INDUSTRIAL PROCESS AND SYSTEM FOR THE INACTIVATION OF LIQUID WASTE

Abstract

The present invention refers to an industrial process and system that is efficient and advantageous for inactivation of liquid wastes contaminated by mutagenic, genotoxic and/or teratogenic substances arising from high potency APIs production using inactivation chemical agents and excluding ozone, heat or UV light source.

Claims

1- Industrial System for inactivation of liquid wastes contaminated by mutagenic, genotoxic and/or teratogenic substances arising from high potency APIs production characterized by comprising the following components: (a) Closed pipeline (30) which displaces, under control, the contaminated liquid waste from a containment box of the production plant to inside of two storage tanks (1) and (2); (b) Storage tanks (1) and (2) made of refractory steel set to receive contaminated liquid wastes; (c) Mechanical filter (40), placed between tanks (1) and (2) and inactivation tanks (3) and (4), in order to retain solid wastes and particles arising from the production process or decantation; (d) Inactivation tanks (3) and (4) made of refractory steel set to receive contaminated liquid waste and chemical agent(s), where the inactivation process is carried out; (e) Tanks (5), (6), (7) and (8) made of polypropylene fiber set to receive the inactivation chemical agents by manual loading; (f) Collector box (60) of possible leakage of contaminated or partially inactivated liquid waste; (g) Collector tanks (9), (10), (11) and (12) of inactivated liquid waste comprising organic solvent solutions, and pipeline (31) to transfer the inactivated liquid waste comprising water content ≥80% to a chemical and biological treatment plant; wherein the above-mentioned storage and inactivation tanks are kept under inert atmosphere and reduced pressure, and the system is closed.

2- System, according to claim 1, characterized by the fact that the pipeline (30) is made of double containment pipes and strength material in order to avoid deterioration and leakage.

3- System, according to claim 1, characterized by the fact that the storage tanks (1) and (2) comprise: i) at the top two inputs, one of them for nitrogen (13) and the other one (14) for the contaminated liquid waste, and one air output (15) for atmospheric control, ii) at the bottom, one output (16) for contaminated liquid waste to inactivation tanks, and iii) control valves.

4- System, according to claim 1, characterized by the fact that two inactivation tanks (3) and (4) comprising: i) at the top: six inputs, four of them (17) , (18) , (19) and (20) for inactivation chemical agents, one of them for nitrogen (21) and the other one (22) for the contaminated liquid waste, and one air output (23) for atmospheric control, ii) at the bottom, one output (24) for inactivated liquid waste, and iii) control valves.

5- System, according to claim 1, characterized by the fact that the tanks (1), (2), (3) and (4) have capacity from 50 L to 1000 L each one.

6- System, according to claim 1, characterized by the fact that tanks (5) , (6) , (7) and (8) have capacity from 5 L to 50 L each one.

7- System, according to claim 1, characterized by additionally comprising two centrifugal pumps (B1) and (B2) to pump the contaminated liquid waste, in controlled amount, to inactivation tanks passing through a mechanical filter (40) in order to retain solid wastes and particles arising from the process or decantation carried out in the storage tanks (1) and (2).

8- System, according to claim 1, characterized by additionally comprising four pneumatic metering pumps (B6), (B7), (B8) and (B9) to pump, in controlled amount, the inactivation agent to the above-mentioned inactivation tanks.

9- System, according to claim 1, characterized by additionally comprising two centrifugal pumps (B3) and (B4) to pump, in controlled amount, the inactivated liquid waste to the collector tanks (9), (10), (11) and (12) when comprising organic solvent solutions, or to the chemical treatment plant when comprising water amount ≥80%.

10- System, according to claim 1, characterized by additionally comprising one pneumatic pump (B5) to pump, in controlled amount, the liquid waste from collector box (60) to the above-mentioned storage tanks.

11- System, according to claim 1, characterized by additionally comprising one automated control system (50).

12- System, according to claim 1, characterized by the fact that the inert atmosphere is kept by nitrogen.

13- System, according to claim 1, characterized by the fact that the contaminated liquid waste comprises organic solvent solutions and/or waste water containing mutagenic, genotoxic and/or teratogenic substances arising from high potency APIs production.

