technology transfer: case studies from the real...

Technology Transfer: Case Studies from the Real World

PDA IsraelTechnology Transfer and Working with CMO/CDMOTel Aviv, 4th March 2019

Ofer Dubinsky, Ph.D.Bio-Technology General (Israel) Ltd.

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Types of Tech Transfer:

• Development to Commercialization (Intracompany)TTP may include scale-up. The goal is to bring a process in adevelopment phase to a robust and reproducible commercial processable to consistently guarantee the market supply.

• Commercial to Commercial (Intercompany)Established process can be transferred from one commercial site toanother commercial site for business continuity or strategic reasons.In some cases, the process may include scale-up or scale-down.

Types of Tech Transfer

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Types of technology transfer:

• Mimic the same process/technology

• Modified the process/technology

• Modified scale

• Modified type of equipments

• Modified raw materials

• Several modifications from the above


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Essential needs for all types of technology transfer:

• Well-tarined multidisciplinary teams

• Involvement of:

QA, QC, Manufacturing,

Engineering, Finance, Maintainance,

R&D, Environmental, Health and Safety,

RA, Legal issues, Project management


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Case # 1

Tech Transfer from Dev. Phase to

Commercial Phase (scale up)

Case 1 - Technology transfer from R&D to Commercial Scale

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• Lyophilization cycles of protein were developed in Israel (1994)

• Small scale lyophilizer was used for development

• CMO in Europe with larger scale lyophilizers for commercial

manufacturing was Identified

• Initial visit in the CMO (1994)

• Contract was signed (end 1994)

• Initial activities were done (01/95)


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• Development work of new formulations and lyophilization cycles

were done in Pharmaceutical & Analytical Development

department at BTG

• Development activities were done with a small lyophilizer with a

capacity of ~400 vials

• BTG didn‘t have the capacity for large scale

lyophilization cycles (50,000 - 54,000 vials)


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• The CMO in Europe gave services (formulation and filling with or

without lyophilization) for pharmaceutical companies all over Europe

• Process details and analytical methods were sent to the CMO

• Q & A by mail and phone calls

• Dedicated parts of equipment‘s were purchased (formulation vessel,

filling needles etc.)

• SOPs were written for manufacturing and analytical activities


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• Samples of the API were sent to the CMO

• Implementation of the analytical methods was done in the QC laboratory in Germany (raw materials, IPC, Release)

• SOPs were written and approved

• Audit was made in the CMO plant

• Validation protocol was prepared by BTG

• First experimental lot was manufactured on 01/1995

• Almost 50% of the vials failed to meet the requirements for water content


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Basic Principles of Freeze Drying


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Lyophilization Cycles: BTG vs. CMO


CMO

CMO

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Lyophilization Cycles: BTG vs. CMO


CMO

CMONo major differences were identified

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Comparison Table: Lyiphilizer in the two Sites


Diff.

x 75-83

x 30

x 2.5-2.8

CMO

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Comparison Table: Lyiphilizer in the two Sites


Diff.

x 75-83

x 30

x 2.5-2.8

CMO

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Different cycles for 4 IU and 12 IU

The problem was worst in 4 IU


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Ways to solve the problem:

• Close look on the cycles in real time

• Modify cycles‘ parameters according to the data obtained during thecycle (needs on-site real time monitoring, conflict with localoperators)

• Validate the modified process on different lyophilizers


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Parts from a full chart of lyophilizer in the CMO


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Modified cycles‘ parameters according to the data obtained during the

cycle (on-site real time monitoring)


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After new cycles were stabilized:

• A new validation protocol was written by BTG

• The protocol contained raw materials, formulation processes,

lyophilization cycles, analytical methods, specifications for the

finished products, responsibilities of BTG and the CMC

• Full validation was performed

• Participation of BTG in the validation


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Final Steps:

• Submission

• Pre-Approval Inspection (PAI)

• Approval for commercial manufacturing 1997

Master specification was approved on August 1997


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Summary:• Total period of the TTP was almost ~3 years

• TT from develpment scale to commerciale scaleand berween two sites

• Different labs and operatores were involved

• BTG prepared the protocol instead of thereceiving site


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Case # 2

Tech Transfer between two Companies

+ Process Modification

Case 2 - Technology transfer from Commercial Site to

Commercial Site

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A new product (Con) was manufactured during development phase

followed by commercial phase in three site:

First site (CMO) - Bacterial fermentation and recovery (DSI)

Second site - Final purification until DS (API)

Third site - Formulation and lyophilization for US market (DP)

After approval in the origin country, the company decided to have all

manufacturing activities except formulation and lyophilization at the

same site where the purification process is done (second site).


