qbd in drug development case study on roller...

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

TRD-PHADBusiness Use Only2

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


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


• 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

Business Use Only5


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


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!

TRD-PHAD

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

8 Business use only

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

TRD-PHAD

Example of QTPP

Business Use Only9

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


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.


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



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



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

TRD-PHAD

CASE STUDY ON ROLLER COMPACTION

Business Use Only14


Dry granulation:• densification• improvement of flowability• avoiding segregation• improvement of the homogeneity of DS

• Cost effective• Ability to process material sensitive to

heat/moisture


Dry granulation is not a rocket science...

QTPP

CQAsCMAsCPPs


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

TRD-PHAD

FISHBONE Roller Compaction

Business Use Only18

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


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)

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

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



2

A : AspectC : Degradation/ StabilityE: Dissolution rate

555


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)



2


555


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


Variable


Ref of

source know

ledge



Probability


Impact


Detectability


Level ofMannitol

Not included in the current formulation

Mannitol added to composition


• Operator error

1


1010101010


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

TRD-PHAD

DoE study based on FMEA RA

Business Use Only22

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

TRD-PHAD

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

Business Use Only23

8 Kg batch sizeBlended in 40 L bin

TRD-PHAD

Roller Compactors

Business Use Only24

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

TRD-PHAD

Process parameters set on roller compactors

Business Use Only25

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”

TRD-PHAD

Results: Plastic and Brittle Behavior of Tested Formulation

Business Use Only26

TRD-PHAD

Impact of DoE variables on Ribbons Porosity

Business Use Only27

Screen size variable removed from this assessment

Results: Roller Compaction / Ribbons Porosity


Differences observed between the two roller compactors


TRD-PHAD

Why these differences between formulations?

Business Use Only29

BRITTLE BRITTLE

PLASTIC PLASTIC


TRD-PHAD

Look in to the recorded compaction forces...

Business Use Only30

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%


TRD-PHAD

... and the loop control?

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GERTEIS GERTEIS

BEPEXBEPEX


TRD-PHAD

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)


TRD-PHAD

Example to fine tune the correction factor

Business Use Only33

Target Porosity [%] Compaction force on Gerteis [kN/cm]

Compaction forceon Bepex [kN/cm]

Correction factor

45 4 4 129 10 7.7 1.3


𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑅𝑅𝑑𝑑𝑅𝑅𝑅𝑅(𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺)

𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑅𝑅𝑑𝑑𝑅𝑅𝑅𝑅(𝐵𝐵𝐺𝐺𝐵𝐵𝐺𝐺𝐵𝐵)= 1.25

TRD-PHAD

Particle size distribution

Business Use Only34

No differences for 0.8 mm screen

Results: Screening

TRD-PHAD

More visible differences using 1.25 mm screen

Business Use Only35

Results: Screening

Particle size distribution

Different trend

TRD-PHAD

Why this different trend?

Business Use Only36

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

Business Use Only37

Results: Screening


Results: Tableting

Tabletability profiles

Plastic powder

Brittle powder

RC brittle formulations, low compaction force

RC plastic formulations, high compaction force


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


Results: Tableting


Tabletability profiles of brittle formulations

Different PSD

Different ribbons porosity

Input:same

formulationand screen (1.25mm)

Comparable TS

Results: Tableting

TRD-PHAD

Tabletability profiles of plastic formulations

Business Use Only42

Results: Tableting

TRD-PHAD

... But looking at ribbons porosity

Business Use Only43

Results: Tableting

TRD-PHAD

Equipment

Plastic formulationScreen opening [mm]

Brittle formulationCompaction Force[kN/cm] Porosity [%]

TensileStrength [MPa]

Compaction Force [kN/cm]

Porosity [%]


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

Business Use Only44

Results Summary

TRD-PHAD

Equipment


Brittle formulationCompaction Force[kN/cm] Porosity [%]



Porosity [%]


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

Business Use Only45

RC loop control able to keep the set compaction forceRC process parameters used able to produce comparable ribbons comparable TS

Results Summary

TRD-PHAD

Equipment


Brittle formulationCompaction Force[kN/cm]

Porosity [%]


Compaction Force[kN/cm]

Porosity [%]


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

Business Use Only46

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


Ref of

source know

ledge



Probability


Impact


Detectability


RC force

4-10 kN/cm testedSet point 6kN/cm

Higher or lower rollercompactionforce



2


888


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


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


Variable


Ref of

source know

ledge



Probability


Impact


Detectability


Level ofMannitol

28.9% Mannitol added to composition


• Operator error

1


88888


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


Thanks to

TRD PHAD Oral Roller Compaction Focus Group

Milos Salodini who performed the DoE study

TRD-PHAD

x90 data

Business Use Only53

Results: Screening


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


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


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


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

qbd in drug development case study on roller...

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