14- System, according to claim 1, characterized by the fact that the high potency API is selected from the group consisting of imatinib mesylate, bortezomib, decitabine, sunitinib malate, temozolomide and zoledronic acid.

15- System, according to claim 1, characterized by the fact that the inactivation chemical agent is a strong inorganic oxidant, an acid, a base water or mixtures thereof.

16- System, according to claim 15, characterized by the fact that the oxidant is selected from the group consisting of sodium hypochlorite, hypochlorous acid, hydrogen peroxide, potassium permanganate and Fenton's reagent.

17- System, according to claim 15, characterized by the fact that the acid is hydrobromic acid and the base is sodium hydroxide.

18- Industrial process for inactivation of liquid wastes contaminated by mutagenic, genotoxic and/or teratogenic substances arising from high potency APIs production using the inactivation system of claim 1, characterized by comprising the following steps: (a) Transfering the contaminated liquid waste arising from high potency APIs production to storage tanks (1) and (2); (b) Pumping the contaminated liquid waste to inactivation tanks (3) and (4) passing through a mechanical filter (40) in order to retain solid wastes or particles arising from the production process or decantation; (c) Loading tanks (5), (6), (7) and/or (8) with inactivation chemical agents appropriate to the high potency API(s) to be inactivated; (d) Pumping a calculated amount of at least one inactivation chemical agent to inactivation tanks (3) and (4); (e) Carring out the chemical reaction between at least one inactivation chemical agent and the contaminated liquid waste inside the inactivation tanks (3) and (4); (f) Collecting sample of the inactivated liquid waste and confirm the inactivation by physico-chemical and mutagenic test. (g) Pumping the inactivated liquid waste to collector tanks (9), (10), (11) and (12) when comprising organic solvent solutions, or to the chemical treatment plant when comprising water amount ≥80%;

19- Process, according to claim 18, characterized by the fact that the contaminated liquid waste comprises organic solvent solutions and/or waste water containing teratogenic, mutagenic and/or genotoxic substances arising from high potency APIs production.

20- Process, according to claim 18, characterized by the fact that the high potency API is selected from the group consisting of imatinib mesylate, bortezomib, decitabine, sunitinib malate, temozolomide and zoledronic acid.

21- Process, according to claim 18, characterized by the fact that the inactivation chemical agent is a strong inorganic oxidant, an acid, a base, water or mixtures thereof.

22- Process, according to claim 21, characterized by the fact that the oxidant is selected from the group consisting of sodium hypochlorite, hypochlorous acid, hydrogen peroxide, potassium permanganate and Fenton's reagent.

23- Process, according to claim 22, characterized by the fact that the acid is hydrobromic acid and the base is sodium hydroxide.

24- Process, according to claim 18, characterized by the fact that the physico-chemical test is a chromatographic one and the mutagenic test is the AMES test.

25- Process, according to claim 18, characterized by comprising, additionally, a treatment step of the inactivated liquid waste in order to recover organic solvents or to reduce total organic carbon.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] FIG. 1 illustrates the industrial system simplified flowchart.

[0034] FIG. 2 illustrates the inactivation of imatinib mesylate monitored by HPLC. A (T=0); B (T=5 min) and C (T=10 min).

[0035] FIG. 3 illustrates inactivation kinetics of imatinib mesylate.

[0036] FIG. 4 illustrates inactivation kinetics of high potency APIs bortezomib, decitabine, sunitinib malate, temozolomide and zoledronic acid.

DETAILED DESCRIPTION OF THE INVENTION

[0037] According to one aspect of the invention, an industrial system for inactivation of liquid wastes contaminated by mutagenic, genotoxic and/or teratogenic substances arising from high potency APIs production is provided.

[0038] The term “liquid wastes” is defined, within the scope of this invention, as comprising organic solvent solutions and/or waste water arising from high potency active pharmaceutical ingredients (HPAPIs) production.

[0039] The term “mutagenic substances” is defined, within the scope of this invention, as substances that, when exposed to cells, are able to induce mutation, or in other words, a damage in DNA molecule that is not repaired in cell replication and is passed to the following generations.

[0040] The term “genotoxic substances”is defined, within the scope of this invention, as substances that have affinity to interact with DNA, which is not necessarily an evidence of health hazardous, however they are potentially mutagenic or carcinogenic, particularly that one able to create genetic mutation that can contribute to tumor development.

