Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Formal QbD pilot program / organization / special project somewhat implemented for Pilot,
implemented for Rollout
Standard development processes built upon QbD principles somewhat implemented for Novice
and Pilot, implemented for Rollout and Fully implemented
QbD principles "built in" to our regular Regulatory CMC processes somewhat implemented
for Rollout, implemented for Fully implemented
Stage-gate process for CMC program review somewhat implemented for Pilot, implemented
for Rollout and Fully implemented
Incentive alignment amongst development & manufacturing implemented for Rollout and Fully
implemented
Talent acquisition and management implemented for Rollout and Fully implemented
Participation in industry / regulatory groups somewhat implemented for Novice, implemented
for Pilot, Rollout, and Fully implemented
Capability / training programs for personnel somewhat implemented for Pilot, implemented
for Rollout and Fully implemented
Standardized equipment somewhat implemented for Rollout, implemented for Fully implemented]
Potential next steps to continue building business case
Moving Iorward, there are many things that can be done to continue to build and
substantiate the business case.
Bring together industry leaders to share case examples encourage sharing oI
real, speciIic numbers
Build library of business impacts Irom pilot and other QbD applications
Confidential Page 19
Continue to invest in a deeper understanding of where value is coming from
and what must be in place to achieve this value
This potentially could involve a project-by-project based analysis, building
an understanding oI baseline development perIormance and how that is
diIIerent than when utilizing QbD (i.e., time and eIIort to develop and Iile
by phase, technical transIer and scale up, process outcomes in terms oI
quality, cost and perIormance, one time costs)
One could bolster this analysis with an examination oI the various operating
systems and management inIrastructures companies have in place to
determine which have the greatest impact on the business case
IMPLICATIONS FOR FDA
Our research has highlighted many challenges to the implementation oI QbD. These
challenges indicate several areas that the FDA may consider addressing in order to speed
QbD adoption. The actions the FDA can take become more tangible when applied to the
segmentation oI drug type and level oI adoption.
Potential options to consider
We have identiIied several options the FDA can consider to enhance QbD adoption.
These options Iall into several areas FDA policy, internal FDA change management,
and external change management.
FDA Policy options
1. Define and codify incentives. Although the FDA may or may not
believe there are beneIits to Iurther deIining and codiIying incentives,
Irom our conversations with industry, it is clear many companies see
this as a powerIul way to incentivize QbD adoption. We recommend
the FDA consider analysis to understand what such incentives could be
(e.g., a Iaster review process, easier to change processes later on), and
what beneIits could come Irom adoption oI these incentives.
2. Develop tangible guidance for QbD execution. Companies,
especially in early stages oI adoption, have identiIied conIusion around
what QbD means and how to actually execute as a huge challenge.
They strongly believe they could beneIit Irom more tangible guidance.
Issues raised Irom the regulatory side against increased direction are
around a Iear oI creating guidance too early, while things are still
being 'Iigured out, as well as Iear oI being too prescriptive. Although
there are valid concerns around the dissemination oI more direction, it
is a clear need within industry that the FDA is able to, and should
meet.
3. Mandate. Some drug areas, Ior example several areas within the
Generics industry (e.g., controlled and modiIied release drugs), have
had numerous saIety issues. For drugs such as these, where there is a
public health risk due to lack oI process understanding, mandating
Confidential Page 20
QbD is a reasonable option. As long as Iirst to Iile` exists in the
Generics industry, there is a strong argument that unless the quality oI
scientiIic understanding is raised Ior all applications, companies will
continue to cut corners` to Iile as quickly as possible disadvantaging
those companies that seek to gain a deeper scientiIic understanding,
and potentially putting patient saIety at risk.
Internal FDA change management
1. Ensure consistency of review process in terms of scientific
knowledge and quality of review. The desire Ior a consistent review
process and well trained reviewers is unanimous throughout industry.
The FDA is aware oI this need and has been working to train and
educate reviewers to prepare them to handle QbD applications. The
FDA is also exploring utilizing teams oI reviewers to handle
applications rather than a single reviewer. The FDA should continue
to pursue consistency in the quality oI its reviews.