Commercial Site

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Preparation that were done by Ku plant (the receiving site):

• Preparation of Tech Transfer protocol for Procedure E

• A new building (No. 4) was built for the new activities

• Farmentor, harvest and recovery lines were purchased and installed

The new fermentor was scaled down vs. the original fermentor

Raw materials for fermentation were

changed

• Time table for TT was prepared

• Most relevant documents were ready by

May 2016


Commercial Site

C

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Time table for the project (03/2016)


Commercial Site

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Commercial Site

As on Q2/2016:

• Initial engineering runs were on May 2016

• Tech transfer to QC laboratories was on going and some

validation were completed

• Additional analytical methods had to be developed

• Preparations were made for process validation

• Draft Validation Master Plan was ready

• Several technical problems were raised during inspection in Ku

plant (on 02/2016).

• Ku personal believed all problems will be solved by the end of

2016


Commercial Site

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2017 2018 20191Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q

Local GMP inspectionDrug substance (Procedure E)Facility IQ, OC, PQ

Manufacturing

Comparability exercise for CT use

Drug product (Procedure C; Scale-Up )

Test manufacturing

Investigational drug manufacturing

Comparability exercise for CT use

Sep

Apr

Feb

May

Sep

Dec

IND amendment

Aug Sep

IQ: installation qualification, OQ: operational qualificationPQ: performance qualification, CT: clinical trial, ID: investigational drug

Updated time table – One year delay (12/2017)

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Time Table (05/2018)


Commercial Site

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Delay due to many unexpected problems• Fermentations’ problems ( growth, yield)

• Harvest

• Recovery

• Cleaning and cleaning validation

• Had to prepare new lots for validation of DS and DP

processes (Process D Process E, Process B Process C)

• The new lots will be needed for clinical trial in US and for

stability study


Commercial Site

Investigational Drug Manufacturing*

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Risk Factors for ID manufacturing delay

1. Timing of local GMP inspection (planned to May 2017)• Our priority is locale approval.• Ku may not produce DS as planned due to preparation of

inspection. In that case, Ku will produce DS using procedure D for local commercial.

2. Completion of PQ for the Fermenter in Ku • Fermenter system was updated in Dec,2016.• IQ/OQ was completed in March, 2017.• Completion of PQ could be delayed by unanticipated issues.


Commercial Site

*From internal document

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Program published on 10/2018


Commercial Site

• The manufacture of PQ batches of API (manufacturing method E) is on-going as scheduled.

PQ (3 lots) of the API of manufacturing method E

Product release of the API

Process validation of the drug product of manufacturing

method C

Stability testing of API of manufacturing method E

Stability testing of drug product of manufacturing method C

Initial time table

Drug Substance (Procedure E) status

Technology transfer of manufacturing and testing methodsto Ku is in progress.

Process validation at Ku was scheduled to start inDecember 2018.

Status

PV cell Manufacture of three lots completed and testing is in progress.

Drug Substance Intermediate (Procedure E)

Planned manufacture of three lots from the end of February to the end of March.

Drug Substance (Procedure E) Planned manufacture of three lots in May.The report is scheduled to be approved at the end of July.

Work progress 01/2019

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Commercial Site

New Gantt prepared on 01/2019

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As of today:• PQ of the lines for DSI in Ku plant is on-going and will be completed

by the end of Q1/2019

• PQ for the DS will be completed on Q2/2019

• Base on Type C meeting with the FDA, P3 study was initiated on November 2018

• Comparability and additional study will be upon compplition of validation of DP manufacturing (Procedure C)

• Over all delay is >3 years


Commercial Site

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Reasons for the delay:• Documents were not completed before initiating Tech Transfer

project

• Too many changes at the same time during Tech Transfer

• The staff in the new plant were not familiar with the new activities

• Building activities and installation of the new equipment‘s did not

meet project‘s time table

• Local management was not familiar with current (FDA) expectations


Commercial Site

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Case # 3

Tech Transfer between two Manufacturing Sites

of the same Company


Commercial Site

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Background• BTG manufacture hGH for many years, from cell bank to DS (API)

