Life Sciences Product Development

Life Sciences Product Development
Weaving People, Processes, and Procedures
Together for Success

Larry K. Wray, PhD
Presented at BIO2DEVICE GROUP
March 2, 2010

© 2010 Larry K. Wray
1

To Set the Stage

 Focus will be on development of in vitro diagnostic (IVD)
tests, but aspects also apply to reagents and life science
tools, and devices
 Weave together the people, process, and procedural
elements of development, along with pitfalls and things
to look out for or anticipate, for a successful outcome
 These elements feed into two structural frameworks
 Business strategy and management (e.g. stage gate reviews)
 Compliance and regulatory requirements (e.g. design control)

© 2010 Larry K. Wray 2

Goal and Outcome
 Cover main elements of product development process,
 But, main goal and focus will be on success elements
from best practices and lessons learned from mistakes
 Resulting in reduced time to market and cost, with
improved quality and margins and in full compliance with
QSR and ISO
 Finish with trends which will change the nature of the
business


What is an in vitro diagnostic product
(IVD)?
 Definition: In vitro diagnostic products are those
reagents, instruments, and systems intended for
use in diagnosis of disease or other conditions,
including a determination of the state of health,
in order to cure, mitigate, treat, or prevent
disease or its sequelae. Such products are
intended for use in the collection, preparation,
and examination of specimens taken from the
human body. [21 CFR 809.3]


IVDs are a type of device

 Regulatory Authority: IVDs are medical devices
as defined in section 210(h) of the Federal Food,
Drug, and Cosmetic Act, and may also be
biological products subject to section 351 of the
Public Health Service Act. Like other medical
devices, IVDs are subject to premarket and
postmarket controls. IVDs are also subject to the
Clinical Laboratory Improvement Amendments
(CLIA '88) of 1988.


LDTs (Laboratory Developed Tests)

 LDTs are tests that are developed by a single clinical
laboratory for use only in that laboratory (aka “home
brews”)
 FDA generally exercised enforcement discretion over
standard LDTs
 Regulated under Clinical Laboratory Improvement
Amendments (CLIA) by Centers for Medicare and
Medicaid Services (CMS)
 Being reconsidered for tests employing complex
algorithms to generate patient results (In Vitro
Diagnostic Multivariate Index Assays, IVDMIAs)

Types of Products

 Immunoassays
 Molecular Diagnostics
 Arrays
 Sequencing
 Laboratory instruments or Point of Care (POC)
 Cancer, cardiac, drugs of abuse/ toxicology,
genetics, fertility/pregnancy, infectious disease,
metabolic, therapeutic drugs, transplant


FDA Waterfall Design Process for Design Control

Design Control Guidance for Medical Device Manufacturers, FDA CDRH, 1997


Stage Gate Process – Standard Used by Most Companies

Pietzsch, J.B. et. al. Stage-Gate Process for the Development
© 2010 Larry K. Wray of Medical Devices, J. Mol. Devices, vol. 3, 20114, 2009 9

PACE- Product and Cycle-Time Excellence
One example of a conceptual and practical background behind the
Stage Gate Process


Picking the right technology and platform

 Performance, e.g. sensitivity, reproducibility, throughput,
etc.
 Laboratory workflow (instrument footprint)
 Cost of instrument and reagents
 Breadth of applications- allows for menu expansion
 Multiplex capability
 Instrument registration- easier to go IVD route if not RUO
 Minimize number of new parts/ proven technology if
meets requirements


Defining the project scope
 Define intended use early- defines studies required
and regulatory path
 If ASRs (Analyte Specific Reagents), consider
whether a test to be developed later
 ASRs are the “active ingredients” (e.g. antibodies,
nucleic acid sequences, etc.) of tests
 Follow design control to make it easier to develop
a test and obtain approval


Project scope continued

 Decide on CLIA vs. IVD route- parallel IVD route if
CLIA to keep options open
 CLIA requirements less stringent than FDA
 CLIA restricted to single lab, can’t distribute
 FDA considering regulating IVDMIAs in CLIA labs
 Common strategy is to launch initially in CLIA lab
and follow with FDA submission


Getting Started

 Assumes the business case has been made and
basic product design decided
 Form project team
 Start team meetings
 Put together project plan
 Start executing on deliverables


The Project Team and Leader

 Include essential participants who need to contribute to projects
success
 Keep it small, with one member with decision making authority
form each functional area
 Typically R&D, manufacturing, marketing, quality, regulatory
 Extended team can include areas such as finance and customer
support
 Minimize turnover
 Decide on rules and norms at the first meeting.
 Make sure responsibilities are clear and understood.
 Hold regularly scheduled meetings and issue meeting minutes with
action item (project leader)


