Biotechnological Medicinal Products

Quality

Requirements for authorised biotech products

EU guideline on the Comparability of biotech products

General quality requirements for investigational

biotechnological products used in clinical trials in
Finland

Frequently asked questions

Appendix: List of biotech quality Note for Guidances (www.nam.fi)

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Authorised biotechnological products

Quality requirements (EU)

Biotech Quality Notes for Guidance

Vol. 3A, dg3.eudra.org/F2/eudralex/vol-3/home.htm
NfG, www.emea.eu.int
(Human Medicines;Regulatory Guidance&Procedures;Notes
for Guidance; Biotechnology, ICH, Quality)
European Pharmacopoeia (e.g. monographs on: dosage forms,
vaccines, products of recombinant DNA technology)
Quality requirements on authorised products guarantee
predictable in vivo characteristics of commercial batches

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Investigational biotechnological products in

clinical trials -Quality requirements (FI)

Regulation 1/2001, Appendix 1: 1. Biological, Chemical and

Pharmaceutical information (www.nam.fi)
Provide adequate quality data
Safety of the trial should be demonstrated in the notification
adequacy of the data determined case by case: product, aim
of the study, phase
Adequate quality requirements impact on the usefulness of the
results optimisation of the clinical stage of the product
development

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Regulation 1/2001
Batch used in the clinical trial
The batch in the clinical trial is the same product that is
presented in the quality part of the notification
used in the pre-clinical studies
All changes in the product (active ingredient, pharmaceutical
form, excipients, specifications, process) must be reported &
justified, and comparability demonstrated and new notification
submitted when necessary

GMP, manufacturing licence of the manufacturing place

prerequisites for the use of any batch in a clinical trial!

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Clinical trials - quality

1. Quality requirements for investigational products are based on
the existing regulations for authorised biotech products
2. In the MAA justification of acceptance criteria for the product is
based mainly on quality data from batches used in pre-clinical
and/or clinical studies
3. Process changes in the development of the product.
Comparability of the new and old product must be
demonstrated to validate the previous pre-clinical and clinical
studies for the new product

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Clinical trials - quality

Relevant guidelines should be taken into account as early as

possible in the development of the product

Read your guidelines NOW

Start with the Note for Guidance on Comparability of Medicinal

Products containing Biotechnology-derived Proteins as Drug
Substances CPMP/BWP/3207/0

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Guideline on Comparability: Change process

change in quality/safety/efficacy?
Strategies of comparison
1. No impact on quality (in process controls, specifications)
2. Impact only on IPC
3. Impact on IPC and need to change specifications
-insignificance on safety&efficacy justified&discussed
4. Impact on IPC, specs and potentially on safety/efficacy
-additional pre-clinical/clinical studies necessary?

Importance of proper characterisation of the batches in the

product development

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

No effect/minor/major effect
Comparable?

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Clinical Trials
Methods
VALIDATE the methods

safety of the clinical trial

relevance of the results

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Clinical Trials - quality documentation

Formulation: composition-history-process

Composition & Strength & Pharmaceutical form

Justification for the formulation&container

aim: patient friendly, ready-to-use, shelf-life 2 years
reality: incompatible, parenteral, unstable
~75 % protein products lyophilised

Manufacturing process of the product - reliability?

method of sterilisation, media fill, lyophilisation

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Clinical Trials
Active ingredient - The Star

Thorough characterisation data the state of art

Development: genetics, seeds, genetic stability, optimisation the
host&media&purification process, compatibility, stability
Validation of the process&stability of intermediate products
Heterogeneity&impurity profile
impact on stability, safety, activity, comparability, PK?
Testing of the quality of the active ingredient batch
justified process controls & justified specifications
characterisation&process&stability&pre-clinical data

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Clinical Trials
Materials

Materials of animal origin - origin, transmissible agents?

Excipients -quality?
Media -composition&sterilisation?
Columns- quality, sanitation, re-use cycles?
Reagents, enzymes -quality, origin?
Containers for sterile products -quality, sterilisation?

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Clinical Trials
Finished product

Finished product characterisation&specifications for batches

justification for the proposed tests&limits
batch results
failures must be explained

MAA Potency test - correlation with clinical response

established in clinical studies

Parenteral products - general requirements: sterility, bioburden,

endotoxins, media fill, particles, residual moisture...

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Clinical Trials
Stability

Finished product and active ingredient data

stability study plan (tests, conditions, samples), results &
justification for the proposed shelf-life
Purpose to guarantee quality safety of the product at the time
of administration minimum acceptable shelf-life
Adequate stability requirement for the product to ever have MA
importance of formulation development

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Typical supplementary information requested

by regulatory authorities

Limits should be stated/tightened and justified.

How is sterility guaranteed?
Impurity profile?
Data from validation of the LAL-test?
TSE
Structure&rationale of the elements of the vector?
Impact of glycolysation, isoforms, aggregates on biological
activity, immunogenicity, PK?
Comparability data available?
Where is appendix 6, p. 14? ...

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Typical questions from the industry

Results from how many batches?

Is stability data necessary?
Can we have longer shelf-life?
How wide limits are acceptable?
Is description of the methods needed?
Is validation necessary?
Is 25 % increase too much?

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Appendix
Guidance on biotechnological products 1

Quality, Preclinical and Clinical Aspects on Gene Transfer

Medicinal Products CPMP/BWP/3088/99
Development Pharmaceutics for Biotechnological and Biological
products CPMP/BWP/328/99
Production and Quality Control of Medicinal Products derived
by Recombinant DNA Technology CPMP
Comparability of Medicinal Products containing Biotechnologyderived Proteins as Drug Substances CPMP/BWP/3207/0
pre-clinical and clinical guidance pending
Production and Quality Control of Monoclonal Antibodies
CPMP

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Appendix
Guidance on biotechnological products 2

Quality of Biotechnological Products: Analysis of the Expression

Constructs in Cell Lines used for Production of r-DNA derived
Protein Products ICH Q5B
Quality of biotechnological products: Stability testing of
Biotechnological/Biological Products ICH Q5C
Quality of Biotechnological Products: Derivation and
Characterisation of Cell Substrates Used for Production of
Biotechnological/Biological Products ICH Q5D
Specifications: Test Procedures and Acceptance Criteria for
Biotechnological/Biological Products ICH Q6B

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos

Appendix
Guidance on biotechnological products 3

Points to Consider on the Manufacture and Quality Control of Human

Somatic Cell Therapy Medicinal Products CPMP/BWP/41450/98
Concept Paper on the development CPMP Points to consider on Xenogeneic
Cell Therapy CPMP/BWP/3326/99
Production and Quality Control of Animal Immunoglobulins and
Immunosera for Human Use, Draft, CPMP/3354/99
Pharmaceutical and Biological Aspects of Combined Vaccines
CPMP/BWP/477/97
Production and Quality Control of Cytokine Products Derived by
Biotechnological Processes CPMP, Allergen Products CPMP/243/96, PlasmaDerived Medicinal Products CPMP/BWP/269/95 ...

Viral Safety and TSE -guidelines

Terveyden tutkimuksesta tuotteeksi -seminaari 30.1.2002

Anna-Maija Autere, Lkelaitos