QbD in Drug DevelopmentCase Study on Roller CompactionMauro Serratoni, PhDDrug Product Project Leader – TRD PHAD OralApplicazione del Quality by Design (QbD) nella fabbricazione dei medicinaliMilan, May 06, 2019
TRD – PHAD OralRoller Compaction Focus Group
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20th July 1969QTPP
CQAs
Risk Assessments
Control Strategy
Continual Improvement
Moon Landing
Take Off, Moon landing, return to Earth
Mission Control “Houston”
Apollo Program
Simulation program, FMEA &
Fishbone
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1961 The Thalidomide scandal prompted an increase in the regulation and testing of drugs before licensing, with a new amendment to FDA rules demanding proof of efficacy and accurate disclosure of side-effects for new medications 1964 Declaration of Helsinki put greater ethical strictures on clinical research.
...and Pharma Industry...
Joseph Moses Juran
Quality Control Handbook in 1951He was an evangelist for quality and quality management started to share and teach his vision of quality in Japan since 1954.He created the QbD as a term in the 1970s and popularized it in the 1990s with several publications
1963
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• In 2002, FDA made the first steps to integrate the QbD concept into cGMPs
• In 2004 FDA released its final report on ‘Pharmaceutical cGMPs for the 21st
Century: A Risk Based Approach’ guideline
• 2004-2009 ICH’s Q8(R2) Pharmaceutical Development’, ‘Q9 Quality Risk
Management’ and ‘Q10 Pharmaceutical Quality System Guidelines’ were released
ONLY IN 21st Century QbD PRINCIPLES HAVE BEEN IMPLEMENTED IN PHARMA INDUSTRY
in the meantime...
TRD-PHAD
Agenda
• Introduction of QbD– QTPP– CQA
•Case Study on Roller Compaction– Risk Assessment & FMEA– Results– Updated Risk Assessment & Updated FMEA
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QTPP
CQAs
Risk Assessments
Control Strategy
Continual Improvement
• Describes the design criteria for the DP to ensure quality, safety and efficacy
• Is the base for development and for definition of CQAs / CPPs and CMAs
• A critical quality attribute (CQA) has been defined as “a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality
• implement a control strategy to assure the DP robustness and reproducibility and therefore the quality, efficacy and safety
• Manage the DP lifecycle in the light of a continuous process improvement with the main aim to de-risk the process
Design Space
• The multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change
• Link raw material attributes (CMAs) and process parameters (CPPs) to CQAs and perform risk assessment
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By beginning with the end in mind:
THE RESULTS OF DEVELOPMENT IS A ROBUSTFORMULATION AND MANUFACTURING PROCESS WITHACCEPTABLE CONTROL STRATEGY ABLE TO:• ENSURE THE PERFORMACE OF THE DRUG PRODUCT,
• MATCH THE ESTABLISHED ACCEPTANCE CRITERIA,
• ENSURE QUALITY, SAFETY AND EFFICACY.
QUALITY BY DESIGN
YOU HAVE TO BUILD QUALITY... NOT TO CONTROL!
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Final Market FormulaFeasibility
Technology / Formulation Feasibility
Scale UpTransfer at launch commercial site
Lab Phase Process
Optimization/DoE
ValidationPrior Submission or before launch
Pilot PhaseProcess Optimization/DoE
Phase I/POC Phase IIa Phase IIb Phase III Registration / Ph IV
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Example of QbD approach in DP development
Prototype Early Phase
QbD-A: Preliminary Risk Assessment to start Pilot Phase mainly focused on CMAs (DS/Excipients) and on potential CPPs, based on knowledge of selected technology and lab scale experiments
QbD-B: Updated Risk Assessment based on Lab/Pilot scale DoE findings; confirmed CMAs and CPPs;Risk assessment to scale up / transfer and preliminary PARs or Design Space
QbD-C: Updated Risk Assessment based on scale up / transfer findings:PARs / NORs / Design Space and Control Strategyfor Validation
QbD-D: Final Risk Assessment based on Validation outcomes, Final PARs / NORs / Design Space and Control Strategy for Commercial
QbD as alive source document for submission
QTPP/CQAInitial
definition
PROCESS DESIGN PROCESS QUALIFICATION
CONTINUED PROCESS
VERIFICATIONClinical Prototype
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Example of QTPP
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QTTP Elements QTTP targetsPotential link to CQAs of DS/DP and Justification
Indication Oncology, treatment of XXXX syndrome
Film coated tablets selected as dosage form were used in the pivotal trials. Link to product efficacy and safety related quality attribute
Route of administration Oral
As an oral form, pharmaceutical equivalence of the clinical and commercial forms is required.
