Questions to the Committee Concerning the Determination of

Little/No Risk Drugs with respect to Product Quality

# 

# Regarding Drug Substances (See Table 1)

1.  Is each of the identified attributes important in determining
    potential risk to product quality? Or are they the potential sources
    of product defects?

2.  Are there other critical attributes which need to be considered?

3.  Assuming all the attributes identified are critical, how can we best
    establish the acceptance criteria for each attribute ?

3a. Should the chemical structure of the drug substance be well
characterized? If yes, what is the definition of "well characterized"?
If not, please state the reasons. Also, should a drug substance with
multiple chiral centers be excluded?

3b. How can a "Simple Synthetic Process" be defined?

3c. What should be the standards for "Adequate Specifications"? How
should product specific (i.e., specific to a manufacturer's product)
impurities be handled?

3d. With respect to physical properties, do you agree that when
polymorph forms or micronization process (particle sizes) can be defined
and controlled, these drugs could be included in the category of
little/no risk? Are there other physical properties that can become a
barrier?

3e. How can a "stable substance" be defined? By shelf-life? By chemical
reactivity ?

3f. How many years of marketing history is considered sufficient?

Regarding Drug Products (See Table 2)

1.  Is each of the identified attributes important in determining the
    potential risk to product quality? Or are they the potential sources
    of product defects?

2.  Are there other critical attributes which need to be considered?

3.  Assuming all the attributes are critical, how can we best establish
    the acceptance criteria for each attribute?

> 3a. Should dosage forms other than immediate release oral solid, oral
> liquid, and simple sterile solutions (e.g., saline, dextrose, trace
> element salts) be excluded?
>
> 3b. Should only products that can be manufactured by multiple
> processes be included (e.g., wet granulation and direct compression)?
> What are the criteria for defining a robust process?
>
> 3c. What should be the standards for "Adequate Specifications"? How
> should product specific (i.e., specific to a manufacturer's product)
> impurities and degradants be handled?

3d. How should a "stable product" be defined? By shelf-life? By the
absence of drug substance and excipient interaction?

> 3e. How many years of marketing history is considered sufficient?
>
> **Table 1. 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
and others (to be defined)

> Physical Property Polymorphism? Particle Sizes?
>
> Stability Stable (to be defined)

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

Others (To be defined)

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**Table 2. Drug Product**

> **[Attributes]{.underline} [Acceptance Criteria]{.underline}**
>
> Dosage form Oral dosage form (IR), 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 and others (to be defined)
>
> Stability Stable (to be defined)

Manufacturing History 10? Years on the market and others (to be defined)

Others (To be defined)