cosa prevedono le norme attuali e cosa ci aspetta in futuro . Ecco l'analisi completa, realizzata da Chemsafe Srl per CPA Italy. Un tema di forte attualità con prossime nuove richieste. Analizziamo cosa prevedono le norme attualmente vigenti e quelle di breve attuazione. Cosa deve aspettarsi l'industria farmaceutica e chimico-farmaceutica sia per il rilascio dal paziente che dal sito produttivo?

1. Environmental Assessment (ERA) of active
pharmaceutical ingredients (API)
Dr. Antonio Conto
ERT®(European Registered Toxicologist) 18.06.2020
PHARMACEUTICALS OCCURANCE in the ENVIRONMENT

2. 1. Pharmaceuticals into the Environment (PIE): a matter of
concern
2. European Medicines Agency (EMA) guidance 2006 and its
ongoing revision
3. Environmental Risk Assessment (ERA) of Active Pharmaceutical
Ingredients (API): the scientific approach
4. CONCLUSION

3. 1. PIE (Pharmaceuticals into the Environment) : a matter of
concern
We are all facing the environmental adverse effects and RA
caused by industrial chemicals but……………….
WHAT ABOUT DRUGS?
WHAT ABOUT THE ACTIVE PRINCIPLE RELEASED
FROM THE DRUG (the product) AFTER USE
OR FROM A DRUG WRONGLY DISPOSED?

5. In nostri Webinar Autunno 2020 Settore Chimico-Farmaceutico
Dettagli 28 OTT CTD ⏰ ULTIMI POSTI disponibili !
www.cpa-italy.org/it/corsi.html

8. HOW DRUGS ENTER THE ENVIRONMENT?

9. PHARMACEUTICALS OCCURANCE in the
ENVIRONMENT
Source: Options from a strategic approach to pharmaceuticals in the environment,
Taks 1 report, revised version 2016, European Commission

10. DICLOFENAC OCCURANCE
Source: Options from a strategic approach to pharmaceuticals in the environment,
Task 1 report, revised version 2016, European Commission

11. OCCURANCE of Top 10 pharmaceuticals
Diclofenac: antinflammatory
Carbamazepine: antiepileptic
Ibuprofen: non-steroidal anti-inflammatory drug
Sulfamethoxasole: sulphamidic, antibacterial
Naproxen: non-steroidal anti-inflammatory drug
Estrone: estrogen
17-Beta-estradiol: estrogen
17-alfa-ethynilestradiol: estrogen
Trimethoprim: antibiotic
Paracetamol: painkiller, antipyretic

12. POTENTIAL Encrocrine Disruptors
Source: Options from a strategic approach to pharmaceuticals in the environment,
Taks 1 report, revised version 2016, European Commission

13. 2. European Medicines Agency
(EMEA) Guidance 2006

14. Phase I Pre
screening
Estimation of exposure
threeshold Limit
PEC ≥ 0.01 µg/L
Consumption data
and
logKow experimental value
Phase II
Tier A
Screening Initian Risk assessment Ecotoxicological and environmental
phase studies for the aquatic
compartment only
Phase II
Tier B
Risk
Assessment
Risk assessment addressed to
each specific environmental
compartment
Ri-definition of the environmetal
concentration (PEC), ecotoxicological
and environmental fate studies
TEST TIER A OECD
Adsorption - Desorption at Equilibrium 106 o 121
Ready Biodegradability 301
Aerobic and Anaerobic Transformation in
Aquatic Sediment Systems
308
Algae, Growth Inhibition Test 201
Daphnia sp. Reproduction Test 211
Fish, Early Life Stage Toxicity Test 210
Activated Sludge, Respiration Inhibition Test 209
TEST TIER B OECD
Aerobic and anaerobic transformation in
soil
307
Soil Micro organisms: Nitrogen
Transformation Test
216
Terrestrial Plants, Growth Test 208
Earthworm, Acute Toxicity Tests 207
Collembola, Reproduction Test ISO 11267
Additional studies to refine the RA
3. Environmental Risk Assessment (ERA) of Active Pharmaceutical
Ingredients (API): the scientific approach

15. NEW EMA GUIDANCE
(expected finalisation
by end 2019 – early 2020)

16. TAILORED RISK ASSESSMENT FOR EDS
(here called EAS = Endocrine Active Substances

17. SCIENTIFIC APPROACH
1. IDENTIFICATION
1.1 Intended Endocrine action
An active substance whose intended pharmacological action targets the endocrine
system exerting an effect on development or reproduction by directly interacting or
interferring with receptors, hormone levels or activities of oestrogens, androgens
or other steroid hormones
1.2 Non intended Endocrine action
Information on potential non-intended endocrine activity should be obtained from
the respective part of the dossier. This includes both “in vitro” and “in vivo”
information. Endocrine-related effects relevent for the identification of an EAS
include agonism, antagonism and modulation of steroid, receptors, steroid
hormone levels and changes in steroidogenic tissue (adrenal and gonads),
steroidogenic enzyme inhibition and direct interaction with the hypothalamic-
pituitary-gonadal axis. The following information should be evaluated with a
Weight of Evidence Approach to decide if the substances should be considered an
EAS and hence, assessed with a tailored RA in Phase II

18. Table n. 15, Overview of recommended effect studies for active substances with an endocrine
mechanism of action and thyroid hormone agonist and antgonist

19. Last statement in the EAS guidance section
Determine the MoA is the crucial point

20. General comment to the new guidance
- There is number of common approaches with the Joint ECHA/EFSA June 2018 for
biocides and pesticides EDS criteria (e.g. focus on EATS modalities and common
testing)
- A clear indication to carry out a tailored evaluation for EAS when identified
irrespective to the PEC action limit
- A clear indication to set the MoA…..
- Expected to be finalized by 2020 without major changes
- It will harmonized the requests from different Competent Authorities

21. CONCLUSION
- PIE poses a great problem for the environment and human health expecially
when ED effects are unavoidable.
- The new ERA guidance regarding the ERA for APIs is going to ask for a tailored
evaluation for ED/EAS irrespective to the PEC action limit.
- Pharma companies will be forced to make such an evaluation before marketing
their new products or when applying major changes in existing products (Type II
variations)
- Generic pharma products are, in some way, still under discussion…..but the new
guidance says that:
- General waiving statement to avoid a full evaluation will not be accepted

22. CONCLUSION
- Pharma companies be prepared to budget
- Some of the big pharma already started new policies to evaluate their APIs for
ERA including the endocrine properties end-point
- Any ban from market??

23. Grazie per la vostra attenzione
Thanks for your attention
Gracias por su atención
Merci de votre attention
Danke fur ihre aufmerksamkeit
ChemSafe Srl
e-mail: a.conto@chemsafe-consulting.com