gp140 clade c production in the per.c6 platform a … · · 2015-08-26gp140 clade c project...

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

Property of Janssen – Do not distribute



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


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


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


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


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


API manufacturing gp140 clade C

10

Process flow chart GP140 Clade CSeed train


GP140 Clade C - 200L working volume Bioreactor


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


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


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


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)


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


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


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


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


AcknowledgementsDAIDS• Jane Halpern• Joellyn Bowser• Vijaya Rangavajhula• Tina Tong• Ronelle Lucas• Mike Pensiero

BIDMC• Dan Barouch• Keith Wells

Janssen and CMO project teams


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)


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


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


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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gp140 clade c production in the per.c6 platform a … · · 2015-08-26gp140 clade c project...

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