2. Harmonize the approach to QbD across the FDA. There is a need to
harmonize QbD practices and requirements across FDA including OPS
and associated Iunctions e.g. compliance and inspectors. The current
state where decisions around QbD are sometimes called into question
or even overturned when areas subsequent to OPS review are involved
has the chance oI eroding or even stopping the momentum around
QbD adoption in industry. FDA should present a uniIied approach to
QbD regardless oI the section oI FDA that a company is interacting
with at a particular time.
However, opinions are split on whether or not the OPS should have a
uniIorm approach to QbD across its three oIIices. Since the oIIices
deal with such diIIerent products, it may be impossible, and potentially
harmIul to try and assign a single approach. At the same time,
completely diIIerent approaches can be very conIusing. The FDA
should establish one clear, broad deIinition oI QbD to be utilized by
OPS. Each oIIice can then tailor that broad deIinition with an
approach that is best suited to its drug type.
External change management
1. Change the method of communication. Industry almost universally
asked Ior more Irequent, 'no risk dialogs with the FDA. The
companies who participated in the pilot programs Ielt they beneIited
Irom the increased, and oIten less Iormal communications. There are
Ieelings that 'no risk dialogs are impossible, as the FDA needs to
protect public saIety and cannot aIIord to oIIer any immunity areas.
There is also a Iear that anything said by the agency, even iI in a
casual` conversation, could be taken as oIIicial opinion.`
Additionally, more meetings would put an even greater resource
constraint on the FDA. Despite the constraints Ior the FDA, there
needs to be a reassessment oI the FDA`s interaction with industry. A
system should be craIted that allows Ior more dialogs in a manner
comIortable to both FDA and industry.
Confidential Page 21
2. Create more buy-in by disseminating case examples. Industry has
made a clear call Ior real, tangible examples oI what the FDA has
actually approved or rejected and why. However, there are legal
barriers Ior the FDA in disclosing this inIormation. The FDA can
work with companies who have had successIul applications, to
develop more understandable examples, with which both sides
(industry and the FDA) are comIortable sharing publically.
Additionally, the FDA can continue to disseminate Iindings and tips on
successIully navigating challenges as they work with companies.
3. Improve international harmonization. There are questions around
whether or not the FDA is responsible Ior addressing international
harmonization oI QbD acceptance. This is an area worth at least
examining as the FDA is currently one oI the biggest proponents oI
QbD and the lack oI international harmonization is one oI the biggest
challenges raised by companies. The FDA should continue to seek
opportunities to work with other regulatory bodies (e.g., joint reviews).
The FDA should work to ensure alignment on what QbD means,
what`s required and how regulatory Ilexibility can be granted.
4. Utilize a 3
rd
party model as a means of catalyzing and
standardizing QbD within industry. There is a call Ior more
substantial direction Irom and interaction with the FDA. Clearly this
is putting a great resource strain on the agency. One way to alleviate
this strain would be to promote the use oI a 3
rd
party model as a means
Ior Iurther education and QbD development.
Implications for different drug types
New Drugs: Rapidly drive adoption. New drugs manuIacturers are the most
mature in terms oI their adoption oI QbD. There is potential Ior the FDA to
continue to push more New Drug companies to adopt QbD, utilizing learnings
Irom other companies` success (i.e., real case examples) to help Iacilitate
understanding and adoption. Although, we have not heard strong anecdotal
case Ior QbD changing the patient saIety Ior New Drugs, it seems this is an
appropriate area to provide incentives Ior adoption.
Generics: Consider mandate or policy change. In the generics arena there
have been a number oI examples where rushing to Iile and a lack oI process and
product understanding has led to serious patient saIety issues. Although this
has yet to be codiIied iI it was codiIied and accepted by the health community
there may be a good argument to make QbD a mandate Ior some types oI
Generic Iilings. Even iI Iull blown QbD is not made a mandate, there is
potential to make the process understanding required within applications more
detailed, and to make some oI the optional` parts oI QBR mandatory.
