strategic considerations for manufacturing process development

Strategic Considerations for Manufacturing Process Development

PDA Israel

Key areas for strategic drug development planning

Ramat Gan, 24th Oct 2018

Oren Hesrhkovitz

GM, Opko Biologics

2

• Biological Drug Manufacturing Overview

• General Strategic Considerations

• Process and Product Development Considerations

Presentation Overview

3

“The goal of manufacturing process development for

the drug substance is to establish a commercial

manufacturing process capable of consistently

producing drug substance of the intended quality”

ICH Q11

Biological Drug Manufacturing Overveiw

4

Biological Manufacturing - General Scheme

Clone

Cell Line DOWNSTREAMUPSTREAM RELEASE SPECIFICATIONS

5

Where to Start ???

Scale

TPP

CMO

Cost and

Budget

Regulation

Clone

CQA

Quality and

Control

Project Management

/team

QbD

Timelines

6

ALWAYS START BY LOOKING AT THE END

7

➢ Where do I develop?? Business Decision In-House Development vs CMO

Development

➢ Who do I need on my team to make it work?

➢ How much will it cost and how much product do I need for different

stages?? Defining early demand vs commercial

➢ How long will it take me ? How can I do it faster? Alignment with the

development plan as CMC is usually the rate limiting step

➢ What is the Process profile? Process early development vs late stage

development -

➢ What is the Target Product Profile?? The path from initial TPP to

commercial TPP in the regulatory environment

Biological Manufacturing - Initial Strategic Considerations

Many Business and Development Strategy Decisions

8

The Bridging Strategy

Balancing your budget early expanses until clinical POC while meeting the necessary process development

requirements

Big Pharma do it right from the beginning, Biotech companies must accelerate the time to clinical POC while keeping the basic regulatory

requirements and allowing reasonable optimization to bridge early process to late process


✓ Regulation – IND consideration

✓ Clinical Study Conduct region✓ Reasonable specification and

scale

9

➢ Pros

✓ Provide process knowledge and understanding which are a huge

advantage in regards to timelines and managing CMO following TT.

Allows the sponsor to conduct house studies following TT to accelerate

process development

➢ Cons

✓ Require relatively early investments and constant costs (Labs,

equipment and dedicated team) . Support by the Israeli Innovation

Institute ?

✓ CMO are usually better facilitated and experienced

Where to Develop your Process - In House Development

capabilities

Where to Develop ?

10

Selecting and Managing a CMO

Eventually you will most probably use a CMO to

manufacture your drug, this is a key vendor and there are so

many options. How to select to right one for you?

11


ConsiderationsCriteria

Big CMOs are much less flexible but more experienced from a regulatory perspective, only consider for late stage processes

Size of CMO

Does the CMO have the infrastructure and equipment you need (e.g. BR scale, disposable vs reusable buffer capacity, columns size and skids and more)

Capability and facility fit to your process

Does the CMO have the range of services you need or many services are provided by a third party. Can he meet your short term and long term needs, will you need to TT down the road

Range of Services

Collect at least 2 relevant client references to understand the quality of their service and potential issues

Reputation and Reliability

Time zone difference and distance Geographic location and accessibility

Regulatory audits track records, when? and outcomes (483?). Compliance with ICH

Regulatory track record

Evaluation by an audit of the quality system and GMP compliance - Key!Quality Control

Have the CMO manufactured a product similar to yours. For complex proteins, it could be essential. Are you heading to process qualification, does he have PPQ and submission experience?

Experience and Expertise

Are they responsive, adhere to timelines, can work with you to develop aggressive timelines?

Commitment and communication

12


ConsiderationsCriteria

How “booked” are they? Sense the water in terms of responsiveness and availability/flexibility at early stage, can work with you to develop aggressive timelines?

Scheduling and availability

Evaluate the mentality /cultural fit that can make the difference between “partnership and battleship”

Mentality/Cultural fit

Apple to apple comparison to alternative CMOs pricing, should fi your budget

Cost

Make sure that you assess the financial stability of your CMO before you start the work

Financial stability

Meet the team, don’t be dazzled by the BDs, Phase distribution, turnover rate, meet the PM, ask for CV, he/she is a key executioner of the program

Other considerations

Look at the CMO as your key partner, build arelationship, insist where you should and be

flexible where you can

13

➢ Development in house requires USP/DSP/QC/RA/QA experienced CMC

integrated team

➢ Managing a CMO requires also an experienced PM that knows how to

manage a CMO and that can apply effective management tools(trackers,

Gantt, Budget)

➢ Consultants – Don’t think you know it all, it is recommended to identify key

consultants in different relevant areas (RA/QA and CMC) with the proper

experience and expertise – it could become critical

➢ Successful team comprises of experienced members but also young

enthusiastic members

Who do I need on my team to make it work?