Mechanism Inhibitor of ABC .....
Clinical requirements/Dosing scheme
2 mg (starting dose) to 30 mg twice daily (b.i.d.), to be titrated individually. Dose may be down titrated to 1 mg every other day or 1 mg once daily (q.d.) or 1 mg b.i.d.
ABC therapeutic doses are 1 mg to 30 mg BID, to be titrated individually.
DP Dosage form Film-coated tabletsSmall, round, oral dosage form selected to improve patient acceptance and compliance.
Dosage Strengths /strength / shape
Xmg, coated tablet round, biconvex with beveled edgeDiameter: approx. 6.1mm, Pharmaceutical equivalence requirement.
Appearance
film coated tablet round, biconvex with beveled edgeColor: yellow, imprint “XX” on one side “YY” on the other side
Must meet the same compendia or other applicable (quality) standards
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QTTP Elements QTTP targetsPotential link to CQAs of DS/DP and Justification
Packaging strategy
Worldwide Alu-Alu blister, Special need (blister pack with clear labelling - not only for tracking compliance, but also for patient to understand and take the correct dose –because of potential cognitive impairment and mood disorder (depression).
Proper container closure system for acceptable shelf life and tablet integrity.
Chemical attributes Identification, assay, CU, degradation products, water content
Must meet the same compendia or other applicable (quality) standards.
Microbial attributes Microbial limits Must meet the same compendia or other applicable (quality) standards.
Drug product storage conditions
Do not store above 30°C, protect from moisture
36 months shelf life based 24 months 25°C/60RH and 30°C/75RH results for all strengths in Alu-Alu Blister (commercial packaging) and HDPE 90/40 with desiccant (clinical packaging).
Exposure/holding time bulk/intermediate
Final Blend, Core Tablets: 4 weeks (30 days in commercial containers)For bulk FCT 12 months shelf life “do not store above 30⁰C” in aluminum bag in metal drum.
hold time data as per related stability report
Transport conditions TEMPCONTROL Based on stability reports
Drug release profile Immediate release not less than 80% Q in 15 minutes
Matches with ABC FCT formulationsalready developed and administered during clinical studies. ABC is BCS class I, drug product dissolution is rapid, low risk to impact on pharmacokinetic.
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Drug product quality attribute Target CQA Justification (link to QTTP)
Appearance: color/shape/score
film coated tablet round, biconvex with beveled edgeColor: yellow, imprint “XX” on one side “YY” on the other side
No
Color and Shape are not directly linked to safety and efficacy. The target is set to ensure patient acceptability and compliance. “Aspect” will be the CQA that will cover the “color and shape” in the risk analysis.
Aspect No critical visual film coated tablet defects observed Yes
Aspect is not directly linked to safety and efficacy. The target is set to ensure patient acceptability and minimize customer complaints.
Disintegration time FCT ≤15 minutes No
Disintegration time is critical for drug release and bioavailability. The disintegration time will be monitored throughout product and process development. Nevertheless, “Dissolution Rate” will be the CQA that will cover the “Disintegration Time” in the risk analysis as well as disintegration time is influencing the dissolution rate.
Identification by HPLC
Corresponds to Reference. The difference in ABC retention time in the test solution must not exceed 2.0% of the reference solution
No
Identification is critical for safety and efficacy, this CQA can be effectively controlled by the quality management system and will be monitored at the drug product release. Formulation and process variable do not impact identity. Therefore, this CQA will not be discussed during risk assessment.
CQAs Definition
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Drug product quality attribute Target CQA Justification (link to QTTP)
Assay by HPLC 95.0% – 105.0% label claim Yes
Variability in assay will affect safety and efficacy. Process variables may affect the assay of the drug product. Thus, assay will be evaluated throughout product and process development.