Biologics: Do not give up on QbD. Although many manuIacturers site QbD
as being impossible, especially with upstream processes our interviews
indicate this is not true. Many biologics manuIacturers are applying QbD to
downstream processes with great results. These manuIacturers believe that
QbD is even more important Ior Biologics as the molecules are more complex,
a deeper understanding will lead to better product. There is no reason why
Confidential Page 22
QbD should not apply to biologics. The FDA should continue to be patient,
disseminate success stories, and hold Iorums concerning QbD Ior Biologics
companies. Over time, the case Ior QbD Ior biologics will become increasingly
clear.
Implications for different levels of adoption
Novice: Ensure understanding. The FDA should ensure Novice`s understand
what QbD really means, and what the potential beneIits are. There is potential
to distribute more case examples and ensure codiIication oI beneIits is clear.
There is also potential to invite novices to workshops or a QbD Academy`
where the basics are covered and the FDA can train ambassadors` to bring a
more nuanced understanding oI QbD back to their company.
Pilot: Help with internal issues. As companies begin piloting QbD, they Iace
many internal issues, including internal misalignment, and limited knowledge
oI QbD techniques. There is potential Ior the FDA to disseminate best
practices` or a more tangible how-to` guide. There is also potential to hold
seminars / workshops where more experienced QbD companies discuss the
challenges they Iaced in implementation and lessons learned. Additionally,
more casual interaction with companies in a collaborative manner will be
crucial as they develop QbD programs.
Rollout: Work through external issues. Companies in the rollout phase have
usually begun to work out their internal issues, and are more Iocused on
external challenges. It will be crucial to improve the interaction with
companies to be more open. Companies at this phase oI adoption are looking
Ior how to have a more collaborative role with the FDA in making the QbD
application process run smoothly. Additionally, it will be very important Ior
the reviews to be consistent and oI a high quality.
Fully implemented: Collaborate. There is potential Ior the FDA to work with
companies at a very mature state oI adoption to build case studies and share
best practices. The FDA can Iacilitate industry leader Iorums where companies
debate some oI the more complicated issues Iacing QbD, such as what is means
Ior suppliers and contract manuIacturers.
Confidential Page 23
APPENDIX
Comprehensive data mining efforts
List of articles examined for this project
Avellanet, John, 'Why Quality by Design? An Executive`s Guide to the FDA`s
Quality by Design. Cerulean Associates, March, 2008.
Fuhr, Ted, Michele Holocomb and Paul Rutten. 'Why 'Quality by Design'
should be on the pharma CEO's agenda March 2009, McKinsey & Co.
Operations Extranet.
Ginsberg, Peter L., Sandeep Bhatia, and Rachel L. McMinn, 'The road ahead
Ior biologics manuIacturing. January 2002.
McKinsey White Paper: 'TransIorming to the Desired state oI cGMPs Ior the
21st Century.
Neway, Justin. 'How to Make the Business Case Ior Quality by Design.
BioPharm, December, 2008.
Paskeit, Diane M., 'QbD and Parentals: Strategies Ior assessment oI leachable
in parental drugs. Contract Pharma, April, 2009,
http://www.contractpharma.com/articles/2009/04/qbd8200and-parenterals.
Pickett, Joseph, 'CMC pilot program succeeding in integrating concepts oI
QbD. Inspection Monitor, February, 2007,
http://www.entrepreneur.com/tradejournals/article/159645395.html.
Quality by Design is Essential in the New U.S. Regulatory Environment, Aegis
Analytical Corporation, www.aegiscorp.com.
Rathore, Anurag. 'Roadmap Ior implementation oI quality by design (QbD) Ior
biotechnology products. August, 2009.
Snee, Ronald D., Philipple Cini, Jason Kamm, and Chester Meyers, 'Quality
by Design: Shortening the Path to Acceptance. Pharmaceutical Processing.
Tunnell Consulting,
http://www.pharmpro.com/ShowPR.aspx?PUBCODE021&ACCT0000100
&ISSUE0802&RELTYPEPR&ORIGRELTYPEATO&PRODCODE000
0&PRODLETTY&CommonCount0.
Snee, Ronald D., 'Quality by design: Four years and three myths later.
Pharmaceutical processing, February 1, 2009,
http://www.pharmpro.com/ShowPR~PUBCODE~021~ACCT~0015856~ISSU
E~0902~RELTYPE~PR~ORIGRELTYPE~ATO~PRODCODE~4315~PROD
LETT~A.html.
