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  • Saturday 18 April 2020

    Process Safety Management (PSM) in Pharma API

    Back here after many days!!!

    Being busy in my profession, unable to concentrate over here and recently my right arm got fractured, thats the reason i'm unable to share here anything even in this lockdown....!!  

    Hope all is well with everyone.
    I've been continuously receiving requests regarding Process Safety management, cooling tower design, pressure swing distillation, swap distillation and many others.

    Today, i would like to post something related to Process Safety Management in a much simple way for everyone to grasp easily.

    Before that, let me deliver some stuff which will make the discussion easier.

    What is Heat of reaction ?

    Heat of reaction indicates the energy required / energy liberated during the path of products formation. It can be either a (+)ve or (-)ve.

    -ve indicates exothermic (energy liberation) and +ve indicates endothermic (energy intake)

    What is the common technique to understand the Heat of reaction ?

    Usually we will prefer RC (Reaction Calorimetry) study to understand the heat of reaction.

    Also Read:

    Checking batch size feasibility for scale-up 
    Guidelines for process development

    What type of system is an RC ?

    Reaction calorimeter is an isoperibolic system, where a constant jacket temperature is maintained to interpret the system changes.

    What is the desired output from an RC study report ?

    Heat of reaction, Adiabatic temperature raise, Thermal accumulation.

    What does decomposition exactly mean ?

    Decomposition means a state of simply degradation or turning into undesired phase, which can be due to overheating or exposure to undesired conditions.

    What are the types of decompositions ?

    There are two types of decomposition, one is exothermic decomposition and the other one is endothermic decomposition.

    What are common techniques to understand decomposition behaviour of materials ?

    Usually, we'll prefer DSC (Differential Scanning Calorimetry), ARC (Accelerated Rate Calorimetry).

    When to select between DSC and ARC ?

    This thing i'll explain in this later post.

    Also Read:
    Evaluate filtration feasibility in ANFD 
    Design a condenser for a reactor

    What are the tests to be performed for dry solid materials ?

    Usually, dry materials will exhibit static nature, burning behaviour. Hence to understand we will perform bulk resistivity, MIE (Minimum Ignition Energy), Fall hammer test etc. Later i'll explain when to use those.

    Now getting in detail, i'll explain you with a general case study which will cover most of the plant scenario's.

    Case Study:
    Lets consider a process having 7 simple steps, where

    i. Chemical A (solid) is going to couple with Reagent B (liquid) through slow addition at 50-60 ℃ in a solvent say Ethyl acetate and
    ii. the formed bi-products are washed with water,
    iii. obtained product undergoes Condensation with compound C (solid) for 6 hours at 70-80℃ in presence of a Catalyst X,
    iv. Post completion of reaction, the product is again washed with some suitable solvent and
    v. the existing solvent ethyl acetate is completely distilled out (dry distillation),
    vi. the obtained residue is slurried in a suitable solvent and filtered,
    vii. the obtained crude is dried at 80-90℃ to obtained desired product.

    Also Read:

    Calculate quantity of moisture adsorbents required for packing 
    Design a decanter for workups


    As an engineer, first of all i need to check the properties of chemicals carefully and then their mutual interactions. if any abnormality is observed, then it should be resolved in the earlier stages itself.
    And as this is a safety management, we need to evaluate everything carefully, else it would end with disasters.

    Second thing is safety testing, need to list out them.
    As per above scenario, i need to check the properties of Solid reactant A.
    we need to check,
    a. Properties of solid RM's (DSC, MIE, bulk resistivity),
    b. Heat of reaction (RC) for initial reaction at 50-60℃,
    c. Decomposition study (DSC / ARC) for initial reaction,
    d. Decomposition study (DSC / ARC) for second reaction,
    e. Decomposition study (DSC / ARC / TSU) for dry residue after distillation,
    f. Decomposition study (DSC / ARC / TSU), Bulk resistivity, Burning test, Minimum ignition temperature using Airborne dust by BAM oven, Dust explosion test using Hartmann apparatus, Fall hammer test, MIE for final dry material.