Planning- Focusing the Fuzzy Front End

 Moving from the “fuzziness” of discovery to the focus of
a development

“In preparing for battle I have always found that plans
are useless, but planning is indispensable.”
Dwight David Eisenhower


From Research to Development

 Companies commonly have Research (also called
Discovery) structured separately from Development
 These can be two very different cultures and mind sets
 Research is more free wheeling, whereas Development is a
more disciplined process, which is appropriate for each role
 In recruiting Development staff the particular
requirements for this process must be kept in mind
 It is important for the R and D groups to work together as
a team to transfer technology to the development
process- a relay race, not a toss over the wall!


The Development Phase Begins

 Limited, but critical set, of performance characteristics
evaluated and found acceptable to determine feasibility
of the approach prior to formally proceeding to
Development.
 Development is not discovery and should be more like building a
bridge, where the materials and plans are available and a cost
and timeframe can be reasonably estimated
 OK to proceed to Development with some risk, but this needs to
be evaluated as part of feasibility determination
 Includes both the product design and manufacturing and testing
processes needed to support the product


Developing the product

 First step is to typically optimize the product, e.g.
component concentrations, run times, etc.
 Software packages are commonly used for various experimental
designs and data display and interpretation
 Used both to optimize the procedures and also for specification
setting
 “Guard Bands” are also typically run, bracketing
acceptable ranges, e.g. component concentrations
 Evaluate with some real patient samples, not just
artificial matrixes! Start this at feasibility or have a
unwelcome surprise!


Design of Experiments (DOE)- A Standard
Approach to Assay Optimization

www.jmp.com SAS Institute


DOE- Response Surface Designs are Used
for Finding Optimal Conditions

www.jmp.com SAS Institute


Other things to incorporate in developing the
product
 Multiple lots of components (internally produced and
incoming from vendors) are evaluated for consistency
and meeting specifications
 Evaluate performance on multiple instrument platforms
to take into account variability
 Do the same with multiple operators
 Start accelerated stability studies on key components


Process development for design transfer to
operations
 In parallel with product development, manufacturing processes and
quality control (QC) tests are developed and documents drafted
 Specifications are developed for in-process and final release testing
and incoming materials
 Important to develop using equipment of same type used in
operations!
 Take into account the work flow and requirements in operations,
which could be different from R&D
 Involve manufacturing and QC personnel early in developing
procedures for transfer
 Bottom line- this needs to be an effective design transfer to
operations so things work independently in their hands!


Process and Test Method Validation

 After manufacturing process and QC test methods are developed
they have to be validated
 Drafting is typically initiated by Development or a Design Transfer
function, but the actual runs should be carried out by operations
personnel in the setting that production and testing is to be
performed
 Data from DOE studies can be used to characterize the process
parameters and the actual validation runs should challenge the
process at extremes of the ranges
 Typically three manufacturing runs are conducted for process
validation, but this number depends upon the individual process(es)
itself


Process Validation: establishing by objective evidence
that a process consistently produces a
result or product meeting its predetermined requirements

Process Validation Guidance, Global Harmonization Task Force (GHFT), 2004


Test Method Validation: Demonstrates that the
method is suitable for its intended purpose (e.g.
product acceptance testing
Type of analytical IDENTIFICATION TESTING FOR IMPURITIES ASSAY
procedure - dissolution
(measurement only)
characteristics - content/potency
quantitat. limit

Accuracy - + - +

Precision
Repeatability - + - +
Interm.Precision - + - +

Specificity + + + +

Detection Limit - - + -

Quantitation Limit - + - -

Linearity - + - +

Range - + - +

Validation of Analytical Procedures: Text and Methodology Q2(R1), International
Conference on Harmonisation (ICH), 2005


The product and processes are optimized
and ready for Design Verification

 The product design is complete when
 Performance requirements are achieved
 Formulation of reagents and assay protocol locked
 Manufacturing and QC procedures developed
 Vendors for incoming materials identified and
qualified (at least preliminarily)
 Risks identified and mitigation procedures developed
 Bottom line- this is the final product configuration (or
close to it)


Design Verification and Validation

 Verification- “we built it right”.
 Accomplished though internal testing
 Validation- “we built the right thing”
 Usually in conjunction with external clinical
studies.
 Both on final protocol, reagents, etc.


