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Quality by Design (QBD) Model For "Liquid Oral Solution" © by Dr. Shivang Chaudhary From Qbd-Expert™
Quality by Design (QBD) Model For "Liquid Oral Solution" © by Dr. Shivang Chaudhary From Qbd-Expert™
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QTPP A MODEL
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development Designed & Developed by
of Feedback
Control system
SHIVANG CHAUDHARY
Chief Knowledge Officer (CKO) & Global Head Quality by Design at QbD Expert™
MS (Pharmaceutics), Ph.D. (Pharmaceutical Sciences), LSSMBB, EDMP (PM), PGDPL
Implementatn of
www.facebook.com/QbDExpert www.linkedin.com/groups/8264051
Control +91 -9904474045, +91-8866327899
Strategy qbdexpert@gmail.com
www.qbdexpert.com
To Develop :
Definition of QTPP
Determination of CQAs
DoE &
Development of Design Space
© Created & Copyrighted by Shivang Chaudhary
PAT &
Development of Feedback Controls
Implementation of
Control Strategy
QTPP
Determination of
CQAs
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy
Definition of
QTPP
Determination of Quality
CQAs The suitability of either a drug substance or a drug product
for its intended use.
Quality Risk
Assessment of
CMAs &
CPPs
Quality by Design (QbD)
A SYSTEMATIC approach
• to development
DoE • that begins with predefined objectives and
& Development
of Design Space • emphasizes product and process understanding
• and process control,
• based on sound science and quality risk management.
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy
Determination of
Determine CQAs (Critical Quality Attributes)
Considering QUALITY [Assay, Uniformity of Dosage units,], SAFETY [Impurities (Related substances),
CQAs Residual Solvents, Microbiological limits], EFFICACY [Dissolution & Absorption] &
MULTIDISCIPLINARY [Patient Acceptance & Compliance]
Quality Risk
Assessment of
Quality Risk Assessment of CMAs & CPPs with CQAs
(1) RISK IDENTIFICATION: by Ishikawa Fishbone
CMAs & (2) RISK ANALYSIS by Relative Risk based Matrix Analysis
CPPs (3) RISK EVALUATION by Failure Mode Effective Analysis
QTPP
Determination of
CQAs
1
How to define
Quality Risk
Assessment of
CMAs &
CPPs
Target Product Profile?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy
Definition of
QTPP
Determination of
CQAs
Note:
• For Pharmaceutical Abbreviated New Drug Application (ANDA- Generics) QTPP will be finalized -on the basis of
Therapeutic Equivalence= Pharmaceutical Equivalence (same dosage form, route of administration, strength & same
quality) + Bio-Equivalence (same pharmacokinetics in terms of Cmax, AUC;
PAT
&Development
of Feedback • Thus QTPP of Generics will be defined based on the properties of the drug substance, characterization of the RLD
Control system
product, and consideration of the RLD label and intended patient population.
• For Pharmaceutical New Chemical Entities (NCE-Innovator) QTPP will be finalized on the basis of Therapeutic Safety &
Efficacy / New Drug Applications (NDA-Novel Drug Delivery Systems as compared to already approved & available
Implementatn of conventional dosage forms)
Control
Strategy
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development PHARMACEUTICAL BIO- PATIENT
of Design Space
Equivalence Equivalence Compliance
Similar For oral solutions, elixirs, syrups, Primary PACKAGING:
tinctures, or other solubilized forms, in
Dosage FORM : Solution vivo BA and/or BE can be waived.
Container : (Glass/Plastic/Metal) &
PAT Dosage DESIGN : IR Generally, in vivo BE studies are waived Closure : (Plastic/Metal/Rubber)
&Development
of Feedback ROUTE of for solutions on the assumption that Ease of Storage & Distribution
Control system release of the drug substance from the Should be stable against hydrolysis, oxidation, photo
Administration : Oral drug product is self-evident and that degradation & microbial growth with at least 12
Dosage STRENGTH : x mg/ml the solutions do not contain any months long term stability at normal room
excipient that significantly affects drug temperature & 28 Days of in-Use Shelf Life
Drug Product QUALITY : absorption
Implementatn of Assay, Impurities, Patient Acceptance
Control Microbiological Limits, Antioxidant & Should possess acceptable flavor, taste & odor
Strategy Antimicrobial content, pH, Viscosity/ Patient Compliance
Sp. Gravity, Leachable/ Extractable within re-dispersible upon shaking/administered
acceptable limits of specification (pourable & palatable)/used/ applied similarly
Note: Plastic/ Rubber should not allow permeation, leaching, extraction or sorption with Reference Product labeling
© Created & Copyrighted by Shivang Chaudhary.
