A reflection on progress made, and challenges to be addressed, in realizing the desired state articulated by the the FDA Initiative on Pharmaceutical Quality for the 21st Century.

1. Design & Control of Pharmaceutical
Products & Processes: FDA’s PAT
Guidance
Ajaz S. Hussain., Ph.D.
Previously a champion at FDA (2000-2004) for the FDA Initiatives on Process
Analytical Technology and Pharmaceutical Quality for the 21st Century
Currently; Vice President Biological Systems Research
Philip Morris International, R&D, Neuchatel, Switzerland
May 11, 2010. Bethesda , Maryland

2. Outline
Background
Motivation for the FDA’s PAT Initiative
What has been achieved?
Challenges that remain
Key questions
Is bio-processing, and the regulatory approach for biologics, more conducive for
PAT/QbD?
How does appropriate comparability assessment of biologics provides a means to
avoid the Popperian trap?
Has the FDA’s PAT Guidance outlived its utility?
A way forward
Ensure applications of new technologies in drug development and manufactruing
are not automatically placed on a regulatory critical path

3. Background
Motivation for the FDA’s “PAT Initiative”
What has been achieved?
Challenges that remain

4. FDA’s PAT Initiative: Vision 2020
One piece of the puzzle – a
“door opener”
Pharmaceutical Quality for
the 21st Century
Critical Path Initiative
“Risk” based decisions based
on mechanistic knowledge
Collaborative vocabulary
Design focused (QbD)
Mechanistic understanding
Knowledge a basis for
regulatory flexibility
Design space
Enhance collaboration
between CMC Review &
CGMP Inspection functions
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070305.pdf
http://www.fda.gov/ohrms/dockets/ac/01/slides/3804s1_02_hussain.ppt#288,28,A Perspective on PAT: One piece of the puzzle

5. Motivation For The FDA‘s PAT Initiative

6. What Has Been Achieved?
Consensus on the “desired
state” of Pharmaceutical Quality
in the 21st Century
ICH Guidelines: Q8, Q9, Q10
An active and growing global
technical community
Increasing number of
publications; rapid growth in
biopharmaceutical sector
Wide recognition of the available
opportunities
http://graphics.eiu.com/files/ad_pdfs/eiu_ORACLE_
PHARMA_WP.pdf

7. Manufacturers Slowly Embracing PAT/QbD
A 2008 Survey
“In four years since 29% no plans to start either PAT/QbD
the ICH outlined the 15% doing PAT as part of a broader QbD effort
concept of design 16% who say they have focused on PAT efforts
space in its Q8 first and are now doing QbD, and
guideline, 15% who plan to launch PAT but not QbD
pharmaceutical
companies – despite
depending on 31% do not use process capability analysis.
innovation for their Who use SPC are mainly using univariate
livelihood – have methods - pharmaceutical manufacturing is
been slow to adopt inherently multivariate
Quality by Design
(QbD)” Paperless recordkeeping is still a ways off at
Ronald D. Snee, February most drug manufacturing facilities.
2009 | Pharmaceutical
Processing
http://www.futurepharmaus.com/Default.aspx?mc=Manufacturers-
slowly&page=fpt-viewarticle

8. What Challenges Remain?
Regulatory approaches
have not evolved
adequately - high
regulatory uncertainty: PAT
Vs. QbD
Specification set after
completing the clinical trials
& based on compendial
standards
The concept of “design” and
“design space” have not
been clearly understood
Limited utility of prior knowledge
in regulator decisions

9. Key questions
Is bio-processing, and the regulatory approach for
biologics, more conducive for PAT/QbD?
How does appropriate comparability assessment of
biologics provide a means to avoid the Popperian trap*?
Has the FDA’s PAT Guidance outlived its utility?
*Reference Manual on Scientific Evidence. Federal Judicial Center 2000
http://bulk.resource.org/courts.gov/fjc/sciman00.pdf

10. Is bio-processing, and the regulatory approach
for biologics, more conducive for PAT/QbD?
Intrinsically systems based – Systems Biology an
opportunity
Appropriate comparability assessment avoids
procrustean standards and illustrates a way to avoid
the Popperian trap
Team approach to CMC review and CGMP
inspections

11. Systems Biology: An opportunity for PAT
based bioprocess development
Osmolarity pH Temperature
A
Gene > mRNA > Protein
B
Nutrition Genome Sequences
Antibiotics Shear stress
Pressure
Transcriptome Genetic Network
“Environome”
Protoeome Metabolic Network
Metabolome
Fluxome
Target Exp. Cell Physiology Bioprocess &
Metabolic. Engg. Kinetics Bioproducts
Environome
Eng. Life. Sci. 6: 455-469 (2006)
Engineering

12. Appropriate Comparability Assessment: A
Means to Avoid the ‘Popperian Trap’?
“Simply put, the Agency adopts an empirical approach to the
fundamental regulatory questions of safety and effectiveness”
“Theories about mechanism of action of a drug or disease
mechanisms play important parts…but they are entirely
subsidiary….”
“These conclusions cannot, in the typical case, be predicted, nor
can they be arrived at by an “understanding” of the underlying
events, an understanding that must always remain incomplete
(and, importantly, incomplete in ways that are unknown to us).”
R. Katz. The American Society for Experimental NeuroTherapeutics. Vol. 1, 307–316, July 2004

