This document discusses analytical method validation and outlines the challenges faced when outsourcing these services. It notes that while full validation according to ICH guidelines may not always be necessary, methods should still be scientifically sound. Some ways to reduce validation efforts discussed include adjusting the scope based on development stage, establishing method feasibility early on, and employing a risk-based approach. The responsibilities of both service providers and sponsors are examined, with the importance of alignment on quality expectations through a detailed agreement emphasized.

1. ANALYTICAL METHOD
VALIDATION - A
PREDICAMENT OF
SERVICE PROVIDER
Sasha Nezlin
VP Analytical Laboratories
Nextar Ltd.

2. ??? WHY VALIDATE ???
What are the benefits of validating analytical methods?
It allows for accurate assessment
of sample information
UNDERSTAND LIMITS AND LIMITATIONS OF THE METHOD:
 Essential part of successful drug development and
characterization
 Proof that the method provides accurate data within the
scope of its intended use
 Ensure safety of product
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

3. ??? WHY OUTSOURCE ???
What are the benefits of outsourcing laboratory services?
It saves total cost, investment and manpower
Outsourcing allows companies:
 to free resources from non-core competencies
 adopt best practices to ensure quality of their products
 to leverage internal resources more effectively
 to turn toward core strengths, therefore further
enhancing competitive position.
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

4. A key question regarding validation at
various stages of drug development:
How much validation is (really) needed
and how much is sufficient
 Needed – business point of view
 Sufficient – regulatory point of view
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

5. Types of tests and parameters to be validated for full development
From M.Bloch in “Method Validation in Pharmaceutical Analysis” Wiley [2005]
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

6. How can we reduce the effort?
Depending on the test considered, some
information on linearity, accuracy, specificity,
precision / repeatability, reporting level / limit of
quantification and limit of detection, is crucial for
any analytics, also during development.
But! this encompasses much of what is needed
for a full validation according to ICH !
Thus the question remains:
What simplifications may be permissible?
Where / how can the validation load be
reduced?
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

7. How can we reduce the effort? (cont.-1)
 Adjust validation scope according to stage of
development - e.g. perform qualification (for
example: wider acceptance criteria, reduce
number of replications, reduce extent of testing,
short report, etc.)
 Execute method feasibility during development –
determine performance characteristics of the
method – thus ensuring that the method will be
able to meet validation acceptance criteria later on
 Employ risk-based approach to prove method
suitability to intended use
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

8. How can we reduce the effort? (cont.-2)
Parameter Discovery Phase I Phase II Phase III /
Registration
1. Linearity V V V V
2. Range V V V V
3. Accuracy --- V V V
4. Specificity / Stress Study --- V V V
5. Precision
- Repeatability V V V V
- Intermediate Precision (API) --- V V V
- Intermediate Precision (RS) --- --- V V
6. Robustness --- --- V V
7. Solutions stability --- V V V
8. Limit of Detection --- --- V V
9. Limit of Quantitation --- V V V
Abbreviations:
V : Validated
--- : Not Validated
RS : Related Substances
API : Active Pharmaceutical Ingredient
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

9. Regarding Validation of Analytical
Methods the Sponsors could be
roughly separated in 3 groups:
1) Know exactly what their
regulatory/validation
requirements are
2) Require CRO input regarding
business/regulatory requirements
3) Are not aware of any
business/regulatory requirements
except for low costs and GMP
certificate in the end
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

10. Real life questions - from
projects performed at Nextar
 Short term stability study (1-3 months) is performed as part
of formulation development – why does the Assay method
has to be developed/qualified as Stability Indicating Method
(SIM)?
 Material for Clinical trial Stage I is manufactured and
released under cGMP requirements – why the analytical
methods have to be verified? Why do they have to be SIM
in order to perform stability study to establish shelf-life for
the duration of clinical study?
 Methods are transferred from Sponsor to support GMP
manufacturing of Clinical Trial Material at Nextar, why
analytical method transfer has to be performed?
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

11. PREDICAMENT  QUANDARY
Definition from the
Merriam-Webster
Dictionary
a difficult, perplexing,
or trying situation 11
ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

12. Responsibility of Service Provider
As analytical chemists we should be aware of
multiple sources of error that could influence
the measurement and therefore the
trustworthiness of results.
Analytical result reported without at least
evaluation of its reliability (sensitivity, accuracy
and precision) cannot be very meaningful or of
help in making informed decisions.
ICH and FDA state that while methods
employed for various stages of development
may not be yet fully validated – they should be
“scientifically sound”. 12
ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