Definition of
QTPP
Determination of
CQAs
2
How to determine
Quality Risk
Assessment of
CMAs &
CPPs
Critical Attributes of Quality?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy
Definition of
QTPP
Determination of
CQAs
PAT Note: CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials) & Finished
&Development
of Feedback drug product. On the basis of Quality [Assay, Uniformity of Dosage units, Redispersibility, Reconstitution time, Aerodynamic
Control system
property], Safety [Impurities (Related substances), Residual Solvents, Osmolarity & Isotonicity, Microbiological limits, Sterility
& Particulate matter], Efficacy [Diffusion, Dissolution & Permeation] & Multidisciplinary [Patient Acceptance & Compliance].
Implementatn of
Control
Strategy
!
Formulation and process variables are unlikely to impact this CQA. Therefore, the CQA will not be investigated and
discussed in detail in subsequent risk assessment and pharmaceutical development.
Determination of
CQAs Formulation & Process variables does not have any impact on this CQA.
No need for any further investigation & discussion.
QTPP
Determination of
CQAs
3
How to assess Risks associated with
Quality Risk
Assessment of
CMAs &
CPPs
Materials & Process?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy
Definition of
QTPP
Determination of
CQAs
DoE
& Development
of Design Space Critical Process Parameter (CPP)
Independent process parameters
• most likely to affect the CQAs of an intermediate or finished drug
PAT
&Development
of Feedback product & therefore should be monitored or controlled
Control system
Implementatn of Note: Risk related to individual CMAs &/or CPPs will be identified, analyzed qualitatively & then evaluated
Control quantitatively in order to reduce the probability of risk through optimization by DoE &/or inline detection by PAT.
Strategy
Strategy
Capping & Sealing rate Dissolved / Headspace
Design & Size of container/closure
Nitrogen purging &/or sparging rate Oxygen content of system
Sealing rate after closure fitting Microbial content of system
Patient Acceptance & Compliance
# Applicable to Solution only; * Applicable to Suspension only; ** Applicable to reconstituted powder only
Environment (Temperature and RH)
© Created & Copyrighted by Shivang Chaudhary.
RISK RISK RISK RISK
IDENTIFICATION ANALYSIS EVALUATION ASSESSMENT
Determination of
CQAs
SOLUBILIZATION BY
SURFACTATNT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy
Definition of
Qualitative Risk based Matrix Analysis of
QTPP Active Pharmaceutical Ingredient’s (API) Attributes
Determination of
Implementatn of
Control
Strategy
Definition of
Quantitative Failure Mode Effect Analysis (FMEA) of Detectability of Risk can
Implementatn of
Control Score based on Score based on Score based on
Strategy PROBABILITY
FOR OCCURANCE
LIKELY SEVERITY PROBABILITY OF
IMPACT ON DRUG FAILURE OF
OF FAILURE PRODUCT CQA. DETECTION.
© Created & Copyrighted by Shivang Chaudhary.
RISK RISK RISK RISK
IDENTIFICATION ANALYSIS EVALUATION ASSESSMENT
Definition of
CRITICAL
QTPP Active Pharmaceutical Ingredient’s (API) Attributes
Required to be Optimized &/Or Controlled
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
API Attributes which got RPN more than 30 were get highest priority among
Implementatn of
all the risks, they should be taken into consideration as most
Control
Strategy Critical Material Attributes of API , which were required
to be optimized &/or controlled
© Created & Copyrighted by Shivang Chaudhary.
RISK RISK RISK RISK
IDENTIFICATION ANALYSIS EVALUATION ASSESSMENT
Definition of
CRITICAL
QTPP Active Pharmaceutical Ingredient’s (API) Attributes
Required to be Optimized &/Or Controlled
Determination of
CQAs
CMAs of
API
Quality Risk
Assessment of
CMAs & A SOLID STATE FORM
CPPs
B PARTICLE SIZE
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy
Definition of
Qualitative Risk based Matrix Analysis of
QTPP Inactive Ingredients’ (Excipients’) Attributes
Determination of
Implementatn of
Control
Strategy
Definition of
Quantitative Failure Mode Effect Analysis (FMEA) of
QTPP Inactive Ingredients’ (Excipients’) Attributes
Excipient Critical Failure Mode
Effect on IP & FP CQAs with respect to QTPP
(Inactive Material (Critical P S D RPN (=P*S*D)
(Justification of Failure Mode)
ingredient) Attribute Event)
Drug Substance may NOT get completely SOLUBILIZED or uniformly
Less than
Determination of Quantity of optimum
DISTRIBUTED >> UNIFORMITY may get affected 3 3 3 27
>> SAFETY & EFFICACY may get compromised
Vehicles/ Solvents
CQAs Vehicle/ Solvent More than Product may get BULKIER to handle
4 3 2 24
optimum >> Patient ACCEPTANCE & COMPLIANCE may get compromised
Source of hydrocolloid is natural i.e. plant or animal based origin
Source of >> potential for microbial attack & growth
Hydrocolloid
Natural >> MICROBIOLOGICAL STABILITY may get compromised 3 3 4 36
Hydrocolloid >> SAFETY of the patient may get compromised
(Suspending VISCOSITY of dispersion medium may be too lower
agent as a Less than >> Rate of SEDIMENTATION will be high
Quality Risk optimum >> PHYSICAL STABILITY may get compromised 4 4 2 32
structured Concentration of >> SAFETY & EFFICACY may get compromised
Assessment of
vehicle) Hydrocolloid VISCOSITY of dispersion medium may be too higher
CMAs & More than
optimum
>> POUR ABILITY of the product may get compromised
>> PATIENT COMPLIANCE may get compromised
4 4 2 32
CPPs If surfactant is positively/ negatively CHARGED
>> INCOMPATIBLE with anionic/cationic drugs /preservatives / primary
Ionic Nature of Cationic/ Anionic
Surfactant in nature
packaging material 3 3 3 27
>> CHEMICAL / MICROBIOLOGICAL STABILITY may get compromised
>> SAFETY of the patient may get compromised
Drug Substance/ Preservatives may NOT getting
effectively SOLUBILIZED/ DISTRIBUTED within system 4 4 3 48
Surfactants (As a >>SAFETY & EFFICACY may get compromised
DoE Solubilizing/
Less than ZETA POTENTIAL of the system may be too low
& Development optimum >> Particles coalesce & flocculated suspension forms
agents) >> Suspension start to form SEDIMENT 4 4 2 32
of Design Space Concentration of >> PHYSICAL STABILITY may get compromised
Surfactant >> SAFETY & EFFICACY may get compromised
ZETA POTENTIAL of the system may be too high
>> Particles repel each other & forms deflocculated suspension which upon
More than
optimum
settled down invariably leads to form HARD CAKE 4 4 2 32
>> PHYSICAL STABILITY may get compromised
>> SAFETY & EFFICACY may get compromised
PAT Within
Neutral Range
SOLUBILITY of the weak acidic / weak basic drugs may get affected
>> EFFICACY may get compromised 3 3 3 27
&Development Buffering Agent pH of the Buffer STABILITY of pH sensitive drugs/ preservatives may get affected
of Feedback Within Acidic/
Control system Basic Range
>> CHEMICAL STABILITY may get compromised 3 3 3 27
>> SAFETY of patient may get compromised
MICROBIAL LOAD may get increased during transportation, storage & in-use
Concentration of Less than
Anti-Microbial
Anti-Microbial optimum
>> MICROBIOLOGICAL STABILITY may get compromised 3 3 4 36
>> SAFETY of patient may get compromised
LEVEL OF OXIDIZED IMPURITIES of the product may get increased during
Concentration of Less than transportation, storage & routine use
Anti-Oxidant
Anti-Oxidant optimum >> CHEMICAL STABILITY may get compromised 4 4 3 36
Implementatn of >> SAFETY of the patient may get compromised
Sweetener/ Concentration of
Control Flavoring agent Sweetener/ Flavor
Not optimum
Product TASTE may not be palatable & agree able
>> Patient COMPLIANCE may get compromised 4 4 2 32
Strategy Coloring agent
Concentration of
Not optimum
APPEARANCE of the product may not be pleasant
>> Patient ACCEPTANCE may get compromised 4 4 2 32
Coloring Agent
Definition of
CRITICAL
QTPP Inactive Ingredients’ (Excipients’) Attributes
Required to be Optimized &/Or Controlled
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Excipients’ Attributes which got RPN more than 30 were get highest priority
Implementatn of
among all the risks, they should be taken into consideration as most
Control
Strategy Critical Material Attributes of Excipients, which were required
to be optimized &/or controlled
© Created & Copyrighted by Shivang Chaudhary.
RISK RISK RISK RISK
IDENTIFICATION ANALYSIS EVALUATION ASSESSMENT
Definition of
CRITICAL
QTPP Inactive Ingredients’ (Excipients’) Attributes
Required to be Optimized &/Or Controlled
Determination of
CQAs CMAs of
EXCIPIENTS
F FLAVOR (%w/w)
Implementatn of
Control
Strategy
Determination of
Implementatn of
Control
Strategy
Definition of CRITICAL
QTPP Processing Parameters
Required to be Optimized &/Or Controlled
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Process Parameters which got RPN more than 30 were get highest priority
Implementatn of
among all the risks, they should be taken into consideration as most
Control
Strategy Critical Process Parameters , which were required
to be optimized &/or controlled
© Created & Copyrighted by Shivang Chaudhary.