Content uniformity
Meets the requirement of the Ph. EP, USP and JP harmonized procedure.
Yes
Content Uniformity (CU) testing is an important assessment of unit dosage form performance Specifications are set according to requirements from EP, USP and JP harmonized procedures. Variability in content uniformity will affect safety and efficacy. Formulation and process variables impact content uniformity, so this CQA will be evaluated throughout product and process development.
Degradation products by HPLC
Any unspecified ≤ 0.2%Total degradation products ≤ 1.5%Identified degradation productsDeg-1 ≤ 0.6%Deg-2 ≤ 0.4%Deg-3 ≤ 0.2%
Yes The limit of degradation products is critical to drug product effectiveness and safety.
CQAs Definition
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Drug product quality attribute Target CQA Justification (link to QTTP)
Water content Not more than 5.0% (for release)Not more than 7.0%(for stability) No
Water content plays a role in the degradation of ABC under conditions of elevated temperature. Degradation during stability depends upon water content at release, temperature, humidity and exposure duration.. Nevertheless, “Degradation product” will be the CQA that will cover the “Water content” in the risk analysis as soon as water content is influencing the degradation rate of the DS.
Drug release dissolution by HPLC
Not less than 80% (Q in 15 minutes) of the declared content according to acceptance table 1 of harmonized Ph.Eur., USP and JP (Release: levels 1 and 2 only; Stability: levels 1, 2 and 3)
Yes
The drug release profile is critical for bioavailability (BA). This target is valid for all ABC FCT strengths.Being a BCS class I compound, overall bioavailability is, however, not considered to be limited by dissolution.
Microbial limits
Meets relevant pharmacopoeia criteriaTotal aerobic microbial count (TAMC): ≤ 103 cfu/gTotal combined yeasts and molds count (TYMC): ≤ 102 cfu/gSpecific microorganisms: Absence of Escherichia Coli in 1g
No
Non-compliance with microbial limits will impact patient safety. However, as long as raw materials comply with compendial microbial requirements, the formulation and process variables are unlikely to impact this CQA. Then, this CQA will not be discussed during formulation and process development risk assessment.
CQAs Definition
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CASE STUDY ON ROLLER COMPACTION
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Dry granulation:• densification• improvement of flowability• avoiding segregation• improvement of the homogeneity of DS
• Cost effective• Ability to process material sensitive to
heat/moisture
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Dry granulation is not a rocket science...
QTPP
CQAsCMAsCPPs
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Dry granulation is not a rocket science, but...
Roll Compaction MillingScreening
RibbonsPorosity,
Tensile Strength
Feed rateCompaction Force
Roll speedGap size
Humidity
DS
Lubricant level
Excipients
Pre-Blend BU
Milling speed Screen sizeScreen type
DissolutionBU/CUWeight RSD%
FriabilityHardness
Disintegration
Granulate physical attributes
(PSD/density)Equipment
Yield
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FISHBONE Roller Compaction
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Product CQAsA - AspectB - Assay
C - Degradation / StabilityD - BU / CU
E - Dissolution Rate
1.1 Room temperature 1.2 Room relative Humidity
5.1 Operator
3.1 Roller Compaction Force / Pressure3.2 Gap size 3.3 Roll Speed 3.4 Feeder Speed 3.5 Feed hopper agitator speed3.6 Fines recycled (yes / no)3.7 Dearation (yes / no)
4.1 Equipment Type (Roller – screw feeder orientation - In-line screening)4.2 Roller compactor diameter 4.3 Roller type / surface design (smooth, knurled)4.4 Roll gap width (flexible or fixed)
2.1 Premix physical attributes (PSD, Ratio DS/Excipient, Excipients grade/supplier, LOD, bulk/tapped density)2.2 Premix holding time
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For the variables which demonstrated a critical impact on end product quality (specifically either an impact score higher or equal to eight (8) or a residual risk resulting in RPN values above 71), a follow-up action must have been defined
RPN value Description Corrective actions0 - 70 tolerable No corrective action is required but may be still installed, if defined
and feasible
71 – 299ALARP range"as low as reasonably practicable”
Corrective actions should be defined, if any are possible. If no corrective actions are possible in this range the remaining risk needs to be justified.
