WO2010135410A1

WO2010135410A1 - Method and tool for estimating gases used in batch processes

Info

Publication number: WO2010135410A1
Application number: PCT/US2010/035375
Authority: WO
Inventors: Naresh Suchak; Steve Finley; John Liesen; Leslie Waller
Original assignee: Linde Aktiengesellschaft
Priority date: 2009-05-21
Filing date: 2010-05-19
Publication date: 2010-11-25

Abstract

A method for estimating the amount of gas required in a production process in manufacturing of pharmaceutical chemicals, products and auditing the gas usage at a given production facility. The method uses the number of gas usage steps involved in the production process and calculates the amount of gas used in each step by individual formulas for each step. The total amount of gas used can then be calculated from these individual step calculations. Cumulative gas requirement from all processes at given site can be compared with the gases supplied in a given time period for the purpose of auditing the gas usage.

Description

METHOD AND TOOL FOR ESTIMATING GASES USED IN BATCH PROCESSES

[0001] This application claims priority from provisional application serial number 61/180,247 filed May 21 , 2009.

BACKGROUND OF THE INVENTION

[0002] The present invention is an improved method and tool to better estimate and audit the quantity of industrial gases used in the batch processing of fine, specialty chemicals and pharmaceutical bulk drugs (also called as Active Pharmaceutical Ingredient or API) by utilizing organic synthesis and biotechnology processes.

[0003] The commonly used industrial gases are Nitrogen, Oxygen, Hydrogen, Carbon Dioxide, Argon, HCI, NH₃ and others. The use of highly reactive gases such as HCI and NH₃ is closely monitored and accounted for. However, gases which are environmentally benign such as N₂, O₂ are often not closely monitored. Nitrogen is the most widely used industrial gas in the process industry for blanketing, inerting, purging, pressure transfer, leak testing, etc. It is used in various types of equipment throughout the manufacturing facility. The use could be either intermittent (in other words discrete) or continuous based on process needs. To account for discrete uses of gases it is often very difficult, especially when in a large facility consisting of a cluster of plants or buildings each with a large number of batch processing equipment; each having many uses for industrial gases and the equipment qualified and validated for more than one product (drugs, or intermediates) with little or almost no instrumentation to measure the amount of gas used.

[0004] A majority of drugs, pharmaceutical chemicals, intermediates, APIs are manufactured using complex batch or semi-continuous recipes. The method described in this invention simplifies complex manufacturing batch recipes and gas usage by decoupling steps that involve gas usage from the rest of the recipe. A close review of these steps exhibits commonality in how these gases are used in manufacturing different recipes or even in different equipment. If the gas usage in these steps can be decoupled, typified and characterized, it can be accounted independent of the recipe, thus the complexity of the production processes need not be mastered to audit the gas usage. Instead, each recipe can be transformed into a number of steps of gas usage for the purpose of estimating gas requirement. By typifying and characterizing each use or each step, simple mathematical formulas can be assigned to compute the amount of gas required in the step. Such a typified step only need parameters (data) from the recipe and some details of equipment associated with the use as inputs to these formulas in estimating gas requirement. Summing estimates of gas requirement from all steps of the recipe provides an estimate of total amount of gas required in producing a typical batch of an intermediate or pharmaceutical chemical such as API.

[0005] in any given facility, production records reveal a number of batches of intermediate compounds, APIs or drugs produced during a given time period. The amount of gas required in producing a particular compound, API or drug is estimated by combining an estimate of gas required per typical batch with the number of batches undertaken during a respective time period. The same approach is repeated for all drugs and intermediates and for all batches produced in a given building to generate the gas requirement directly linked to batch processes. In addition, there may be other operations or processes in the building that requires use of gases on continuous, semi- continuous or discreet basis but are not directly covered by individual batch recipes. Identical approach is followed which consists of decoupiing steps of gas use, typifying and summing up steps of processes or operations in estimating indirect use in the given building. Therefore, total estimate of gas requirement for a given building is generated by adding estimates required directly for recipes and for balance of the operations in the building. [0006] Furthermore, adding estimates of gas requirement for all buildings engaged in the production campaign to estimates of gases required in auxiliary facilities such as tank farms provides the total need for gas at that production site.