[0041] The term “teratogenic substances” is defined, within the scope of this invention, as substances that are able to produce damage to the embryo or fetus during pregnancy. These damages can be reflected as early loss of pregnancy, malformations or functional changes (growth retardation, for example), or neurobehavioural disorders, as intellectual disability.

[0042] The term “high potency APIs” is defined, within the scope of this invention, as active pharmaceutical ingredients that generate high pharmacological effect even in low doses, or in other words, that have a narrow therapeutic window. We can exemplify high potency APIs as: cytostatic, hormones, among others.

[0043] FIG. 1 illustrates the industrial system of this invention for inactivation of liquid wastes contaminated by mutagenic, genotoxic and/or teratogenic substances arising from high potency APIs production, which comprises the following components: [0044] (a) Closed pipeline (30) which displaces under control the contaminated liquid waste from a containment box of the production plant to inside of two storage tanks (1) and (2); [0045] (b) Storage tanks (1) and (2) made of refractory steel set to receive contaminated liquid wastes; [0046] (c) Mechanical filter (40), placed between storage tanks (1) and (2) and inactivation tanks (3) and (4), in order to retain solid wastes or particles arising from production process or decantation; [0047] (d) Inactivation tanks (3) and (4) made of refractory steel set to receive contaminated liquid wastes and chemical agent(s), where the inactivation process is carried out; [0048] (e) Tanks (5), (6), (7) and (8) made of polypropylene fiber set to receive inactivation chemical agents by manual loading; [0049] (f) Collector box (60) of possible leakage of contaminated or partially inactivated liquid wastes; [0050] (g) Collector tanks (9), (10), (11) and (12) of inactivated liquid waste comprising organic solvents and pipeline (31) to transfer the inactivated liquid waste comprising water content ≥80% to a chemical and biological treatment plant; [0051] wherein the mentioned storage and inactivation tanks are kept under inert atmosphere and reduced pressure, and the system is closed.

[0052] The various items that form the invention's inactivation system will be detailed below based on FIG. 1.

[0053] The closed pipeline (30) displaces under control the contaminated liquid waste from a containment box of the production plant to inside of two tanks (1) and (2). Pipeline (30) is made of double containment pipes (jacketed pipeline) and material that presents good or excellent strength to various solvents, such as Teflon, polyvinyl chloride (PVC), polypropylene homopolymer (PPH), among others, in order to avoid deterioration and leakage of contaminated waste.

[0054] The inactivation system is kept under inert atmosphere in order to avoid explosions. The inertization of the system is carried out with inert gas, which can be argon, nitrogen or any other gas that presents these properties. Preferably, the inert gas is nitrogen. Once inertized, the system remains in this condition and it is not necessarily continued addition of inert gas because the system is closed.

[0055] The storage tanks (1) and (2) are made of refractory steel and comprise: i) at the top, two inputs, one for nitrogen (13) and the other one (14) for the contaminated liquid waste, and an air output (15) for atmospheric control, ii) at the bottom, one output for the liquid waste (16) to inactivation tanks, and iii) control valves.

[0056] The two inactivation tanks (3) and (4) comprise: i) at the top: six inputs, four of them (17), (18), (19) and (20) for inactivation chemical agents, one for nitrogen (21) and the other one (22) for the contaminated liquid waste, and one air output (23) for atmospheric control, ii) at the bottom, one output for the inactivated liquid, and iii) control valves.

[0057] The capacity of tanks (1), (2), (3) and (4) can vary from 50 L to 1000 L each one. Preferably, these tanks have a capacity of 1000 L each one.

[0058] The tanks (5), (6), (7) and (8) are made of polypropylene fiber and are set to receive the inactivation chemical agents by manual loading. Their capacity can vary from 5 L to 50 L. Preferably, these tanks have a capacity of 50 L each one.

[0059] The inactivation system also comprises two centrifugal pumps (B1) and (B2) to pumpthe contaminated liquid waste in controlled amount to the inactivation tanks (3) and (4), passing through a mechanical filter (40) in order to retain solid wastes or particles arising from the process or decantation that occurs in the storage tanks (1) and (2).

