gp140 clade c production in the per.c6 platform a … · · 2015-08-26gp140 clade c project...
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Melinda, Goddess of HealingMelinda’s artwork reflects her journey living with HIV.
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gp140 Clade C production in the PER.C6platform
A successful collaboration between DAIDS, BIDMC and Janssen
I. BeeksmaCMC Program Director
Presentation Agenda
gp140 clade C program – background information
gp140 Clade C development & manufacturing program– Project organization– Technology transfer from R to D– Development & manufacturing strategy– API manufacturing gp140 clade C– DP manufacturing gp140 clade C and adjuvant
Results
Lessons learned
Q & A
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Gp140 clade C project background information
Partnership- Cooperation between DAIDS, Beth Israel Deaconess Medical Center
(BIDMC) and Janssen
Gp140 Protein- Stable gp140 trimer designed at Dr. Chen Lab, Harvard- Trimeric protein produced for clinical development using PER.C6 platform- 2 drug product concentrations requested by clinical team- Adjuvantated clinical setting
Adjuvant- Aluminium salt in buffer matrix comparable to gp140 clade C drug product
formulation
Vaccine regimen- gp140 clade C trimeric protein is part of prime/boost vaccine regimen
Clinical (Phase 1/2a)- Bed-side mixing protocol at hospital pharmacy
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A prime-boost vaccine regimen aiming at global coverage
Ad26 Mosaic vectorsgag-pol-env
MVA Mosaic vectorsgag-pol-env
Soluble trimer gp140 env protein
Soluble trimer gp140 env protein
+/-
+/-
or
Prime Boost
0 3 12months 6
Regimen to be selected after Phase 1/2a
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Ad26 Mosaic vectorsgag-pol-env
Ad26 Mosaic vectorsgag-pol-env
4
Project Organization for gp140 Clade C
gp140 CMC steering
group
CMC Leader
Project Management
Qualified Person
Quality Officer (optional)
Analytical development
(optional)
Janssen CMO manager &
team lead DS
Drug Product Development
(optional)
Procurement
CMO Project Management
Compound development
team
Compound development
leaderProject
manager
Strategic Marketing
Clinical ImmunologyPre-clinical
ClinicalDevelopment
CMC leader
RA
Toxicology
Biomarkers
Next slide
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Project Organization for gp140 Clade C
Development & Manufacturing
Team
Janssen CMO manager & DS
team Lead Wouter
WieringaCMO project manager
Quality Officer Janssen
Analytical leads & SME’s Janssen
CMO Analytical, Stability &
Development lead
CMO QA Lead
CMO Manufacturing API & DP leads
SME API Janssen
DP lead and SME’s Janssen
DAIDS & BIDMC team DAIDS/BIDMC team was
embedded in the development/manufacturing team and proven to be successful
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Development & Manufacturing Strategy (1)- Production clone
- selected out of 5 lead candidates (accelerated PER.C6 clone generation program, 100 clones at the start)
- Selection lead clone to enter early development based on;- Pre-clinical data package- Compound characterization- Manufacturability (2 l bioreactor experiments)- Genetic stability- Cell line Safety testing
- Early development – activation of CMC project organization, incl. CMO- Research Cell Bank (RCB) based- Medium screening in 2 l bioreactor model- Analytical development- Preliminary process design incl. Resin & Filter screening- Contract establishment with CMO
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Development & Manufacturing Strategy (2)
- Development- Feeding strategy in bioreactor model at different scales- Purification and filtration process definition & optimization- Formulation studies incl. Adjuvant & F&F process design- Assay development & qualification- Product characterization based on qualified assays- RCB end of life time study- In parallel execution of cGMP Master Cell Bank (MCB) manufacturing
- Final key deliverables: MCB, process descriptions for API & DP including specification sheets, assay qualifications
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Development & Manufacturing strategy (3)- Tox DS & DP manufacturing
- Derived from MCB- 200 l working volume- Assays qualified- Satelite runs for contingency and process investigation purposes- TOX DP fill under cGMP conditions, at scale
- CTM DS & DP manufacturing- Derived from MCB- 200 l working volume- Satelite runs for contingency and process investigation purposes- Viral clearance studies in qualified scaled down model- MCB end of life time study- CTM DP fill with back up strategy (DS split)
- clinical demand- Re-supply flexibility
- Stability strategy- DS lead stability : TOX (engineering run) at scale- DP lead stability : TOX (engineering fill under cGMP conditions) at scale- CTM DS & DP: Formal ICH studies
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API manufacturing gp140 clade C
10
Process flow chart GP140 Clade CSeed train
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GP140 Clade C - 200L working volume Bioreactor
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GP140 Clade C - Down stream Processing: 9 unit operation process
Bind/Elute chrom.
