analytical method validation -a predicament of service provider

ANALYTICAL METHOD VALIDATION - A PREDICAMENT OF SERVICE PROVIDER

Sasha NezlinVP Analytical Laboratories

Nextar Ltd.

ANALYTICAL METHOD VALIDATION – A PREDICAMENT OF SERVICE PROVIDER

2

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

??? WHY VALIDATE ???


3

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.

??? WHY OUTSOURCE ???


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


5

Types of tests and parameters to be validated for full development

From M.Bloch in “Method Validation in Pharmaceutical Analysis” Wiley [2005]


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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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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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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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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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 SIMin 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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PREDICAMENT QUANDARY

Definition from the Merriam-Webster

Dictionary

a difficult, perplexing, or trying situation


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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”.


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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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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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QA Policy of Nextar Ltd. (cont. – 1)S

tep

TasksFormulation

/ R&DPre-clinical Clinical phase I

Clinical

Phase II

Clinical

Phase III

Production

for marketing

8.

Lab

ora

tory

co

ntr

ols

Testing

methods for

RM. PM ,

IPC and

Finished

goods

release

should be

scientifically

sound,

suitable and

reliable for

the specific

purpose.

Testing

methods for

IPC and

Finished

goods

release

should be

scientifically

sound,

suitable and

reliable for

the specific

purpose.

Laboratory testing

should be carried

out to evaluate

quality attributes:

identification,

strength, purity as

appropriate.

The manufacturer

should establish

acceptance

criteria for testing

and release on a

basis of relevant

information and

on a basis of

scientific

knowledge and

experience

provided by

Sponsor

Appropriate SOP

(including verification

procedure)

Laboratory testing

should be carried out

to evaluate quality

attributes:

identification,

strength, potency

purity as appropriate.

The manufacturer

should establish

acceptance criteria

for testing and

release on a basis of

relevant information

and on a basis of

scientific knowledge

and experience

Appropriate SOP, validation protocol &

report (relevant to the intended use)

Laboratory testing to evaluate quality

attributes: identification, strength,

potency, purity as appropriate. The

manufacturer should establish

acceptance criteria for testing and

release on a base of relevant

information and on a base of scientific

knowledge and experience


16

QA Policy of Nextar Ltd. (cont. – 2)S

tep

TasksFormulation /

R&DPre-clinical Clinical phase I

Clinical

Phase II

Clinical

Phase III

Production

for marketing

9.

Sta

bil

ity

Testing

methods for

Stability

studies

should be

scientifically

sound,

suitable and

reliable for

the specific

purpose.

Optionally

Stability testing

using

representative

samples to

monitor the

stability and

quality of

formulation

developed

product

Optionally:

Stability testing

using

representative

samples to

monitor the

stability and

quality at least

for duration of

animal study.

Appropriate SOPs

including Stability

protocol and validation

report (as suitable for

the intended use)

Stability testing using

representative samples

to monitor the stability

and quality of phase 1

IMD at least for duration

of human study in

appropriate stability

chambers and storage

conditions. Establish

acceptance criteria for

Stability testing on a

basis of relevant

information and

scientific knowledge

and experience.

Appropriate SOPs, including for SIM

(stability indicating method), stability

protocol validation protocol & report (as

suitable for the intended use)

The manufacturer should perform

Stability testing using representative

samples to monitor the stability and

quality of product in appropriate stability

chambers and storage conditions.

Establish acceptance criteria for

Stability testing on a basis of relevant

information and scientific knowledge

and experience.


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SERVICE PROVIDER PROFILE

Nextar chempharma solutions Ltd. represents Israel's firstfully integrated one-stop-shop contract development andmanufacturing 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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NEXTAR Service Spectrum for Development of Your

BioPharmaceuticals

PK/ADME profiling

Formulation development

QA/QC services

Method Development and Validation Bioanalytical

ServicesRaw material

testing & release GMP

Production

Custom chemical synthesis

Contract manufacturing & packaging


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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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Thank you!

Questions?

analytical method validation -a predicament of service provider

Documents

establish

evaluate quality

analytical

finished goods

stability

analytical

steptasksformulation

gmp certificate