300 – 1000 intolerable
Corrective actions have to be defined to bring the RPN down to at least the ALARP range. If no corrective actions are possible or the RPN remains in this region, a control strategy must be in place to mitigate the residual risk
Risk assessmentFMEA evaluate the potential deviations or failure modes of the parameter from its set point orknown range and evaluated the impact, detectability and probability of occurrence of this deviation.A 1-10-level scale is used to rank the parameters with the following criteria:Probability (likelihood of the deviation to occur), scoring 1 (low) to 10 (high)Impact (severity of the deviation for the quality), scoring 1 (low) to 10 (high)Detectability (ability to detect the deviation during operation), scoring 1 (high) to 10 (low)
calculate the overall RPN (Risk priority number) for each variable and CQA.The lowest risk RPN is 1 (1 x 1 x 1) and for highest risk RPN is 1000 (10 x 10 x 10)
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Variable
Current value/set-point/range
Ref of
source know
ledge
Deviation of variable orparameter from its current value orpotential failure
Potential cause(s)mechanism(s) of failure or deviation and probability justification
Probability
Potential impact on output quality
Impact
Current detection mode or control mechanism3
Detectability
RPNFollow-up action/mitigation strategy responsibility
RC force
6 kN/cm tested during preliminary lab scale trials
Higher or lower rollercompactionforce
• Fail to follow manufacturing Instruction,
• Operator error• Machine failure
2
A : AspectC : Degradation/ StabilityE : Dissolution rate
101010
Information in MI,batch record,recorded andmonitored by theoperator
1202020
DoE study to investigate suitable range of RC
Rollers speed
2 rpm tested atLabScale
Higher or lower roll speed
• Fail to follow manufacturing Instruction,
• Operator error• Machine failure
2
A : AspectC : Degradation/ StabilityE: Dissolution rate
555
Information in MI,batch record,recorded andmonitored by theoperator
1101010
Roller spee fixed at lower level due to small batch size, controlled via BR, double signature on BR
Roll gap size 2.0 mm
Variationdepending onotherparameters,(feeding, rollspeed)
• Fail to follow manufacturing Instruction,
• Operator error• Machine failure
2
A : AspectC : Degradation/ StabilityE : Dissolution rate
555
Information in MI,batch record,recorded andmonitored by theoperator
1101010
Gap on Gerteis equipemnt automatically adjusted to keep constant the RC Force.
Screwfeeder speed
Adjustedto get therollerforce
Not fixed relatedto roll force andgap size
• Machine failure 2
A : AspectC : Degradation/ StabilityE: Dissolution rate
888
Recorded andmonitored by theoperator
1161616
Screw feeder automatically adjsuted to keep constant the RC Force, thus amount of powder compacted/min
Rollercompactor type
Gerteis MiniPactor
Use of differentRC (BEPEX)
• different equipment available
8
A : AspectB : AssayC : Degradation/ StabilityD : BU/CUE : Dissolution rate
1010101010
Information in MI,batch record
111
111
8080808080
Different equipment has to investugated to check the impact on mnf process
Roller Compaction - FMEA
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Variable
Current value/set-point/range
Ref of
source know
ledge
Deviation of variable orparameter from its current value orpotential failure
Potential cause(s)mechanism(s) of failure or deviation and probability justification
Probability
Potential impact on output quality
Impact
Current detection mode or control mechanism3
Detectability
RPNFollow-up action/mitigation strategy responsibility
Level ofMannitol
