april 26, 2018 south san francisco conference center ... · scribe: rob mccombie, genentech....

April 26, 2018

South San Francisco Conference Center

Roundtable Discussion Summary

Table 1

Platform Data/Approaches Enabling Faster Filing and Approval

Facilitator: Dominique Kissick, Genentech, a Member of the Roche Group

Scribe: Nomalie Jaya, Seattle Genetics, Inc.

Scope:

Platform data may be leveraged to reduce product specific process and product

characterization and/or validation required for the market application for accelerated

designation programs.

Discussion Notes:

1) Discussion at this table covered the concepts of platform data and approaches

and started the conversation with definitions around what is platform data vs.

approach?

• Platform data can be generated using platform analytical methods and

processes, and can include relevant data observed across programs (e.g.

specification-setting and shelf life-setting data). These data can be used in a

fit-for-purpose or phase appropriate manner. Platform safety data may be

generated, for example, if sufficient clinical information exists for common

drug-linkers used for ADC production.

• Platform approach may include a unifying approaches across programs (e.g.

sequential approaches to process changes, application of platform analytical

methods throughout all development phases), Use of Quality Target Product

Profile (QTPP) to define nice-to-have and need-to-have items designated for

accelerated approval product.

2) There was discussion around how to leverage platform data and approaches to

facilitate BTD product filings; participants did not have first hand experience

successfully filing using such approaches:

• If granted BTD, teams should have an early cross functional discussion to

ensure program success by determining which countries to file in given the

indication and patient population, etc.

• Teams should initiate early cross-functional discussions to project gaps and

potential bottle necks.

3) The table also discussed additional considerations (such as post-approval

commitments and international markets) for leveraging platform knowledge:

• Teams should make a risk assessment on the trade-offs made when leveraging

platform knowledge enabling a faster initial marketing application vs additional

data required to be supplemented after approval, which would complicate the

post-approval landscape.

• Additional data specific to the product might be required depending on local or

regional requirements. Global acceptability of platform knowledge and filing

strategy should be assessed early.

4) The table discussed how to leverage prior knowledge to bolster platform

knowledge:

• While a lot of companies have information that can be categorized as prior

knowledge, there were not many good examples on how this information was

documented and adequately leveraged.

• GNE example by John Eschelbach on maintaining a living technical report

that captures information from platform processes and analytics was cited as

a good way to document platform information. However, it was agreed that

this type of knowledge management requires buy-in from Sr. Leadership as

there is large upfront resource requirement.

• It was agreed that it would be useful to have an intercompany collaboration

to discuss best practices to documenting platform information and creating

definitions for what is accepted as platform information.

April 26, 2018



Table 2

How to Set Commercial Acceptance Criteria from Limited Clinical

Exposure and Manufacturing Experience

Facilitator: John Eschelbach, Genentech, A Member of the Roche Group

Scribe: Guifeng Jiang, Boehringer Ingelheim

It is very difficult to set the commercial acceptance criteria with the limited clinical

exposure. There is no easy answer considering such complex task. The key is

to utilize the prior product/process knowledge and set up frequent

communications to get aligned earlier, to plan earlier….. Process capability can

not be a justification to widen the clinical exposure range. Instead, setting the

range with product knowledge, understand cQA , which linked to safety, efficacy ,

patient population, etc, all together in a scientific way…

Leverage using prior knowledge…

• Topic 1: Conduct clinical studies with planed manufacturing variability materials.

• It is a good way to propose, however, it is not practical

• The process knowledge will be required to intentionally create

manufacturing variability

• It will be expensive if over shooting the range, fail the batch

• Clinical trial professionals are not willing to take the risk, may mess up

clinical trial

• Topic 2: Conduct clinical studies with more batches to gain variability

• It is not practical , too expensive to do

• Multiple batches with very tight specs may not help

• Utilize raw materials with different lots to induce manufacturing variability up

front

• It may be a good idea to scale out, multiple batches, not scale up

• Gain clinical variability; Avoid comparability

April 26, 2018



Table 3

What, if any, CMC elements of a BLA submission may be deferred post-

licensure for biologics designated as Fast Track or Breakthrough Therapy?

