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RE: Validation Strategy for NONMEM

From: Vilicich, Mark <Mark.Vilicich>
Date: Thu, 23 Oct 2008 11:35:15 -0700

Thank you for everyone's insight into this.
The insight into performance considerations is excellent Joachim and
Jun, thank you.
It would be great to hear from you or anyone else with experience
running NONMEM on a VMware environment as we are considering it. Since
we are starting with a very small set of users, it offers the ability to
dedicate greater CPU power and memory to NONMEM as our analytic needs
grow over time.
Regarding validation; requiring proof of reproducible results seems
appropriate and Jeff's mention of developing a level of "confidence in
the performance of a NONMEM installation" alludes to the risk based
approach in my mind and helps guide validation efforts to where the
value is.
How could one generically describe a spectrum of testing levels for
NONMEM based on a spectrum of risk such as-high, medium, low? What would
be the minimum tests done for a base level of confidence versus what
testing is included to support greater confidence (i.e. the high risk
situation) in reproducibility? Do NONMEM's or NMQUAL's standard provided
testing cover that spectrum or just the base level of confidence?
Thanks in advance for your responses,


From: owner-nmusers
On Behalf Of Joachim.Grevel
Sent: Wednesday, October 22, 2008 7:44 AM
To: nmusers
Subject: Re: [NMusers] Validation Strategy for NONMEM

Dear Jun,

the outside reference used: NONMEM (Version VI) with Wings for NONMEM;
installed using NMQUAL version 6.3.2 (Metrum Institute); Intel Visual
Fortran compiler (Version 10.1 ) or GNU Fortran g77 (Version 3.1 release
20020514); compiler options for Intel Fortran were /nologo /nbs /w
/4Yportlib /Gs /Ob1gyti /Qprec_div. ; compiler options for g77 were
-fno-backslash -O; hardware: Intel Core Duo 7500 2.19GHz processor on an
IBM Thinkpad Model T61 with 1 Gb RAM. The operating system was Windows
XP Professional 2002 Service Pack 3.

We internally used: NONMEM (Version VI,2) PsN (Version 2.2.5) installed
without NMQual; gfortran compiler with option -O ; hardware: HP PROLIANT
DL585 G2 Servers with many cores (speed 2,8 GHz) with 16 Gb RAM and the
LINUX (SUSE Enterprise Edition 10 SP1 64 Bit) operating system with SUN
Grid engine (N1).

We reproduced the reference models well. Speed was equal with ANVAN6
(long runtimes in the hours). But with precompiled models ADVAN4 and
with naked PRED the Intel compiler was sometimes twice as fast (runtimes
< 1 min).

Hope this is helpful for some of you about to make decisions about hard-
and software.


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

"Jun Shen" <jun.shen.ut

10/22/2008 04:08 PM

Re: [NMusers] Validation Strategy for NONMEM


Dear Joachim,

Can you share some of your findings? What system configuration seems to
be optimal (hardware/OS system, compiler, any aiding software)? Thanks.


On Wed, Oct 22, 2008 at 1:21 AM, <Joachim.Grevel

Dear all,

one of the more useful things we did was an exchange of data files and
models with a prominent member of our modeling community. This way we
challenged various aspects of our installation, found some soft spot,
corrected it, and wrote a document that is worth more than the ink and
the paper. Yet again, all we did was assuring that our results match
those of a number of other installations (different compilers, operating
systems, processors). Furthermore, we got an idea of the comparative
speed of our installation. These are useful things to have documented
when you are a system administrator and modeler at the same time.


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

"A.J. Rossini" <blindglobe

10/21/2008 10:41 PM

Re: [NMusers] Validation Strategy for NONMEM


There is useless validation, and then there is useful validation. The
latter is about making sure your computational results are
reproducible, the former is about making sure that your documentation
can be photocopied. It's sort of the same thing, if you aren't a

Unfortunately, most on this list tend to be modelers.

On Tue, Oct 21, 2008 at 7:37 PM, <Michael.J.Fossler
> After reading this, it is no wonder scientific productivity is at an
> all-time low. Imagine if Marie Curie had to qualify her
> equipment, or if Alexander Fleming had to validate his petri dishes
> culturing Penecillium. One day scientists are going to push back
> these IT people, who just make busy work for everyone.
> Joachim.Grevel

> Sent by: owner-nmusers
> 21-Oct-2008 03:18
> To
> nmusers
> cc
> Subject
> Re: [NMusers] Validation Strategy for NONMEM
> Dear Mark,
> I am engaged in this question since the beginning of this year (not
> 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
> 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
> (in our case here about 15) which describe Installation, Installation
> Validation, Qualification of Users, Modeling Strategy, Review
> 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
> 'validated' or 'qualified'. Here my apologies to the excellent folks
> Metrum, but for various reasons, we ended up not using NMQual.
> 6. You have to know what you are trying to build before you
> 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
> time lines.
> I hope I helped more than I confused,
> Joachim
> __________________________________________
> 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
> To
> <nmusers
> cc
> Subject
> [NMusers] Validation Strategy for NONMEM
> Dear All,
> I am interested in perspectives on strategies for "validating" NONMEM.
> 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
> staff here, the challenge I see is in scaling the validation strategy
> provide the most efficient environment for doing analysis that is
> to both internal and external audits based on the associated GxP risk
> Below are the concepts I've cobbled together, though instead of my
> reinventing the wheel I appreciate anything you could share. Any and
> gems of insight you can share whether it regard the big picture or
> detailed specifics, IT centric or business process related. You may
> them back to the listserver or me directly as you feel appropriate.
> Details:
> ~~~~~~~~~~~~~~~~~~~~~~~~~~~
> From searching the archives and other random bits of knowledge on
> part of the validation strategy is to recognize that NONMEM is not to
> literally validated. NONMEM may be considered more of a development
> environment, optimized for developing specialized forms of complex
> and modeling. As a development platform, an approach could be that
> itself is qualified and each specific analysis is validated
> To support establishing a defensible NONMEM environment, I've also
> discussions on integrating common software development best practices
> 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
> the NONMEM environment and ability to reproduce the outcomes.
> Also, reading in the archives about the differences in the numeric
> of NONMEM analyses based on the hardware platform, etc. are helpful to
> up front and to consider in the validation strategy so it is not
destined to
> failure if the target environment is multiplatform or otherwise
> 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
> including both the application and the model development process, more
> and targeted at the primary risk targets?
> Does this scientific software environment lend itself to use of modern
> software development methodologies that go far beyond basic iterative
> approaches. These methodologies are being used in software development
> the regulated/GxP industry.
> I've seen the excellent presentation from 2004 that Joga Gobburu from
> FDA gave, seems like there has been some progression of thought or
> on the proposals included there. Any references to follow-up
information on
> it would be helpful?
> Regards ,
> Mark Vilicich
> Early Development
> mark.vilicich
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"Commit early,commit often, and commit in a repository from which we
can easily roll-back your mistakes" (AJR, 4Jan05).

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Received on Thu Oct 23 2008 - 14:35:15 EDT

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