Confidential Page 24
Somma, Russ, 'How Quality by Design Is Changing Drug Development: Without
QbD thinking, sponsors` attempts to address FDA 'complete response letters may be
doomed. SommaTech Consulting, http://www.pharmaqbd.com/node/90.
Somma, Russ and Andre A. Signore. 'Embracing Quality by Design: Applying
concepts can help CMOs Create Value,
http://www.ipsdb.com/pdI/insight/EmbracingQualitybyDesignApplyingQbDconcept
scanhelpCMOscreatevalue.pdI.
Spurgeon, Tom. 'Quality by design in Solid Dosage Processes: How will QbD impact
manuIacturing?
http://www.ipsdb.com/pdf/insight/EmbracingQualitybyDesign_ApplyingQbDconcepts
canhelpCMOscreatevalue.pdf.
Conferences / Presentations
'Implementation oI Quality by Design in New Product Development, GSK, Peter
Watmough (senior development scientist), Laura Morris (process development
engineer).
Peri, Prasad, 'Quality by Design (QbD) Approaches Ior Orally inhaled and Nasal
Drug Products (OINDPs) in the USA. OIIice oI New Drug Quality Assessment
(ONDQA), OPS, CDER. RDD Europe 2007.
PhARMA perspective conIerence: 'Potential barriers to QbD implementation.
September, 2009.
'Sandoz: Pioneering Global development oI Biosimilars, Bio Super Session, June
17th, 2008, Freidrich Nachtmann, PhD. Head oI Biotech Corporations, Sandoz
GmbH.
Somma, Russ. Using Quality by Design (QbD) in Designing Efficient, FDA
Compliant Pharmaceutical Manufacturing Processes and Facilities: What is the
Impact? SommaTech, LLC.
Winkle, Helen. 'Evolution oI the Global Regulatory Environment: A Practical
Approach to Change, PDA / FDA Joint Regulatory Conference: Implementing
Quality by design. September, 2007.
Yu, Lawrence. 'Pharmaceutical Quality by Design: Regulatory Perspectives.
Additional quotes supporting challenges
Internal Misalignment: Disconnect between leadership and middle management
'People are at diIIerent stages within diIIerent Iunctions in terms oI Iiguring
out how to do things leadership agrees with the general mantra, but the
groups that need to execute don`t understand how to deliver
'Middle management understands QbD but the lower or higher into the
organization you get there are misunderstandings
We have pockets and silos oI QbD going on but are not united overall
Internal Misalignment: Misalignment horizontally across the organization
'R&D is 100 incentivized on the quantity oI Iilings they get
Confidential Page 25
'The biggest challenge is getting alignment within a company to support
many players need to be involved Ior this to be executed successIully
'The groups that stand to get the most beneIit Irom QbD are not the same that
bear the brunt oI the (perceived) risks and costs
'There is no credit` Ior helping out with these issues |understanding biologics
CQAs| and so the progress is slow
Internal Misalignment: Culture of conservatism
'We need to ensure everyone understands the paradigm shiIt today the best
CMC strategy is to not show all your cards
'Smart people get into a company and are trained to do things a certain way
they get stuck we have to open people`s minds back up to understand QbD
'There is a resistance to eliminating QC resources
'People believe development is an art Iorm and ask, how can you make a
platIorm out oI an art Iorm?`
'We have a history oI playing by the old rules
Internal Misalignment: The amount of change required within company is not
feasible
'Adoption oI QbD will require remodeling oI the entire operating model it`s
a huge change
'In order to get the beneIits Irom this we would have to totally redesign our
entire development process QbD is not enough oI a priority to do that
'For this to work it`s more than just QbD you need lean alignment, 6 sigma,
and an organizational culture element
'We needed to restructure manuIacturing and development to recognize the
multi-Iunctionality necessity to support these initiatives
'SigniIicant change is required at manuIacturing site when you implement
QbD
'Although it`s now implemented, this new radical approach |redesigning
development program| took a while to get an embed and get real acceptance
Internal Misalignment: QbD remains low on the priority list
'When a manager looks at the list oI things he needs to do, QbD
implementation is not high up there
'Unless this is a mandate Irom above, there is no reason to do this beIore
something else
Lack of belief in business case
'Planning Ior a QbD Iiling requires a huge investment oI time and eIIort early
in development, beIore you even know iI the product will make it to launch
'There is a lot oI uncertainty over timing oI and investment requirements Ior
QbD implementation
'Re-usability oI knowledge gained on one product in support oI another is
uncertain
'I`m not sure QbD will have any beneIits that will truly change the saIety /
eIIicacy oI a drug
'We have some drugs Ior which the increased Ilexibility would not be helpIul
'We need to build out scenic understanding this requires many resources,
many people, many hours, and many expensive studies
'This costs more because it really is around making more and more batches
amount oI analytical testing
Lack of technology to execute: Insufficient solution for controlling variability of
raw materials
Confidential Page 26
'QbD does not address raw materials that`s the biggest cause oI variability
Ior us
'A robust raw material management system needs to be in place to Iacilitate
QbD implementation. Critical raw materials signiIicantly impact product
quality and should thereIore be thoroughly characterized
3
'We need a better understanding oI excipients, what are their properties?
