# Summary Minutes of the Manufacturing Subcommittee

# Advisory Committee for Pharmaceutical Science

> **September 17, 2003**
>
> The Manufacturing Subcommittee of the Advisory Committee for
> Pharmaceutical Science of the Food and Drug Administration, Center for
> Drug Evaluation and Research met on September 17, 2003, at the
> Advisors and Consultant Staff Conference Room, 5630 Fishers Lane,
> Rockville, Maryland. The meeting was chaired by Judy Boehlert, Ph.D.
>
> **Manufacturing Subcommittee of the Advisory Committee for
> Pharmaceutical Members (voting):**
>
> Patrick DeLuca, Ph.D. (ACPS), Robert (Gary) Hollenbeck, Ph.D. (ACPS)
>
> Judy Boehlert, Ph.D., Daniel Gold, Ph.D., Thomas Layloff, Jr., Ph.D.,
> Garnet Peck, Ph.D., G.K. Raju, Ph.D., Nozer Singpurwalla, Ph.D.
>
> **Manufacturing Subcommittee of the Advisory Committee for
> Pharmaceutical Science Consultants(voting):**
>
> **Acting Industry Representative (non-voting):**
>
> Efraim Shek, Ph.D.
>
> **Guest Speakers:**
>
> Edmund Fry, Colin Gardner, Greg Guyer, Ph.D., Tobias Massa, Ph.D.,
> Gerry Migliaccio, Kenneth Morris, Ph.D.
>
> **FDA Guest Speakers**:
>
> Joe Famulare, Ajaz Hussain, Ph.D., Norman Schmuff, Ph.D., Janet
> Woodcock, M.D.
>
> **FDA Participants:**
>
> Diana Koliatis
>
> **Open Public Hearing Speakers:**
>
> **September 17, 2003:**
>
> Robert Menson, Ph.D.
>
> These summary minutes for the September 17, 2003, meeting of the
> Manufacturing Subcommittee of the Advisory Committee for
> Pharmaceutical Science of the Food and Drug Administration were
> approved on \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
>
> I certify that I attended the September 17, 2003, meeting of the
> Manufacturing Subcommittee of the Advisory Committee for
> Pharmaceutical Science of the Food and Drug Administration meeting and
> that these minutes accurately reflect what transpired.
>
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Hilda Scharen, M.S. Judy Boehlert, Ph.D.
>
> Executive Secretary Chair
>
> The Committee discussed Quality by Design and its relationship to
> Risk-based Regulatory Scrutiny. The members and the invited
> consultants were provided the background material from the FDA prior
> to the meeting.
>
> The meeting was called to order at 8:30 a.m. by Judy Boehlert, Ph.D.
> (Committee Chair). The Committee members, consultants, and FDA
> participants introduced themselves. The conflict of interest statement
> was read into the record by Hilda Scharen, M.S. The agenda proceeded
> as follows:
>
> **[September 17, 2003:]{.underline}**
>
> Introduction Ajaz Hussain, Ph.D., FDA
>
> **Quality by Design and Risk-Based Scrutiny**
>
> Quality for the 21^st^ Century: Summary of FDA/PQRI Workshop Tobias
> Massa, Ph.D., Eli Lilly & Co.
>
> Defining Quality of a Pharmaceutical Product Janet Woodcock, M.D., FDA
>
> Components of "Quality by Design": Performance Measurement G.K. Raju,
> Ph.D., MIT
>
> Assessing Quality-by-Design: A CMC Review Perspective Norman Schmuff,
> Ph.D.

###### Break

> **Proposals for Regulatory Assessment of "Quality by Design"**
>
> Using Manufacturing Science and Risk Management principles Gerry
> Migliaccio, Pfizer Inc.
>
> to achieve "Quality by Design"
>
> Quality by Design -- A Generic Industry Perspective Edmund Fry, IVAX
> Corp.
>
> Risk --Based Development for Quality by Design Kenneth Morris, Ph.D.,
> Purdue University
>
> Regulatory Assessment of Quality by Design: A CGMP Perspective Joe
> Famulare, FDA
>
> Quality by Design: Next Steps to Realize Opportunities Ajaz Hussain,
> FDA
>
> Open Public Hearing

###### Lunch

> Committee Discussion and Recommendations

###### Break

> **Quality by Design and Risk Based Regulatory Scrutiny**
>
> Designing Quality in Design Colin Gardner, Transform Pharmaceuticals
> Inc.
>
> Use of Risk Management in Pharmaceutical Manufacturing Greg Guyer, Ph.
> D., Merck & Co., Inc.

Committee Discussion and Recommendations

Closing Remarks

Adjourn

***[Questions to the Committee]{.underline}**:*

1.  Quality by Design:

    -   Articulate a clear description of the term *quality by design*

    -   Identify the type of information and knowledge most useful to
        assess *quality by design*

    -   Regulatory approach for assessment of pharmaceutical development
        knowledge to maximize its value without impacting drug
        development

*The committee found general agreement that Quality by Design is a
dynamic active process that continues in the development stages and
post-approval of a product. The knowledge useful to assess Quality by
Design is the identification of stress relevance and the critical
control point, and robustness of these critical control points. The
regulatory approach for assessment is output oriented.*

*The committee recognized the clear advantage of making progress in an
existing system where the goal would be to have creative incentives for
a broader development context so that the companies do it and
communicate it to FDA.*

*For process development knowledge, it is essential to first understand
the boundaries and basic failure modes of this process in terms of its
safety and efficacy issues, and predictability issues. They are the
basis for the range of the variables and specifications. In making
product development formulation it is essential to understand
variability, manage variability, the critical process, and end point.
The focus on post-approval changes provides a flexible means to engage
industry and enhance collaboration. There was also agreement that the
issues discussed helped frame this view point and were consistent with
the PAT Guidance.*

> *In summary, the committee agreed that the notion of quality is self
> evident. They committee further defined quality by design as being a
> systematic process of achieving desirable quality by a careful and
> methodical scrutiny of all the attributes that go into characterizing
> quality, from the inception of a product to its end use, involving all
> its stakeholders (the patient, the manufacturer, the physician, and
> the regulator).*

2\. Relationship between *Quality by Design & Risk Based Regulatory
Scrutiny*

In this discussion we seek subcommittee recommendations on ways to link
the concept of *risk based regulatory scrutiny to quality by design.*

*The committee defined the concept as using process understanding as a
means for Quality by Design. In PAT, a high level of process
understanding was defined as being able to understand the change and
impact, and thereby the risk assessment, on the process.*

*There was a general agreement among the committee members that a less
burdensome change management system based on development information
provided, as well as testing protocol is needed to qualify change.*

*The committee concluded that the post-approval change scenario offers a
way forward to bring pharmaceutical development information and to learn
how to better utilize that information. It was emphasized that
pharmaceutical development reports are not only important for
post-approval changes. The committee felt this incoming information
would help in training FDA personnel, as well as starting to build a
culture of "information sharing" between FDA and industry.*

*In summary, the committee felt that the Quality by Design and risk
assessment concepts would assist in the NDA review process and help
alleviate fears of delayed post-approval changes. The committee agrees
that the current products being developed in ICH guidance will be run in
parallel to the CDER's efforts. The committee's thought process and
discussions were consistent with the information contained in the Draft
Process Analytical Technology(PAT) guidance and represented a good basis
for ICH deliberations.*

The meeting was adjourned at approximately 4:30 p.m. on September 17,
2003.