250 µ
CMAs & Thickness
PCTFE: 38µ PCTFE: 38µ PCTFE: 38µ
product during transportation,
storage or routine-use
CPPs Processing Parameters
Base Film Cavity To ensure batch to batch
130-150°C 135-145 °C 135-140 °C
Forming Temperature (°C) consistency in blister pack
Lidding Foil barrier properties without
150-170°C 160-170 °C 165-170°C
DoE Sealing Temperature (°C) leakage in lidding foil or defect
& Development in base film to achieve target
of Design Space Machine Line Speed shelf life of drug product during
100-250 BPM 125-225 BPM 150-200 BPM
(Blisters Per Minute) transportation, storage or
routine-use
Environmental Conditions
Temperature 21-25°C 21-25°C 21-25°C To ensure batch to batch
PAT Humidity 20-40 % RH 20-30 % RH 20-30 % RH uniformity in surrounding
&Development
of Feedback Under Nitrogen Under Nitrogen Under Nitrogen environmental factors during
Control system O2 or N2 on line processing of packaging
Laminar Flow Laminar Flow Laminar Flow
Packaging Under Packaging Under Packaging Under to provide protection from
UV- Visible Light Sodium Vapor Lamp Sodium Vapor Lamp Sodium Vapor Lamp temperature, moisture,
light & oxidation
Implementatn of
Control
Strategy

© Created & Copyrighted by Shivang Chaudhary.

 “Quality doesn’t cost, it always pays”

Created & Copyrighted by

SHIVANG CHAUDHARY
Chief Knowledge Officer (CKO) & Global Head Quality by Design at QbD Expert™
MS (Pharmaceutics)- NIPER, Ph.D-東大, LSSMBB-ISI, EDMP (PM)- IIM-A, PGDPL-NALSAR
www.facebook.com/QbDExpert www.linkedin.com/groups/8264051
 +91 -9904474045, +91-8866327899
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