RISK RISK RISK RISK
IDENTIFICATION ANALYSIS EVALUATION ASSESSMENT
Definition of CRITICAL
QTPP Processing Parameters
Required to be Optimized &/Or Controlled
Determination of CPPs of
CQAs CONTROLLED SOLUBILIZATION
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT A %SURFACTANT
&Development
of Feedback %HYDROCOLLOID
Control system B
C MIXING TIME
Implementatn of
Control
Strategy
QTPP
Determination of
CQAs
4
How to evaluate & optimize risks by
Quality Risk
Assessment of
CMAs &
CPPs
Designing of Experiments?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy
Definition of
QTPP
CQAs
A Systematic Series of Experiments,
• In which purposeful changes are made to input factors to identify
Quality Risk causes for significant changes in the output responses &
Assessment of
CMAs & • Determining the relationship between factors & responses to
CPPs evaluate all the potential factors simultaneously, systematically and
speedily;
• With complete understanding of the process to assist in better
DoE
& Development
of Design Space
product development & subsequent process scale-up With
pretending the finished product quality & performance.
Design Space
PAT
&Development
of Feedback
The Multidimensional Combination & Interaction of
Control system
• Critical Material Attributes and
• Critical Process Parameters
Implementatn of
that have been demonstrated to provide assurance of quality.
Control
Strategy Note: Working within the design space is not considered as a change.
Movement out of the design space is considered to be a change
Quality Risk
Assessment of
CMAs &
CPPs C STIRRING TIME
B HYDROCOLLOID
DoE A SURFACTANT
& Development
of Design Space
RISKS
PAT
&Development
of Feedback INADEQUATE VISCOSITY INADEQUATE ZETA POTENTIAL HIGH RATE OF SEDIMENTATION
Control system
Determination of
NO. OF LEVELS 3
Quality Risk
EXPERIMENTAL DESIGN SELECTED
Assessment of
“High”
CMAs & BOX BEHNKEN DESIGN
CPPs
STIRRING TIME
& Development
of Design Space (NO OF TRIALS) =15
“Low”
A SURFACTANT
PAT
&Development
of Feedback
Control system 3 NO. OF LEVELS
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
PREDICTION EFFECT EQUATION OF INDIVIDUAL RESPONSE BY QUADRATIC MODEL
Sedimentation Volume Ratio = Zeta potential=
+0.030-0.024A-0.089B-0.020C -44.67+12.00A+5.62B+0.38C-2.25 AB-0.25AC+1.00BC
+0.010AB+2.500E-003AC+2.500E-003BC+0.067A2+0.11B2+0.030C2 -6.92A2-2.67B2-1.17C2
Implementatn of
Control Viscosity = Content Uniformity=
Strategy +44.67+3.25A+8.38B+1.13C +1.73-0.20A-0.50B-0.15C
+0.000AB+0.050AC+0.000BC+0.41A2+0.76B2+0.26C2
-0.75AB-0.25AC+0.000BC-1.08A2-3.83B2+0.17C2
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Optimization of
Determination of Sweetener Flavor & Color
CQAs Ratio in liquid oral mixtures
Quality Risk
Assessment of
CMAs &
CPPs
3 COLORANT
DoE
& Development 2 FLAVOR
of Design Space
1 SWEETENER
PAT RISK
&Development
of Feedback
Control system
UNACCEPTABLE TASTE OF LIQUID ORAL MIXTURE
PATIENT ACCEPTANCE
Implementatn of COMPROMISED
Control
Strategy
SWEETENER
Quality Risk liquid orals; ultimate response to be measured was
Assessment of
CMAs & Patient Acceptability Score which was a function of
CPPs proportion of all 3 components in combination
• All 3 factors were components of a mixture, their
operating ranges were not same but their total
must be 2.0 %w/w of formulation & there were
upper bound constraints on the component
DoE
& Development proportions in the formulation mixture
of Design Space
• Thus, Constrained Mixture Design is selected, in
opposite to Simplex Mixture, as a special class of
RSM for optimization of proportions especially
applicable when there are upper or lower bound
PAT constraints on the component proportions.
&Development
of Feedback
Control system TOTAL NO OF EXP RUNS (TRIALS) 16
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Optimization of
Determination of
Preservative system for
CQAs In use Stability of Multidose Liquid Orals
Quality Risk
Assessment of
CMAs & C BUFFERING AGENT
CPPs
B ANTIOXIDANT
DoE A ANTIMICROBIAL
& Development
of Design Space
PAT RISKS
&Development
of Feedback
Control system
INADEQUATE ANTIMICROBIAL CONC. INADEQUATE ANTIOXIDANT CONC
CQAs
NO. OF FACTORS 3
NO. OF LEVELS 2
Quality Risk
Assessment of EXPERIMENTAL DESIGN SELECTED
CMAs &
CPPs 23 FULL FACTORIAL DESIGN WITH
BUFFERING AGENT
= 11
(NO OF TRIALS)
PAT
&Development A ANTIMICROBIAL
of Feedback
Control system
CMAs CQAs
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
REDUCTION in Microbial Load after 14 days =+99.42 +0.35A +0.075B +0.15C -0.050AB -0.075AC +0.025ABC
Implementatn of
Control OXIDIZED Impurities after 14 days=+0.46 -0.035A -0.18B -0.052C +7.50E-003AB +5.00E-003AC + 0.010BC -2.50E-003ABC
Strategy
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
QTPP
Determination of
CQAs
How to Identify & Optimize CMAs & CPPs of
Primary Packaging Process by Stability Studies?
