all for one, one for all - the chinese bmv guidance in perspective to other guidelines

Peter van Amsterdam

Head Bioanalytics, Abbott Established Pharmaceuticals Division

CPSA Shanghai, 17 Apr 2015, Shanghai

17-Apr-2015 All for one, one for all 2

The views and conclusions presented in this slide deck are those of the author/presenter and do not necessarily reflect the representative affiliation or company's position on the subject.

The focus is on the small molecules / chromatographic assays realm of the bioanalytical world.

The works of the Alexandre Dumas are freely used as a metaphor to depict developments and illustrate differences and similarities between guidance documents.

1802-1870

1844



1921

and many many more

2011


The evolution of Regulated Bioanalysis


2020 1960 1970 1980 1990 2000 2010

TLC, GC

(LC-UV)

immunoassays

Sub μg/mL

GC2, GC-MS

GC-NPD/ECD

HPLC-UV/FL/EC

immunoassays

ng/mL

TLC

Immunoassays

bioassays

μg/mL

GC2, GC-MS, GC-

NPD/ECD

HPLC-UV/FL/EC,

LC-MS/MS,

Old school

Immunoassays

Sub ng/mL

LC-MS/MS,

New generation

Binding assays

AMS

ICP-MS

pg/mL

New generation

LC and MS(/MS)

and Binding assays

Sub pg/mL?

Sensitivity doubles every 2 years (Peter’s law of bioanalysis)

Adapted from Philip Timmerman,

“Regulated Bioanalysis: A Proposed

Global Harmonization Process”

”2nd JBF, Tokyo, 2012

A tremendous increase of sample analysis power over the

last 50 years.

Same technology is (more or less) available around the

globe and applied with (more or less) the same level of

quality and success.

But what happened in the regulatory field?


1990s & 2000s: The AAPS / FDA story



Crystal City I Shah

2001 FDA

Guidance

CC-I CC-II CC-III Crystal City

Conferences

Conference

papers

Additional

white papers

Regulatory

Guidance

CC-IV

(ISR)

CC-IV Fast

1990 2000 2010

CC III Viswanathan

CC II Shah (chrom.)

Miller (LBA)

DeSilva

Adapted from Philip Timmerman,

“Regulated Bioanalysis: A Proposed

Global Harmonization Process”

”2nd JBF, Tokyo, 2012

US (AAPS / FDA) to lead the way

Conference report Crystal City I became THE reference point for many bioanalytical scientists and was basically used as ‘Guidance’

FDA 2001 BMV Guidance substantiated the influence of the CC-I BMV concept in the bioanalytical world

Further fine-tuning of the BMV concept and interpretation of the FDA guidance in CC-III and CC-IV


2008 EMA concept paper on BMV

2009 EMA draft BMV guideline

2011 EMA final BMV guideline

2010 GBC founded



2001 FDA Guidance for Industry: Bioanalytical Method Validation

2002 ANVISA Manual for Good Bioavailability and Bioequivalence Practices.

Module 2: Analytical Step

2003 ANVISA Resolução - RDC Nº 899: Guide for Validation of Analytical and Bioanalytical Methods

2004 ANMAT Normativa Aplicable a la Etapa Analítica Para la Realizacion de Estudios de Biodisponibilidad - Bioequivalencia

2011 EMA Guideline on Bioanalytical Method Validation

2012 ANVISA Resolução - RDC Nº 27: Dispõe sobre os requisitos mínimos para a validação de

métodos bioanalíticos empregados em estudos com fins de registro e pós-registro de

medicamentos.

2013 ANMAT Normativa de Buenas Practicas de Laboratorio Aplicable a Los Centros Bioanalíticos

Para Estudios de Biodisponibilidad I Bioequivalencia

MHLW Guideline on Bioanalytical Method Validation in Pharmaceutical Development

FDA DRAFT Guidance for Industry: Bioanalytical Method Validation

2014 MHLW Guideline on Bioanalytical Method (Ligand Binding Assay) Validation in Pharmaceutical

Development

CFDA (PhC) DRAFT Guidance on Bioanalytical Method Validation

Can we get the genie back in the bottle?

What can e.g. GBC do?

Is there benefit in having a guidance document from an international organization (ICH, WHO, OECD, …)

Is there really a problem?

What do we want to achieve?

o Harmonization on a detailed level?

o Alignment on main principles?


Global Guidance on Bioanalytical Method Validation



Selectivity Matrix effect

EMA 6 sources, no pools

< 20% at LLOQ, < 5% for IS

Attention to: co-medications and metabolites

6 sources, no pools

Calc. MF and IS norm MF, CV IS norm MF < 15%

Attention to excipients and special populations

In addition: hemolyzed & lipemic

FDA, Draft 2013 Same principle as EMA, but no specifics given Open (=judgment of scientists)

