Compte rendu Comité BPL 12 Mars 2020 - Animatrices : Catherine LIANG, Laurence ROBLET Excusée Johanna EUDE

Compte rendu Comité BPL
                                12 Mars 2020

Animatrices : Catherine LIANG, Laurence ROBLET Excusée Johanna EUDE,

Participants

• Animatrices : Catherine LIANG, Laurence ROBLET

•   Catherine CORBILLET
•   Charles GUINEZ
•   Angeline JULIA
•   Delphine MAGAT
•   Absente excusée : Johanna EUDE

AGENDA

• Texte OCDE N°19 :Caractérisation de l’élément
  d’essai

• Retours d’inspection

6th Global QA Conference Sendai - High level summary
                                           Feb 2020
    •   As it was also the case at the EU QA conference hold in Dublin, there has been a strong focus on new
        technologies, electronic data , regulatory challenges associated with merging technologies AND, for the
        first time, some considerations on the impact of Quality Assurance role.
    •   The participation of several regulators from the OECD GLP working group gives a special interest to this
        conference, because of their participation to the conference as speakers or participants to the multiples
        round tables.
    •   They also were aligned that regulatory authorities do not intend to be a stopper in the development/use
        of new technologies in drug development and GxP but are looking for providing regulatory support and
        hopefully will collaborate with industry to define the regulatory framework.
    •   It is recognized that training/education of regulators in new technologies is crucial for them to
        understand these, in the perspective to develop inspection methods and to respond to new
        technologies regulatory challenges. In a similar way it also is crucial to educate QA professionals and
        increase their awareness and understanding of new technologies in order for them to have an holistic
        approach , be able to assess regulatory risk and provide appropriate support to their organizations.
    •   It was on several occasions highlighted that how a system is used is equally as important as how it is
        built and validated (Culture to be built up). Human factors are underestimated.
    •   For GLP, it was confirmed that GLP principles are quite universal. There is no real need to change them
        BUT there is work to be done to assess the regulatory risks and define how they should apply in GxP
        environment.
    •   The OECD GLP working group will work on three new advisory documents that should arrive in coming
        months/year
    •   Digital pathology ( sept 2020) , Cloud computing and use of AI ( 2021/2022)

Future focus of GLP within each country?

PMDA (Japan): pathological samples/evaluation. Related to
DI, the way it relates to site work
ANSM (France) : medical devices, cloud based applications.
Exists in GLP facility now but no tool/guidance for inspection.
FDA (US) : biologics, characterization/stability of biologics ( is
the substance is present? Active ? …)
MHRA (UK) : medical devices, DI is absolutely Key, will
continue to work on it, Artificial intelligence and validation
related Q
NATA (Australia) : DI, AI as above, archiving stil a challenge in
AUS
FAMIC (Jap agro) : examine against OECD 19.

THEMATIQUE OCDE 19 Q&A round table
•   Panel on the OECD N° 19 with representative/inspectors from the following monitoring authorities.
Louise Calder NATA TGA Australia
Thomas Lucotte, ANSM France
Andrew Gray MHRA UK
Hitoshi Shibata FAMIC Japan
Charles Bonapace FDA US
Kenji Nakano PMDA Japan
•   Retention of test item, why is this necessary ?
To verify the identity of the test item (color, texture, labelling….) some OECD CMA wants to be able to check so
cannot be removed from OECD GLP

•   During inspection what do you often observe ? findings ?
During inspection we check the location as described in report
Usually it is retained. Very little cases it is not.
If not found, it may have impact on the outcome of the inspection, will depend from the rest of the inspection

•   Timing of characterization? when should it be done?
OECD 19 says that it should be completed by the end of the study. FDA says before initiation or concomitantly, must
be provided to the SD as soon as possible ? both are similar., however having information upfront is the best

THEMATIQUE OCDE 19 Q&A round table
• Timing of characterization? when should it be done?
OECD 19 says that it should be completed by the end of the study. FDA says before initiation or concomitantly, must be
provided to the SD as soon as possible ? both are similar., however having information upfront is the best

• Cosmetic : Mixture of TI. how do you determine whether or not the TI is aimed to be analyzed.
See the position paper and decision tree : If the TEST ITEM is a single substance you can develop a method, if it is a mix ( in
process or final product, you cannot technically analyse it and in that case it is expected to have as much information/data
that demonstrate the test item preparation/dilutions etc….