[0060] The inactivation system additionally comprises four pneumatic metering pumps (B6), (B7), (B8) and (B9) to pump the inactivation agent in controlled amount to the mentioned inactivation tanks.

[0061] The inactivation system additionally comprises two centrifugal pumps (B3) and (B4) to pump the inactivated liquid waste in controlled amount to collector tanks (9), (10), (11) and (12) when comprising organic solvent solutions, or to the chemical and biological treatment plant when comprising water content ≥80%, through the pipeline (31).

[0062] The inactivation system additionally comprises a pneumatic pump (B5) to pump the liquid waste in controlled amount from the leakage collector box (60) to mentioned storage tanks (1) and (2).

[0063] The inactivation system of the present invention additionally comprises an automated control system (50) that allows to monitor and control the liquid waste level in the tanks, valves and pumps performance, as well all system's utilities, such as compressed air, nitrogen, in order to provide security to the system's operator.

[0064] The contaminated liquid waste comprises organic solvent solutions and/or waste water containing mutagenic, genotoxic and/or teratogenic substances arising from high potency APIs production, which includes imatinib-mesylate, bortezomib, decitabine, sunitinib malate, temozolomide and zoledronic acid, but is not limited to them.

[0065] The inactivation chemical agents are selected based on the API that one wants to inactivate. The most usual ones are the strong inorganic oxidant agents such as sodium hypochlorite (NaOCl), hypochlorous acid (HClO), hydrogen peroxide (H.sub.2O.sub.2), potassium permanganate (KMnO.sub.4) or Fenton's reagent (Fe.sub.2.sub.++H.sub.2O.sub.2), but it is not limited to them. Inactivation can also be performed by acids such as hydrobromic acid (HBr); bases, such as sodium hydroxide (NaOH), or even water, depending on the compound to be inactivated.

[0066] The inactivation chemical agent used in the inactivation system of this invention is a strong inorganic oxidant, an acid, a base, water or mixtures thereof.

[0067] Oxidant agent is preferably selected from the group consisting of sodium hypochlorite, hypochlorous acid, hydrogen peroxide, potassium permanganate and Fenton's reagent, but it is not limited to them.

[0068] Acid is hydrobromic acid and base is sodium hydroxide.

[0069] The structure of the inactivation system was built with strong ventilation and all utilities and equipment inside the building were designed to comply with ATEX Zone 2 IIB T4 (classification of explosion-proof equipment).

[0070] Finally, if a leakage occurs, organic solvent solutions and waste water contaminated or partially inactivated are recovered in a collector box (60) and can be pumped to storage tanks in order to be inactivated again.

[0071] According to another aspect of this invention, an industrial process is provided in order to inactivate liquid waste contaminated by mutagenic, genotoxic and/or teratogenic substances arising from high potency APIs production using the industrial system proposed and represented in FIG. 1, which comprises the following steps: [0072] (a) Transfering the contaminated liquid wastes arising from high potency APIs production to storage tanks (1) and (2); [0073] (b) Pumping the contaminated liquid wastes to inactivation tanks (3) and (4) passing through a mechanical filter (40) in order to retain solid wastes or particles arising from the production process or decantation; [0074] (c) Loading tanks (5), (6), (7) and/or (8) with inactivation chemical agents appropriate to the high potency API(s) to be inactivated; [0075] (d) Pumping a calculated amount of at least one inactivation chemical agent to inactivation tanks (3) and (4); [0076] (e) Carring out the chemical reaction between at least one inactivation chemical agent and the contaminated liquid waste inside inactivation tanks (3) and (4); [0077] (f) Collecting sample of the inactivated liquid waste and validate inactivation by physico-chemical and mutagenic tests. [0078] (g) Pumping the inactivated liquid waste to collector tanks (9), (10), (11) and (12) when comprising organic solvent solutions, or to the chemical treatment plants (50) when comprising water amount 80% through pipeline (31);

[0079] The contaminated liquid waste comprises organic solvent solutions and/or waste water containing mutagenic, genotoxic and/or teratogenic substances arising from high potency APIs production, which include imatinib mesylate, bortezomib, decitabine, sunitinib malate, temozolomide or zoledronic acid, but are not limited to them.

