Pharmaceuticals, Their Manufacturing Methods, Ecotoxicology, and Human Life Relationship

This paper was published in Pharmaceutical Processing in November 2007 [Malhotra, Girish: Pharmaceuticals, Their Manufacturing Methods, Ecotoxicology, and Human Life Relationship, Pharmaceutical Processing, November 2007 Pg 18-23]. Since the publisher is not using the site, it is being re-published in my blog as my perspective. There is no financial affiliation with any organization. 

Research on impact of pharmaceuticals on effluent is subject of continued interest.  

November 2007

A look at the impact of improper pharmaceutical waste treatment

A recent study¹ by Dr. Joakim Larsson of The Sahlgrenska Academy at Göteborg University, of the effluent water from the Patancheru wastewater treatment facility in Hyderabad, India is going to cause a global uproar about environmental regulations and pharmaceutical and chemical operations, if it has not already done so.² In and around Hyderabad, a who's who of the Indian pharmaceutical and active pharmaceutical ingredient producers and formulators have their plants. This study gives us a snapshot of the wastewater treatment plant operated by Patancheru Enviro-Tech Limited (PETL), its operating efficiency and allows us to conjecture about the state of affairs around the chemical and pharmaceutical plants. 

In his recent paper, Larsson speculates on the "impact of effluents" from active pharmaceutical plants worldwide. Every active pharmaceutical ingredient (API) and drug (combination of chemicals) are chemicals. They all have disease curing (toxic to bacteria) and life extending value. Effluent waters of API and drug manufacturing facilities have residues of these chemicals. Their levels can be toxic to the aquatic and soil life and have broad implications. 

Larsson notes that the cumulative level of 11 different APIs in the effluent water is about 36.96 milligrams per liter. These levels are a small percentage of the water outfall from the common effluent treatment plant (CETP). He suggests that the cumulative "fluoroquinolone [ciprofloxacin is a fluoroquinolone] concentration in ecotoxicological context is higher than the maximal therapeutic human plasma levels." Thus, the API concentrations at these levels have a toxicological influence on the environment, are a cause of concern, and should to be controlled. 

We need to recognize that there may be very few or no individual and/or collective ecotoxicological standards for many of the chemicals produced. Discussion of their levels and influence is outside the realm of this document. Dr. Larsson suggests that the samples from PETL contained the "highest levels of pharmaceutical ingredients in any effluent." However, there is no identification and comparison to any "other" effluents. 

Background Information (Side Bar)

1. No details about PETL are available.
2. Matrix Labs (Mylan Labs), Neuland Laboratories, and Aurobindo Pharma are fluoroquinolone producers sending their wastewater to Patancheru CETP. Along with other companies, they are shareholders of this facility.⁵ 
3. The current BOD, COD, TDS, and TSS standards Patancheru CETP has to achieve are not available. It is expected that they have to meet the standards set by APPCB. 
4. There are no ecotoxicological standards for PETL CETP and many of the APIs. 
5. There is considerable litigation about pollution due to Patancheru CETP. 

Establishing Safe Levels

 

In our efforts to curb water and soil pollution, we will have to establish individual and respective safe toxic levels of various organics and control them to below defined levels in water bodies and soil around the producing plants. Recognition of toxicity of these disease-curing chemicals presents us with two ways to reduce their levels below toxic levels:

1. Improve pharmaceutical processing and manufacturing technologies, which are considered inefficient and antiquated.³
2. Reduce organic levels in effluent water below their toxic levels. 

The initial design capacity of the PETL wastewater treatment plant is not known. However, it is expected that necessary enhancements and provisions have been made to the plant over the years to keep the operating efficiencies at the optimum level. Table 1 shows the operating results of the PETL wastewater treatment plant.

The Andhra Pradesh Pollution Control Board (APPCB) and other government bodies have to decide if the performance of the PETL operated CETP meets their set standards. From a pure numbers standpoint, it seems that there is reduction in the levels of BOD, COD, TDS, and TSS.

In addition, appropriate regulatory bodies have to decide on the toxicological impact of organics in the effluent water and the solids being sent to the landfill. Some of the background information that would be useful is not covered in the Larsson paper and is not available from APPCB⁴ (see side bar). 

Process Improvements Lead To Lower Waste

	In, mg/L	Out, mg/L
BOD (biochemical oxygen demand)	1,300	270
COD (chemical oxygen demand)	6,000	1,400
TDS (total dissolved solids)	9,000	5,000
TSS (total suspended solids)	500	300

                        

Table 1

Since all API's are a chemical and every drug is a formulation of chemicals to facilitate dispensing, implications of Dr. Larsson's work can be extended to any chemical produced anywhere. Individual organic component concentrations in the effluent point to the manufacturing efficiency of any API manufacturing facility worldwide and it needs a review. 
Based on the concentration of organics in the effluent water Patancheru CETP outfall has about 45 kilos of ciprofloxacin per day. We do not know the concentration of the ciprofloxacin coming into the treatment facility. There are two assumed scenarios:

1. Wastewater treatment facility is not able to remove any ciprofloxacin from the incoming water.
2. Wastewater treatment is removing "X%" of the ciprofloxacin from the incoming water and the rest going with the sludge.

