The Challenges of Adopting Innovation and Technological … presentation... · 2019-08-30 · The Challenges of Adopting Innovation and Technological Changes in the Pharmaceutical

The Challenges of Adopting Innovation and Technological Changes

in the Pharmaceutical Sector in the Absence of Regulation.

Shawn R. Gould

Director, Pharmaceutical Regulatory Compliance

Johnson & Johnson Regulatory Compliance

VIII Symposium Sinusfarma, Brasilia, June 18-19, 2019

Disclaimer

• The thoughts and opinions expressed in this presentation belong solely to

the author and do not necessarily represent Johnson & Johnson, Janssen

Supply Chain, or any other subset of J&J.

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Agenda

3

Introduction

Health Authority Innovation

Industry Innovation (in the absence of regulations)

Conclusions

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Introduction

• David Churchward – Deputy Unit Manager, Inspectorate Strategy and

Innovation (expert GMP Inspector) at MHRA

• Application of current GMP to

new technology … • Why Innovate?

4

Introduction

• David Churchward – Deputy Unit Manager, Inspectorate Strategy and

Innovation (expert GMP Inspector) at MHRA

• What about Regulatory

Innovation?

5

Introduction

• Regulation is not intended to be a barrier to innovation …

… but written in general terms to

allow flexible implementation.

Regulations frequently give a

framework of what is

needed but not specifics on how.

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Introduction

How do we best proceed?

Rely on foundational principles of:

• Current Good Manufacturing

Practices

• Sound science

• And risk based approach to

problem solving

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Health Authority Innovation

Historical Perspective of Regulation

• Regulations are frequently passed in response to a public health issue

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Health Authorities Have Made Efforts to

Become More Proactive

• Quality Systems guidance - 6-System Audit

• Pharmaceutical Quality for the 21st Century

• Working with ICH to harmonize regulation across the globe

• Workshops, forums, symposia, and continued industry interaction

• Mutual Reliance Agreements

• Proposed Quality Metrics Initiative

• Prescription Drug User Fee Act / Generics / Biosimilars

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Innovative Review Strategies and Designations

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• Fast Track

– Designed to facilitate the development, and expedite the review of drugs to

treat serious conditions and fill an unmet medical need

• Serious Condition - based on whether the drug will have an impact on such

factors as survival, day-to-day functioning, or the likelihood that the condition, if left

untreated, will progress from a less severe condition to a more serious one.

• Unmet Medical Need - providing a therapy where none exists or providing a

therapy which may be potentially better than available therapy

https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track

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• Fast Track

– More frequent meetings with FDA to discuss the drug's development plan and ensure

collection of appropriate data needed to support drug approval

– More frequent written communication from FDA about such things as the design of the

proposed clinical trials and use of biomarkers

– Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met

– Rolling Review, which means that a drug company can submit completed sections of

its Biologic License Application (BLA) or New Drug Application (NDA) for review by

FDA, rather than waiting until every section of the NDA is completed before the entire

application can be reviewed.

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• Breakthrough Therapy

– Designed to expedite the development and review of drugs that are intended to treat a

serious condition and preliminary clinical evidence indicates that the drug may

demonstrate substantial improvement over available therapy on a clinically

significant endpoint(s)

– Clinically significant endpoint generally refers to an endpoint that measures an effect

on irreversible morbidity or mortality (IMM) or on symptoms that represent serious

consequences of the disease.

https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy

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https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy


• Breakthrough Therapy

– A drug that receives Breakthrough Therapy designation is eligible for the

following:

• All Fast Track designation features

• Intensive guidance on an efficient drug development program, beginning

as early as Phase 1

• Organizational commitment involving senior managers

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• Accelerated Approval

– When studying a new drug, it can sometimes take many years to learn whether a drug

actually provides a real effect on how a patient survives, feels, or functions. A positive

therapeutic effect that is clinically meaningful in the context of a given disease is known

as “clinical benefit”.