Design Verification

 Preapproved protocols with acceptance criteria to assess product
performance
 Per Design Control, Customer Requirements are translated into
Product Requirements
 Product Requirements determine acceptance criteria
 Performance characteristics such as specificity, accuracy, precision,
linear range, and reproducibility are assessed
 Studies are typically done in house
 Evaluation of more than one performance characteristic can be
combined in a given study
 Protocols can be used as templates for other products, saving time
and promoting consistency of approach


Clinical Laboratory Standards Institute (CLSI)
(formerly NCCLS) is a Source of Standards and
Guidelines Recognized by FDA
 EP05-A2 Evaluation of Precision Performance of Quantitative Measurement
Methods; Approved Guideline-Second Edition
 EP06-A Evaluation of the Linearity of Quantitative Measurement
Procedures: A Statistical Approach; Approved Guideline
 EP07-A2 Interference Testing in Clinical Chemistry; Approved Guideline-
Second Edition
 EP14-A2 Evaluation of Matrix Effects; Approved Guideline-Second Edition
 EP17-A Protocols for Determination of Limits of Detection and Limits of
Quantitation; Approved Guideline
 EP21-A Estimation of Total Analytical Error for Clinical Laboratory Methods;
Approved Guideline
 EP25-A Evaluation of Stability of In Vitro Diagnostic Reagents; Approved
Guideline
www.clsi.org


Design Validation

 Commonly the same as clinical studies
 Clinical studies an FDA requirement, at least for PMAs
 Not required under CLIA
 Usually 3-4 sites
 3 for reproducibility
 1 for analytical performance
 Purpose is evaluation in customer hands, although important to
assure proper set-up at sites, e.g. instruments in calibration
 Sometimes advisable to go to FDA for pre-IDE (pre-submission)
meeting to review approach prior to initiation of studies
 Documentation is critical, particularly for traceability, additional
analysis of data, or repeat sample runs


Regulatory Submission

 Data is a combination of internal (analytical) and external (clinical)
studies
 Development typically prepares the technical part of the package,
with Regulatory Affairs being responsible for the submission per se,
along with follow-up and ongoing coordination with FDA and
international agencies
 Repeat: for a new technology or novel intended use, best to meet
with FDA prior to clinical studies for pre-IDE
 Approvals typically in about 90 days for 510ks and a year for PMAs,
but “clock” can stop during review, delaying approvals
 CE Marking for EU, which can either be self-certified or require a
Notified Body


Projects that ran into problems and lessons
learned- Transferring New Technology
 A project plan for a new molecular diagnostic product line was
developed and communicated without taking into account new
technology transfer
 A new DNA amplication technology was licensed and transfer
was underway. Timelines were committed to prior to
demonstration of feasibility. The technology was not as
straightforward to incorporate into a product, as originally
anticipated. As could be expected, the project slipped and the
entire program was impacted.
 Lesson: New technology might not be directly adaptable for a
new application, without optimization or modification. Account
for this as part of project and business planning.


Problems and lessons- Moving from a Tool
to an IVD
 A 510k was submitted for a molecular diagnostic with an instrument
platform that had not been cleared
 A product was developed using a Research Use Only (RUO)
instrument and associated reagents, with the assumption that
this would be acceptable to FDA, based on previous experience
and “assumptions”. The agency would not accept this, resulting
in much time and expense retrofitting the instrument, along with
developing specifications for reagents and consumables.
 Lesson: If you plan to ultimately submit for FDA approval,
develop the product under design control on a cleared platform
or plan on submitting the platform for approval.


Problems and lessons- Incorporating New
Processes
 A new process was introduced into a major component of a product
under development
 A new labeling process was introduced for a probe in an In Situ
Hybridization (ISH) product. The process was not reproducible,
resulting in the project being be put on hold. Loss of credibility to
the team and at least a year delay on the project resulted.
 Lesson: Don’t try to parallel a new, untested, major process
change while trying to develop a product in which it will be a
major component. If this is desired, allow the time and have a
more feasibility based timeline. New processes need to go
through process development!


Problems and lessons- Maintaining Good
Laboratory Practices
 An Analyte Specific Reagent (ASR) was later decided to be
submitted as a 510k
 ASRs are components of products, which are not required to be
developed under Design Control.
 This ASR was not even done under Good Laboratory Practices
(GLP), with a lack of documentation, for example.
 The project was delayed significantly and much of the work had
to be repeated.
 Lesson: Think ahead. Employ at least GLP in developing any
component, but better to at least follow the main elements of
Design Control. It’s OK to add more later, not to have to repeat
work!