In this flow diagram, single substance can be analyzed, if it is a mix, formulation analysis may not be required providing other
dispositions/procedures (weights recording, qualitative data…)

• Inspectors may have a different opinion than the TFM during an inspection?
The inspection will not challenge the scientific: technical decision.

• How the OECD 19 impacts the way inspections are conducted ?
We spend more time on the test item related information/data

THEMATIQUE OCDE 19 Q&A round table
•   Second Q&A session with Questions selected from a collection of question prior to the conference
•   Louise Calder, NATA Australia
    Thomas Lucotte, ANSM France
    Andrew Gray, MHRA UK
    Hitoshi Shibata, FAMIC Japan
    Charles Bonapace FDA US
    Kenji Nakano PMDA Japan

•   Is the reference standard for analysis within the scope of the document in your country ?
PMDA : is in the scope. Because the test item is often used as a reference standard in bioanalysis/analysis
The objective is to ensure that the measuring test is valid. So it is used for comparison
FAMIC (J) agro : quality of the refe standard may affect the reliability of the residu analysis. Same position than
PMDA(J)
ANSM : substance standards can be a reagent. It is not intended to be administrated to animals. Are considered
out of the scope.
FDA : bioanalytical are expected to be conducted in accordance with GLP. Reference standard y=usually is
characterized by default to ensure the reliability of results.
UK/NATA: out of the scope. Used in the validation study. No need to archive sample

THEMATIQUE OCDE 19 Q&A round table
•   In your practice, are there any cases/conditions that environmental monitoring is not required during
    transportation of test item ? if so, what are the cases/conditions?
•   There may be some cases where environnemental monitoring is not necessary, but this should be
    documented by a risk assessment or stability data

PMDA : highly recommended. OECD 19 that stipulate it is to be monitored.it can be crucial
ANSM : two answers : environmental conditions monitoring is not required if the test item is not sensitive and if
this is supported by stability data.
To justify absence of monitoring, other checks can be done
The relevant measurement and needs should be justified by risk assessment.
FDA : depends on what is known on the test item. If it there is no concern about light degradation, sensitivity to
Temperature in a certain range etc…..
MHRA: expect facility to have done a risk assessment to assess what I required for a particular test item.
NATA : what is stipulate in the study plan is not what is observed during transportation.
FAMIC : aligned with the above

THEMATIQUE OCDE 19 Q&A round table

•   What kinds of Quality System other than GLP are acceptable for test item characterization
PMDA (Japan) : GLP/GMP
ANSM (France) : the environment which the characterization has been performed should be known and the SD
should have confident . not in the scope of GLP. GMP is broadly accepted
FDA (US): very similar to ANSM. GLP is an exception. e. If not GLP it is a GLP exception BUT is not essential.
What is important is to get the information that the TI is suitable for its purpose of use
MHRA (UK) : test item should be characterized , can be under GLP/GMP
NATA (Australia) : no required Quality System. It is more and more often performed under a Quality System it is
the SD who has to assess the validity and quality of the data provided and knowing the quality environment helps
him making the decision.
FAMIC (Agro Jap): usually in GLP, if not need to be reported. No further requirement.

            So no Quality System required but SD should make the decision in the quality of the data.

THEMATIQUE OCDE 19 Q&A round table

•   What kinds of quality system other than GLP are acceptable for test item characterization.
ANSM. For chemicals it is expected to be GLP

•   For formulation analysis, any other quality systems than GLP are acceptable ?
PMDA/FAMIC : field test : GLP
Other : GLP/GMP
ANSM: If formulation analysis is part of the study and is not conduct in a GLP test site, the impact should be
assessed in the report as a GLP exception
FDA : same as ANSM; all phases in a GLP study should be conducted according GLP while I am not sure that
GLP is better than GMP (!) in this area, this will be a GLP exception
UK : if an assessor see GMP instead of GLP, he will not reject the study
NATA : OECD 19 expect it to be conducted in compliance with GLP. If it comes pre formulated, and there is some
kind of quality system

THEMATIQUE OCDE 19 Q&A round table
•   Would you expect that formulation analysis should be done in Ames test
PMDA : YES
ANSM: YES. Required. If not it is GLP exception reported with its impact. As above
FDA :YES : formulation concentration analysis. The purpose is what if the test is negative? which degree of confidence
will you have in the test results?
MHRA : preferably yes, but could be justified not to do it….
NATA : same as MHRA
FAMIC pesticide : same as MHRA/NATA

