**Chemistry, Manufacturing, and Controls**

**Reducing the Regulatory Burden**

**Background Information**

# Advisory Committee for Pharmaceutical Science Meeting

**November 15, 2000**

## Rockville, MD

**Risk Based CMC Review**

**(Reducing CMC Requirements for Drugs of No or Little Risk with respect
to Quality)**

A Summary of the New CDER Initiative

Yuan-yuan Chiu, Ph.D.

1.  Objectives

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a)  Elimination of most NDA/ANDA manufacturing supplements for no/little
    risk drugs: All CMC changes except those listed in FDAMA section
    116**\*** (i.e., changes of DS/DP specifications, DP
    components/compositions, changes requiring an in-vivo study) will be
    reported through the AR of an approved NDA/ANDA for no/little risk
    drugs on a list to be published in an Agency Guidance. However, for
    sterile products on the list, changes to the sterilization process
    will be filed in accordance with PAC guidance (i.e., may require
    supplements).

b)  The AR of an approved NDA/ANDA for a drug on the published list will
    contain reduced CMC information and data to be described in an
    Agency Guidance (See item 5).

c)  An original ANDA (TANDA (Truncated ANDA)) for a drug on the
    published list will consist of the same reduced CMC information and
    data as required for the AR of the approved NDA/ANDA for the same
    drug (See item (b) above). BE may be waived based on BCS. This
    change will require rule making.

> \* In accordance with SUPAC and other PACs where down regulations are
> provided

2\. To establish a list of products meeting sound scientific criteria
for no or little risk with respect to quality, for examples:

(a) Drug Substance:

> [Attributes]{.underline} [Acceptance Criteria]{.underline}
>
> Chemical Structure Well characterized, others (to be defined)
>
> Synthetic Process Simple process (to be defined)
>
> Quality Adequate specifications, known not to contain toxic impurities
> others (to be defined)
>
> Physical Property Polymorphism? Particle sizes?
>
> Stability Stable substances (to be defined)

Manufacturing History 10? years on the market, others (to be defined)

Others (To be defined)

(b) Drug Product:

> [Attributes]{.underline} [Acceptance Criteria]{.underline}
>
> Dosage form Oral dosage form (Immediate Release), simple sterile
> solutions, others (to be defined)
>
> Manufacturing Process Easy to manufacture (to be defined),
>
> Simple sterile solutions excluding changes that may affect sterility
> assurance
>
> Quality Adequate specifications, others (to be defined)
>
> Stability Stable products (to be defined)

Manufacturing History 10? years on the market, others (to be defined)

Others (To be defined)

3\. The drug list compiled based on the established scientific criteria
will be evaluated based on safety:

> [Attributes]{.underline} [Acceptance Criteria]{.underline}

BCS (?) Highly soluble and highly permeable?

Clinical Concerns Non-NTI drug? not for critical care?

Others (To be defined)

4\. The eligibility of a manufacturer to be under this program will be
based on GMPs considerations:

> [Attributes]{.underline} [Acceptance Criteria]{.underline}
>
> Manufacturing History No recall due to quality reason? others (to be
> defined)

DS Manufacturer Acceptable GMP status/record (to be defined)

DP Manufacturer Acceptable GMP status/record (to be defined)

Others (To be defined)

5\. To draft a Guidance describing the reduced CMC information and data
to be submitted at a one-time basis to the AR of the approved NDA/ANDA
for the listed drugs. Such information and data may be modeled after
Quality Summary of CTD-Q (e.g., a flowchart of synthetic process in lieu
of detailed description**,** structure characterization, identification
and qualification of impurities (monograph and new), composition and
components, specifications, etc.). Only changes to this CMC information
and data will need to be reported under a supplement (See 1.a above) or
in a subsequent AR. The same reduced CMC information and data will be
adequate for an original TANDA for the listed drugs from a generic drug
manufacturer if determined to be eligible for this program based on GMP
consideration.

6.  The following requirements are not changed:

a\) There will be no reduction of studies, data, and documentation that
companies need to perform and generate so to ensure the identity,
purity, strength/potency, and quality of the product. These data and
documentation will be kept on site and available for FDA inspection.

b\) There will be no change to the Pre-Approval Inspection program for
TANDA

7.  To achieve the objective of this project, the following process and
    timelines are proposed:

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a)  Initial working group to propose "attributes and acceptance
    criteria" (done)

b)  Y. Chiu to brief OPS Chemistry DDs who will then inform chemistry
    team leaders (done)

c)  Initial working group to brief Dr. Woodcock (done, 7/17/00)

d)  Initial working group to present to CCC (done, 7/18/00)

e)  Initial working group to present at Field/Drug Committee meeting
    (done)

f)  Initial working group to meet with ORA representatives (done)

g)  To form a technical working group(s) including OC and ORA staff to
    refine "attributes and acceptance criteria" and to plan for
    scientific workshops (done). CMCCC will have oversight of the
    technical working group. (done)

h)  To inform RPS on rule making for TANDA (done)

i)  Internal discussion at ONDC Scientific Rounds on September 25, 2000
    (done)

j)  Presenting at Trade meetings in October, 2000 (done)

k)  Seeking input from ACPS in November, 2000

l)  Scientific Workshop co-sponsored with AAPS in June-July of 2001 to
    discuss "attributes and acceptance criteria"

m)  To seek MPCC input on safety concerns.

n)  In 1^st^ quarter of 2002 to publish draft Guidance on "attributes
    and acceptance criteria", and to propose rule permitting TANDAs

o)  To form a technical working group to draft a Guidance on the reduced
    CMC information for the one time AR submission of an approved
    NDA/ANDA and an original TANDA, as well as the documentation of CMC
    changes filed through an AR of an NDA/ANDA/TANDA

p)  In 4^th^ quarter of 2002 to publish finalized Guidance on
    "attributes and acceptance criteria" and a draft Guidance proposing
    a list of drug candidates, the one time AR submission for an
    approved NDA/ANDA with reduced CMC information required and for an
    original TANDA, as well as documentation and reporting changes
    through an AR of an NDA/ANDA/TANDA

q)  In 3^rd^ quarter of 2003 to publish the finalized Guidance on drug
    list and reporting requirements for implementation, and final rule
    permitting TANDA.

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8.  To implement the program successfully, the following things will be
    done:

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a)  Training to industry and reviewers will be provided.

b)  Joined inspection team (reviewer and Field investigator) will be
    formed to randomly audit the scientific and validation data of those
    products regulated under TANDA and AR for CMC changes.

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9.  To work through CDER's Product Quality Research and PQRI, and with
    outside "system engineers", the "attributes and acceptance criteria"
    can be modified and the drug list expanded.