13. Outsourcing Validation
 One Size Never Fits All
 Define Quality Expectations
 Spend time on the Quality Agreement
 Choose a service provider whose quality
philosophy is aligned with yours
 Stay involved (regular discussions)
 Technical review using your own analytical
and regulatory expertise
 Ultimate responsibility for product quality
remains with the Sponsor
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

14. QA Policy of Nextar Ltd.
SOP 00S011 “QUALITY ASSURANCE POLICY”
APPENDIX I FOR SUMMARY OF QA REQUIREMENTS
Based on cGMP for Phase 1 Investigational Drugs
(Guidance for Industry), FDA, 2008
Manufacture of IMP (Vol. 4, Annex 13, July 2003)
Guideline on the preparation new IMP (Guidance
for Industry), FDA, 1992
PIC/S GMP GUIDE (PE 009-08, Jan 2009)
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

15. QA Policy of Nextar Ltd. (cont. – 1)
Step
Formulation Clinical Clinical Production
Tasks Pre-clinical Clinical phase I
/ R&D Phase II Phase III for marketing
8. Testing Testing Laboratory testing Appropriate SOP Appropriate SOP, validation protocol &
methods for methods for should be carried (including verification report (relevant to the intended use)
RM. PM , IPC and out to evaluate procedure)
Laboratory testing to evaluate quality
IPC and Finished quality attributes:
Laboratory testing attributes: identification, strength,
Finished goods identification,
should be carried out potency, purity as appropriate. The
goods release strength, purity as
to evaluate quality manufacturer should establish
release should be appropriate.
attributes: acceptance criteria for testing and
Laboratory controls
should be scientifically
The manufacturer identification, release on a base of relevant
scientifically sound,
should establish strength, potency information and on a base of scientific
sound, suitable and
acceptance purity as appropriate. knowledge and experience
suitable and reliable for
criteria for testing The manufacturer
reliable for the specific
and release on a should establish
the specific purpose.
basis of relevant acceptance criteria
purpose.
information and for testing and
on a basis of release on a basis of
scientific relevant information
knowledge and and on a basis of
experience scientific knowledge
provided by and experience
Sponsor
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

16. QA Policy of Nextar Ltd. (cont. – 2)
Step
Formulation / Clinical Clinical Production
Tasks Pre-clinical Clinical phase I
R&D Phase II Phase III for marketing
9. Testing Optionally Optionally: Appropriate SOPs Appropriate SOPs, including for SIM
methods for including Stability (stability indicating method), stability
Stability testing Stability testing
Stability protocol and validation protocol validation protocol & report (as
using using
studies report (as suitable for suitable for the intended use)
representative representative
should be the intended use)
samples to samples to The manufacturer should perform
scientifically
monitor the monitor the Stability testing using Stability testing using representative
sound,
stability and stability and representative samples samples to monitor the stability and
suitable and
quality of quality at least to monitor the stability quality of product in appropriate stability
reliable for
formulation for duration of and quality of phase 1 chambers and storage conditions.
the specific
Stability
developed animal study. IMD at least for duration Establish acceptance criteria for
purpose.
product of human study in Stability testing on a basis of relevant
appropriate stability information and scientific knowledge
chambers and storage and experience.
conditions. Establish
acceptance criteria for
Stability testing on a
basis of relevant
information and
scientific knowledge
and experience.
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

17. SERVICE PROVIDER PROFILE
Nextar chempharma solutions Ltd. represents Israel's first
fully integrated one-stop-shop contract development and
manufacturing services company.
 Located at the Weizmann Science Park in Ness Ziona
 35 experienced highly skilled professionals
 Over 1200 m2 state-of-the-art facilities & equipment
 cGMP and GLP accreditation from regulatory agencies:
 GLP recognition by ISRAC (07/2008); re-inspection
December 2009
 GMP Inspection by District Pharmacy, Ministry of Health
(12/2008)
 GMP Certificate from Ministry of Health Institute for
Standardization and Control of Pharmaceuticals: granted for
contract manufacturing of IMP and contract Quality Control
analytical testing (11/2009)
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

18. NEXTAR Service Spectrum
for Development of Your
BioPharmaceuticals
Method
Development
Bioanalytical
Raw material and Validation
Services
testing &
release GMP
PK/ADME Production
profiling Contract
Formulation manufacturing
development & packaging
Custom chemical QA/QC
synthesis services
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

19. As we have demonstrated above – requirements of
ICH / FDA / GMP, business drivers and yes … common
sense – all of those go hand in hand and stipulate
that analytical methods should be “scientifically
sound”
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

20. Thank you!
Questions?
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ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER