The regulations which describe the process and requirements to assess the genotoxicity of products which are classified as cosmetics (EC1223/2009), medical devices (ISO 10993) or pharmaceuticals (ICH S2(R1)) have all recently been, or are currently being, reviewed and updated. The primary intention of all these regulations is to protect the public from exposure to potentially hazardous materials but the requirements for the assessment of the genotoxicity of the products can be varied and confusing. Here, we describe the various approaches to genotoxicity assessment and discuss if the recent and proposed updates may be missing an opportunity to better align across regulatory classifications

Genotoxicity Testing Requirements for Cosmetics, Medical Devices and Pharmaceuticals – a Missed Opportunity for Alignment of Regulations? Philip Clay Chorley Consulting Ltd, Alderley Edge, Cheshire, UK, SK9 7SH phil.clay@chorleyconsulting.co.uk

Introduction

•  Cosmetics •  The SCCS's notes of guidance for the testing of

cosmetic ingredients and their safety evaluation •  Medical Devices

•  ISO 10993 part 3. Tests for genotoxicity, carcinogenicity and reproductive toxicity

•  Medicinal Products •  ICH S2 (R1). Genotoxicity testing and data

interpretation for pharmaceuticals intended for human use

However, there has recently been much activity by various technical groups to review and update the guidance which seems to be leading to greater divergence between the documents. Most recently the following have become available (albeit in *draft versions for many). •  Medical Devices

•  Supplement to ISO 10993-3. Guidance on tests to evaluate genotoxicity (ISO/TC 194/SC/WG3)*

•  FDA/CDRH. Use of International Standard ISO 10993, ‘Biological Evaluation of Medical Devices Part 1: Evaluation and Testing (2013)*

•  Others •  The UK Committee on Mutagenicity of

Chemicals in Food, Consumer Products and the Environment (COM). Guidance on a Strategy for Genotoxicity Testing of Chemical Substances (2011)

•  EFSA - Scientific opinion on genotoxicity testing strategies applicable to food and feed safety assessment (2012).

The requirements of the most recent documents can be summarised:

Testing Strategies

Conclusions

It is important to understand the subtle differences in the definitions of different regulatory classifications of products as incorrect classification may lead down the wrong route of evaluation. Cosmetic (EC 1223/2009)

any substance intended to be placed in contact with the external parts of the human body or with the teeth and the mucous membranes of the oral cavity with a view exclusively or mainly to cleaning them, perfuming them, changing their appearance, protecting them, keeping them in good condition or correcting body odours. Medical Device (93/42/EEC)

any material or other article intended to be used for human beings for the purpose of diagnosis, prevention, monitoring, treatment or alleviation of disease and which does not achieve its principal intended action pharmacological, immunological or metabolic means. Medicinal Product (2001/83/EC) Any substance presented as having properties for treating or preventing disease in human beings; or any substance which may be used in human beings, either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical Diagnosis.

•  EC1223/2009. Regulation (EC) No 1223/2009 of The European Parliament and of The Council of 30 November 2009 On Cosmetic Products (Recast)

•  ISO 10993-3:2003 Biological evaluation of medical devices -- Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity

•  ICH S2 (R1). Genotoxicity testing and data interpretation for pharmaceuticals intended for human use. June 2012

•  EFSA - Scientific opinion on genotoxicity testing strategies applicable to food and feed safety assessment (2012).

•  The UK Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment (COM). Guidance on a Strategy for Genotoxicity Testing of Chemical Substances (2011)

•  The Medical Device Directive (Council Directive 93/42/EEC of 14 June 1993 concerning medical devices2001/83/EC (as amended by 2007/47/EC)

•  Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use.

Not all of the examples above would necessarily require evaluation of their genotoxicity prior to launch but may do depending on their composition, nature and duration of body contact/exposure. Higher classes of medical devices, as well as those with more invasive body contact may be more likely to require genotoxicity testing. Cosmetics, medical devices, or medicinal substances containing novel materials are more likely to necessitate testing. Where mandated, genotoxicity testing should follow the relevant regulatory guidance. Genotoxicity testing requirements for the different product classifications are described in the further regulations or guidance documents:

Attendance at the meeting was supported by a bursary from UKEMS

Personal care products may fall into different regulatory classifications. Here are some examples of products which may appear very similar to the consumer or even to the inexperienced formulation scientist but can be classified differently based on subtle differences in ingredients, claims or regulations. Lip Products Boots Essentials Lip Salve Original • Keep your lips hydrated • Added SPF 15 Virumed® • cold sore cream • blocks UV rays . exposure to sunlight

increases the risk of a cold sore

Personal lubricants • Malaysia - Personal Hygiene Product (Rinse off) • EU – moisturiser • FDA – moisturiser • EU – “relieves vaginal dryness” • FDA – “condom compatible” Products containing urea • EU no restrictions in cosmetics • >10% urea = Medicine in APAC region

Same or Different?

Classification of Products

074

References

The expert technical groups responsible for the various sets of guidance for genotoxicity assays have recently been working extremely hard to update and refine the proposed testing strategies and detailed assay methodologies. Alignment of the review cycles of the different regulations as well as closer co-operation and communication between the various groups may improve the alignment of the test requirements. This would help reduce the complexity of differing requirements faced by regulatory affairs and safety assessment professionals which ultimately can only improve the protection of human health.

10993-3 Cosmetics FDA/CDRH

ICH option 1

ICH option 2

COM/EFSA

In vitro

Ames Ames Ames Ames Ames Ames

IVC or MLA or

MLA+IVC

MLA MLA or IVC or IVMN

MLA or IVC or IVMN

- IVMN

- IVMN - - - -

In vivo

Not

required if clear –ve in vitro

No in vivo

testing permitted

BMMN or BMCA or PBMN

BMMN or BMCA

BMMN Not

required if clear –ve in vitro

Comet or UDS or AE or TGR

The strategy in 10993-3 is looking increasingly out of step with other guidance, more recently updated. It is suggested that the ongoing review of this document should consider if closer alignment can be achieved. Furthermore, a number of the OECD test guidelines are under review and are due for approval in 2014. There is an opportunity for these changes to be included in the ISO 10993-3 update.