Facilitator: John Boyle, Bayer

Scribe: Rob McCombie, Genentech

IntroductionFDA has programs that are intended to facilitate and expedite development and review of new drugs to

address unmet medical need in the treatment of a serious or life-threatening condition: fast track designation

and breakthrough designation.

FDA guidance indicates that the sponsor of a product that receives an expedited development designation

should pursue a more rapid manufacturing development program to accommodate the accelerated pace of

the clinical program. The sponsor should be prepared to propose a commercial manufacturing program that

will ensure availability of quality product at the time of approval.

Although sponsors must ensure the availability of quality product at the time of approval, FDA may exercise

some flexibility on the type and extent of manufacturing information that is expected at submission / approval.

Sponsors are encouraged to meet early with the FDA to discuss CMC elements to be available at submission

/ approval and those to be the subject of postmarketing commitments / requirements.

This round table discussion will focus on the question of what elements are required at submission / approval

versus those that could be the subject of postmarketing commitment.

Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics (May 2014)

What factors influence FDA flexibility?

FDA states BLA package must be complete

• Early engagement and agreement with FDA is beneficial

• Number of PPQ batches Must be agreed with FDA early on

• An Ultra Orphan designation may influence number of PPQ batches (may be 1

prior to filing, 1 at PLI, 1 after approval).

It is orphan status rather than BTD that in general can allow reduced validation

package

• Consider leveraging prior knowledge e.g. virus clearance or resin reuse

• Officially FDA does not consider seriousness of indication (e.g. oncology versus

chronic), but delegates real-life experience is different

• One delegate noted FDA did not need tox to Ph I comparability data for their oncology

indication

Does state of quality system influence flexibility?• Some attendees stated, yes

• Broadly, no, most attendees said robustness of quality system did nit seem to be a

factor in FDA review and acceptance of BLA package

ValidationProcess still needs to be validated

- Can validation package for other programs be leveraged and applied

- Identify gaps between platform process validation and package for submission

- Focused revalidation of gaps

• What is nice to have for manufacturability as opposed to really required? Do you really

need refiltration for example?

• Reliability and ability to supply to market are one goal of validation (is this still satisfied

– process and site history?)

• Number of validation batches

- Engineering batches may support reduced PPQ batches

- Process and product complexity is important in assessing number of batches

- Appetite for risk also influences – as does indication

- Comparability protocol is key to leveraging previous processes

• Validation activities that may be deferred PA

- Refiltration

- Extended Hold times

- Shipping studies (risk assessment – may not be acceptable)

Material control and qualification and AnalyticsMaterial control and qualification

• Unknown impact of unknown changes to raw materials

• Do companies prequalify certain vendors and raw materials to expedite raw material

qualification?

- Attendees ;Yes, in general

Is there any activities for Cell Banking that may be reduced?

• Attendees; No – nothing done differently for breakthrough– general consensus is that

the risk of non-acceptance by HA and potential consequences is huge

Analytical methods

• Leverage platform methods may expedite development

• One attendee noted they had received more flexibility seen around potency assay with

deferral of certain validation activities to post-approval

Do methods need to be validated for PPQ?

• Attendees: Mostly, yes

• Use may depend on level of changes to method, how was data captured?

• Microbial – expectation is to validate control on 3 batches

• Rabbit pyrogen testing is an requirement on three batches

Specification setting

Specification justification is challenging for BTD program

• Clincial exposure is important I setting specifications. For BTD products, often only a

handful of batches have been used in the clinical studies

• Different regulators review and challenge specifications differently (e.g. can you

justify wider than clinical exposure based on similar molecules in similar indications?

Can you justify non safety impacting attributes that an MoA reflecting potency

sufficiently captures risk to efficacy from ranges outside clinical exposure?

• Do you deliberately vary the manufacturing process to vary CQAs levels in the

clinic

- No, not deliberately

- Note that FDA view may be that specification should still be based on clinical

exposure – limited number of batches is not an excuse!

April 26, 2018



Table 4

Challenges to analytical and bioassay development

efforts within a short time frame.

Facilitator: Ho Young Lee, Genentech

Scribe: Malou Gemeniano, Audentes

Table 4: Challenges to analytical and bioassay development

efforts within a short time frame.