Not included in the current formulation
Mannitol added to composition
• Fail to follow manufacturing Instruction,
• Operator error
1
A : AspectB : AssayC : Degradation/ StabilityD : BU/CUE : Dissolution rate
1010101010
Information in MI,batch record,recorded andmonitored by theoperator
1
2020202020
DoE study to investigate suitable impact on process and DP CQA
Roller Compaction - FMEA
Outcome of FMEA:DoE/development experiments to test
• impact of different equipment on process manufacturing
• addition of brittle excipient
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DoE study based on FMEA RA
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Gerteis - Bepex
Plastic Brittle
4 kN/cm 4 kN/cm10 kN/cm 10 kN/cm
0.8 mm1.25 mm0.8 mm 1.25 mm 0.8 mm 1.25 mm
DoE: 24 full factorial design with four center points(CP: Gerteis, PB formulation, 7kN/cm, 1.0 mm)
5 compression forces at 2 dwell times
- Equipment
- Formulation
- Compaction force
- Screen
Variables:
0.8 mm 1.25 mm
- Tableting
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Formulations composition (w/w)
MicrocrystallineCellulose PH102 Mannitol
Croscarmellose Sodium
SilicaColloidal anhydrous
Magnesium Stearate
Plastic 96.25 - 3.00 0.25 0.50
Brittle 67.35 28.90 3.00 0.25 0.50PlasticBrittle 81.80 14.45 3.00 0.25 0.50
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8 Kg batch sizeBlended in 40 L bin
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Roller Compactors
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Gerteis Mini-Pactor®250/25 Bepex Hosokawa Pharmakompactor L200/30P
RC characteristic Gerteis Mini-Pactor®250/25 Bepex Hosokawa Pharmakompactor L200/30P
Roller diameter [mm] 250 200
Roller width [mm] 25 30
Roller finishing Knurled Knurled
Arrangement of roller Inclined Horizontal
Gap Adjustable Fixed at 2.0 mm
Granulator OscillatingStar or Closed type Rotor
Oscillating:Frewitt Oscillo 6
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Process parameters set on roller compactors
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Parameter Gerteis Bepex
Level -1 0 +1 -1 +1
Compaction force [kN/cm] 4.0 7.0 10.0 3.3 8.0
Compaction force [kN] 10.0 17.5 25.0 10 24
Gap [mm] 2.5 2.0
Roller speed [rpm] 2.3 3.0
Correction Factor* used for Gap and Compaction Force = 1.25𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑅𝑅𝑑𝑑𝑅𝑅𝑅𝑅(𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺)
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑅𝑅𝑑𝑑𝑅𝑅𝑅𝑅(𝐵𝐵𝐺𝐺𝐵𝐵𝐺𝐺𝐵𝐵)= 250/200 = 1.25
Roller speed:[𝐺𝐺𝐺𝐺𝐺𝐺 ∗ 𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ ∗ 𝐶𝐶𝑊𝑊𝐶𝐶𝐶𝐶𝐶𝐶𝑚𝑚𝑓𝑓𝑓𝑓𝐶𝐶𝑓𝑓𝑓𝑓𝐶𝐶𝑓𝑓 ∗ 𝐶𝐶𝐺𝐺𝑚𝑚]𝐺𝐺𝑅𝑅𝑅𝑅𝑑𝑑𝑅𝑅𝑑𝑑𝐺𝐺= [𝐺𝐺𝐺𝐺𝐺𝐺 ∗ 𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ ∗ 𝐶𝐶𝑊𝑊𝐶𝐶𝐶𝐶𝐶𝐶𝑚𝑚𝑓𝑓𝑓𝑓𝐶𝐶𝑓𝑓𝑓𝑓𝐶𝐶𝑓𝑓 ∗ 𝐶𝐶𝐺𝐺𝑚𝑚]𝐵𝐵𝑅𝑅𝐵𝐵𝑅𝑅𝐵𝐵
*“Sprockel & Stamato, Design and scale-up of dry granulation processes, 2010”
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Results: Plastic and Brittle Behavior of Tested Formulation
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Impact of DoE variables on Ribbons Porosity
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Screen size variable removed from this assessment
Results: Roller Compaction / Ribbons Porosity
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Differences observed between the two roller compactors
Results: Roller Compaction / Ribbons Porosity
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Why these differences between formulations?
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BRITTLE BRITTLE
PLASTIC PLASTIC
Results: Roller Compaction / Ribbons Porosity
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Look in to the recorded compaction forces...