14

➢ Start with modeling what would be your material demand to support your development, toxicological studies and Phase 1 and 2 demands.

➢ Consider the following :

✓ Clinical design and doses ;o What is your expected therapeutic window?

o What would be your formulation concentration to accommodate the required doses and volume constrains – use vials/cartridge base calculation

o Is it a single/multi center site, blinded? Many countries? All of this will lead to calculating your clinical margins (20-100%). For complex studies, use forecasting tools !

✓ Non-Clinical :o At early phase, tox will be more demanding then clinical demand

o Consider the required exposure margins, if possible, it could be helpful to conduct non-GLP study to determine the MTD and reduce doses in the GLP study

o Demand for additional PK/PD and pharmacological studies

✓ CMC :

o Consider stability requirements, release and retain (X2), 15-20% loses in DS and DP, required material for further development of process and formulation, product characterization and other activities

How much and How many


15

➢ Once you know your short term demand, simulate what could be your

commercial need. Yes, it is too early , but essential to understand what scale

of a process you might need to get to eventually.

➢ Consider the following :o Demand - Therapeutic range, dose frequency, market size and share

o Process – Clone productivity, process yield → gr/L purified DS

How much and How many


Short term demand Commercial demand

Regulatory Considerations

16

Regulatory considerations for process scale up and general process changes during development

COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS

SUBJECT TO CHANGES IN THEIR MANUFACTURING PROCESS

ICH Q5E

• Although process changes are integrated part of drug development, your initial process should reflect and set the basis for reasonable changes implemented during development. ICH Q5E provide the regulatory frame work for comparability exercise . Scope is dependent on the clinical stage

• Some regulatory authorities are more sensitive to process changes. Even within the FDA (CBER vs CDER) there are different approaches.

• Manage your predicted changes wisely to tie it with the overall development plan


17

Test Development and qualification

Testing Support

Drug

Candidate

Screening

and Transfer

UP

ST

RE

AM

DO

WN

ST

RE

AM

RE

SE

AR

CH

FO

RM

UL

AT

I

ON

Cell Line

Developme

nt

Initial Process

Development

Cell Line

SelectionProcess Characterization

Process

Development

Developability/Pre-formulation

Transfer to

MFG (GMP

Manufacturing)

AN

AL

YT

ICA

L

Methods

Validation

Year 1 Year 2 Year 3 Year 4 Year X

Formulation Formulation Robustness

Process Development and Tech Transfer

Phase 1 Phase 2 Phase 3

Risk

assessment

and Process

Lock

PPQ

Process Characterization

Risk

assessment

and Process

Lock

PPQ

How Long ?

18

➢ Cloning – Always on the critical path. huge variability in time to clone between different vendors.

➢ Start your process development from stable pool, then RCB and only then with MCB

➢ Select CMOs with aggressive timelines

➢ Use Internal/CMO with high throughput tools (Amber, Robocolumn, analytical tools)

➢ Start your process development using a platform where possible (e.g.Abs),and experience with similar protein (glycosylation )

How to accelerate your process development?

19

Once you defined your business wise process development strategy , you need to start to get into the details of your target drug and process

profiles

20

Relevant ICH Guidlines for of Process Development and

Manufacturing of Biological Prodcuts

21

QbD is a systematic approach to drug development

that begins with predefined objectives and

emphasizes product and process understanding and

process control, all based on sound science and

quality risk management.

QbD is a systematic approach to drug development that begins with predefined objectives and emphasizes product and process

understanding and process control, all based on sound science and quality risk management.

Quality by Design

22

Quality by Design

23

ALWAYS START BY LOOKING AT THE END

24

Target Product Profile (TPP) – It is a more business perspective of the final

characteristics of your drug that should consider commercial landscape.

Important parameters will include the following:

✓ Formulation –liquid vs lyo → handling

✓ Storage conditions – cold vs RT → storage convenience and supply chain

✓ Storage duration – Shelf life → at least 1y at desired storage temp

✓ Delivery system – Syringe/device → patients convenience

Quality Target Product Profile (QTPP) - A prospective summary of the

quality characteristics of a drug product that ideally will be achieved to ensure

desired quality, taking into account safety and efficacy of a drug product

Target Product Profile and Quality Target Prduct Profile

25

➢ QTPP is essential for understanding how your final commercial drug will

look at the end

➢ You should define the QTPP with that in mind, and determine based on a

risk assessment, what is your QTPP for Phase 1 and 2, and can you bridge

the gap during development to your Phase3/commercial QTPP

➢ You need to assess the criticality of each quality attribute

➢ Critical Quality Attribute (CQA): A quality attribute that must be controlled

within predefined limits to ensure that a product meets its intended safety,

efficacy, stability, and performance


26

Consider adding an achievable specifications for early Phases that will bridge to your commercial QTPP