Initial UF / DFHost cell debris
removal
Low pH Hold Viral Inact.
Flow through chrom.
Viral Removal Filtration
Flow/Throughchrom.
Final UF/DF Bulk Fill
Unit I
Unit IIUnit III
Unit IV
Unit V
Unit VI
Unit VII
Unit IXUnit VIII
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gp140 Clade C – DP manufacturing
Receive & Storage of Drug Substance
Drug Substance Thawing & Acclimatization
Pooling & Mixing of DS
In-line Bio burden reduction & In line sterile
filtration
FillingStoppering and Capping
Visual inspection & AQL testing
Shipment to Clinical Supply Unit
Labeling of vials & Quarantine storage
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Results (1)
Timelines
(Early) development phase Jan 2013 – Oct 2013
– Cell line transfer (RCB) to CMO May 2013
Tech transfer, TOX and cGMP manufacturing Nov 2013 – Oct 2014
IND submission Nov 2014
IND approval Dec 2014
Phase 1/2a study start Dec 2014
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Results (2)
Key deliverables
Development of a cGMP USP & DSP Manufacturing Process
Development & qualification of In Process-, Release and Characterisation assays
Formulation development gp140 clade C, including adjuvant
Manufacturing & Release of Tox Batch Drug Substance & Drug Product
Manufacturing & Release of CTM Drug Products (diluent, low dose & high dose, adjuvant)
Generation of (lead) stability data for diluent, low & high dose gp140 DP and adjuvant
Process Viral clearance studies
Overall process recovery at 200 l scale (Bulk harvest vs. Formulated DS)
TOX 32 % CTM 34% Late stage development run 39% (excludes final UF/DF step)
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Specific FDA Comments gp140 clade CProduct Collaborators FDA Feedback
gp140 clade C Trimeric protein
BIDMCJanssenDAIDS
Pre-IND1. Report purity as configuration percentages
(trimer/hexamer) percentage of total protein content
2. DNA fragment size characterization requested
3. Confirmation stability gene expression cassette requested for MCB
4. Provide overview toxic residual process impurities
5. Confirm generation of pharmacy manual studies
IND1. Non-hold question: Provide data on adjuvant
immunogenicity pre and post terminal sterilization
2. Non-hold question: Provide stability data throughout the course of the proposed stability program
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Lessons learned (1)Subject Result
1. OrganizationalProject organization with dedicated teams and SME’s
Integrated team with BIDMC and DAIDS
Clear distinctions between program strategic and business related thinking vs. operational execution
- Full transparancy on program status
- Joint review of batch dossiers
2. Support and control: On site presence at CMOInvolvement of early development function in techtransfer to CMO
Person in Plant
On site batch dossier review with Janssen and DAIDS/BIDMC team during manufacturing program & release testing
Steep learning curve
Early identification of issues, fast escalation and decisionmaking process with CMO
Fast track release lead times
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Lessons learned (2)Subject Result
3. Process fit to plant: - Early assessment of raw material suitability in
“platform” cGMP setting at CMO. E.g. Filter compatability
- Early and continuous alignment with CMO on selection of unique critical process parameters (e.g. residence time vs. Flow rate in chromatography steps
Avoids loss of material
Avoids delay in process description finalization and/or repeat of DOE studies
