Principles & Content Outline Peter Pekos, President Dalton Pharma Services May 13, 2008

1. Preparing an IND
Application: CMC
Principles & Content Outline
Peter Pekos, President
Dalton Pharma Services
May 13, 2008
May 2008 P Pekos

2. Company Profile
• over 80 employees • 26 at Ph.D. / M.Sc. level
• 42,000 sq ft facility in Greater Toronto Area
• Adjacent to Toronto’s York University
• Proximity to Toronto area pharma, biotech, medical research facilities
• Integrated synthesis laboratories • Research library
• cGMP manufacturing suites • Biopolymer synthesis laboratory
• Secure, controlled environment • Analytical laboratory
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3. Services
Contract Research
Custom Synthesis
Contract Analysis
API Manufacturing
Sterile Filling
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4. Drug Development Support
SAR elucidation Batch Records
Small Focused Libraries Analytical
Bulk intermediates & impurity standards • Method Development
• Method Validation
Process Optimization & Scale Up • Stability Programs
Lead Optimization • Impurity Identification
Regulatory Support
Prodrug synthesis
• CMC
API Manufacturing (GMP) • IND
Sterile Filling (GMP) • NDA
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5. Disclaimer
 Views presented here are provided to
illustrate the general process and issues of
preparing for an IND
 Each therapeutic development program may
differ in the details particular to that drug
 Be sure to consult all laws, regulations and
guidances that apply to your situation
May 2008 P Pekos

6. Business Of Medical
Manufacturing
 All the issues common to any manufacturing
business, plus…
• Your product acts DIRECTLY on your consumers
• Most products are inherently dangerous
• Simple to use and to misuse
• Highly intrusive regulatory environment
 Conversely, the regulatory environment
provides for a process to manage business
risk as well as risk to the public
• Consider each Health Authority as a resource to
consult with, not an adversary!
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7. Investigational New Drug
Application
 IND regulations exempt the investigation of a
new drug (or new drug use) from the
regulations governing the production and
marketing of a commercial drug product.
 Seeks to balance protection of the public with
the need to introduce new therapies.
 Current regulations at 21 CFR 312.22 and
312.23 contain the general principles
underlying the IND submission and the
general requirements for an IND's content
and format
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8. IND regulation of CMC
 Balancing protection with investigation leads
to a graduated, “bootstrapping” approach
• Early studies provide limited data to assess risk
vs. benefit, consistency and control, etc., so
minimize the initial human exposure
• As the program develops, the accuracy, precision,
and breadth of your data is expected to improve
over time
• By the time of a marketing application, the
sponsor must demonstrate they are ready and
able to meet the full requirements for a marketed
drug
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9. FDA View on Early CMC Data
“It is recognized that modifications to the
method of preparation of the new drug
substance and dosage form, and even
changes in the dosage form itself, are
likely as the investigation progresses. The
emphasis in an initial Phase 1 CMC
submission should, therefore, generally be
placed on providing information that will
allow evaluation of the safety of subjects
in the proposed study.”
GUIDANCE FOR INDUSTRY. CONTENT AND FORMAT OF INVESTIGATIONAL
NEW DRUG APPLICATIONS (INDs) FOR PHASE 1 STUDIES OF DRUGS,
INCLUDING WELL CHARACTERIZED, THERAPEUTIC, BIOTECHNOLOGY-
DERIVED PRODUCTS (Nov 1995)
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10. Causes for “Clinical Hold” based
on CMC section of your IND
 Unknown or impure components
 Chemical structures of known or highly likely toxicity
 Product that cannot remain chemically stable throughout the
testing program proposed
 Product with an impurity profile indicative of a potential
health hazard or an impurity profile insufficiently defined to
assess a potential health hazard
 Poorly characterized master or working cell bank
 Refer to 21 CFR 312.23(a)(7)
(see http://www.fda.gov/cder/guidance/phase1.pdf)
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11. Basic CMC Strategy for IND
 Develop pre-clinical data or cite research to
answer these two questions:
• Does the chemistry of either the drug substance
or the drug product present any signals of
potential human risk?
• Does the manufacturing of either the drug
substance or the drug product present any signals
of potential human risk?
 Continue to address these questions
throughout your development program!
May 2008 P Pekos