[0080] The inactivation chemical agents are selected based on the API that one wants to inactivate. The most usual ones are the strong inorganic oxidant agents such as sodium hypochlorite (NaOCl), hypochlorous acid (HClO), hydrogen peroxide (H.sub.2O.sub.2), potassium permanganate (KMnO.sub.4) or Fenton's reagent (Fe.sub.2.sup.++H.sub.2O.sub.2). Inactivation can also be performed by acids, such as hydrobromic acid (HBr); bases, such as sodium hydroxide (NaOH), or even water, depending on the compound to be inactivated.

[0081] The inactivation chemical agent used in the inactivation process of the present invention is a strong inorganic oxidant, an acid, a base, water or mixtures thereof.

[0082] The oxidant agent is preferably selected from the group consisting of sodium hypochlorite, hypochlorous acid, hydrogen peroxide, potassium permanganate and Fenton's reagent, but is not limited to them.

[0083] Acid is hydrobromic acid and base is sodium hydroxide.

[0084] Since the inactivation process can be carried out in acid or basic conditions, it is not necessary to neutralize the contaminated liquid waste pH in order to perform the inactivation process.

[0085] According to one embodiment of the invention, it is possible to inactivate liquid waste that contain mutagenic, genotoxic and/or teratogenic substances arising from a single high potency API production using at least one inactivation chemical agent appropriated to the API that one wants to inactivate.

[0086] According to another embodiment of the invention, it is possible to inactivate liquid wastes containing mutagenic, genotoxic and/or teratogenic substances arising from two or more high potency APIs production using inactivation chemical agents appropriated to APIs that one wants to inactivate.

[0087] Additionally, the process comprises a secondary treatment step of the inactivated liquid waste in order to recover organic solvents by distillation or to reduce the total organic carbon for water.

[0088] The effectiveness of the inactivation process is validated by physico-chemical tests, such as HPLC analysis, and mutagenic tests, such as AMES test to confirm complete degradation of high potency API and elimination of mutagenic and genotoxic activity.

[0089] Ames Test (Salmonella typhimurium his reversion assay), is a short-term in vitro bioassay that detects gene mutations has been widely used for mutagenic ability determination of a wide range of chemical substances and complex mixtures, besides providing correlation with carcinogenicity.

[0090] The following examples are merely illustrative, and should be employed for a better understanding of the claimed system and process, however they should not be used in order to limit the scope of the present invention.

EXAMPLE 1

Inactivation Kinetics of Imatinib Mesylate

[0091] The inactivation kinetics by HPLC of a liquid waste comprising 20 mg/mL imatinib mesylate aqueous solution was evaluated using a 1% hypochlorous acid aqueous solution as inactivation chemical agent, as illustrated in FIGS. 2 and 3. It is possible to verify that 10 minutes of exposure were enough for complete inactivation of imatinib mesylate by hypochlorous acid.

[0092] The equipment used was a High-Performance Liquid Chromatography-HPLC, Agilent Tech. Model 1260.

[0093] Analytical Method: [0094] Solution A: Prepare a mixture of methanol and acetonitrile (300:200) and homogenize. [0095] Mobile Phase: transfer 1.65 g of sodium dihydrogen phosphate dihydrate to a beaker. Dissolve in 550 mL of purified water and adjust pH to 8.0±0.2 using trimethylamine and homogenize. Add 450 mL of solution A, homogenize and filter using a membrane of 0.45 μm.

[0096] Chromatographic Conditions: [0097] Column: Develosil ODS HG-5 (4.6×150 mm, 5 μm)−Phenomenex [0098] Flow: 1.0 mL/min. [0099] UV Detector: 230 nm [0100] Injection volume: 20 μL [0101] Column temperature: 30° C. [0102] Chromatographic time: 50 minutes [0103] Retention time for imatinib: about 18 minutes [0104] Sample temperature: 5° C.

EXAMPLE 2

Inactivation Kinetics

[0105] The inactivation kinetics by HPLC of high potency APIs bortezomib, decitabine, sunitinib malate, temozolomide and zoledronic acid was evaluated using chemical agents and analytical methods appropriate for each API. FIG. 4 illustrates the inactivation kinetics of these APIs and it was possible to verify that the evaluated APIs are completely inactivated by chemical agent action in different exposure time.