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Re: Validation Strategy for NONMEM

From: Joachim.Grevel
Date: Tue, 21 Oct 2008 09:18:08 +0200

Dear Mark,

I am engaged in this question since the beginning of this year (not
finished yet), and I am happy to share some basics of my experiences:

1. It is important to specify where the data for NONMEM analysis come
from. If they come from a GCP source and are already QA-ed when they
arrive at the doorstep of NONMEM then your system will only subject to GCP
regulation. Otherwise, you also have to comply with GLP.

2. There is no way around what is called here a 'Validation Plan' and
a 'Risk Analysis'. These documents will trigger a slate of other documents
(in our case here about 15) which describe Installation, Installation
Validation, Qualification of Users, Modeling Strategy, Review Processes,
System Life Cycle Management etc.

3. We found it useful to differentiate between 'Exploratory Work' and
'Submission Work'.

4. Before you worry about passing inspection by the FDA, you need to
worry about passing inspection of your own company QA officers.

5. Just installing NONMEM with NMQual does not render you new system
'validated' or 'qualified'. Here my apologies to the excellent folks at
Metrum, but for various reasons, we ended up not using NMQual.

6. You have to know what you are trying to build before you concern
yourself about QA processes. A number of separate installations on PCs
linked to a file server is a different animal from a server-based
installation with a grid engine.

7. It all takes more time than you think: make generous budgets and
time lines.

I hope I helped more than I confused,


Joachim GREVEL, Ph.D.
MERCK SERONO International S.A.
Exploratory Medicine
1202 Geneva
Tel: +41.22.414.4751
Fax: +41.22.414.3059
Email: joachim.grevel

"Vilicich, Mark" <Mark.Vilicich
Sent by: owner-nmusers
10/17/2008 10:08 PM


[NMusers] Validation Strategy for NONMEM

Dear All,

I am interested in perspectives on strategies for "validating" NONMEM.
Also, experiences from or with the FDA since the FDA is: a key user,
customer of analysis and auditor of NONMEM use in the industry. Without a
large nonmem staff here, the challenge I see is in scaling the validation
strategy to provide the most efficient environment for doing analysis that
is defensible to both internal and external audits based on the associated
GxP risk level.

Below are the concepts I've cobbled together, though instead of my
reinventing the wheel I appreciate anything you could share. Any and all
gems of insight you can share whether it regard the big picture or some
detailed specifics, IT centric or business process related. You may send
them back to the listserver or me directly as you feel appropriate.

From searching the archives and other random bits of knowledge on NONMEM,
part of the validation strategy is to recognize that NONMEM is not to be
literally validated. NONMEM may be considered more of a development
environment, optimized for developing specialized forms of complex
analysis and modeling. As a development platform, an approach could be
that NONMEM itself is qualified and each specific analysis is validated

To support establishing a defensible NONMEM environment, I've also read
discussions on integrating common software development best practices such
as version control of the "programming" of nonmem, NMQual and other
commercial and custom tools for capturing all the metadata related to
running a specific NONMEM job. These themes support defining the state of
the NONMEM environment and ability to reproduce the outcomes.

Also, reading in the archives about the differences in the numeric
outcomes of NONMEM analyses based on the hardware platform, etc. are
helpful to know up front and to consider in the validation strategy so it
is not destined to failure if the target environment is multiplatform or
otherwise complex.

Gaps noticed/topics not discussed:
Is there opportunity in looking at the risk based approached sanctioned by
the FDA a few years ago that would make the total validation deliverable,
including both the application and the model development process, more
lean and targeted at the primary risk targets?

Does this scientific software environment lend itself to use of modern
agile software development methodologies that go far beyond basic
iterative approaches. These methodologies are being used in software
development for the regulated/GxP industry.

I've seen the excellent presentation from 2004 that Joga Gobburu from the
FDA gave, seems like there has been some progression of thought or actions
on the proposals included there. Any references to follow-up information
on it would be helpful?

 Regards ,

Mark Vilicich
Early Development

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Received on Tue Oct 21 2008 - 03:18:08 EDT

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