Arthur Fabian, PhD

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(No Transcript)
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Revising CFR 314.70
FDA Public Meeting
February 7, 2007
Rockville MD
Arthur Fabian, PhD
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SST Business Model

• Represent numerous API Intermediate
  Manufacturers worldwide.
• Market and Sell APIs Intermediates to both the
  Brand and Generic Industries in the US.
• Provides a unique Regulatory vantage-point.

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SST Regulatory Model
SST
Type II DMF Holder
(A)NDA Sponsor
API Manufacturers/Suppliers
Customers
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Industry Regulatory Model
Type II DMF Holder
(A)NDA Sponsor

• Historical Model for Generic Industry

• Widespread model (40) for the Brand Industry
  due to Outsourcing

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SSTs Business Interest

• Maintain Supplier competitiveness.
• Introduce new synthetic methods, equipment,
  alternate sites, specifications, PAT techniques.
• Encourage Change / Innovation.
• Same goal as Agencys Quality Initiative.

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Presentation Perspective

• Drug Substance DMF Holder
• rather than
• Drug Product (A)NDA Sponsor

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Presentation Topics

• Five Points to Consider in the revision
• Relevance of the Risk-Based Paradigm
• Outside the Box Ideas

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Point 1
Revise Changes Guidance prior to CFR 314.70
Revision
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Point 2
Separate Drug Substance from Drug Product
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Separate Sections

• Requires authors to adopt a presently absent Drug
  Substance mindset.
• Filing recommendations for scale and equipment
  changes for small molecule APIs would be present.
• Change from Centrifugation to Filtration would
  not be a PAS.

Particle Design of APIs Through Crystallization,
W.Beckmann, Schering AG, American Pharmaceutical
Review, Vol 9, Issue 6, pg 110 ff, Sept. 06
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Point 3
Include DMF Holders
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DMF Holders

• Filing mechanism format Sponsor/DMF Holder
• PAS/AM, CBE-0/AM, AR/AM.
• Expand the use of DMF Annual Update
• Minor Changes via AR/AU.
• No additional documentation to FDA.

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Point 4
Recognize the Final Step Continuum
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Present Guidance
All Process Changes after the Final Intermediate
(FI) require a Pre-Approval Supplement !!
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Final Step Changes Guidance

Last Step
FI API


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Final Step Science-Based
Post Synthetic Operations
Chemical
Purification
FI CAPI PAPI
FAPI

CAPI Crude API

PAPI Purified API
FAPI Final API
Drying, Milling, Micronization, Blending,
Packaging
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Final Step Science-Based
Equivalence here
steps
A FI Crude PAPI
FAPI
Change here
PAS should not be necessary !
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Phased Approach
Chemical
Purification
Post synthetic Operations
FI CAPI PAPI
FAPI

Yes No No
Yes No Yes
No Yes No
No Yes Yes
No No Yes
Yes Yes No
Yes Yes Yes
No No No, ie different FI






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Chemical Phase Only
Post synthesis
Chemical
Purification
FI CAPI PAPI
FAPI
Yes No
No
Equivalent CAPI?
Equivalent PAPI?
No
No

Yes
Yes
CBE-30/AM

PAS/AM
CBE/AM
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Purification Phase Only
Post synthesis
Purification
Chemical
FI CAPI PAPI
FAPI
No Yes
No

Equivalent PAPI?

Yes
No
CBE-30/AM
PAS/AM
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Post Synthesis Phase Only
Post synthesis
Chemical
Purification
FI CAPI PAPI
FAPI
No No
Yes

Equivalent FAPI?

No
Yes
PAS/AM
CBE-30/AM
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Chemical Purification Phases
Post synthesis
Chemical
Purification
FI CAPI PAPI
FAPI
Yes Yes
No

Equivalent PAPI?
Yes/No
Equivalent CAPI?

No
Yes
PAS/AM
CBE-30/AM
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Chemical Post synthesis Phases
Post synthesis
Chemical
Purification
FI CAPI PAPI
FAPI
Yes No
Yes

Equivalent FAPI?
Equivalent PAPI?
Yes/No
Yes/No
Equivalent CAPI?

Yes
No
PAS/AM
CBE-30/AM
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Change in all Three Phases
Post synthesis
Chemical
Purification
FI CAPI PAPI
FAPI
Yes Yes
Yes

Equivalent FAPI?
Equivalent PAPI?
Yes/No
Yes/No
Equivalent CAPI?

Yes
No

CBE-30/AM
PAS/AM
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Change in no Phases new FI
Post synthesis
Chemical
Purification
FI CAPI PAPI
FAPI
No No
No

Equivalent PAPI?
No
Equivalent CAPI?

No
Yes
Yes
PAS/AM
CBE-30/AM
CBE-30/AM
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Point 5
Major Change Redefinition
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Proposed Redefinition

• Major Process Changes
• Must impact the API, not an upstream Intermediate
• Proof of Equivalence needs supporting data beyond
  a specification comparison.
• This definition amenable to Scale and Equipment
  Changes, but other factors need consideration.
• Site and Specification Changes need a different
  analysis.

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Relevance of the Risk-Based Paradigm ?
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Risk-Based Paradigm

• FDA only pre-approves Changes affecting the API
  and requiring more complex equivalence data, ie,
  Major.
• Totally analogous to the Risk-Based Inspection
  Model.
• Does not offer select companies reduction of
  filing mechanism not needed.

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Science - Based Paradigm !
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Outside the Box Ideas

• High Quality CMC Information, not high volume.

• CBE 60/90 as Bridge to reducing PAS.

• Special DMF Amendment for Changes no link to
  (A)NDA Sponsor filing.

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To Summarize........
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Thank You for your Attention !