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BEPEX Mean force: 3.7 ± 0.8 kN/cmPorosity: 50%
GERTEIS Mean force: 3.8 ± 0.4 kN/cmPorosity: 45%
GERTEIS Mean force: 3.9 ± 0.4 kN/cmPorosity: 46%
BEPEX Mean force: 4.3 ± 0.3 kN/cmPorosity: 42%
Results: Roller Compaction / Ribbons Porosity
TRD-PHAD
... and the loop control?
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GERTEIS GERTEIS
BEPEXBEPEX
Results: Roller Compaction / Ribbons Porosity
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How have similar porosity?Calibration curve for Bepex:porosity vs recorded compaction force
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Example for plastic formulation: • Set force on Gerteis at 4 kN/cm provided a porosity of 45%• Force recorded on Bepex: 3.3 kN/cm (10kN), porosity obtained: 50%• Force to be set on Bepex according to calibration curve: 4 kN/cm (12 kN)
Results: Roller Compaction / Ribbons Porosity
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Example to fine tune the correction factor
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Target Porosity [%] Compaction force on Gerteis [kN/cm]
Compaction forceon Bepex [kN/cm]
Correction factor
45 4 4 129 10 7.7 1.3
Results: Roller Compaction / Ribbons Porosity
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑅𝑅𝑑𝑑𝑅𝑅𝑅𝑅(𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺)
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑅𝑅𝑑𝑑𝑅𝑅𝑅𝑅(𝐵𝐵𝐺𝐺𝐵𝐵𝐺𝐺𝐵𝐵)= 1.25
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Particle size distribution
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No differences for 0.8 mm screen
Results: Screening
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More visible differences using 1.25 mm screen
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Results: Screening
Particle size distribution
Different trend
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Why this different trend?
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During RC on Bepex, part of the powder passed through therollers without being compacted
Results: Screening
TRD-PHAD
• The differences in geometry and working process between the equipment could have an impact on the particle size of the granules produced
• Screen with smaller mesh opening could potentially flat the PSD differences
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Results: Screening
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Results: Tableting
Tabletability profiles
Plastic powder
Brittle powder
RC brittle formulations, low compaction force
RC plastic formulations, high compaction force
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Impact of DoE variables on tablets tensile strength
Results: Tableting
Mannitol behavior: Souihi et al., Design Space Estimation of the Roller Compaction Process, I&EC Research, 2013
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Results: Tableting
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Tabletability profiles of brittle formulations
Different PSD
Different ribbons porosity
Input:same
formulationand screen (1.25mm)
Comparable TS
Results: Tableting
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Tabletability profiles of plastic formulations
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Results: Tableting
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... But looking at ribbons porosity
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Results: Tableting
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Equipment
Plastic formulationScreen opening [mm]
Brittle formulationCompaction Force[kN/cm] Porosity [%]
TensileStrength [MPa]
Compaction Force [kN/cm]
Porosity [%]
TensileStrength [MPa]
Gerteis 4 45 2.13 1.25 4 44 2.75
4 46 2.57 0.80 4 43 3.29
10 28 1.09 1.25 10 31 2.21
10 30 1.13 0.80 10 31 2.05
Bepex 3.3 50 2.47 1.25 4.6 41 2.87
4.3 42 2.00 0.80 4.6 40 3.04
7.9 28 1.09 1.25 7.9 29 2.21
7.7 29 1.00 0.80 7.9 29 2.22
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Results Summary
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Equipment
Plastic formulationScreen opening [mm]
Brittle formulationCompaction Force[kN/cm] Porosity [%]
TensileStrength [MPa]
Compaction Force [kN/cm]
Porosity [%]
TensileStrength [MPa]
Gerteis 4 45 2.13 1.25 4 44 2.75
4 46 2.57 0.80 4 43 3.29
10 28 1.09 1.25 10 31 2.21
10 30 1.13 0.80 10 31 2.05
Bepex 3.3 50 2.47 1.25 4.6 41 2.87
4.3 42 2.00 0.80 4.6 40 3.04
7.9 28 1.09 1.25 7.9 29 2.21
7.7 29 1.00 0.80 7.9 29 2.22
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RC loop control able to keep the set compaction forceRC process parameters used able to produce comparable ribbons comparable TS
Results Summary
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Equipment
Plastic formulationScreen opening [mm]
Brittle formulationCompaction Force[kN/cm]
Porosity [%]
TensileStrength [MPa]
Compaction Force[kN/cm]
Porosity [%]
TensileStrength [MPa]
Gerteis 4 45 2.13 1.25 4 44 2.75
4 46 2.57 0.80 4 43 3.29
10 28 1.09 1.25 10 31 2.21
10 30 1.13 0.80 10 31 2.05
Bepex 3.3 50 2.47 1.25 4.6 41 2.87
4.3 42 2.00 0.80 4.6 40 3.04
7.9 28 1.09 1.25 7.9 29 2.21
7.7 29 1.00 0.80 7.9 29 2.22
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RC loop control not able to keep the set compaction forceDifferences in ribbons porosity and in TS, mitigated when brittle material used
Results Summary
TRD-PHAD
• Ribbon Porosity has to be properly investigated and, in roll compaction, Ribbon Porosity is one of the main driver able to impact/jeopardize the further manufacturing steps.