Their Iunctionalities?
Lack of technology to execute: Limited understanding of implications of quality
attributes
'You will never know enough about your materials and process to be able to
change as you go through
'This is a really big problem Ior large molecules, we are just not very clear
about what aspects are doing what
'We just don`t understand the biological signiIicance oI CQAs there is
misplaced conIidence in being able to Iigure this out
'Vaccines will be an issue, we have always built consistency into the process
without knowledge oI what was going on, we need better technology to get
there
Lack of technology to execute: Knowledge of QbD techniques limited
'In order to make some oI the new types oI measurements we will need to
develop new skill sets and get new technology
'Developing the technical tools and standardized processes necessary was a
big challenge
Lack of technology to execute: Difficulty with data management
'In order to make some oI the new types oI measurements we will need to
develop new skill sets and get new technology
'There is a challenge monitoring a product in late development to understand
how a process is playing out since there is such a huge volume oI inIormation
'We will need more statisticians with diIIerent skill sets and more education to
be able to handle all this new data
'For older products we are having diIIiculty with knowledge management, the
data could be stuck on someone`s hard drive somewhere
Alignment with 3rd parties
'It will be diIIicult Iiguring out the best way to provide guidance Ior outside
partners heavily engineer vs. brute Iorce . it will be more complicated to
bring them along since all resources are not under complete control
'QbD is a space to redeIine relationships with suppliers hopeIully it will
give more Ireedom in terms oI changing suppliers
'Suppliers come more into play as we think about sources oI variability
Inconsistency of treatment of QbD across FDA
'The FDA is not aligned, the only thing they are aligned on is where you Iile
'Although a number oI people in the FDA are supportive oI QbD this is not
consistent
'ONDQA has a very philosophical deIinition based on scientiIic prooI '
4
3
Rathore, 'Roadmap
4
McKinsey White Paper: Transforming to the Desired state of cGMPs for the 21st Century
Confidential Page 27
'OIIice oI Generic Drugs has taken a more pragmatic approach and provided
an explicit, required process Ior submitting via Question based Review
(QbR)
5
'We had trouble with a recent drug where we put all the appropriate controls
in place, passing our own bio-equivalency tests, then, the bio-equivalence
department asked us to change our method since that was not what they
typically see
'We got all the way to the end and then the biopharma side overturned what
the reviewers had already approved. This was a major blow.
'There are many diIIerent opinions within the FDA on how to apply QbD to
solution, we came to an understanding with chem group that was overturned
by biopharm group at the end
'There is a big disparity between center and Iield. We worked with the center
on QbD Iiling, then in an inspection the inspector didn`t know what QbD
meant
Lack of tangible guidance for industry
'The QbD lingo is cutting edge and sexy but there is very little inIormation
out there about how to actually do it on the ground
'FDA has not explained what is expected Irom a QbD Iile that has to be
proven clinically
'We understand what you are asking Ior broadly, but there are hundreds oI
variables there`s got to be an end in mind a tangible one we can deliver
on
'The path the FDA would like us to take to get here is not clear
'We know DOE is not suIIicient anymore we need more but it`s unclear
how to invest
'We don`t trust that the FDA will actually accept this Iiling in a consistent
manner
Regulators not prepared to handle QbD applications
'The FDA needs to increase the depth oI expertise oI reviewers and inspectors
in the various approaches to quality by design, Ior example chemometrics,
engineering and modeling
'High turnover seems to be an especially big problem
'Reviewers who come out oI industry Iall back to what their organization used
to do
'Dealing with reviewers who don`t Iully support this or understand this really
slows us down a lot
'How can we be comIortable that the recipient oI our Iile will understand?