• To focus our discussions, we distinguish the topics to the following:

• Cell based potency assays versus Physiochemical assays

• Product with Platform concepts (Mabs) and products with non-

platform concepts (e.g. Bispecifics, Fc fusion)

• To focus our discussions, we also narrowed topics to Analytical

readiness to the following

• for early development of the process

• Process characterization

• PPQ

• Commercialization – BLA

• We did not discussion phase appropriate realizing that in any

accelerated program or Break through program, Phase 1 may become

Phase 3 very quickly.

• For physiochemical assays, if there is platform knowledge, these are

fairly easy and bringing these up to maturity to support an

accelerated program is simple

- you start with Phase 1 and grow the control system accordingly.

- one strategy is if you know that the product has a potential to be

in an accelerated program, one can start early validation of the

assays

• For Cell Based assays that have platform knowledge, one can start

method characterization and robustness earlier

Table 4: Challenges to analytical and bioassay

development efforts within a short time frame.

• For physiochemical assays, with no platform knowledge, assay

development could be a challenge in some cases. One may start out

these methods as characterization and be prepared to move them to

QC and slowly grow the control system if acceptable.

• For Cell Based assay with no platform knowledge,

- start with binding assays or surrogate assays in the control

system for the early stages

- Include a assay that is a more relevant detection of mechanism

of action as characterization

- talk to the agency regarding its inclusion into the control system

and bridging strategies





• In summary:

• Product characterization has to be done early to help determine

which assays to focus on.

• There is no leeway for methods for what ever designation – All

methods must be validation by BLA

• Discuss with Agency regarding Cell based assay strategies and

relevance. There has been now precedence with Breakthrough

products without a cell based assay

April 26, 2018



Table 5

What are the Future (Late Stage) Considerations (or Lack of Them) while

Developing Early Stage Processes?

Facilitator: Ekta Mahajan, Genentech, a Member of the Roche Group

Scribe: Kris Antonsen, BioMarin Pharmaceutical Inc

Notes:

How do you manage changes?

• Gap analysis at clinical phase transitions

• Try to avoid changes (e.g., cell line, new impurities) that might trigger

new tox or clinical work

How much up-front work during phase 1?

• Most dev’t work is saved for phase 3 but can vary between companies.

• Focus early investment on getting material quickly to downstream

development groups, a clonal, stable cell line, and a good formulation.

• If early work is extensive, there is a risk that tightly controlled processes,

with small lot number, can constrain options (e.g., on purity) at later

stages – it’s difficult to widen specs prior to phase 3. Approaches could

include more small batches at an early stage.

Does more up-front work reduce post-approval changes?

• Typically NORs are established during late development

• Better to make concessions on yield than on product quality

What about changes to DS storage, primary container?

• Best to be conservative at first. This gives time to collect data on

alternatives.

Comparability risks to take

• It helps to limit the number of comparability exercises to undertake; this

argues for extra early work

• Nonclonal cell lines pose a risk; later cloning could lead to product

changes

• qTPP a major driver for the comparability

• Limiting site changes can reduce risk. E.g., if the manufacturing site

changes, consider keeping testing at the old site

• Be careful in making late-stage changes; could cause stability changes

that are difficult to recover from

• Understanding the rationale for differences when making technology

changes and identify steps to ensure product quality is not impacted.

April 26, 2018



Table 6

Implementing High-throughput Analytical Methods to Support

Process Development

Facilitators: Ageliki Tzovolos, Genentech, a Member of the Roche

Group

Scribe: Eike Zimmermann, Boehringer-Ingelheim

Notes:

Definition and scope of High-Throughput analytics

• Includes sample prep automation and overall automation, as well as a

new technology for the actual assay.

• Can be 100s of samples, not necessarily 1000’s as in research.

• Used to increase overall throughput, as well as avoid analyst to analyst

variability.

Challenges

• For late stages/QC environment, technology needs to be suitable for

GMP, IQ/OQ, CFR21 part11 compliant. If replacing a current/traditional

technology, demonstrate resolution, precision, accuracy are equal or

better.