• When differences in porosity are observed due to different equipment/process, introduction of Brittle materials could mitigate these differences at level of granules quality and tabletability behaviour
• Carefully investigate compressibility/compactibility/tabletability behaviour of your formulation at different levels (pre-blend / granulate/ final blend) to properly select the excipients to be used
• Milling/Screening step, if properly set, can help to provide comparable granules when differences during roll compaction have been highlighted
Business Use Only47
TRD-PHAD
• When different roller compactors are foreseen to be used, compaction profile is recommended in order to calibrate/find out correction factor for setting key process parameters on different equipment with the main aim to prepare ribbons having similar porosity.
• Even if there is control in place to maintain the set force, you have to monitor what actually happens during the runs to figure out the reasons of different achievements and therefore to properly react in terms of formulation and/or roll compaction parameters.
• When you run a DoE, don’t stop your results evaluation at level of PARETO... there is a world to be discovered behind...
Business Use Only48
TRD-PHAD
Variable
Current value/set-point/range
Ref of
source know
ledge
Deviation of variable orparameter from its current value orpotential failure
Potential cause(s)mechanism(s) of failure or deviation and probability justification
Probability
Potential impact on output quality
Impact
Current detection mode or control mechanism3
Detectability
RPNFollow-up action/mitigation strategy responsibility
RC force
4-10 kN/cm testedSet point 6kN/cm
Higher or lower rollercompactionforce
• Fail to follow manufacturing Instruction,
• Operator error• Machine failure
2
A : AspectC : Degradation/ StabilityE : Dissolution rate
888
Information in MI,batch record,recorded andmonitored by theoperator
1161616
Higher roller compaction force decreases the tabletability behavior of final blend with the risk to fail the tablet core physical IPCs (hardness, aspect, friability). For further development range of 4-8 kN/cm will be used
Screwfeeder speed
Adjustedto get therollerForce
G Not fixed relatedto roll force andgap size
• Machine failure
2 A : AspectC : Degradation/ StabilityE: Dissolution rate
666
Automatically controlled by machine.Recorded andmonitored by theOperator
1121212
Screw feeder automatically adjsuted to keep constant the RC Force, thus amount of powder compacted/min
B 9888
1727272
CPP for Bepex, to be constanly monitored and further investigated
Rollercompactor type
Gerteis MiniPactorBepex
Use of differentRC
• different equipment available
8
A : AspectB : AssayC : Degradation/ StabilityD : BU/CUE : Dissolution rate
99999
Information in MI,batch record
111
111
7272727272
When bepex used risk to fail DP acceptance criteria is high due to poor loop control in place, risk can be potentially mitigated by different formulation and/or equipment setting
Roller Compaction – Updated FMEA
TRD-PHADBusiness Use Only50
Variable
Current value/set-point/range
Ref of
source know
ledge
Deviation of variable orparameter from its current value orpotential failure
Potential cause(s)mechanism(s) of failure or deviation and probability justification