[0007] Computing software such as a spreadsheet tool readily allows such estimations to be applied to variety of equipment and processes (recipe) for estimating gas demand. Therefore, this method and the tool allow one to gather and process a large amount of data with relative ease and versatility. Estimates from individual plants and buildings are added along with any other additional uses that a production site may have. This approach of estimating gas usage can also be termed as "Demand". In the gas usage audit methodology, this Demand is compared against actual consumption or "Supply" of gas metered at a gas generating facility or by the supplier to the site or facility and distribution to various buildings or production plants. Large discrepancies between "Demand" and "Supply" to overall site or individual plant / building prompts closer review to determine sources of excessive or wasteful consumption.

SUMMARY OF THE INVENTION

[0008] The invention provides for a method for estimating the amount of gas required in a process and auditing gas usage at a given production facility comprising the steps:

a) decoupling steps that involve gas usage from the rest of the recipe of a process selected from the group consisting of batch, semi-batch and continuous processes;

b) typifying gas use in the decoupling steps;

c) characterizing gas usage by assigning mathematical and logical formulas to each of the characterized and typified use; d) listing parameters(and data) required for each of characterized and typified use e) transforming the decoupled steps of the recipe into a list of typified steps that require use of gas;

f) extracting parameters for typified use from recipes, production records and operating procedures

g) calculating the amount of gas used in the each of the typified steps;

h) calculating the total of step g) to generate a gas requirement estimate for a particular recipe of process or equipment;

i) repeating steps a) through h) for all recipes at a site to generate gas requirement for each of the recipe;

j) generating gas usage estimates for each component selected from the group consisting of intermediate compound, API and drug by combining production data in a given period with the gas requirements for each the recipe;

k) repeating steps a) through h) for processes or operations on equipments and practices not covered in the recipe to estimate auxiliary uses;

I) totaling gas usage estimates from all recipe, process, equipment and auxiliary uses at the site in a defined time period; and

m) creating an audit of gas usage by comparing estimates obtained from step I) with a measured consumption or supply of metered gas at the site. [0009] The invention is a methodology and tool for estimating use of industrial gases in a large manufacturing facility engaged in manufacturing of pharmaceutical chemicals (intermediates and bulk drugs) utilizing organic synthesis and biotechnology in batch or semi-continuous mode where gas flow at each point of use is not measured due to its practicality and intermittent or discrete or periodic nature of use. The method and the tool can calculate the use of gases in batch, semi-batch or continuous processes.

[0010] Providing a flow totalizer is often not considered practical due to the large number of use-points in a given production process. Although the example presented and the description in this disclosure is relevant to production of API (Active Pharmaceutical Ingredients) or bulk drugs, it has applicability in the genera] organic synthesis process industry and other process industries that have a large number of discrete uses. The applicability of this method however is not limited to batch process and can provide gas use estimation for semi- batch and continuous processes. This method as stated earlier can be used in estimating gas use in many processes in many different manufacturing industries that use industrial gases in a batch, semi-continuous and continuous mode for variety of applications such as inerting, cooling, chilling, cleaning, drying, blanketing, purging, diluting, packaging etc.

[0011] The tool developed to accomplish the estimation described in this approach consists of an electronic spreadsheet with simple forms. The recipe page of the spreadsheet has pull down menus to enter steps that use gas in a given recipe. This allows the user to choose equipment employed in the production campaign by simple key clicks. It also allows entering operation parameters required for estimating gas use using fill-in type fields.

[0012] In a separate master list, details pertaining to equipment and facility are entered which are referenced in computing estimates of gas usage. Additional tables comparing production data and gas supply data generates a visual contrast between "Supply" and "Demand" of gas. The graphs and usage analysis data are already generated to provide more insight in the gas usage at any given site.

[0013] The gas is preferably nitrogen or oxygen. The process is selected from the group consisting of batch, semi-batch and continuous processes. The production facility is selected from the group consisting of a bulk drug facility, a facility for manufacturing pharmaceuticals and a facility for manufacturing chemicals.

[0014] The recipe is discrete or semi-continuous and can be a series of steps in a process for manufacturing a compound selected from the group consisting of intermediate compounds, APIs and drugs.

[0015] The estimating is in the form of an electronic spreadsheet and the recipe is for the production of a chemical compound selected from the group consisting of intermediate compounds, APIs and drugs.

[0016] The menu is preferably a drop down menu and the menu can display a list of validated equipment in the production facility. The equipment is selected from the group consisting of reaction vessels, separation equipment and feed tanks.

