Liraglutide precursor

Explosiveness

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

explosiveness, other

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reason / purpose for cross-reference:

read-across source

Parameter:

other: Differential Scanning Calorimetry

Remarks on result:

not thermal sensitive if heated under defined confinement

Interpretation of results:

GHS criteria not met

Conclusions:

No data was available for Liraglutide precursor. The explosiveness was determined based on read across to MI3 (S3). Determination of the explosive properties MI3 (source substance) was performed in accordance to EC Directive 92/69/EEC Methods A14. It is concluded that the potential for explosion is unlikely to be present based on the following three observations/results. (1) The oxygen balance was considered to be outside the region of potential concern. There are no potential auxoplose/plosophore groups present in MI3 and no thermal events was observed in the thermogram (I.e. no decomposition exotherms). Consequently, the same conclusion for the target substance (Liraglutide precursor) applies, justified by the read-across hypothesis

Executive summary:

No data was available for Liraglutide precursor. The explosiveness was determined based on read across to MI3 (S3).

The target substance liraglutide precursor is a single-chain polypeptide consisting of 31 amino acids having an almost identical amino acid sequence as the human glucagon-like peptide 1 (GLP-1) that has 30 amino acids of which 29 amino acids in common with the target substance.The target substance is a part of the active pharmaceutical ingredient: liraglutide (S1) as the liraglutide molecule has been obtained from the liraglutide precusor be the addition of a plamitoyl-ϒ-glutamate unit attached to the amino acid lysine in position 26 of the precursor.

S3 and S4 substances are somewhat larger polypeptides as consisting of 53 and 50 amino acids in the polypeptide chain.

 

Each of the amino acids in the above mentioned substances are and very polar molecules and when linked together in polypeptides the very polar nature of the polypeptides are considered as having very similar physicochemical properties irrespective whether they contain 31 (T) or 50 amino acids (S3,S4) for which physicochemical properties have been obtained.

Determination of the explosive properties MI3 (source substance) was performed in accordance to EC Directive 92/69/EEC Methods A14. It is concluded that the potential for explosion is unlikely to be present based on the following three observations/results. (1) The oxygen balance was considered to be outside the region of potential concern. There are no potential auxoplose/plosophore groups present in MI3 and no thermal events was observed in the thermogram (I.e. no decomposition exotherms). Consequently, the same conclusion for the target substance (Liraglutide precursor) applies justified by the read-across hypothesis.

Reference 2

Endpoint:

explosiveness, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003.06.30 - 2003.07.14

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method A.14 (Explosive properties)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL (MI3)
- Appearance: cream powder
- Source and lot/batch No.of test material: QC202426
- Expiration date of the lot/batch: June 2004
- Purity test date: 2003-06-18
- Purity: 84% w/w (stated ny Sponsor)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Frozen below - 10°C

Key result

Parameter:

other: Differential Scanning Calorimetry

Remarks on result:

not thermal sensitive if heated under defined confinement

Conclusions:

Determination of the explosive properties MI3 (dried) was performed in accordance to EC Directive 92/69/EEC Methods A14. MI3 is considered not to be explosive (the potential for explosion is unlikely to be present)

Executive summary:

Determination of the explosive properties MI3 (dried) was performed in accordance to EC Directive 92/69/EEC Methods A14. It is concluded that the potential for explosion is unlikely to be present based on the following three observations/results. (1) The oxygen balance was considered to be outside the region of potential concern. There are no potential auxoplose/plosophore groups present in MI3 and no thermal events was observed in the thermogram (I.e. no decomposition exotherms).

Description of key information

Data on target substance not available. Thus, read-across has been applied using data from source substance (S3).

The target substance liraglutide precursor is a single-chain polypeptide consisting of 31 amino acids having an almost identical amino acid sequence as the human glucagon-like peptide 1 (GLP-1) that has 30 amino acids of which 29 amino acids in common with the target substance.

The target substance is a part of the active pharmaceutical ingredient: liraglutide (S1) as the liraglutide molecule has been obtained from the liraglutide precusor be the addition of a plamitoyl-ϒ-glutamate unit attached to the amino acid lysine in position 26 of the precusor.

S3 and S4 substances are somewhat larger polypeptides as consisting of 53 and 50 amino acids in the polypeptide chain.

 

Each of the amino acids in the above mentioned substances are and very polar molecules and when linked together in polypeptides the very polar nature of the polypeptides are considered as having very similar physicochemical properties irrespective whether they contain 31 (T) or 50 amino acids (S3,S4) for which physicochemical properties have been obtained. Thus, the results from physicochemical guideline testing for S3 and S4 for melting point, boiling point, flammability, self-ignition, and explosionwere identical and can be considered as representative for the target substance as well. With respect to vapour pressure the vapour pressure for single amino acids is extremely low (below 0.4 Pa) and thus, the vapour pressure for polypeptides would be expected to be even lower.

Key value for chemical safety assessment

Explosiveness:

non explosive

Justification for classification or non-classification

Determination of the explosive properties MI3 (dried) was performed in accordance to EC Directive 92/69/EEC Methods A14. It is concluded that the potential for explosion is unlikely to be present based on the following three observations/results. (1) The oxygen balance was considered to be outside the region of potential concern. There are no potential auxoplose/plosophore groups present in MI3 and no thermal events was observed in the thermogram (I.e. no decomposition exotherms). Consequently, the same conclusion for the target substance (Liraglutide precursor) applies justified by the read-across hypothesis