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy
Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN
Determination of
LIQUID ORAL PACKAGING PROCESS
CQAs FOR LIQUID ORAL SOLUTION DOSAGE FORM DEVELOPMENT AS PER QbD
C CAP
Quality Risk
Assessment of B CAP LINER
LINER SEALING & CAPPING F
CMAs &
CPPs
POST-GASSING E
BOTTLE FILLING D
DoE
& Development A BOTTLE
of Design Space
RISKS
Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN (Contd)
Available Options of Primary Packaging Material
CQAs
Al CAP Al CAP Al CAP
Quality Risk
Assessment of
CMAs & Plastic HDPE Bottle Plastic PP Bottle Plastic PET Bottle
CPPs
D Glass USP IV F Glass USP II
Al CAP Al CAP
DoE Al Cap Liner 1 mil
& Development Al Cap Liner 1 mil
of Design Space
PAT
&Development
of Feedback G Glass USP I
Control system
Al CAP
Implementatn of
Control
Strategy
Glass USP I Bottle
Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN (Contd)
Selection of Primary Packaging Material
Positive Control Test Pack (For Selection of Packaging material Negative
Tests (Plastic Plastic Plastic Glass Glass Control (Glass
HDPE) PP PET USP Type IV USP Type II USP Type I)
Determination of Barrier Properties
CQAs Oxygen Permeation High Moderate Low None None None
Water Vapor Permeation Low Very Low Very Low None None None
Resistance to Acids Fair Good Fair Fair Good Excellent
Resistance to Alkalis Good Very Good Good Very Poor Fair Excellent
Resistance to Alcohols Good Good Good Poor Excellent Excellent
Resistance to Mineral oils Fair Fair Good Fair Excellent Excellent
Quality Risk
Assessment of Resistance to Solvents Good Good Fair Poor Good Excellent
CMAs & Resistance to Heat Fair Good Fair Good Good Excellent
Resistance to Cold Excellent Fair Good Good Excellent Excellent
CPPs Resistance to Sunlight Fair Fair Fair Fair Fair Fair
Resistance to High Humidity Good Excellent Excellent Good Excellent Excellent
Processing / Storage Parameters
Colorless, Transparent, Transparent, Optically Clear, Optically Clear,
Clarity / Translucency Translucent
DoE Translucent Clear Clear Transparent Transparent
& Development Toughness / Impact Resistance Good Fair to Good Excellent Fair Fair Good
of Design Space Autoclavable / Sterilizable Yes Yes Yes Yes Yes Yes
Extractable / Leachable Low Low Moderate High Moderate Low
Weathering- Flaking –Alkalinity Low Low Moderate High Moderate Low
Breathing – Permeation – O2/CO2 High Moderate Low None None None
PAT
&Development
of Feedback
SELECTION CRITERIAS
Control system
MECHANICAL PHYSICAL CHEMICAL BIOLOGICAL ECONOMICAL
STRENGTH BARRIER COMPATABILITY SAFETY ACCEPTABLE
-Strong enough to Protection from Does not react with Extract able/ Leachable Total Cost,
Implementatn of withstand handling -heat & moisture -Product Contents Should be Unit Price acceptable
Control -should fit in -oxygen /any gas / vapor -Packing Ingredients -absent / within limits with comparable
Strategy packaging line -UV / Visible light -not impart its color odor -biological safe Advantages
-long life -microorganism taste to drug product -nontoxic
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 Positive Test Pack (For Selection of Packaging material Negative
Specification-CQAs Analysis
Tests Control for Optimized Finished Product Formulation) Control
(Acceptance Criteria)
Determination of (0 Days) (Plastic Plastic Plastic Glass Glass (Glass
CQAs HDPE) PP PET USP Type IV USP Type II USP Type I)
Weathering
Physical Description Clear, Transparent Complies Complies Complies Complies Complies Complies
Flaking
Imp A1: NMT 0.5% 0.15 0.39 0.35 0.30 0.29 0.22 0.20
Related Substance Imp B2: NMT 0.5% 0.18 0.37 0.34 0.28 0.30 0.31 0.28
Quality Risk (Impurity) / HPLC Imp C3: NMT 0.5% 0.10 0.25 0.22 0.17 0.17 0.14 0.13
Assessment of Imp D4: NMT 0.5% 0.07 0.19 0.20 0.18 0.19 0.20 0.18
CMAs & Max UNK:NMT 0.5% 0.14 0.35 0.31 0.30 0.33 0.29 0.23
CPPs Total : NMT 3.0% 0.66 1.59 1.44 1.29 1.31 1.18 1.06
Assay
95% to 105% 98.8 96.7 97.1 97.6 97.5 98.2 98.4
(API)
Assay
90% to 110% 99.7 85.6 87.6 89.5 92.1 98.4 98.9
(Antimicrobial)
DoE Assay
90% to 110% 98.6 83.4 86.5 87.3 96.1 97.6 97.8
& Development (Antioxidant)
of Design Space
pH of system 6.5-7.5 7.1 6.8 6.6 6.9 8.4 7.3 7.2
Microbial Contents Absent Absent Absent Absent Absent Absent Absent Absent
Viscosity 40-50 cps 46 cps 44 cps 44 cps 42 cps 46 cps 47 cps 45 cps
Specific Gravity 0.9-1.2 g/ml 1.1 g/ml 1.0 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml 1.1 g/ml
Extractable / Na2O, CaO,
PAT Leachable
Within Limits /