ANVISA 6 sources, no pools


NO Attention to: co-med and metabolites

Required: hemolyzed & lipemic

8 sources: 4 normal, 2 lipemic, 2 hemolyzed, no

pools

Calc. MF CV MF < 15%

NO Attention to excipients and special populations

MHLW 6 sources, no pools


NO Attention to: co-medications and

metabolites

6 sources, no pools

Calc. MF CV MF < 15%


NO: hemolyzed & lipemic

CFDA 6 sources, no pools


NO Attention to: co-medications and

metabolites

6 sources, no pools

Calc. MF and IS norm MF, CV IS norm MF < 15%


In addition: hemolyzed & lipemic

Aspect Overlaps … but …

Full validation ANVISA, CFDA, FDA*), MHLW

Reference standards CFDA, MHLW ANVISA: CoA information

FDA*): extra requirements

Selectivity CFDA, MHLW, FDA*) ANVISA: Lipemic & hemolyzed

Carry-over CFDA, FDA*), MHLW ANVISA: experimental set-up

LLOQ All Note: BE requirement EMA

Calibration curve CFDA, MHLW ANVISA: weighting and non-linear models

FDA*): exclusion of calibrators

Accuracy & Precision CFDA, MHLW ANVISA: add 5th QC = dilution QC

FDA*): outliers & QCs match sample conc.

Dilution integrity ANVISA, CFDA, FDA*), MHLW Note: ANVISA: dilution is part of A & P

Matrix effect CFDA, FDA*), MHLW ANVISA: 2x lipemic & hemolyzed

MHLW: CV_MF < 15%

All for one, one for all 16 17-Apr-2015

Taking EMA as reference……


Stability CFDA ANVISA & MHLW: triplicate

FDA*) also IS stock stab & injection repro.

Recovery ANVISA, CFDA FDA*) & MHLW: recovery chapter

Endogenous analyte CFDA, MHLW ANVISA & FDA*): endogenous analytes chapter

Partial validation All Note: species change within a matrix or matrix

change within a species may require a full

validation (EMA)

Cross validation All Note: MHLW accepts 20% difference

Reporting ANVISA, CFDA, MHLW FDA*) recommendations



*) 2013 draft


Analytical run All

Acceptance criteria All

Calibration range All

Reanalysis of study samples All Note: EMA requirement with

respect to patient safety

FDA*): specific no. of replicates

Reintegration All FDA*): original & reintegration

data

Incurred sample reanalysis ANVISA, CFDA, MHLW FDA*): 7%

System suitability ANVISA, CFDA FDA*) & MHLW requirements

Reporting ‘All’ Note: some detailed req.



*) 2013 draft

INTERIM CONCLUSIONS

EMA and CFDA (PhC) are very similar

MHLW is quite similar to EMA & CFDA, but some differences on detailed level exist

US FDA draft, although essentially similar, has a number of requirements different to ANVISA, CFDA, EMA, MHLW

ANVISA, although essentially similar, has a number of requirements different to CFDA, EMA, FDA draft, MHLW

AND THUS …..



EMA, MHLW and CFDA (PhC) are very similar in set-up and content

‘Yes’

Australia: refers to EMA BE & BMV and FDA BMV

Canada: specifically refers to EMA BMV

‘Maybe’

India: general chapter in BE guideline.

ASEAN: chapter in BE guideline, refers to OECD GLP

Gulf States: chapter in BE guideline, clearly inspired by EMA

‘Not yet’

Brazil: same principles as others BMVs, but a lot of specific requirements

Argentina: general ‘Good Analytical Procedures’ + general principles of BMV


Can we get the genie back in the bottle? No

What can e.g. GBC do? o Add main BMV principles to existing/new ‘global’ quality documents?

o Prepare/publish the ‘global BMV white paper’?

Is their benefit in having a guidance document from an international organization (ICH, WHO, OECD, …) o Yes, but may take long and added value is perhaps limited

Is there really a problem? o Maybe not. Not if new or revised guidelines follow the ‘Eurasian standard’

What do we want to achieve? o Harmonization on a detailed level? Would be nice, but not an issue if there is

mutual acceptance for global studies/filings

o Alignment on main principles? This we already have


CONCLUSIONS

CFDA (PhC), EMA and MHLW guidelines show great

similarity in set-up and contents.

(each of) These three guidelines can be considered as the

‘Eurasian Standard’ for BMV

A number of other countries/regions are already or may

likely follow this standard

Guidelines of ‘The Americas’, although essentially similar,

have a number of local requirements different to the

‘Eurasian Standard’


CPSA-Shanghai for giving me the opportunity to present at their

meeting.

EBF members and Steering Committee for the learning

experiences.

The GBC Founding & Steering Committee members and

Harmonization Team leads for the learning experiences

The regulators and inspectors for stimulating us to continuously

improve our work

You, for your attention

and Alexandre Dumas for his inspiring novels

All for one, one for all 17-Apr-2015 24

1963 FDA drafting the GMP concept

1964 Declaration of Helsinki

1973 New Zealand draft GLP concept

1978 FDA GLP final

1978 FDA GMP final

1981 OECD GLP

1982 MHLW GLP

1983 EPA GLP

1989 Revised EPA GLP

1989 ICH global standards for Clinical Research

1997 21 CFR 11

1997 Revised OECD GLP

1997 ICH GCP

2001 EU Clinical Trials directive

2005 EU GCP directive

2009 MHRA GCP for laboratories

2009 WHO GCLP

2012 EMA 'GCLP' reflection paper


Hmmm…. GCP

some 20 yrs

later than GLP

and GCLP 30

yrs later ?

all for one, one for all - the chinese bmv guidance in perspective to other guidelines

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