– A surrogate endpoint used for accelerated approval is a marker - a laboratory

measurement, radiographic image, physical sign or other measure that is thought to

predict clinical benefit, but is not itself a measure of clinical benefit

– For example, instead of having to wait to learn if a drug actually extends survival for

cancer patients, the FDA may approve a drug based on evidence that the drug shrinks

tumors, because tumor shrinkage is reasonably likely to predict a real clinical benefithttps://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval

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https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval


• Priority Review

– A Priority Review designation will direct overall attention and resources to the

evaluation of applications for drugs that, if approved, would be significant

improvements in the safety or effectiveness of the treatment, diagnosis, or prevention

of serious conditions when compared to standard applications.

– Significant improvement may be demonstrated by the following examples:

• Evidence of increased effectiveness in treatment, prevention, or diagnosis of condition;

• Elimination or substantial reduction of a treatment-limiting drug reaction;

• Documented enhancement of patient compliance that is expected to lead to an improvement in serious outcomes; or

• Evidence of safety and effectiveness in a new subpopulation.

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https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review

https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review

Innovative Review Strategies

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Serious

Condition

Unmet

Medical Need

Surrogate

Endpoint

Improvement

over available

therapy

Fast Track Y Y - -

Breakthrough

Therapy(Y) (Y) - Y

Accelerated

ApprovalY Y Y -

Priority Review Y - - Y

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Continuing to Evolve Regulatory Innovation

• Continue to collaborate

with international

organizations to

streamline guidance and

regulations… ICH Q12 and

Q13 are prime examples!

• Mutual Reliance

agreements ensure quality

products without excessive

(and non-value added)

inspections

• Consistency … both within

and between agencies

Industry Innovation (in the absence of regulation)

• Reality is that Regulation will always lag Innovation …

… better to say Innovation will always lead Regulation

• Evolution of Pharmaceutical Processing

Industry Innovation Examples(in the “absence” of regulation)

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• Sterile Filtration– 0.45μm

– 0.22 μm

– Dual membrane filters

– Redundant filters in series

• Aseptic filling– Laminar Flow Hood

– Restricted Area Barrier System

– Isolator

– Closed processing / filling

• These are worthwhile improvements which improve drug product quality!

• Continuous Manufacturing

• Gene Therapy / CAR-T

• Process Validation

Industry Innovation Examples(in the “absence” of regulation)

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Continuous Manufacturing(in the “absence” of regulation)

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FDA Perspectives on Continuous Manufacturing, Sharmista Chatterjee, Ph.D, January 2012

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https://www.pharmamanufacturing.com/assets/Media/2016/1604/Janssen-CM.pdf


• Early Adaptors of Continuous Manufacturing


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Pharma's slow embrace of continuous manufacturing, Ned Pagliarulo, BioPharmaDive, Sept 24, 2018

• So why aren’t we there already? Why is this taking so long?

– Continuous Manufacturing brings many benefits to the table

• Faster / more flexible manufacturing

• Fewer Processing Steps / Less down time

• Smaller footprint

• On-line monitoring and control … better, more consistent quality


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• So why aren’t we there already? Why is this taking so long?

– Continuous Manufacturing brings some disadvantages

• Leading edge vs bleeding edge technology

• Expansive base of batch production manufacturing facilities / Expensive to

install as a singular system

• Value Proposition to transition from batch to continuous process for existing

products (batch process now vs CM in 9 months at ??? extra cost)

• Regulatory uncertainty


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• Regulatory uncertainty

– "A lot of companies that are looking to get into continuous are global companies. Even

though the U.S. Food and Drug Administration is a strong advocate of this, there is to a

certain extent the uncertainty from other markets in terms of how easy it would be to get

approvals.“

- Douglas Hausner,

Associate Director - Manufacturing Research Cente

Rutgers School of Engineering

– "The lack of global harmonization of regulatory requirements for [continuous manufacturing]

has been identified as the primary barrier to adopting this promising emerging technology,“

- PhRMA spokesperson


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Pharma's slow embrace of continuous manufacturing, Ned Pagliarulo, BioPharmaDive, Sept 24, 2018


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• Regulatory uncertainty … if you remove it, they will come.


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• Regulatory uncertainty … if you remove it, they will come.