Problems and lessons- Design Transfer to
Operations
 Failures occurred frequently in QC on the same product which
passed routinely in Development
 A sequencing based product was transferred to operations which
previously had no problems in Development. No one could
seem to make in in Ops, but when it came back to Development,
no problem. Additional training (this was a somewhat technique
dependent protocol) and review of specifications was required.
 Lesson: Involve operations early in transferring a new process
or QC procedure and develop procedures and specifications that
take into account people, process, equipment, and facilities in
operations. It’s not transferred if they can’t make it!


Problems and lessons- Setting
Specifications for Incoming Materials
 A molecular diagnostic, which had been on the market for several
years, suddenly stopped working
 Upon investigation, the vendor introduced a new process for
making a key component. The material still met incoming specs!
Ultimately the issue was resolved by refining the specifications
and negotiating a modification in the process with the vendor.
 Lesson: Understand attributes of a component that critical and
set specifications accordingly. Don’t just incorporate off the self
specs that might have been set for a different application. Also,
use vendors whose processes are under control and are ISO
certified, if at all possible. If possible, write into supply
agreements requirements for vendors to inform you of process
changes to materials.


Problems and lessons- Communicating with
the FDA
 Additional studies supporting submission of a major product for an
established manufacturer had to be done after the submission went
to FDA (and after several months of review).
 Samples were not always available, along with resources, to
conduct the studies. This resulted in a significant delay in
approval (well over a year), increased cost, lost sales and
market share, and considerable trauma to the organization.
 Lesson: Communicate early with FDA (e.g. pre-IDE) and make
sure the communication is understood both ways. Don’t make
assumptions, e.g. “they won’t require this” or “they haven’t asked
for this before”. Document samples and studies well. Read
Decision Summaries of comparable products.


Emerging Trends for IVDs

 Personalized Medicine
 Detailed information from the Human Genome Project is
revolutionizing IVDs
 Differentiate disease susceptibility, drug reactions and response
 Moving from single markers to multiplex assays which
incorporate algorithms for data interpretation (IVDMIAs)
 More extensive studies can be required to demonstrate
clinical utility
 Companion diagnostics- challenges in coordinating drug-
diagnostic development and with regulatory path


Emerging Trends (2)

 Technology is developing rapidly
 Next generation sequencing (NGS)
 Approaching the $1000 personalized sequence

 Arrays- DNA printed on plastic, glass, or silicon chips
 Allows investigation of 1000s of sequences (e.g. SNPs,
Single Nucleotide Polymorphisms)
 Microfluidics
 “Lab on a Chip”- Point of Care (POC) testing

 Much of this will and is migrating from tools to diagnostics
space with product development and regulatory
implications

Lab-on-a-Chip (LOC)

Agilent Technologies www.agilent.com


Emerging Trends (3)

 With the new FDA administration, the
regulatory climate is changing
 More restrictive use of 510ks- tightening
definition of predicate devices
 More oversight over LDTs, e.g. IVDMIAs


Emerging Trends (4)

 Healthcare costs, legislation, and taxes
 Questions to ask of a proposed new product
 How will this impact healthcare decisions?
 What impact will this have on cost?

 Who will pay for it?

 Impactof potential legislation unclear
 What will the impact of any changes to tax
code be on innovation?


Emerging Trends (5)

 Emerging economies
 Growing new markets, e.g. China
 Understanding new markets and regulatory climate
 New technology shift overseas
 New technology will increasingly come from outside
U.S.
 Product development and clinical trials are also
shifting overseas
 All of this calls for a less U.S. centric view


Some Take Homes

 The right team and team dynamics is critical
 Early planning is important
 Define intended use and strategy
 Anticipate obstacles and formulate alternative paths
 Understand the technology and processes thoroughly,
optimize, and set appropriate specifications
 Maintain good documentation, follow GLP, QSR/ISO
 Design and develop to customer requirements (both external
and internal)
 Communicate with FDA early and understand expectations


Some Resources

 Food and Drug Administration www.fda.gov
 FDA Office of In Vitro Diagnostics (OIVD)
http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagn
ostics/default.htm
 European Commission (Medical Devices)
http://ec.europa.eu/enterprise/sectors/medical-devices/index_en.htm
 European Diagnostics Manufacturers Association www.edma-ivd.be
 Global Harmonization Task Force (GHTF) www.ghtf.org
 International Conference on Harmonization (ICH) www.ich.org
 Clinical and Laboratory Standards Institute (CLSI) www.clsi.org
 IVD Technology www.devicelink.com/ivdt
 American Association for Clinical Chemistry www.aacc.org


Contact Information

Larry K. Wray, PhD
(925) 596-4344
lkwray@msn.com


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