'You never know what Ieedback you are going to get these days, it`s a very
inconsistent interIace
'There is a disconnect between compliance and Iield groups, we oIten get
diIIerent Ieedback
'FDA is not leveraging the data we are giving reviewers are green and don`t
understand the processes
'Regulators have diIIerent expectations and ask diIIerent questions Ior smaller
companies than bigger companies
5
McKinsey White Paper: Transforming to the Desired state of cGMPs for the 21st Century
Confidential Page 28
'Not everyone at FDA understands, they need more education and
development oI CMC staII. I`ve seen conIlicts within the FDA especially
with post approval, once you get approval gap in terms oI level oI
understanding
The way promised regulatory benefits is currently being shared does not inspire
confidence
'There is a questionable payback it is unclear how much regulatory
Ilexibility will actually be given
'The lack oI clarity makes it harder Ior us internally and increases skepticism
and reliance on the internal business case
'FDA has still not shown us the Ilexibility we can get Irom this
'At the end oI the day it is still unclear whether the FDA will actually back
these Iilings
'It is a challenge to understand what the agency actually wants, and what sort
oI Ilexibility it will provide
'People are wary is this really going to come to pass?
'What we really need are Ior the regulatory beneIits and Ilexibility that have
been promised to be codiIied, delivered and then realized
'We started this because we were promised regulatory beneIits not we can`t
even talk about them its` like they have amnesia
'We do need more clarity on short term apparent return on investment vs. real
ROI
'FDA needs to show business beneIits
'There is a lack oI clear regulatory incentives; without it you are giving an
advantage to someone who just seeks approval at the minimalist cost and
hurting companies who take a holistic approach
Misalignment of international regulatory bodies
'Duplication oI industry resources to satisIy international markets that are not
willing to accept the content oI a QbD Iiling submitted to the FDA
'Lack oI clarity on how QbD and associated Ilexible regulatory approaches
will be received by countries outside oI ICH
'Beyond FDA who else will accept this Iiling?
'Since there is no global harmonization, why move away Irom traditional
Iiling?
'It is much more diIIicult in secondary markets it takes longer to review
because they ask a lot oI questions several times
'We are very concerned about the response to this outside the US and Europe.
We sell products in 75 countries, most are not a part oI the ICH
'This is an FDA initiative, the rest oI the world is watching and waiting
'We managed a joint FDA EMEA audit there were too many people with
diIIering opinions and in diIIerent places with QbD
'You have the Japanese saying you are doing QbD so we want this stuII, you
have Europeans saying we want this other stuII
'Japan`s structure oI submission documents, is so that you can`t apply Ior
Ilexibility on Iormulation
Current interaction with companies is not conducive to QbD
'There needs to be a diIIerent way to interact, may even be joint teams doing
parallel reviews together
'Historically, there is not a lot oI comIort talking with the FDA
Confidential Page 29
'This needs to be more oI a collaborative process it should be a mutual
education activity
'Pilots asked a lot oI tough questions, there were several diIIicult interactions.
When we are treated with suspicion, it does not Ieel like collaboration
'There is a Ieeling that the FDA has yet to act on any Ieedback that the
industry has been giving
'It would be helpIul iI we could make changes without writing a PhD thesis
every time
Additional Exhibits
Additional Exhibit 1: Correlation between supporting mechanisms and level of
adoption
Cost drivers
Process / procedure development
Human resources (e.g., new human
resources, trainings)
nfrastructure (e.g., analytical tools)
Knowledge management
capabilities
Projected total cost to
implement
$100 $200 K
$0 - $200 K
< $200 K
$0 - $200K
Total < $1 MM