13. EMEA Guidelines: Prior Knowledge in the
Development of a Biosimilar Erythropoietin
EMEA Guideline on
Similar Biological
Medicinal Products.
http://www.emea.europa.eu/pdfs/human/bi
osimilar/043704en.pdf (Accessed 29
November 2009)
Guidance on Similar
Medicinal Products
Containing Recombinant
Erythropoietin
http://www.ema.europa.eu/pdfs/human/bio
similar/9452605en.pdf (Accessed 29
November 2009)
EPAR Binocrit®
http://www.ema.europa.eu/humandocs/PD http://www.sandoz.com/assets/content/en/product_range/biosimilar_pr
Fs/EPAR/binocrit/H-725-en6.pdf esenation/Pioneering_Global_Development_of_Biosimilars_BIO_2008
(Accessed 29 November 2009) _FNa_FINAL.pdf

14. EMEA Guidelines: Prior knowledge in the development of a biosimilar erythropoietin
Prior knowledge ⇒ Regulatory & Other Recommendations
Process design for a comparable active ingredient, adequate control of process
• Human erythropoietin structural & and related impurities, viral clearance, (per ICH guidelines)
role. Product design – special attention to formulation and delivery device
• Physico-chemical and biological methods
are available Clinical Efficacy Reference product,
• Expression system – mammalian cells • Efficacy and safety in renal anemia may Analytical Characterization &
allow extrapolation to other Design specifications
• All epoetins in clinic- similar amino acid indications.
seq. endogenous but differ in the • Comparable efficacy in at least two Plan for an integrated &
adequately powered, double blind iterative development &
glycosylation pattern.
randomized, parallel group trials. comparability assessment
• Glycosylation influences PK and may
affect efficacy and safety • Both routes: IV & SC Design to be comparable!!
• Current therapeutic indications • Trials should include “correction phase”
• Same mechanism of action
• Non-clinical
Wide therapeutic window Clinical Safety
Pharmacodynamics
• Route of administration & different dose • Comparative safety data from efficacy trials
Comparative bioassays
considerations • 12-months comparative immunogenicity
• Usually well tolerated provided data pre-authorization
Toxicological studies
stimulation of bone marrow is controlled • Sensitive and validated method for anti-
• Variability in the rate of hemoglobin At least one repeat dose toxicity
epoetin antibodies
increase and know factors & local tolerance
Pharmacovigilance Plan Clinical PK
• Exaggerated PD –complications
• Routine & additional pharmacovigilance Comparative -Single dose (IV
• Anti-body induces PRCA in renal anemia
• Risk minimization activities and Sc). Equivalence margins
patients – SC route. Incidence rate very
• For example: PRCA, Tumor growth Clinical PD
low to be detected pre-approval
potential, Thrombotic vascular events, and Part of PK, consider dose-
• Possible angiogenic & tumor promoting
Potential off-label use response curve
Italics – additional recommendations (author)

15. Has the FDA’s PAT Guidance Outlived its
Utility?
No, the PAT Guidance outlines regulatory principles
which are not optimally incorporated into ICH Q8; for
example:
“In the absence of process knowledge, when proposing a new
process analyzer, the test-to-test comparison between an on-
line process analyzer and a conventional test method on
collected samples may be the only available validation option.”
“In some cases, this approach may be too burdensome and
may discourage the use of some new technologies”
“A focus on process understanding can reduce the burden for
validating systems by providing more options for justifying and
qualifying systems …..”
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070305.pdf

16. Without the PAT Guidance Document …
New knowledge can be paralyzing
The ability to measure brings with it the
responsibility to explain
In a complex organizational setting it is often
difficult to find a champion who will take on this
challenge in an uncertain regulatory environment
The PAT Guidance provided a regulatory solution
to such a challenge

17. Critical Path Initiative: Biomarker
Qualification
Janet Woodcock, M.D.
Deputy Commissioner/Chief Medical Officer
January 28, 2007
http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/default.htm

18. Mechanistic Understanding of Safety
http://iccvam.niehs.nih.gov/meetings/10thAnnivSymp/Woodcock.pdf

19. Biomarker Qualification: Contributing Role of
Mechanistic Understanding?
Utility of mechanistic
understanding within the
FDA can get stuck in the
‘Popperian trap’
http://iccvam.niehs.nih.gov/meetings/10thAnnivSymp/Woodcock.pdf

20. A Way Forward……
Ensure applications of new technologies in drug
development and manufacturing are not
automatically placed on a regulatory critical path
Reduce regulatory uncertainty
Avoid “PAT Vs. QbD” perceptions, team effort, training,..
Leverage the comparability approach & the US
biosimilar pathway as an opportunity to illustrate how to
avoid the ‘Popperian trap’
Consider summarizing accepted prior-knowledge for
regulatory decision-making