Absent Absent Absent DMT, EG K2O, BaO,
Na2O, CaO B2O3, Na2O
&Development Nontoxic-safe (<10 ppm) (<5 ppm)
of Feedback Constituents Al2O3, B2O3
Control system 1Impurity 2Impurity 3Impurity
generated due to oxidation generated due to temperature effect generated due to moisture effect 4 Impurity generated due to light exposure
Here , Drug Substance in Liquid formulation is susceptible to oxidation, hydrolysis, temperature, light, pH Change & Microbial Growth.
(A) Plastic containers possess major problems due to high permeability of gases & vapors & sorption of preservatives & flavors by packaging material itself.
(B) While Soda Lime Glass containers in damp atmosphere moisture condenses on the surface of glass container & extracts weekly bonded alkali ions. When the surface
Implementatn of becomes dry in high temperate atmosphere, white deposit of alkali carbonate is produced by reaction with CO2 from the air. If the film is allowed to remain, further
Control condensation dissolves away some of the silica with a loss of surface brilliance or clarity, known as “weathering”. This silica rich layer on the surface of the glass container fall
away & can be seen as glistering flakes in the contents. Known as “Flaking”.
Strategy Thus, with respect to (i) Physical Appearance / Clarity (ii) Assay of API & Preservatives (iii) impurities generated upon storage (iv) pH Change (iv) extractable & leachable
profiling ; Treated Sulphured Soda Lime Glass (USP Type II) with high hydrolytic resistance due to surface treatment (dealkalized by SO2) was selected as primary pack
Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN (Contd)
Accelerated Stability Study with Finalized Primary Pack : USP Type II Glass– Exhibit Batch
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy
Definition of
PDbD
QTPP PACKAGING DEVELOPMENT bY DESIGN (Contd)
Implementation of Controls for Packaging of– Commercial Batches
QTPP
Determination of
CQAs
5
How to control risks by
Quality Risk
Assessment of
CMAs &
CPPs
Process Analytical Technology?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy
Definition of
QTPP
Determination of
CQAs
PAT
&Development
of Feedback Note: Through PAT, Online Feedback Controlling System for each & individual CMAs &/or CPPs will be
Control system
developed through designing of controls by analysis at line/ on line/ in line analyser system
Implementatn of
Control
Strategy
Determination of
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
VEHICLE PREPARATION WITH CONTROLLED SOLUBILIZATION pH & VOLUME MAKE UP WITH
SWEETENER, FLAVOR & COLOR WITH HEATING & MIXING VEHICLE & STORAGE
A B C
Implementatn of
Control
Strategy CRITICAL PROCESSING STEPS
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
VEHICLE PREPARATION CONTROLLED SOLUBILIZATION pH & VOLUME MAKE & STORAGE
of Feedback
Control system Bulk Uniformity by At line Bulk Uniformity by At line Precipitation analyzed by
UV-VISIBLE/ IR,-RAMAN UV-VISIBLE/ IR,-RAMAN At Line Malvern PSA or
HPLC/ GC Spectroscopy HPLC/ GC Spectroscopy Online SVR/ SHR/ DF
Risk Analysis of CMAs & CPPs with respect to CQAs at Raw Scale Developmental level
Implementatn of
by ON LINE / AT LINE Analyzers for Prediction of Real Time Data &
Control Designing of Control Strategies at Commercial Scale
Strategy
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
VEHICLE PREPARATION CONTROLLED SOLUBILIZATION pH & VOLUME MAKE & STORAGE
of Feedback
Control system Bulk Uniformity by In line Bruker Bulk Uniformity by In line Bruker Precipitation analyzed by
FT-NIR Spectroscopy for FT-NIR Spectroscopy for In Line Lasentec FBRM or
homogenized state of solution homogenized state of solution Particle Video Monitoring
CQAs
Quality Risk
Assessment of
CMAs &
CPPs
DoE
& Development
of Design Space
PAT
&Development
Auto controlling of Auto controlling of Auto Maintaining of
of Feedback
Control system VEHICLE PREPARATION CONTROLLED SOLUBILIZATION PHYSICAL & CHEMICAL STABILITY
Bulk Uniformity by adjusting Bulk Uniformity by adjusting By adjusting
Heating Temperature Heating Temperature Stirring Speed
Heating Time Heating Time Stirring Time
Mixing Speed Mixing Speed Storage Temperature
Mixing Time Mixing Time Dissolved & Headspace Oxygen
Implementatn of
Application of Auto-controllers at real time Manufacturing scale
Control For Continuously attaining Acceptable ranges of CMAs & CPPs
Strategy with respect to desired CQAs
QTPP
Determination of
CQAs
6
How to
Quality Risk
Assessment of
CMAs &
CPPs
Implement Controls
for Commercial Manufacturing?