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Gene Therapy / CAR-T(in the “absence” of regulation)

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Gene Therapy / Chimeric Antigen Receptor – T-cells(in the “absence”

of regulation)

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• Challenges in CAR-T manufacturing

– Gene Therapy is a newer technology without a mature regulatory history


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– Complex supply chain / chain of custody• Apheresis center

• Cryopreservation

• Plasmid manufacturing

• Vector manufacturing (drug substance)

• CAR-T manufacturing (drug product)

• QC testing … many times at contract

laboratories

• Return of modified T-cells to patient at bedside

– HIGHLY variable starting material• Different genetic backgrounds

• Stages of disease

• Medical history

• Patient weight

• Distance from manufacturing center

• Global expectations of Gene Therapy products

– Recommendations for Microbial Vectors Used for Gene Therapy; Guidance for Industry –

September 2016

– Advanced Therapeutic Medicinal Product – EMEA - November 2017

– Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy

Investigational New Drug Applications (INDs); Draft Guidance for Industry – July 2018


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https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-microbial-vectors-used-gene-therapy

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/chemistry-manufacturing-and-control-cmc-information-human-gene-therapy-investigational-new-drug


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• Regulatory turmoil, while still dealing with

– Technical challenges

– Logistic nightmares / chain of custody problems / supply chain complexity

– Starting material variability

• Remember, there are still ways to positively impact these applications:

– Accelerated Approval … but this can create it’s own problems

– Fast Track / Breakthrough Therapy status … • More frequent meetings

• More frequent written communication / feedback


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Process Validation(in the “absence” of regulation)

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Process Validation (in the “absence” of regulation)

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• Guidance was published

with no modification to

the regulations


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• Guidance was published

with no modification to

the regulations

Difference between FDA Documents: Acts, Regulations, & Guidances

• Federal Food, Drug, and Cosmetic Act (FD&C Act)

– Enacted by Congress in 1906

– Establishes legal framework within which FDA operates

• FDA Regulations (Code of Federal Regulations – CFR)

– FDA follows the Administrative Procedure Act to issue FDA regulations

– Involves process known as “notice and comment rulemaking” that allows for public input on proposed regulations prior to issuance

– Issued by FDA

• FDA Guidance (Guidance for Industry – Process Validation)

– FDA follows the procedures required by its “Good Guidance Practice” regulation to issue FDA guidance (21 CFR 10.115)

– Guidance is issued by the agency and is not legally binding on the public or FDA


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• How is the FDA Guidance enforced?

• §211.100(a) – (a) There shall be written procedures for production and process control designed to assure that

the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

• §211.110(a) – To assure batch uniformity and integrity of drug products, written procedures shall be established

and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate

samples of in-process materials of each batch. Such control procedures shall be established to monitor the output

and to validate the performance of those manufacturing processes that may be responsible for causing variability

in the characteristics of in-process material and the drug product.

• §211.110(b) - Valid in-process specifications for such characteristics shall be consistent with drug product final

specifications and shall be derived from previous acceptable process average and process variability

estimates where possible and determined by the application of suitable statistical procedures where appropriate.

Examination and testing of samples shall assure that the drug product and in-process material conform to

specifications.


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• Regulations were

reinterpreted without

changing the actual text.

• A review of Warning

Letters for 2018 shows

that Process Validation is

cited VERY frequently.

January 2018 PV Warning Letter

• You did not perform process performance qualification studies for

your (b)(4) OTC drug product, and you lack an ongoing process control

monitoring program to ensure stable manufacturing operations and

consistent drug quality











• Highlighted wording was found in total of 12 of

the 21 warning letters issued between Jan -

Sept 2018


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• Lifecycle Process Validation Implementation has generally gone well for big

pharma, but there have still been may difficulties

• Guidance was issued in 2011 … many Warning Letters still in 2018

• New expectations like Continued Process Verification have very wide

interpretations by industry. The Guidance only explains so much.


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Conclusions

• Regulation is not meant to be a barrier to innovation,

– But it can contribute to uncertainty

– In certain situations, it could be the deciding factor in a company deciding to

pursue or reject a potential product

• Regulators have tools to encourage and facilitate good communication /

decrease unknowns.

• Industry and Health Authorities should continue to engage at all levels and

at every opportunity to continue to find joint solutions and to build sensible

regulations / guidance documents.

Conclusions

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Thank you.