[0017] Each of the steps is associated with a formula to estimate gas usage.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The method and tool of the invention is exemplified in a bulk drug facility and its complex usage of one industrial gas, nitrogen. The facility is supplied by an on-site gaseous Nitrogen generation plant and has a back up supply from a liquid nitrogen tank for critical applications. The supplier has only provided metering of gas on a supply line carrying Nitrogen from the onsite plant and the back up tank. This large facility has a cluster of twenty five buildings/units. Sixteen buildings have their entire production carried out in batch or semi-batch mode. Each of these sixteen buildings has between fifty and one hundred points of use (i.e. connections from where nitrogen is withdrawn into equipment for various uses).

[0019] In a process operated in a batch mode, equipment generally consists of reaction vessels, separation equipment and feed tanks. Nitrogen is used in a reactor for multiple purposes. So from one point of use, each reactor can have several industrial gas uses dictated by a recipe which may be discrete or semi- continuous.

[0020] Each point of use may or may not have instrumentation to measure flow or cumulatively account for gas use. In this example, there can be a variety of purposes for gas consumption from a single point of use, and given the variety of drugs or product that could be produced during a production campaign at any single point of use, several hundreds to thousands of points of use and the lack of flow measurement instruments make accounting of gas usage a mammoth or practically impossible task.

[0021] Facilities routinely estimate their future needs by reviewing historical consumption rather than estimating from process demand. Adding further to the complexity is the fact that these facilities are engaged in producing chemicals, compounds, drugs or intermediates having cyclic demands. Due to globalization and expiry of patents, some older drugs are moved out of the production campaigns and replaced with newer drugs. Thus, there is a major flaw in estimating future gas needs based on historical consumption. Since the contribution of cost of industrial gases to overall cost is a very small expense in the manufacture of drugs, estimations with increments over past consumptions do not face tough scrutiny. Sometimes, increased future needs are often justified against improving safety; especially in the case of Nitrogen which is mainly used for preventing explosive conditions due to solvent vapor and fugitive emissions. [0022] Pharmaceutical and fine chemical producers, by making this decision to inflate and over account for future need, unnecessarily drain resources and promote wasteful consumption of the gas.

[0023] For example, a wasteful use in manufacturing of drugs in batch reactors includes: unnecessarily keeping a manhole or hand-hole of a reactor open in between two batches and during preparation of a batch. The reactor gas ullage is often connected to a common exhaust duct directly by pipe or via condenser. The exhaust duct is maintained under negative pressure to prevent the escape of fugitive emissions from the process vessel. Generally, the low oxygen concentration is maintained in the exhaust ducts to prevent explosive vapor mix by purging Nitrogen. So by keeping the manhole or hand hole of a reactor open unnecessarily, the oxygen concentration in the exhaust duct rises, triggering a large release of purge Nitrogen in the exhaust duct to dilute the oxygen concentration.

[0024] Further wasteful uses include continuing Nitrogen purge long after a reactor or process vessel is decommissioned or taken offline from production campaign. Continued flushing of solvent and effluent lines with Nitrogen long after pumping or concluding of transfer operations and leaky valves in blanketing tanks are some additional examples those contribute in excessive use of nitrogen. Leaky gas film mechanical seals of equipment not in service are also noticed widely in manufacturing facilities.

[0025] To further explain the invention, iet us elaborate on steps stated earlier in this invention.

[0026] The first step in the proposed method is decoupling use of industrial gas from rest of the recipe.

[0027] Recipe generally consists of large number of operational steps some of which are directed towards use of gas. In decoupling, the steps that involve gas use are identified and separated from rest of the recipe details.

[0028] A small part of recipe was selected to illustrate decoupling and typifying steps and is illustrated below.

[0029] In this illustration the first column is recipe step number and the second column is description of the recipe step.

[0030] By examining the recipe, the steps 4, 7, 11 and 19 are identified to have embedded gas use. These gas uses are decoupled from the complex recipe steps and expressed as generic gas use steps in the adjacent column labeled as "Decoupled steps".

[0031] Furthermore, the decoupled steps can be typified and the gas use characterized by assigning mathematical formula or rule to quantify the typified gas use. The fourth column in the table provides "Typified steps" corresponding to "Decoupled steps".