DoE
& Development
of Design Space
PAT
&Development
of Feedback
Control system
Implementatn of
Control
Strategy
Definition of
QTPP
Determination of
CQAs
Control Strategy
Quality Risk
Assessment of
A planned set of controls for CMAs & CPPs-
CMAs & derived from current product and process understanding
CPPs
• During Lab Scale Developmental Stage
• Scaled Up Exhibit-Submission Stage
DoE that ensures process performance and product quality
& Development
of Design Space
• During Commercial Stage
PAT
&Development Note: For finalizing & implementation of Control Strategy for each & individual CMAs &/or CPPs; ranges
of Feedback
Control system studied at lab scale developmental stage will be compared with pilot plant scale up & pivotal
scale exhibit batches to ensure consistent quality of finished product
Implementatn of
Control
Strategy
CQAs Polymorphic
To ensure batch to batch
2Ө values x, y, z x, y, z x, y, z consistency in
Form
Dissolution
To ensure consistence
Determination of Vehicle/ Solvent Heating Temperature 60-80°C 63-77°C 65-75°C
compatibility,
CQAs Preparation
acceptability, purity &
with Sweetener,
Microbial Stability
Flavor, Color
Mixing Time 30-60 min 35-55 min 45 min
Quality Risk
Assessment of Controlled Heating Temperature 60-80°C 63-77°C 65-75°C To ensure batch to batch
CMAs & Solubilization by consistency in Solubility,
Surfactant & Pour ability, Physical
CPPs hydrocolloids Mixing Time 30-60 min 37-53 min 40-45 min Stability & Compatibility
pH Adjustment
with Buffer Heating Temperature 60-80°C 63-77°C 65-75°C To ensure batch to batch
DoE &Final Volume consistency Chemical &
& Development
of Design Space make up Microbiological stability
with vehicle
Mixing Time 30-60 min 37-53 min 40-45 min
& final Mixing
2.0
0.50
0.045 0.050
100
5.0
100
5.0
100
0.45
1.9
4.5
4.5
Determination of
90
90
90
CQAs
0.040
0.40
1.8
4.0
4.0
80
80
80
75˚C
0.035
1.7
0.35
3.5
70
70
3.5
70
Quality Risk
Assessment of
CMAs & 65˚C
0.30
0.025 0.030
1.6
3.0
60
60
3.0
CPPs
60
0.25
1.5
2.5
50
50
2.5
50
45 min
DoE
0.020
0.20
1.4
2.0
40
40
2.0
40
& Development
of Design Space 35% 40 min
0.15% 1.5% 1.30 %
0.015
0.015%
0.15
1.3
1.5
30
1.5
30
30
30%
1.0%
0.01
PAT
1.2
0.10
1.0
0.012%
1.0
20
20
20
&Development 0.10% 1.0%
of Feedback 0.8% 1.15 %
0.000 0.005
Control system
0.05
1.1
0.5
0. 5
10
10
10
0.00
0.0
0
1
0
0
0
Implementatn of
Control Surfactant Hydrocolloid Anti Anti Buffer Sweetener Controlled Controlled
Strategy Microbial Oxidant Solubilization
Temperature
Solubilization
Stirring Time
150
150
150
150
2.0
1.5
10
1.5
1.4 g/mL
140
140
140
140
1.8
9
Determination of
1.4
1.4
CQAs
130
130
130
130
1.6
1.3
8
1.3
7.5
1.2 cP
120
120
120
120
7
1.4
1.2
1.2
Quality Risk 1.2 g/mL
Assessment of
CMAs & 110% 110% 110% 110% 6.5
110
110
110
110
1.2
1.1
6
CPPs
1.1
1%
100
100
100
100
1.0
1.0
1.0
5
1.0 cP
DoE
0.9
90
90
0.8
90
90
0.9
& Development 90% 90%
of Design Space 90% 90%
0.8
0.8
0.6
80
80
80
80
0.7
0.7
PAT
70
70
70
70
0.4
2
&Development
of Feedback
Control system
0.6
0.2
60
60
0.6
60
60
0.5
50
50
50
50
0.5
0
Implementatn of 0%
Control API Assay Total Weight Anti Anti pH Viscosity Density / Sp.
