Comparison of:
Recommendations for Improving “what we know” and current guideline Environmental Risk Assessment of Pharmaceuticals Prof. Christina Rudén, Stockholm University Dr. Marlene Ågerstrand, Stockholm University
• Identify and reduce environmental risks from pharmaceuticals • Financed by Mistra • 2008–2015 • ~ 10 million Euro
PARTNERS
Policy Brief available at: www.mistrapharma.se
Does the EMA‐guideline reflect the perceived environmental risks?
Recommendations are based on • Results from PIE research • Reviews of available Environmental Risk Assessments (ERA) • Lessons learned from other regulatory frameworks, e.g. REACH, Plant Protection Product Regulation (PPP) and Biocidal Product Regulation (BPR)
1. Require ERA also for products put on the market before 2006 Why? • We need environmental data for all substances • Old substances are not safer than new Other frameworks? • Applied in REACH, PPP and BPR
1. Require ERA also for products put on the market before 2006 How? • The scope of the guideline need to be re‐written Obstacles? • Who assess generic products – see suggestion 3. • Increased costs – but see suggestion 4
2. Add Requirements to Assess the Risk for Development of Antibiotic Resistance Why? • It is the greatest concern with regards to environmental antibiotic emissions • Including the environmental dimensions of antibiotic resistance (including selection from antibiotics) is stressed in several, recent policy documents
2. Add Requirements to Assess the Risk for Development of Antibiotic Resistance How? • Base regulation on not exceeding minimal selective concentrations • Predicted MSC to start with, then refine with experimental MSCs over time Obstacles? • How is selection within treatment plants covered, i.e. before discharge to surface water
3. Perform only one ERA per API Why? • 3R principle, reduce duplication of work • Easier to assign risk management measures Other frameworks? • Joint applications in REACH and PPP
3. Perform only one ERA per API How? • REACH: Consortiums are established and members agree on who takes the lead, who pays what, and what to do with companies that join the consortium at a later stage. Obstacles? • Exposure assessment may differ for the production phase. REACH allows for different exposure assessments.
4. Refine the Tiered Approach Why? • To put greater focus on the problematic API, and thereby make better use of the efforts made • To make use of available knowledge
4. Refine the Tiered Approach How? • PEC, simplified bioconcentration studies and read‐ across to derive action limit, rather than just PEC • Preclinical and clinical toxicological and pharmacological data to guide choice of test species and endpoints • Mode of action based tests Obstacles? • Time‐consuming + more challenging for risk assessors
5. Perform mixture toxicity assessments on APIs with similar MoA Why? • Single assessments does not reflect the actual risk Other frameworks? • In general not, but there are exemptions.
5. Perform mixture toxicity assessments on APIs with similar MoA How? • Concentration Addition? Mixture Assessment Factor? Other? Obstacles? • Refinement of PEC needed? How to calculate PEC for several products?
6. Mandate use of all available ecotoxicity studies Why? • All studies of sufficient reliability & relevance should be used • Non‐standard studies can fill important data gaps Other frameworks? • Applied in REACH and BPR
6. Mandate use of all available ecotoxicity studies How? • Demand that peer‐reviewed literature is used • Evaluate all available data (e.g. according to the CRED‐method) • Document the process and decisions Obstacles? • Time‐consuming + difficult for risk assessors
7. Include environmental risks in the risk‐benefit analysis Why? • Assessments are often missing or of low quality – means to make industry deliver ERAs in time • Some argue that severe risks for environmental effects should be a reason for denying market approval Other frameworks? • Apply in BPR and PPP
7. Include environmental risks in the risk‐benefit analysis How? • Consequences are needed for non‐compliance. • No market approval? • Fine? • Other?
• Only deny approval if equally effective products are available Obstacles? • Fear that it will slow down market introduction and reduce the ability to give patients the best possible treatment
8. Require review of ERAs at regular intervals Why? • New knowledge (toxicity + exposure + monitoring data) should be used • To enable use of MECs (see also suggestion 9) Other frameworks? • Apply in REACH, PPP and BPR
8. Require review of ERAs at regular intervals How? • When relevant studies arise (REACH) • Every 5‐10 years (PPP, BPR) Obstacles? • Costs
Lä 9. Include data on emissions from production in ERAs
Why? • Represent highest environmental concentrations found • Moral dilemma of outsourcing pollution outside of EU • Lifecycle perspective needed • Needed for the credibility of the industry Other frameworks? • Local legislation has not proven to be sufficient
9. Include data on emissions from production in ERAs How? • MEC better than PEC • Murray‐Smith, Bengtsson‐Palme approaches • Severe violations, followed by no/insufficient measures taken towards improvement, should lead to withdrawal of market authorization Obstacles? • Irregular discharges • Manufacturing often not in the EU
10. Increase transparency Why? • To enable third party review of assessments and production • To ensure external use of data and reduce animal testing • To increase credibility of the process Other frameworks? • ECHA presents REACH‐data online • Learn from other sectors (e.g. textile) • Common to report site of origin for consumer products and food items
10. Increase transparency How? • Database online (hosted by EMA?) on the assessment • Include manufacturing site data (possible exclusion for narcotics, anabolic steroids etc)
Obstacles? • Legal constraints? • Resistance from industry?
Thank you! www.mistrapharma.se
Christina Rudén, Stockholm university,
[email protected] Marlene Ågerstrand, Stockholm University,
[email protected]