12. INTRODUCTION TO cGMP
 Legal basis for cGMP
 What does that “c” mean?
 General Principles
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13. FD & C Act; 501 (a) (2) (B)
 “A drug shall be deemed adulterated if:
• … the methods used in, or the facilities or
controls used for its manufacture, processing,
packing or holding do not conform to or are not
operated or administered in conformity with
current good manufacturing practice to assure
that such drug meets the requirements of this Act
as to safety and has the identity and strength, and
meets the quality and purity characteristics, which
it purports or is represented to possess.”
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14. cGMP Legal Principles
 Quality must be built into product
• By “taking care” in making medicine
• Can’t test quality into product
 Missing or inadequate cGMP risk harm
• Products(s) may be adulterated (defects need not
be shown before action brought)
• Firm is responsible
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15. cGMP Legal Principles
 Non-compliance may lead to your product
failing to meet your label claims:
• Super-potency or sub-potency
• Contamination
• Misbranding
• Bioavailability (e.g., altered pharmacology)
• Safety and efficacy
 The mere risk of harmful consequences
justifies legal action and remedy!
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16. cGMP Legal Principles
 “c” = “Current” = Dynamic
• Standards evolve over time, e.g., ICH efforts of
the past decade, and US process overhaul
underway right now*
*http://www.fda.gov/OHRMS/DOCKETS/98fr/E7-23292.pdf
 “Good” Practices
• Minimal acceptable standards
• Not necessarily “best practices”
• Unless “best” is, in fact, the current minimal
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17. cGMP Legal Principles
 Feasible and valuable
• No “percentage” in practice threshold
• Doesn’t have to be “predominant”
• Enforceable even if no one else is currently
practicing it
• Although a stronger case is made if someone else
has adopted that practice
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18. cGMP Scope
 Any ingredient (including excipients)
 Finished dosage forms administered to
humans and/or animals
• OTC, Rx products
• Biologics, veterinary drugs
• Drugs undergoing study (IND)
 Manufacturers, test laboratories, packagers
(including pharmacies), and warehouses
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19. Excluded from cGMP
 Drug products compounded per Section 503
Pharmacy Compounding (FDAMA)
 Position Emission Tomography (PET)
agents, but draft rule published in 2007
suggests these will be covered too:
• May be met by producing PET drugs in
accordance with the United States Pharmacopeia
(USP) general chapter on compounding PET
radiopharmaceuticals
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20. General cGMP Responsibilities
 Prepare, review, approve and distribute SOP
 Ensure adequate qualifications, training, and
experience for personnel operating under cGMP
 Follow SOP and MBR
 Review MBR and executed BR
 Evaluate all deviations, investigate and resolve
critical deviations
 Ensure sanitary facilities
 Calibrate and maintain equipment and facilities, and
document that maintenance
 Review and approve validation protocols and reports
 Establish a change control process
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21. General Quality Principles
 Quality is everyone’s job  Establish a Quality
 Sponsors must establish a Control Unit (QCU)
quality system • Independent of
production management
 Responsibilities must be
• Responsible for QC and
clearly stated QA (QA could be done
 Real-time quality records separately)
 Investigate all deviations • Notification process for
defects, recalls,
 Quarantine before release inspections, and serious
GMP deficiencies
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22. Quality Control Unit
 Must be involved in all  Cannot delegate main
quality issues responsibilities
 Must review and • Lot release or rejection
approve all quality- • Establishing raw
related documents material, WIP, packaging
and labeling acceptance
 (See: Quality Systems system
Regulation, 21 CFR • Batch record review prior
part 820) to release
• Deviation investigation
resolution
• Quality audits and
validation reviews
• Stability data
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23. Content of IND
Item 7: CMC
[21 CFR 312.23 (a) (7)]
May 2008 P Pekos