Management of
Product
Life
Cycle
© Created & Copyrighted by Shivang Chaudhary.
What is Continual Improvement?
During Routine
Commercial Manufacturing Continual
Risk Review & Risk Communication
between Stockholders of:
FORMULATION
R&D
QUALITY ANALYTICAL
CONTROL R&D
QUALITY REGULATORY
ASSUARANCE AFFAIRS
MANUFACTURING
PLANT
For continual assurance that the process remains in a state of control
(the validated state) during commercial manufacture.
For Excellent Product
Management of
Lifecycle Management
Product Throughout the product lifecycle, the manufacturing process performance will be monitored to ensure that
Life it is working as anticipated to deliver the product with desired quality attributes. Process stability and process capability
will be evaluated. If any unexpected process variability is detected, appropriate actions will be taken
Cycle to correct, anticipate, and prevent future problems so that the process remains in control.
© Created & Copyrighted by Shivang Chaudhary.
“Continual Trend Analysis” in Process Control Charts
Assessment of Common (Chance) Cause Vs. Special (Assignable) Cause
Common Causes
8 Consecutive Points or 10 out of 11 points or 12 out of 14 points
Central Line or 14 out of 17 points or 16 out of 20 points fall on same Side of Control Line
0 0
0 1 8 Consecutive Points or2 10 out of 11 points or 12
3 out of 14 points or 14 4
out of 17 points or 16 out5 of 20 points 6
fall on same Side of Control Line
-1 -1σ Limit
4 Out of the 5 Consecutive Points below -1 Sigma & above -2 sigma
-2 -2σ Limit
2 Out of the 3 Consecutive Points below -2 Sigma & above -3 sigma
-3 -3σ Limit
Lower Control Limit Any Point below -3 Sigma
Assignable Cause
-4
Sample Number
Management of
Product Other Trend Rules: 6 consecutive points in a row trending up OR down (same side)
Life 14 consecutive points in a row alternating up & down (same side)
Cycle 8 consecutive points in a row more than 1σ from center line (either side)
15 consecutive points in a row within 1σ of center line (either side)
© Created & Copyrighted by Shivang Chaudhary.
Process Variations
Common (Chance) Cause Vs. Special (Assignable) Cause
Management of
Product
Life
Cycle
© Created & Copyrighted by Shivang Chaudhary.
Conclusion
Through QbD, Risk associated with each & every CMAs & CPPs
with respect to CQAs identified from QTPP were effectively & extensively assessed
out by FMEA (Failure Mode Effective Analysis), which decided “which risk should get
first priority?” based upon Severity * Probability * Detectability of individual risk.
which generated safe & optimized ranges of which ensured timely measurement of critical
CMAs & CPPs with respect to desired CQAs par quality and performance attributes of raw and
overlaid DESIGN SPACE, where all the desired in-process materials or parameters
in process & finished product CQAs are to control the quality
met simultaneously. of finished product.
Justification for
Risk
Reduction
BEFORE
Detectability of content
Justification for uniformity was increased by
Risk implementing in line FT-NIR
Reduction during mixing stage
© Created & Copyrighted by Shivang Chaudhary.
Conclusion
BEFORE
Probabilities of POOR
WETTING of API was reduced
by optimizing ranges of
Surfactant via DoE generated
Design Space (DS)
Probabilities of increased
Sedimentation was reduced by
optimizing ranges of
Hydrocolloid via DoE generated
Design Space (DS)
Probability of Microbial
Spoilage upon storage was
reduced by optimizing ranges
of Anti-microbial via DoE / DS
Justification for
Risk Probability of Oxidation
upon storage was reduced by
Reduction
optimizing ranges of Anti-
Oxidant via DoE / DS
BEFORE
Detectability of Solvent/
Vehicle Purity was increased
by utilizing inline FT-NIR PAT
Detectability of Content
Uniformity was increased by
utilizing inline FT-NIR PAT
Detectability of pH was
increased by inline pH Meter
Detectability of Desired
Particle Size Distribution was
increased by utilizing FBRM/
PVM Sensors as PAT Tool
Justification for
Risk Detectability of online
dissolved / headspace O2 & pH
Reduction
during filling & packaging was
increased by utilizing in line
DO meter & pH meter as PAT
© Created & Copyrighted by Shivang Chaudhary.
“Quality doesn’t cost, it always pays”