•   What is the difference between retest date and expiry date :
MHRA : expiry date :when the compound can no longer be used unless you have a retest to demonstrate it is valid
A retest date is an analysis date. if not supported by stability data, it is useless. If it is supported by data it is a stability
information.
PMDA : Retest/expiry date are defined in ICH. Retest is for API, expiry date is for Final product. Expiry date is after
approval. Retest date if supported by stability data, will be consider as a valid stability information.
ANSM : what is not acceptable is to have retest date , which is not supported by any kind of data. SD decision
Retest could be arbitrary date. If there is enough supporting data the retest date and expiry date could be considered
similar for GLP preclinical use

THEMATIQUE OCDE 19 Q&A round table
•   §41 describes that the final report should describe who is responsible for test item characterization and
    who performed it. Who should be the R ?
ALL : the report should be clear about who did what

•   What do you mean by “ these may be determined through separate lab experiments “ in paragraph 62?
The Homogeneity/Concentration/ Stability could be done in a separate study, it should be stipulated in the Study
Plan

CASE STUDY

Test Item : Constant T cell engager will be hybridized to the exemplary single sequence of Variable Strand, which is a specimen
resulting from Xs platform, shown to have a cell death-inducing effect, limited to tumor cells.
the facility will receive the constant strand and the variable strands separately and will mix them in various proportions to get the
target concentrations.
The final test item will be a mixture of the constant strand and SEVERAL variable Strands

What would you expect to have to achieve OECD 19/GLP requirements ?

Note : The bioanalytical methods to detect each of the Strands will be implemented to analyze the plasma levels of the arms and would allow to
demonstrate the 1:1 anticipated stoichiometric ratio of the Constant : Variable arms. After the correlation between to two arms is established, PK
analysis will be based on the detection and quantification of the Constant Strand only. ( partie constant)

Suggestion : - les deux “strands” doivent être caractérisés.
                - la procedure de mélange doit être définie et documentée
                - le mélange doit aussi être caractérisé soit à chaque préparation soit sur un rationnel si seul un des deux éléments ( = partie
                  constante est mesurable)
               - si la démonstration est faite que l’analyse de la partie constante est proportionelle au ratio d’association des deux parties (
                 constant et patient spécifique) , dans ce cas il est acceptable que le dosage (méthode validée) sur la partie constante soit utilisée
Il est important que les explications soient présentées dans le plan d’étude et le rapport.

CASE STUDY
Le donneur d’ordre livre des formulations de principe actif prêtes à l’emploi. (drug product)
Ce sont des formulations d’un principe actif qui ont été soumis à une dégradation forcée (BPF) de manière à
reproduire le produit fini à la fin de la période d’utilisation shelf life). L’élément d’essai considéré sont les
formulations fournies puisque l’objet de l’étude porte sur les formulations avec impuretés. .
Elles ont une concentration « nominale » en début d’étude ( concentration réelle fournie en fin d’étude)
L’une de ces formulations doit être diluée par l’installation d’essai. L’analyse de la concentration sera faite par le
donneur d’ordre, dans un labo BPF

Comment géreriez vous cette situation? Exclusion BPL? Périmètre de l’étude? Multisite?
Suggestion :
Dans tous les cas il y a une exclusion BPL que le DE doit rapporter dans son attestation BPL.
Ensuite pour la gestion dans l’étude :
Option 1 : Gérer cette situation en étude multisite, avec nomination d’un RS ( phase non BPL)
Option 2 : Il nous semble aussi acceptable d’exclure du périmètre de l’étude l’analyse de la concentration de cette
dilution, ( OCDE 19 ) et d’indiquer que cette analyse est sous la responsabilité du donneur d’ordre

RETOUR D’INSPECTION

 Tendance :

 - Archivage : Test item/ Echantillothèque
 - Etude : Process étude
 - Installation
 - Délégation DIE

ROLE DE L’ASSURANCE QUALITE

• Le rôle de l’assurance qualité évolue:

• Les avancées technologiques et l’intelligence artificielle vont engendrer
  une vision différente de l’AQ

• Les inspecteurs FDA sont en cours de formation sur l’intelligence
  artificielle

• Quel que soit le système le maillon faible est souvent le facteur
  humain. Les système sont validés, les outils sont sécurisé mais
  ……………l’homme ?

MERCI !

Contact: GLP@sofaq.fr