regulatory interpretation of characterization studies · biological terms, to the active substance...

Regulatory Interpretation of Characterization Studies

1-4-2015 RM van der Plas©

Regulatory interpretation of characterisation studies A practical assessor’s view

R.M. van der Plas

Assessor biological products

CBG-MEB, NL

Disclaimer: Personal views only, meant to initiate further discussion. Does not necessarily reflect current or future view of MEB, EMA, CHMP, or other regulator body


Form follows function

• A certain active substance causes a certain biological effect >> the compound has some specific interaction with some specific ‘receptor’

– Receptor = broadly defined

• Epitope of Mab

• If a different substance has a different effect, this must be caused by some difference in the structure of the active substance

– Structure <> clinical effect

– Axiom of molecular pharmacology

– Applies also to side-effects and immunogenicity



Form follows function (2)

• Structure <> clinical effect

• Structure should be known and controlled (trivial)

• Consistent structure = consistent clinical effect

– Specifications

– Reference standard/material

– Pharmacopoeia

– Comparability/biosimilarity

– Same active substance issue/terminology matters



ICH Q6B ‘specifications for biologicals’

• Section 3

• The setting of specifications for drug substance and drug product is part of an overall control strategy which includes (..) testing for consistency of lots. When combined in total, these elements provide assurance that the appropriate quality of the product will be maintained.

• (..) specifications are chosen to confirm the quality rather than to characterise the product (..)



ICH Q6B ‘specifications for biologicals’ (2)

• Section 4

• Selection of tests to be included in the specifications is product specific. (..) Acceptance criteria should be established and justified based on data obtained from lots used in preclinical and/or clinical studies, data from lots used for demonstration of manufacturing consistency, and data from stability studies, and relevant development data.



ICH Q6B ‘specifications for biologicals’ (3)

• Section reference standard

• Selection of tests to be included in the specifications is product specific. (..) Acceptance criteria should be established and justified based on data obtained from lots used in preclinical and/or clinical studies, data from lots used for demonstration of manufacturing consistency, and data from stability studies, and relevant development data.



ICH Q8(R2) pharmaceutical development (QbD)

• Critical Quality Attribute (CQA):

– A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.

• Quality:

– The suitability of either a drug substance or a drug product for its intended use. This term includes such attributes as the identity, strength, and purity (ICH Q6A).

• Quality Target Product Profile (QTPP):

– A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.



ICH Q8(R2) pharmaceutical development (QbD) (2)

• Pharmaceutical development

• Identifying potential critical quality attributes (CQAs) of the drug product, so that those product characteristics having an impact on product quality can be studied and controlled;

• Determining the critical quality attributes of the drug substance, excipients etc., and selecting the type and amount of excipients to deliver drug product of the desired quality;

• Role of characterisation not explicitly stated; however, central role implicit

• Link to process development



Implications: Characterisation

• Significant progress, but some open issues

• Protein content

– Absolute amoutn of protein surprisingly difficult to determine

• Aggregates

– No gold standard

– SE-HPLC (routine) difficult to correlate with AUC, FFF, DLS, etc.

• CQAs linked to immunogenicity

– HCPs/danger signals

– Metal ions (tungsten)

– ‘Conformational changes’



Implications: Specification

• Two batches do not need to be ‘identical’

– Batch to batch variability

– Drift

– Manufacturing changes

• Specifications maintain consistency & link to clinical batches

– Use of reference materials

– Controlled variability



Role of European Pharmacopoeia

• Minimum requirements for substances and products, based on validated tests

• Minimum requirements for tests

• Establishing public reference standards

– Guarantees that results between labs are ‘identical’

– Facilitates OMCL testing



Definition of a biosimilar • Article 10.4 (of Directive 2001./83 as amended)

– Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided.

• Article 10.2

– “generic medicinal product” shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.(..)



Definition of a biosimilar • Annex I

– The provisions of Article 10(1)(a) (iii) may not be sufficient in the case of biological medicinal products.

– If the information required in the case of essentially similar products (generics) does not permit the demonstration of the similar nature of two biological medicinal products, additional data, in particular, the toxicological and clinical profile shall be provided.

– When a biological medicinal product as defined in Part I, paragraph 3.2 of this Annex, which refers to an original medicinal product having been granted amarketing authorisation in the Community, is submitted for a marketing authorisation by an independent applicant after the expiry of data protection period, the following approach shall be applied.