Key Consideration During Process Development

29

Cell Culture “Upstream” DevelopmentGOAL: Productivity and Quality

Purification “Downstream” DevelopmentGOAL: Purity and CQA

Drug Product “Formulation & Fill/Finish” Development

GOAL: Stability, Minimize stress conditions

All of development shares the goals of:

SafetyEfficacyConsistency

Process Development Stages

30

Cell Line (Clone) Development

Cell Line (Clone) Selection

Protein DNA

Robot picks clones*Clonality confirmed

Clone Performance EvaluatedClone Pool Created

Clones scaled-up

Clones evaluated in AmberProductivityProduct Quality

Top clones confirmed in larger BRs

Cell Line Development

31

➢ Productivity Counts !!! Yield per gram will define your scale/development

costs and your COGs

➢ Timelines diversity among CMOs

➢ Questions you must ask:

✓ Expression system – less copies is better

✓ Well characterized parent cell line

✓ Proven document for no animal derived components

✓ Monoclonality – take a picture, not just statistic

➢ MCB/WCB – meet the regulatory requirement (ICH Q5D, EU Pharmacopeia)

Cell Line Development

32

The objective of the upstream development is to selectthe conditions which will maximize the cells

productivity while maintaining a cost effective process (raw material cost , process duration) , meeting your desired target product quality (glycosylation, other PTMs, contaminants) and have a consistent process

Upstream Development

33


CELL

Amino Acids

Sugars

Vitamins

Lipids

pH

Temperature

Product (mAb)

Waste

Host Cell Proteins (HCPs)

Oxygen

How many cells?Which Media and Feed ?How long is the process?What is the target Product Quality profile??

Osmolality

34

Small-Scale5L Glass BRX

Pilot Scale~200-500L BRX

Full Scale2,000-18,000L BRX

Scale-up

Scale-up data should build confidence that the process we are running in MFG is the same as the process we developed on the bench (and changes we make on the bench will have the same impact in MFG!)

Must-haves:• Consistent performance between scales• Independent and dependent variables same between scales

Scale-up


35

➢ Productivity Counts !!! Yield per gram will define your scale/development

costs and your COGs

➢ Use high throughput systems such as Amber to screening a wide range of

conditions using Design of Experiment (DoE) tools to optimize your

development scope, process knowledge and timelines

➢ No animal origin components

➢ Early assessment of BR mode (fed batch , perfusion)

➢ Scalability of your (or CMO) model -Tech Transfer

➢ Development of tools to assess product quality

➢ Early assessment of consistency


36

The objective of the downstream development is toselect the conditions which will meet your product

QTPP while maintaining a cost effective process (raw material cost , process duration and complexity ) , and

consistency

Downstream Development

37

Screening of chromatography

media

Determination of unit

operations, sequence and

unit Parameters

Optimize yield while meeting

your QTPP

Optimize process

efficiencies Identify

potential Critical Process

Parameters (CPP)


Impurity (internal to process)

➢ Product related impurities (aggregate, related forms)

➢ Process related forms o Host Cell Proteins (HCP)

o DNA

o USP/DSP components/additives

Contaminant (external to process) •Viruses

•Bacteria, endotoxin


39

➢ Demonstration of viral clearance may be required. Exceptions: certain source materials (e.g., E. coli, yeast) or in the event of unmet medical need

➢ Perform small scale clearance study that mimics the clinical purification process

Spike Drug Substance with a model virus to demonstrate viral removal by several logs beyond the potential loadCHO cell substrate – demonstrate retroviral clearanceHuman cell substrate - demonstrate clearance of enveloped and non-enveloped viruses (e.g., parvoviruses)Design the process upfront to adequately assess potential risks

➢ Two orthogonal robust steps (e.g., low pH, nano-filtration, solvent/detergent treatment, heat) typically included in the purification process

Viral Clearance for Phase 1

40

➢ The endless battle between yield and purity

➢ Using standard resins – Cost driver

➢ Buffer consumption – Cost and CMO fit

➢ Viral Inactivation steps

➢ Ambient Process –product is stable throughout the process in ambient

conditions

➢ Process complexity and duration (step duration and holding times)

➢ Development of tools to assess product quality

➢ Early assessment for consistency


Balance Yield versus Purity

YIELD PURITY

41

Conclusions and Final Remarks

Define your business development strategy

Define your product and process target profiles

Define your early vs late stage development cost

till clinical POC using a risk based bridging strategy

strategic considerations for manufacturing process development

Documents