4. Success rateExample: pre-culture contaminationsCross functional investigations with SME’s on site and controlled implementation of corrected actions
Execution of parallel satellite runs at small scale to create back up and facilitate investigations
Fast close out of deviations
Fast implementation of corrective actions
Minimize delays
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Lessons learned (3)
Subject Results in
5. Raw materialsEU vs. US QA requirements vs. CMO platform –release testing of raw materials
EU requires ID testing on each container
Avoidance of compliance risks
6. DocumentationEarly finalization of material and product specification sheets (before TOX)
Minimize comparability risk
7. Technical writingParallel product manufacturing and IND technical writing
Program lead time reduction
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AcknowledgementsDAIDS• Jane Halpern• Joellyn Bowser• Vijaya Rangavajhula• Tina Tong• Ronelle Lucas• Mike Pensiero
BIDMC• Dan Barouch• Keith Wells
Janssen and CMO project teams
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Back up slides
23
gp140 Clade C – Process Results
cGMP gp140 MCB Produced and Released
TOX DP gp140 batch 1 (2389 vials, high dose)
CTM DP gp140 batch 2 (4888 vials, low dose)
CTM DP gp140 batch 3 (2747 vials, high dose)
CTM DP gp140 batch 4 (2378 vials, high dose)
gp140 CTM Diluent (4941 Vials)
Adjuvant CTM (2200 vials)
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gp140 DP TOX vs. CTM – Page 1
Spec Tox1 mg/ml
CTM1 mg/ml
CTM0,20 mg/ml
Protein concentration 0.16 - 0.24 mg/mL0.8 – 1.2 mg/ml 1.0 mg/mL 1.0 mg/mL 0,21 mg/ml
Endotoxin ≤ 4.00 EU/mg protein (TOX)≤ 10 EU/mg protein (CTM) < 0.8 EU/mg < 0.8 EU/mg ≤ 4.0 EU/mg
pH 6.5 +/- 0.5 6.5 6.5 6.5
Osmolality 270 – 370 mOsm/kg 321 mOsm/kg 317 mOsm/kg 318 mOsm/kg
SEC - HPLC Report % Trimer 89,2% 88,2% 89,3%
Report % Hexamer 10,5% 11,6% 10,7%
Report % HMW 0,1% 0,1% 0,0%
Report % LMW 0,2% 0,06% Not detected
Appearance Practically free from visible particles Pass Pass Pass
Binding ELISAReport result (TOX)
50-150% relative binding to the RM (CTM)
105% 94% 96%
Assay
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gp140 DP TOX vs. CTM – Page 2Assay Spec Tox
1 mg/mlCTM
1 mg/mlCTM
0,20 mg/ml
Residual DNA (Tested on BDS) ≤ 10 ng/dose (Dose = 0.25 mg) ≤ 37.5 pg/dose
< LOQ (0.144 ng/mg or <
37.5 pg/dose) N.A.
Slot Blot Identity confirmed as gp140 Confirmed Confirmed Confirmed
SDS-Page reduced
Purity : Report (Tox)Purity: Main Band ≥ 80.0%
No new Bands at > 4.0% as compared to the Ref. Std.
Purity: Main Band ≥ 90 %
Purity: Main Band ≥ 82.5%
No new Bands at > 4.0% as compared to
the Ref. Std.
Purity: Main Band ≥ 83.6%
No new Bands at > 4.0% as compared
to the Ref. Std.
Residual HCP(Tested on BDS) Report result 160 ng/mg 335 ng/mg N.A.
Container closure Integrity (dye ingress) 100% negative reading 100% negative
reading100% negative
reading100% negative
reading
Sterility No growth No growth No growth No growth
Development BDS-1 , 12 L BDS-2, 12 L BDS-3, 12 L
Residual HCP 383 ng/mg 259 ng/mg 188 ng/mg
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Adjuvant manufacturing process
Receive and Release
Wash out storage solution
Condition in formulation buffer
Fill under continuous homogenization of
solution
Sent out vials for terminal sterilization
Post Sterilization Visual inspection & AQL testing
Shipment to Clinical Supply Unit
Labeling of vials & Quarantine storage
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