• Formulation and lyophilization was done by third company abroad

• Ferring has the capability to perform formulation and lyophilizationin-house in one of the manufacturing plant in Europe (FerringGmbH)

• This plant was familiar with most of the analytical methods

Case 3 - Technology transfer from Manufacturing Site to

Manufacturing Site

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Multi-Steps Program:1. BTG will ship hGH API to Ferring GmbH (FGmbH, start 2012-2013)

2. Ferring GmbH will be responsible for FP manufacturing, packaging

and release

3. Tech Transfer of freeze-drying process to FGmbH

4. Validation & Stability studies

5. Comparability study

6. Submission


Commercial Site

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Time line (from project minute, for 1 out of 3 formulations):• Risk analysis planed is to be finalized by W16/2014• Validation protocol draft to be final (by Ferring Kiel, the receiving site) by

W18/2014• Filtration test: will be completed during 2014• Tech batch: scheduled CW24/2014 (accelerated stability and water

content test)• PV1 Production scheduled CW26/2014 (Mfg: end Jun 2014, Exp May

2016).• 4 weeks are recommended in order to analyze the data• FDA Submission Nov 2014 (PAI)• Packaging at risk at SMP Feb 2015• FDA Approval Mar 2015


Commercial Site

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Activities:

• Scale down from 55,000 vials to 44,380 vials

• Implementation and adjustment of current SOPs to FGmbH

Comparison table of the compounding and filtration parameters (part)


Commercial Site

CMO

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Activities:

Comparison lyophilization, filling and closing


Commercial Site

Lyophilization cycle was similar to that in WA

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The manufacturing, packaging and release testing site changes for the

drug product are as follows (from the submission):


Commercial Site

CMO, Germany

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Submission to FDA: Ferring GmbH as a new manufacturing site for the drug product Alternate analytical site for testing the Drug Product Replace BTG with Ferring FICSA as the secondary packaging site Change from the red chlorobutyl stoppers to the grey bromobutyl

stoppers for the drug product Replace the polystyrene tray with a plastic tray for the secondary

packaging


Commercial Site

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Summary• All activities were on time

• Tech Transfer had been completed on time

• Submission was made and the new manufacturing site had been

approved for formulation, lyophilization and release of the FP

• New packaging site in FICSA


Commercial Site

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Case # 4

Tech Transfer of DP from One Commercial Site

to Second Commercial Site

Case 4 - Technology transfer of FP from Commercial Site to

Commercial Site

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Background• Ferring GmbH (FGmbH) have several Finished Products which are

marketed as Pre-Filled syringes

• FGmbH was short in capabilities to fill all syringes

• BTG was capable to formulate and aseptically fill syringes

• BTG was chosen as an alternative site for manufacturing

Case 4 - Technology transfer of FP from Commercial Site to

Commercial Site

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Technology Transfer was initiated on 2015

Documents were written by BTG and approved by FGmbH


Commercial Site

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Main activities:

• Adaptaion of filling machine to the new syringes

• Purchase dedicated equipments for formulation

• Draft SOPs were written (manufacturing, IPC testing, packaging...)

• Workers‘ training

• Engineering runs

• Preparation for validation


Commercial Site

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Engineering Runs:

• Summary of Engineering runs

• Small and full scale runs


Commercial Site

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Next steps:

• Media Fill (3 runs)

• Risk assesment

• All relevant SOPs were locked

• Validation runs (3 lots, full scale)

• Summary report


Commercial Site

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Commercial Site

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Additional activities:

• Cleaning validation

• Release process by BTG

• Shipment validation

• Summary report – Tech Transfer

• BTG PQR for the new product Sep 2017 – Aug 2018


Commercial Site

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PQR for the first Year


Commercial Site

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Summary

Tech Transfer is a complicated process

Detailed preparation must be done in advance (purchasing,

documents, training)

Preferably, do not make changes but mimic the original

procedure

Changes can be made after implementation of the original

process.

PAI may be done as part of approval the new process/line


Commercial Site

Thank You