API in Our Environment

The presence of pharmaceuticals in drinking water is not a new issue. In the 1970’s, several researchers reported the presence of clofibric acid, a breakdown product of several blood lipid regulators, and salicylic acid, a breakdown product of aspirin, in waste water. Environmental issues concerning heavy metals are well known, and are well legislated. The target now is to understand the issues of micropollutants and their effects and how to remove them from the environment effectively.

The term "micropollutants" means organic or mineral substances whose toxic, persistent and bioaccumulative properties may have a negative effect on the environment and/or organisms. They are present in many products that we consume daily (drugs, cosmetics, phytosanitary products, insecticides, etc.), at home or in industry.

API Treatment

Progress in laboratory analysis is increasingly highlighting their presence in the aquatic environment at extremely low concentrations, in the order of one nanogram per litre or microgram per litre (hence the term micropollutants).

Some of these substances are liable to have potentially chronic direct or indirect effects on ecosystems (e.g. the feminisation of fish due to endoctrine-effect substances in the aquatic environment), and even on human health.

Conventional water and wastewater treatment methods allow many pharmaceutical pollutants to pass through unchanged, entering the environment and ultimately the drinking water. One problem with assessing risk of pharmaceuticals in drinking water is the very large number of pharmaceuticals in use today. Information on the occurrence of pharmaceuticals in drinking water is available only for a limited number of compounds. In addition, many pharmaceuticals are biologically degraded to active metabolites that have not been evaluated.

Good manufacturing practices (GMP) are the practices required in order to confirm the guidelines recommended by agencies that control authorization and licensing for manufacture and sale of food, drug products, and active pharmaceutical products. These guidelines provide minimum requirements that a pharmaceutical or a food product manufacturer must meet to assure that the products are of high quality and do not pose any risk to the consumer or public.

Good manufacturing practices are overseen by regulatory agencies in the United States, Canada, Europe, China, and other countries.

GMP has its place in reducing micropollutants in the environment, but is only part of the solution. Pharmaceutical wastewater treatment very rarely includes recycling, this would violate GMP rules.

In some cases solvents, nitrates etc can be recovered, so it essential that manufacturers know how to approach the issues of pharmaceutical wastewater and regulatory restrictions.

Recycle and legislation

Another example of possible recycle and reuse is the production of X–Ray Contrast Media (CM) containing organic bound iodine. After incineration or UV oxidation by gas scrubbing, the iodine can be recovered as a saleable product.

The European Union does not have legal binding limits for pharmaceutically active compounds (PhACs), but measures are expected in the near future. In the meantime PhACs producers are tending to apply the PNEC ( Predicted No Effect Concentrations  ) the UK government make reference to the OSPAR Agreement 2014-05 - Protecting and conserving the North East Atlantic and it resources.

ChemTrust, a UK-based chemical NGO, has called for stricter controls on pharmaceutical and veterinary products to reduce environmental levels and unintended exposure of humans and wildlife. Its report, published on 7 December 2014, asks for environmental risk assessments (ERAs) to be overhauled and older drugs to be reassessed.

The report finds that 613 pharmaceutical active ingredients have been found in the environment worldwide. Freshwaters are most contaminated, and medicines have even been found in fish and animals.

German surface waters have been analysed, producing an ecotoxicological  impact risk assessment chart ( Fig 1 ). The ratio of PNEC and MEC ( Measured Environmental Concentration ) indicates the potential risk to the environment from PhACs substances, ratios 1 and above indicates where action is required.

Both natural hormones (i.e. estrone (E1), 17α-estradiol (17α-E2), 17β-estradiol (E2)) and synthetic hormones 17α-ethinylestradiol (EE2) have the potential to behave like endocrine disrupting compounds (EDC) in the environment. EDCs can cause reproductive disturbances in fish, including reduced fertility, masculinization of females and feminization of males. EE2 is considered to be more potent than E1 and E2.

Steroidal estrogens go through a transformation in the environment and in the effluent in contact with activated sludge, estrogens are cleaved and held within transformation under oxic conditions, therefore sorption of estrogens onto sludge contributes to their elimination from the water phase but the estrogens remain in the solids phase. EE2 remains persistent throughout wastewater treatment process with 10 to 15% passing into the environment.

Treatment of Active Pharmaceutical Ingredients (API)

Most active pharmaceutical ingredients are xenobiotic and show poor bio availability, degradation can be improved with extended retention times. However, waste treatment systems are designed for low concentrated waste with high flowrates and good bio availability. Therefore to treat industrial chemical / pharmaceutical production waste a dedicated non biological treatment approach is required.

Table 1 Shows clearly that treatment techniques based on oxidation are the most efficient and safe option to treat PhACs or Active Pharmaceutical Ingredients (API).

Table 1

Technique Principle Elimination of Xenobiotics/APIs Remark on Process CAPEX OPEX
Activated Carbon Sorption Concentration on fixed phase Good sorption properties are required. Generation of waste. Low High
Advanced Oxidation Chemical Oxidation YES Different elimination levels can be achieved. Low-medium Medium
Biological Treatment Biological Oxidation Only in rare cases      
Evaporation Concentration Concentration Distillate often polluted as many ingredients are purgable or steam-purgable. High High, also due to concentrate disposal
Flocculation/Filtration Mechanical NO, bad efficiency on removal of organics No relevance in pharmaceutical industry. Low Low
High Pressure Oxidation Chemical Oxidation YES   Very High Low
External Incineration Thermal Oxidation YES   Low, as storage only Very High
Incineration on Site Thermal Oxidation YES   High Very High
Membrane Mechanical Separation Concentration of API with lower flow rate Membranes are sensible for fouling. Concentrate has to be disposed externally. Medium High, also due to concentrate disposal.

Treatment of ethinylestradiol, and other PhACs including thyroid hormones and narcotics has been achieved at a number of PhACs production plants, including Haupt Pharma in Münster – Germany with the installation of an Advanced Oxidation Process (AOP).

The company Haupt Pharma are specialist producers of cytotoxics, thyroid hormones, narcotics, sex hormones and beta-lactams. The wastewater produced from the Cleaning in Place is treated by AOP to efficiently remove all hormones prior to discharge to the municipal sewer. Table 2 provides the results achieved with AOP.

Table 2

Parameter Data Result
Flow rate 12m3/d No change
COD 2000-4000 mg/L Ca. 20% reduction rate
Sexual hormones like EE2 ≈ 10-100 mg/L < 0.01 mg/L
Bioavailability ≈ 65%  ≈ 90%
OPEX ≈ 1-3 €/m3  

In some cases a hybrid technique combining AOP and biological treatment provides a good solution. For example  1,4-dioxane, EDTA ( Fig 2 ), pyrrolidones, aromatics are treated by UV Oxidation producing a bio available waste that can be subsequently treated through a biological system to reduce COD and suspended solids. Fig 3 Shows selective destruction of ethinylestradiol (EE2).

Fig. 2: Selective destruction of EDTA with UV Oxidation

Fig. 3: Pharmaceutical Waste - EE2 Destruction