• Data processing becomes bottleneck. Any automated processing needs

to be validated in QC.

• Could we introduce too many false positives? On the other hand with

higher throughput, additional replicates can mitigate this risk.

• Automation is often more complex, may need back up instruments or

manual method as back-up.

Notes:

Which areas of process development will benefit most

• Most beneficial to timeline in early development as it increases

throughput for screening. Select samples will be tested for traditional

methods as bridge to QC.

• For implementation in later stages, business case needs to be made that

additional resources and costs are beneficial and don’t impact timeline.

• Some assays are easier to automate than others, e.g. ELISAs are easier;

cell based assays and MS are more difficult.

• Smaller companies may not have the resources to implement such

technologies.

• One additional consideration is that if using a CRO/CMO, those likely will

not have those new technologies. On the other had, it would be on our

wish list to have a premium CRO taking care of those technology

developments

April 26, 2018



Table 7

Accelerating process development for gene therapy to market

Facilitator: Rafi Mohammad, Bayer US LLC

Scribe: David Passmore, RubrYc Therapeutics

Process Development for Gene Therapies

Scope: we defined gene therapy as delivery of genes, using AAV for example,

and cells that have been genetically modified, CAR-T for example.

Key Regulatory concern is patient safety, and patients are typically monitored for

longer periods of time as compared to traditional drugs and other biologics

Patients that receive gene or cell therapies are generally very sick with a high

unmet medical need. This patient demographic leads to short development times.

The high cost structure of patient-specific cell therapy results in very expensive

drug prices and resistance from payers. How can the industry get costs down?

Challenges for Process Development of AAV: (1) it hasn’t been done before, lack

of prior knowledge; (2) viral clearance for a viral product; (3) commercially

available equipment is generally designed for protein therapies not gene therapies

Manufacturing—single use, disposable. No platform experience, building a

new platform

Clinical results: only 2 approved gene therapies both with very limited patient

populations

Difficult to develop relevant potency assays for both AAV and CAR-T

AAV is single dose only because of anti-viral antibodies generated by the

patient. A single dose must last the lifetime of the patient, this may not be

achievable

Future Directions: new and improved viral vectors, gene editing methods

such as CRISPER-CAS-9, universal CAR-T cells, CAR-T for solid tumors and

T-Cell Lymphomas

Process Development for Gene Therapies

April 26, 2018



Table 8 Title: Opportunities for Rapid Cell Banking, Testing and Release of Material

Table 11 Title: Regulatory Impact and Strategies to Prepare ROW Filings with Tox and

Reference from Pool of Clone Material and to Align Non-clinical and Clinical with the

Concept of Pool of Clones for Tox

Table 8 Facilitator: James Giulianotti, Genentech, a Member of the Roche Group

Table 8 Scribe: Yanli Mi, Ph.D. (Hebe Sciences LLC)

Table 11 Facilitator: Susan Chen, Boehringer Ingelheim

Table 11 Scribe: Chris Yu, Genentech, a Member of the Roche Group

Table 8 Scope: Master Cell Bank (MCB) testing can be time-consuming and

extensive. The risks of initiating production before MCB is fully released are primarily

potential contamination to the facility and disruption to production schedule. Waiting

for full release will set back production by weeks. This table will discuss the MCB

testing and share test strategies (e.g., conditional release) for accelerating production

and mitigating the risks.

Table 11 Scope: One approach accepted by FDA and successfully used to save time

is to manufacture GLP‐Tox material using pools of high‐producing CHO clonally

derived cell lines, instead of waiting for selection of the final clonally derived cell line. A

pool of clones can be used to produce material for IND-enabling toxicology studies

during the time the final clone is being selected for clinical material production, such

that the toxicology studies can be accelerated significantly, leading to a potential

acceleration of 4 months for the IND submission. The expectation is that the pool of

clones will generate material of similar product quality and stability for use in IND-

enabling toxicology studies as was derived from the final production clone.

Master Cell Bank (MCB) Safety Test Panel for

Conditional Release for Production Prior to Full

Release • Statement:

- Time can be saved (at risk) if the MCB is used for production prior to interim or

”conditional” test release. A minimum number of safety tests can be performed to reduce

risks. Typically interim release testing is determined by company specific guidance.