[0032] In the present example, the gas use in the decoupled steps "Inerting by pressure cycle" and "Inerting by vacuum cycle" both are typified as "Inerting" step.

[0033] The typified step "Inerting" is characterized by assigning mathematical formulas to estimate gas requirement.

[0034] For an empty reactor (vessel) to be inerted with nitrogen:

the total purge gas requirement in vessel volumes is calculated by multiplying the number of purge cycles (n) with vessel volume (V_v) and number of vessel volumes per pressure cycle (N).

V₇ = n * Vv* N

Where:

V_T = total volume of inert gas required for purge sequence in ft³ or Nm³ n = number of purge cycles

Vv = volume of vessel in ft³ or Nm³

N = number of vessel volumes of purge gas per pressure cycle The number of vessel volume per pressure cycle is determined using the formula: N = m * ( P-1)

Where:

P = vessel pressure required to reach concentration in n cycles, absolute atmosphere (atma) m = 1 for P > 1 (pressure cycle) and m = -1 when P < 1 (vacuum cycle)

[0035] Listing of parameter for each typified use involves identifying parameter or data required for computing gas volume.

[0036] The typified step "Inerting" requires parameter "n", number of cycles of pressure or vacuum, pressure ¹¹P" and volume of the vessel to be inerted

Vv .

[0037] Instead of specifying number of purge cycles, if target oxygen concentration in the vessel is prescribed in the recipe, "n" is calculated by following formula,

P = ( ( Q - C_p) Z (Ct - C_p) ) "¹⁷"

Where:

C_t = target oxygen concentration in the vessel (%) C_p = oxygen concentration in the purge nitrogen gas (%) Cj = initial oxygen concentration in the vessel (%)

[0038] The value of n derived from the calculation must be rounded up to the integer value in computing gas requirement.

[0039] Next step is to extract parameters from recipe, operating procedures and plant data required for calculating gas in typified step. In this example, for "Inerting", the parameter (data) required is

a) "n" , number of pressure/vacuum cycles which is 2 cycles (in case of both pressure and vacuum cycle as stated in the recipe step

b) "P", final pressure, 3.5 atma for pressure cycle and 0.15 atma for vacuum cycle

c) "Vv" Vessel volume to be inerted (1.5 m3 for R-100 and 0.5 m3 in G-100 from plant data)

Therefore, the gas volume required for the recipe step 7 is,

V_τ n ^* Vv^* N

2 ^* 0.5 * (0.85) 0.85 m3

Similarly, the gas volume required for the recipe step 11 is

2 ^* 1.5 * (2) 6.0 m3

[0040] In the above example we have demonstrated how

i) Gas use steps are decoupled from recipe steps;

ii) Decoupled steps are typified and characterized (associating mathematical or estimating relation with typified use);

iii) Parameters (data) are identified for computing a typified gas use; iv) Parameters (data) are extracted from recipe, plant and operations data for its use with typified step;

v) Estimating gas requirement in the typified steps.

[0041] Here is an illustration of a small section of the "Data Entry" page of spreadsheet based audit tool. The manufacturing location is selected from a drop-down box under the column with heading "Building". This drop-down menu is linked to a master table containing previously entered data about the facility (such as buildings or plants in the facility or the site). Each building has a validated list of bulk drugs (API) or intermediate compounds or process operations. So by choosing "Building", the spreadsheet automatically selects list of bulk drugs or process operations which could be manufactured in that building. The name of the drug or intermediate or process operation is selected from this list using a drop-down menu under titled "Compound / Operation". The recipe steps or process operations step are entered in the column 4. Based on the description of the recipe step or operations step, if there is a use for industrial gases, suitable "Decoupled step" is selected from the predefined list. Each 'Decoupled step" is automatically linked to one "Typified Step".

[0042] For each bulk drug, there are sets of validated equipment which are automatically populated in the drop down menu list. The user selects which set of equipment is used in the time period under consideration of the audit or the recipe.

[0043] Here is the partial list of "Decoupled Steps" and corresponding characterized Typified Steps" useful in auditing drug manufacturing facility. These steps could be further modified should there be a need.

[0044] Partial List of Decoupled steps of N₂ Usage :

[0045] As stated earlier these steps are characterized for any generic equipment and are independent of the recipe. In addition to choosing the characterized step, operating parameters from the recipe, plant data and operations parameter are also entered in the appropriate spaces in the "Data Entry" spreadsheet for each step.