Probability
Potential impact on output quality
Impact
Current detection mode or control mechanism3
Detectability
RPNFollow-up action/mitigation strategy responsibility
Level ofMannitol
28.9% Mannitol added to composition
• Fail to follow manufacturing Instruction,
• Operator error
1
A : AspectB : AssayC : Degradation/ StabilityD : BU/CUE : Dissolution rate
88888
Information in MI,batch record,recorded andmonitored by theoperator
1
99999
DoE study provide evidence that Mannitol can flat difference in terms of Ribbons porosity obtained when differentequipment are used. Level of this excipients has to be further invetsigated/optimized
Outcome of updated FMEA:
• Roller Compaction F is CQAs to be monitored• Impact of RC used to be further investigated and
calibrated• Level of brittle excipient to be defined
Roller Compaction – Updated FMEA
TRD-PHADBusiness Use Only51
Thanks to
TRD PHAD Oral Roller Compaction Focus Group
Milos Salodini who performed the DoE study
TRD-PHADBusiness Use Only52
TRD-PHAD
x90 data
Business Use Only53
Results: Screening
TRD-PHADBusiness Use Only54
Results: Screening ... but looking at x50
TRD-PHAD
... but looking at x50
Business Use Only55
400
300
200
400
300
200
104
400
300
200
1.250.80 300
Compaction F * Sieve Openin
Compaction F * % of Mannito Sieve Openin * % of Mannito
Compaction F * Equipment
Compaction Force [kN/cm]
Sieve Openin * Equipment
Sieve Opening [mm]
% of Mannito * Equipment
% of Mannitol [%]
0.801.25
[mm]Opening
Sieve
030
Mannitol [%]% of
BepexGerteis
Equipment
Mea
n of
PSD
x50
[µm
]
Interaction Plot for PSDx50 [µm]Fitted Means
Results: Screening
TRD-PHADBusiness Use Only56
Tabletability profiles of brittle formulations
Results: Tableting
TRD-PHAD
Disintegration test
Business Use Only57
Trial # Disintegration test [min:sec]
RCS-P1-Ge7 RCS-P2-Be7
1 02:23 02:20
2 02:30 02:20
3 02:42 03:02
Trial # Disintegration test [min:sec]
RCS-P1-Ge8 RCS-P2-Be8
1 02:18 02:10
2 02:02 02:10
3 02:18 02:18
TRD-PHADBusiness Use Only58
Batch # Compaction force [kN/cm] Sieve opening [mm] % of mannitol EquipmentRCS-B1-Ge1 4 1.25 30 GerteisRCS-B1-Ge2 10 1.25 30 GerteisRCS-P1-Ge3 4 1.25 0 GerteisRCS-P1-Ge4 10 1.25 0 GerteisRCS-B1-Ge5 4 0.80 30 GerteisRCS-B1-Ge6 10 0.80 30 GerteisRCS-P1-Ge7 4 0.80 0 GerteisRCS-P1-Ge8 10 0.80 0 GerteisRCS-PB-Ge9 7 1.00 15 GerteisRCS-PB-Ge10 7 1.00 15 GerteisRCS-PB-Ge11 7 1.00 15 GerteisRCS-PB-Ge12 7 1.00 15 GerteisRCS-B2-Be1 4 1.25 30 BepexRCS-B2-Be2 10 1.25 30 BepexRCS-P1-Be3 4 1.25 0 BepexRCS-P2-Be4 10 1.25 0 BepexRCS-B2-Be5 4 0.80 30 BepexRCS-B2-Be6 10 0.80 30 BepexRCS-P2-Be7 4 0.80 0 BepexRCS-P2-Be8 10 0.80 0 Bepex
TRD-PHAD
• Use of two different granulators:– Gerteis Granulator equipped with Star Type Rotor – Frewitt Oscillo 6
• Parameters:– 70 [rpm] for Gerteis Granulator CW 125°(100° - 150°) CCW 350° (340 –
360°)– 85 [oscillations/min] for Frewitt Oscillo 6
• Square wire screens 0.80 mm, 1.00 mm and 1.25 mm
Business Use Only59
Screening Parameters
TRD-PHAD
• 15 kN• 20 kN• 25 kN• 30 kN• 35 kN
Business Use Only60
Five different forces
Two machine speed(dwell time)
• 25% (8 msec)• 75% (2 msec)
Equipment: Styl’One Evolution – round flat punch 11.28mm
Tableting Parameters
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