However, to enable full release of drug substance material testing per ICH guidelines

must be completed.

• Discussion Points:

- GMP facility usage impacts the minimum testing requirements for interim release of

MCBs. Facilities with single use or non commercial drug substance manufacturing may

be willing to take greater risks with less testing for interim release. Sometimes companies

cannot afford to wait for > 13 weeks to get assay results.

- However, if MCB is released pre-maturely, contamination, investigation and clean-up of

the facility can cost more time to recover the damages.

- It is recommended to have the minimum test panel specified for conditional release

before the use of the MCB for production. The minimum tests include the safety test

(Microplasma, sterility and IVV tests), in order to detect potential contaminants.

Comprehensive cell bank characterization is initiated on the MCB after conditional

release.

To Manufacture GLP‐Tox Material Using Pools Cell Lines

Prior to Selecting Final Clonally Derived Cell Line• Statement:

- Toxicology material is generally produced by the GMP production process using the final

CHO clonally derived cell line, often a lengthy process involving extensive

characterization of cell growth, robustness, stability and product characterization across

a panel of clonally derived cell line candidates.

• Discussion Points:

- It is acceptable but risky practice to pool 4-6 clones together for tox and phase I study.

- It is recommended to trace and document the clonality and ensure the non-

heterogeneity from the cell bank, and to re-assure the clone population for clinical uses.

- Pooled non-clonal cell banks pose more business risks than safety concerns for the

patients. However, sometimes the speed for faster timelines outweigh other risks.

- It is recommended to use analytical tools for clone selection and cell culture parameters

to identify a clone with matching product quality attributes for Tox material when entering

clinical phases of development.

- Ideally, a clonally derived cell line is typically used to generate material for IND-enabling

toxicology studies. However, generating purified protein for GLP tox studies represents

an important and often rate limiting step in the biopharmaceutical drug development

process. GLP‐Tox material needs to be representative of clinical materials.

April 26, 2018



Table 10

Strategies to reduce “white space” –

the handoffs between groups on the project calendar

Facilitator: Jenny Chen, Nektar Therapeutics

Scribe: David Hahn, Genentech, Inc.

Where do you see white space that needs to be eliminated?

• A significant white space was identified as ”waiting for analytical output to support process

development moving forward”.

• Possible strategies to reduce the white space

• Establish in-house capability instead of using a CRO for key samples.

• Although this strategy can lead to longer-term issues due to unsustainable work

hours for analytical staff. Potential solutions would be 1) hiring more staff, if

possible; 2) inter- or intra- group cross training.

• Focus on critical data required to drive decisions and get those data as quickly as

possible.

(This may require moving forward at risk while longer lead time results, such

as sterility and mycoplasma, are still pending.)

• Consider the use of at-line or near-line methods to provide immediate feedback for key

attributes, where feasible.

• Coordination between groups is essential for eliminating white space.

• For example, the analytical group needs to deliver the control system, but can’t do this

without GMP samples. The purification group needs to deliver GMP campaigns, but can’t

do this without the control system.

• Early tox lot is usually scarce, yet required by the analytical group as reference material

for each GMP lot release.

Where do you see white space that needs to be eliminated? (continued)

• Waiting for CMO slots can be a significant challenge for an accelerated program.

• Secure slots ahead of time before there is clarity about which program will use the slots,

and swap projects as needed.

• Lack of alignment on work to be done and goals for projects can lead to white space for key

data when resources are spent on less important data (or front-loading) instead.

Other ideas for speeding development that came up during discussion

• Careful attention to risk management is needed.

• In an accelerated program, nobody gets to be in their comfort zone, and competing goals

need to be balanced.

• To support process development, initiate stability with tox lot to understand control system

earlier and better.

• It was noted that availability of sufficient samples can be an issue with this strategy.

• Continuous manufacturing of biologics is a potential strategy to speed up process

development and to simplify scale up.

• However, some analytical tests can be time consuming. Typically the next process would

already be running by the time data are available.)

april 26, 2018 south san francisco conference center ... · scribe: rob mccombie, genentech....

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