[0046] Each of the typified steps is associated with a formula to estimate gas usage.

[0047] Therefore, in the spreadsheet tool, for every typified step, gas usage is estimated. Summing the gas usage estimates from all typified steps provides an estimate of gas used in a batch of chemicals produced as per the recipe. [0048] Characterizing the gas usage depends on the practices followed in the process operations and varies from production site to site. Therefore some customization may be required in characterizing the gas usage steps for any given site.

[0049] As stated earlier, production records reveal a number of batches carried out during a given time period. In a separate table, production records are incorporated using a drop down menu to account for each drug produced, i.e., batches taken during the given time period. Having the estimated gas usage in producing a batch of each drug and knowing the number of batches of each drug produced, gas consumed during that time period can be calculated for all the drugs in that building. In addition, use of gas for process operations not directly linked with recipe or batch are also estimated using the same too! for the given building.

[0050] The same approach is repeated for all buildings to provide the total gas used in the production campaign. Also, the tool has a provision to add estimates from gas usage in auxiliary facilities such as tank farms; hence estimating gas usage in terms of "Demand" at that site. The tool also has a provision to include metered supply data to highlight the discrepancy between "Demand" and "Supply". Additionally, the tool generates graphs and usage analysis data to provide more insight and in-depth analysis in the gas usage at the given site.

[0051] While this invention has been described with respect to particular embodiments thereof, it is apparent that numerous other forms and modifications of the invention will be obvious to those skilled in the art. The appended claims in this invention generally should be construed to cover all such obvious forms and modifications which are within the true spirit and scope of the invention.

Claims

Having thus described the invention, what we claim is:

1. A method for estimating the amount of gas required in a process and auditing gas usage at a production facility comprising the steps:

a) decoupling steps that involve gas usage from the rest of a recipe of a process selected from the group consisting of batch, semi-batch and continuous processes;

b) typifying gas use in said decoupling steps;

c) characterizing gas usage by assigning mathematical and logical formulas to each of said characterized and typified use;

d) listing parameters and data required for each of said characterized and typified use;

e) transforming the decoupled steps of said recipe into a list of typified steps that require use of gas;

f) extracting parameters for typified use from recipes, production records and operating procedures;

g) calculating the amount of gas used in the each of said typified steps;

i) repeating steps a) through h) for all recipes at a site to generate gas requirement for each of said recipe; j) generating gas usage estimates for each component selected from the group consisting of intermediate compound, active pharmaceutical ingredient and drug by combining production data in a given period with said gas requirements for each said recipe;

k) repeating steps a) through h) for processes or operations on equipments and practices not covered in said recipe to estimate auxiliary uses;

m) creating an audit of gas usage by comparing estimates obtained from step I) with a measured consumption or supply of metered gas at said site.

2. The method as claimed in claim 1 wherein said process is selected from the group consisting of batch, semi-batch and continuous processes.

3. The method as claimed in claim 1 wherein said production facility is selected from the group consisting of a bulk drug facility, a facility for manufacturing pharmaceuticals and a facility for manufacturing chemicals.

4. The method as claimed in claim 1 wherein said estimating is in the form of an electronic spreadsheet.

5. The method as claimed in claim 1 wherein said recipe is for the production of a chemical compound selected from the group consisting of intermediate compounds, active pharmaceutical ingredients and drugs.

6. The method as claimed in claim 1 wherein said gas is nitrogen.

7. The method as claimed in claim 1 wherein said gas is oxygen.

8. The method as claimed in claim 1 wherein said menu is a drop down menu.

9. The method as claimed in claim 1 wherein said recipe is discrete or semi-continuous.

10. The method as claimed in claim 1 wherein said equipment is selected from the group consisting of reaction vessels, separation equipment and feed tanks.

11. The method as claimed in claim 4 wherein said electronic spreadsheet displays the names of said intermediate compounds, active pharmaceutical ingredients and drugs.

12. The method as claimed in claim 8 wherein said menu displays a list of validated equipment.

13. The method as claimed in claim 1 wherein said recipe is a series of steps in a process for manufacturing a compound selected from the group consisting of intermediate compounds, active pharmaceutical ingredients and drugs.

14. The method as claimed in claim 13 wherein each of said steps is associated with a formula to estimate gas usage.