24. Item 7 of the IND: CMC
 7.1 Introduction
 7.2 Drug Substance
 7.3 Drug Product
 7.4 Diluent (if applicable)
 7.5 Placebo (if applicable)
 7.6 Test Procedures
 7.7 Environmental Assessment
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25. Introduction: Section 7.1
 Drug Substance/Product  Container/closure
description: description
• chemical name, structure,  Diluent used to administer
physical, chemical, and/or product, if applicable
biological characteristics,  Name, address, and
and generic name (if description of each location
available) and internal ID used in the manufacture of
code. the Product and
 Names and amounts of Substance(s)
Drug Substance(s) used in • Reference existing IND or
DMF if available, if not,
Product provide, floor plans,
 Names and amounts of equipment lists, and
excipients, including material flows for each
location
preservatives or delivery
 Summary flow chart of
enhancers manufacturing process
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26. Drug Substance: Section 7.2
 A brief process description:  Full name and street
list reagents, solvents, and address of each
catalysts used. A detailed manufacturing location
flow diagram is  Information on the stability
recommended. of the Drug Substance
 Methods and specs for during the tox & clinical
identity, strength, quality, programs
and purity • A brief description of the
• Reference Standard(s) stability program and test
• Brief description of the test methods
methods • Preliminary tabular data
• Proposed acceptable limits based on representative
material may be submitted
• Recommend including CofA in lieu of final data
• Validation data and • Neither detailed stability
established specs may be data nor the stability
requested for biotech or protocol should be
human/animal source drugs submitted
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27. Drug Product: Section 7.3
 Citing USP-NF may be sufficient  Methods & specs used for identity, strength,
 List components & quality level quality, and purity:
• Active Pharmaceutical Ingredients • Reference Standard(s)
• Excipients (including alternatives) • Brief description of methods used
• Everything used in the • Proposed acceptable limits
manufacturing process, not just • Recommend including CofA
appearing in the final formulation • Assess bioactivity for biotech drugs
• For novel excipients, additional info • Validation data and established specs may be
may be necessary. requested for biotech or human/animal source
• Summary table of composition drugs.
 The full name and street address of  Information on the stability of the Drug
each manufacturing location Product during the tox & clinical programs
 Brief description of manufacturing and • A brief description of the stability study and the
packaging procedures test methods in the container/closure
system and clinical storage conditions
• Include sterilization process for sterile
• Preliminary tabular data based on
products
representative material may be submitted.
• Flow diagrams are recommended
• Neither detailed stability data nor the stability
• Specify Container/Closure system protocol should be submitted
proposed for clinical studies
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28. Label information (7.3.9)
 A copy of all labels and labelling to be provided
to each investigator:
 A mock-up or printed representation of the
proposed labelling.
• Investigational labels in USA must carry a caution
statement as required by 21 CFR 312.6(a).
• “Caution: New Drug - Limited by Federal (or United
States) law to investigational use.”
 NB: Label production and use regulated!
 NB: Other nations have different rules for labels!
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29. Dilulent/Placebo
Sections 7.4 & 7.5
 A brief general description of the
composition, manufacture, and control of any
• Diluent used to reconstitute the product, if needed
• Placebo to be used in the proposed clinical trial(s)
 Recommend using diagrammatic and/or
tabular information where possible
 NB: Placebo lots require the same care as
active lots and consume similar time and
resources!
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30. Environmental Impact Section
 Most investigational drugs able to claim
categorical exclusion from an environmental
assessment under 21 CFR 25.24
 Possible exceptions: Cytotoxics or processes
that create large volume of hazardous waste.
• See Guidance for Industry for the Submission of
Environmental Assessments for Human Drug
Applications and Supplements, November, 1995.
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31. Electronic IND Submissions:
eCTD format
 Differs substantially from paper outline
described here, but same principles apply
 Still optional for CDER submissions
 May offer long term advantages for eventual
marketing applications, but technology and
process is still evolving
 Consult current CDER guidance:
http://www.fda.gov/cder/regulatory/ersr/ectd.
htm
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32. Other CMC Considerations
 Investigator’s Brochure references CMC info
 Integrate the Tox and Clinical protocols with CMC via
the Pharmacy Manual
• Storage, handling, and disposal of the drug
• If required, preparing/compounding the drug for
administration (e.g., reconstitution with Diluent)
• Specifications and stability limits for any contact materials
(e.g., IV bags, catheters, syringes, pumps, etc.)—often
overlooked, risking clinical timeline
 Combination products (e.g., with device) governed
by additional rules, see:
http://www.fda.gov/oc/combination/
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33. cGMP Resources
 Internet WWW site by DMPQ
• http://www.fda.gov/cder/dmpq
• CGMP regulations and ongoing changes
• Division subject contacts
• Medical gases
• Active pharmaceutical ingredients
• Human Drug cGMP Notes
• Etc.
May 2008 P Pekos

34. Other Web Resources
 ICH website (future of harmonized
regulation?)
• Quality guidelines:
• http://www.ich.org/cache/compo/276-254-1.html
 CDER handbook (useful background, but not
current)
• http://www.fda.gov/cder/handbook/
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35. Thank you
Special Acknowledgement to
Mark Winnett
May 2008 P Pekos