technology transfer: case studies from the real...
TRANSCRIPT
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.
2
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
3
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
Types of Tech Transfer
4
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
Types of Tech Transfer
5
Case # 1
Tech Transfer from Dev. Phase to
Commercial Phase (scale up)
Case 1 - Technology transfer from R&D to Commercial Scale
6
• 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)
Case 1 - Technology transfer from R&D to Commercial Scale
7
• 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)
Case 1 - Technology transfer from R&D to Commercial Scale
8
• 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
Case 1 - Technology transfer from R&D to Commercial Scale
9
• 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
Case 1 - Technology transfer from R&D to Commercial Scale
10
Basic Principles of Freeze Drying
Case 1 - Technology transfer from R&D to Commercial Scale
11
Lyophilization Cycles: BTG vs. CMO
Case 1 - Technology transfer from R&D to Commercial Scale
CMO
CMO
12
Lyophilization Cycles: BTG vs. CMO
Case 1 - Technology transfer from R&D to Commercial Scale
CMO
CMONo major differences were identified
13
Comparison Table: Lyiphilizer in the two Sites
Case 1 - Technology transfer from R&D to Commercial Scale
Diff.
x 75-83
x 30
x 2.5-2.8
CMO
14
Comparison Table: Lyiphilizer in the two Sites
Case 1 - Technology transfer from R&D to Commercial Scale
Diff.
x 75-83
x 30
x 2.5-2.8
CMO
15
Different cycles for 4 IU and 12 IU
The problem was worst in 4 IU
Case 1 - Technology transfer from R&D to Commercial Scale
16
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
Case 1 - Technology transfer from R&D to Commercial Scale
17
Parts from a full chart of lyophilizer in the CMO
Case 1 - Technology transfer from R&D to Commercial Scale
18
Modified cycles‘ parameters according to the data obtained during the
cycle (on-site real time monitoring)
Case 1 - Technology transfer from R&D to Commercial Scale
19
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
Case 1 - Technology transfer from R&D to Commercial Scale
20
Final Steps:
• Submission
• Pre-Approval Inspection (PAI)
• Approval for commercial manufacturing 1997
Master specification was approved on August 1997
Case 1 - Technology transfer from R&D to Commercial Scale
21
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
Case 1 - Technology transfer from R&D to Commercial Scale
22
Case # 2
Tech Transfer between two Companies
+ Process Modification
Case 2 - Technology transfer from Commercial Site to
Commercial Site
23
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).
Case 2 - Technology transfer from Commercial Site to
Commercial Site
24
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
Case 2 - Technology transfer from Commercial Site to
Commercial Site
C
25
Time table for the project (03/2016)
Case 2 - Technology transfer from Commercial Site to
Commercial Site
26
Case 2 - Technology transfer from Commercial Site to
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
Case 2 - Technology transfer from Commercial Site to
Commercial Site
27
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)
28
Time Table (05/2018)
Case 2 - Technology transfer from Commercial Site to
Commercial Site
29
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
Case 2 - Technology transfer from Commercial Site to
Commercial Site
Investigational Drug Manufacturing*
30
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.
Case 2 - Technology transfer from Commercial Site to
Commercial Site
*From internal document
31
Program published on 10/2018
Case 2 - Technology transfer from Commercial Site to
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
33
Case 2 - Technology transfer from Commercial Site to
Commercial Site
New Gantt prepared on 01/2019
34
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
Case 2 - Technology transfer from Commercial Site to
Commercial Site
35
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
Case 2 - Technology transfer from Commercial Site to
Commercial Site
36
Case # 3
Tech Transfer between two Manufacturing Sites
of the same Company
Case 3 - Technology transfer from Commercial Site to
Commercial Site
37
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
38
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
Case 3 - Technology transfer from Commercial Site to
Commercial Site
39
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
Case 3 - Technology transfer from Commercial Site to
Commercial Site
40
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)
Case 3 - Technology transfer from Commercial Site to
Commercial Site
CMO
41
Activities:
Comparison lyophilization, filling and closing
Case 3 - Technology transfer from Commercial Site to
Commercial Site
Lyophilization cycle was similar to that in WA
42
The manufacturing, packaging and release testing site changes for the
drug product are as follows (from the submission):
Case 3 - Technology transfer from Commercial Site to
Commercial Site
CMO, Germany
43
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
Case 3 - Technology transfer from Commercial Site to
Commercial Site
44
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
Case 3 - Technology transfer from Commercial Site to
Commercial Site
45
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
46
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
47
Technology Transfer was initiated on 2015
Documents were written by BTG and approved by FGmbH
Case 4 - Technology transfer from Commercial Site to
Commercial Site
48
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
Case 4 - Technology transfer from Commercial Site to
Commercial Site
49
Engineering Runs:
• Summary of Engineering runs
• Small and full scale runs
Case 4 - Technology transfer from Commercial Site to
Commercial Site
50
Next steps:
• Media Fill (3 runs)
• Risk assesment
• All relevant SOPs were locked
• Validation runs (3 lots, full scale)
• Summary report
Case 4 - Technology transfer from Commercial Site to
Commercial Site
51
Case 4 - Technology transfer from Commercial Site to
Commercial Site
52
Additional activities:
• Cleaning validation
• Release process by BTG
• Shipment validation
• Summary report – Tech Transfer
• BTG PQR for the new product Sep 2017 – Aug 2018
Case 3 - Technology transfer from Commercial Site to
Commercial Site
53
PQR for the first Year
Case 4 - Technology transfer from Commercial Site to
Commercial Site
54
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
Case 4 - Technology transfer from Commercial Site to
Commercial Site
Thank You