Scenario 1: The treatment facility is not able to remove any ciprofloxacin from the water and all of it is going in the effluent water. Based on 70% yield of the manufacturing process, one can calculate that the theoretical capacity of all the plants that manufacture ciprofloxacin to be about 150 kg/day and lose about 45 kg/day in the water. At $50 per kg, the dollar loss is estimated at about $0.8 million per year at active value and about $8 million per year at the drug counter value. If the plants can improve their yield from 70 to 85%, the increased revenue for the manufacturing plants would be about $0.4 million per year. This yield improvement would also reduce the organic loading of the water leaving their respective facilities and PETL.

Scenario 2: We do not know the ciprofloxacin concentration of the incoming water or the sludge leaving the site. If the wastewater treatment facility were able to remove, for example, about 50% of the incoming ciprofloxacin in sludge and the rest goes with the effluent water, then the theoretical manufacturing capacity of the ciprofloxacin plants would be about 300 kg/day. Under these assumptions, plants loose 90 kg of ciprofloxacin per day at 70% yield. At $50.00 per kg., the API loss is estimated at about $1.6 million per year. Yield improvement of 15% would give additional revenue of about $0.8 million per year at the API level. Over the counter values are about 10 times these values. 

It is possible that many drugs and actives are pollutants in one form or other. We might be faced with a question of making a choice and balance between human needs, life extension, and environmental wellness. At some point, we humans will have to make a choice between feasible, acceptable, and affordable on each of these issues. 

Work similar to Dr. Larsson's could be done at other active pharmaceutical ingredient manufacturing, drug formulating, and chemical producing sites around the globe. It would be interesting to see the results of similar work and the potential recourse one would take to remedy the situation. 

The Patancheru study suggests that there is reduction in the value of parameters from the wastewater treatment. However, various lawsuits imply that the water and land around the facility is polluted. If the CETP operated by PETL is meeting the set standards then these lawsuits raise questions about the adequacy of the current water and soil environmental regulations for the area and around the world. If we have to meet ecotoxic standards then such standards have to be established for every chemical or their mixtures as each chemical has some ecological toxicity. This as I indicated earlier would be an arduous and expensive task. I would not venture to speculate the expense and a finish date. 

If we have to reduce the organics below the toxic level then their levels have to be established. Remediation technologies will be needed to achieve the set limits. Some existing technologies could be used and others might have to be developed. We might need to change the water pollution standard for every water body in each country. This would have to be done for soil also. Implementation of various technologies might increase the selling price of our drugs multiple times and could make them expensive. Simple-to-use measurement technologies and instrumentation to track toxic levels and can be easily used by a trained technician will have to be developed. Most likely, we do not have such methods and procedures and it could be quite an expensive and time-consuming undertaking. 

In the meantime…

While the eco-toxic data is being developed, we have another opportunity to reduce the organic levels in the effluent. Costs related to this effort are lower and there are economic benefits. We need to improve process technology and manufacturing methods of API (chemical) and drug manufacturing plants. It is the obligation of everyone associated with the pharmaceutical and chemical industry especially in process chemistry innovation, product and process development, commercialization, and manufacturing to improve the existing technologies, as they are not the best. Our pharma technologies are most inefficient and this has been echoed by USFDA and others ^6-11. Improved manufacturing technologies have dual benefit of higher profit and reduced ecological damage while serving human needs. This might look difficult and challenging but is the least expensive option and has a quick pay back. 

1. D.G. Joakim Larsson, Cecilia de Pedro, and Nicklas Paxeus, Effluent from drug manufactures contains extremely high levels of pharmaceuticals; Journal of Hazardous Materials, Volume 148, Issue 3, 30 September 2007, Pages 751-755 
2. Chemical Week: Study Finds Significant Pollution from Indian Pharma Producers, September 12, 2007 Page 39 
3. Innovation and Continuous Improvement in Pharmaceutical Manufacturing. The PAT Team and Manufacturing Science Working Group Report. http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf 
4. APPCB List of Industries Region Wise accessed September 14, 2007 http://www.appcb.org/list_of_industries_region_wise.html 
5. Annual Reports of Matrix Labs; 2006-2007, Neuland Laboratories, and Aurobindo Pharma: 2006-2007 accessed September 19, 2007 
6. Malhotra, Girish, Batch or a Continuous Process: A Choice; Pharmaceutical Processing, March 2005, Page 16 
7. Malhotra Girish, API Manufacture-Simplification and PAT; Pharmaceutical Processing, November 2005, Pages 24-27 
8. Malhotra, Girish, Less is More in API Process Development; Pharmaceutical Manufacturing, July/August 2005, Pages 50-51 
9. Malhotra, Girish: QBD: Myth or Reality?; Pharmaceutical Processing, February 2007, Pages 10-16 
10. Malhotra, Girish: Continuous Processes Maintain Profitability; Drug Discovery and Development, June 2007, Pages 30-31 
11. Malhotra, Girish: Big Pharma: Who's Your Role Model, Toyota or Edsel?; Pharmaceutical Manufacturing, June 2007, Page 40