– Information to be supplied shall not be limited to Modules 1, 2 and 3 (pharmaceutical, chemical and biological data), supplemented with bio-equivalence and bio-availability data. The type and amount of additional data (i.e. toxicological and other non-clinical and appropriate clinical data) shall be determined on a case by case basis in accordance with relevant scientific guidelines.

– Due to the diversity of biological medicinal products, the need for identified studies foreseen in Modules 4 and 5, shall be required by the competent authority, taking into account the specific characteristic of each individual medicinal product.

– The general principles to be applied are addressed in a guideline taking into account the characteristics of the concerned biological medicinal product published by the Agency. In case the originally authorised medicinal product has more than one indication, the efficacy and safety of the medicinal product claimed to be similar has to be justified or, if necessary, demonstrated separately for each of the claimed indications.



Definition of biosimilar

• Guideline on Similar Biological medicinal products (CHMP/437/04 Rev 1 ):

– ‘A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product) in the EEA. Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise needs to be established.’

– ‘The active substance of a biosimilar must be similar, in molecular and biological terms, to the active substance of the reference medicinal product. For example, for an active substance that is a protein, the amino acid sequence is expected to be the same.’

• ‘Similar but not identical’

• ‘A biosimilar is not a generic’



Definition of biosimilar

• EMA Q&A (EMA/837805/2011)

– What is a biosimilar medicine?

– ‘(..) The active substance of a biosimilar and its reference medicine is essentially the same biological substance, though there may be minor differences due to their complex nature and production methods.’

– http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/WC500020062.pdf



Similar is more important than ‘not identical’.

• In the ‘similar but not identical’ doctrine, regulators have always stressed the aspect of similar; a biosimilar cannot be ‘different’.

• Identicality never exists

– From a scientific (characterisation) viewpoint, two generics will not be identical either; given sufficient resources, it will always be possible to find some difference between two products.



Assessment in practice

• EPAR ‘summary for the public’:

– Omnitrope is a ‘biosimilar’ medicine. This means that Omnitrope is similar to a biological medicine that is already authorised in the European Union (EU) and contains the same active substance (also known as the ‘reference medicine’). The reference medicine for Omnitrope is Genotropin.

• (European Medicines Agency. Omnitrope, EPAR summary for the public (2008) http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000607/WC500043689.pdf)

– This statement consistently used in other summaries for the public.


http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000607/WC500043689.pdf




Similar implies: ‘not different’

• FDA:

– ‘Biosimilarity means that the biological product is highly similar to the US-licensed reference biological product notwithstanding minor differences in clinically inactive components; and that there are no clinically meaningful differences between the biologic[al] product and the reference product in terms of the safety, purity, and potency of the product’

– see 351(i) of PHS Act



Scientific approach

• Requirements for generics (‘same active substance; same pharmaceutical form; bioequivalent’) have been kept in mind; these requirements have been tailored towards biologicals.

– Requirements for generics and biosimilars are ‘similar but not identical’, i.e. not different in principle.



Terminology matters

• ‘Same active substance’ is not a scientific requirement (with scientific terminology), it is a regulatory requirement (with regulatory terminology).

– A biosimilar cannot contain a ´New Active Substance´ in the regulatory meaning of this term, even if detailed scientific analysis will reveal some differences

• Cf Notice to Applicants

– Same INN, same Ph. Eur. monograph

• Cave exceptions (e.g. suffixes),

• Biological Qualifier separate from ‘true’ INN

– Cf. batch to batch variability/drift



Source of confusion: terminology

• Confusion of terms ‘active substance’ and ‘drug substance’

– Directive 2001/83 refers to ´(same qualitative and quantitative composition in) active substances’

• Active substance. Any substance intended to be used in the manufacture of a medicinal product and that, when so used, becomes an active ingredient of the medicinal product. Such substances are intended to furnish a pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body. (Ph. Eur.)

• Drug Substance (Bulk Material): The material which is subsequently formulated with excipients to produce the drug product. It can be composed of the desired product, product-related substances, and product- and process-related impurities. It may also contain excipients including other components such as buffers. (ICH Q6B)



Drug substance

(never identical)

Active substance

(always the same)



Encore: Practical statistics

• Biosimilar GL quality aspects:

– ‘Descriptive statistics may be useful’.

• Inferential statistics very controversial

– Data set generally often too limited for robust/reliable statistical analysis

– Statistical significance and (clinical) relevance are not identical (or even similar)

– Correct tools not established (see e.g. Tolerance Intervals vs Student’s T-testing)

• Status in the field:

– Assessors strongly prefer to take specific decisions (during assessment) on actual analytical data.

– Statistical tools/analysis give rise to extensive objections


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