    Now let me explain you in detail about the above mentioned testing:

    a. Solid RM testing:

    i. Decomposition of A through DSC - As operating temperature is 50-60℃, there shouldn't be any exotherms below 60℃, if any we have to check the energy/enthalpy associated with it and if the energy is below 50 J/g then it can be easily controllable, if in range of 50-150℃ some mitigations are required, if far above 150℃ then the reaction temperature need to be optimised to avoid exotherms.

    ii. MIE value of it - if the MIE value is below 3 mJ then we need to ensure proper earthing and continuity which can dissipate at any point of static generation.

    iii. bulk resistivity - if the resistivity is high, automatically the static will accumulate and will gain a potential to fire, usually the resistivity will be in range of 10^12 to 10^13 ohm-m.

    Below is the classification of resistivity:
    < 10^8         :  Conductive;
    10^8-10^10 :  Moderately conductive;
    > 10^10       :  Resistive;

    b. Heat of reaction (RC) for initial reaction at 50-60℃:

    Usually for semi-batch reactions, we'll prefer RC study, which will make us understand the rate of energy liberation or rate of energy intake.
    From an RC study report, we need to make a note of
    i. Heat of reaction per Kg of KSM,
    ii. Heat of reaction per Kg of final reaction mass,
    iii. Considering final mass, adiabatic temperature raise,
    iv. Thermal accumulation,
    v. Gas evolution (if any).

    Using this data, we have to calculate the MTSR (Maximum Temperature to Synthesis Reaction).
    MTSR = Operating temp. + (Thermal Accumulation x Adiabatic temp. raise)

    MTSR indicates maximum attainable mass temperature during a semi-batch reaction.

    Lets say, as per RC study,
    Heat of reaction be 800 KJ/Kg of KSM,
    Heat of reaction per Kg of final reaction mass be 100 KJ/Kg,
    Considering final mass, adiabatic temperature raise is 50 ℃,
    Operating temp. = 55 ℃,
    Thermal accumulation observed 30%;

    Now lets start our evaluation,
    Specific heat = 100 / 50 = 2 KJ/Kg.℃,
    MTSR = 55 + ( 30/100 x 50) = 70 ℃,

    Byhere evaluation of RC data is completed.
    Here i would like to clarify many guys about MTSR, many of the reports will interpret MTSR as,
    MTSR = operating temp. + adiabatic temp. raise;

    The above equation is also an correct one, because it means 100 % accumulation, now let me re-write it by considering 100% accumulation,
    MTSR = operating temp. + 1 x adiabatic temp. raise;

    Now look at it, both are same, but only difference is 100% accumulation (worst scenario) and the other is with observed accumulation during RC.

    And if someone asks me which to consider, i would prefer worst scenario i.e., 100% accumulation which might happen due to sudden dump of reagent B into mass, the reason is if we are safe even in the worst scenario, then there wont be any risk.

    Also Read:
    Calculate quantity of moisture adsorbents required for packing 
    Design a decanter for workups

    c. Decomposition study (DSC / ARC) for initial reaction:

    DSC curve will have plot of Enthalpy VS time / temp.,
    We need to list out the endotherms / exotherms and the energy associated with them.

    Whenever an endotherm is observed during reaction, the risk is not considerable, whereas if there is an exotherm, it should be considered and evaluated.

    Below is the classification of exotherms,

    Enthalpy: 0 - 50 J/g; Risk: not considerable;
    Enthalpy: 50 - 150 J/g; Risk: low/considerable;
    Enthalpy: 150 - 250 J/g; Risk: medium;
    Enthalpy: > 250 J/g; Risk: high;

    Lets say in our case, we have three exotherms,
    1st exotherm: Onset temp. 40 - 60 ℃; Enthalpy: 63 J/g;
    2nd exotherm: Onset temp. 140 - 187 ℃; Enthalpy: 30 J/g;
    3rd exotherm: Onset temp.  > 300 ℃; Enthalpy: 250 J/g;

    The risk of exotherms will be,
    1st exotherm: Low risk;
    2nd exotherm: Not considerable;
    3rd exotherm: High risk.

    Now the question is 'our reaction fall into which category risk ?',

    As per the RC study, MTSR with 30% accumulation is 70℃ and
    with 100% accumulation is 55 + 50 = 105℃;

    So in worst scenario, the maximum attainable temp. is 105℃ and we have 1st exotherm covered in the range. which is of low risk, hence it can be classified as low.

    Basically reactions are classified in 5 classes based on Stoessel's Criticality Index.

    If you can see, the first two classes reactions are of low risk,
    the next two classes reactions are of moderate risk, which are acceptable in plant scale with some mitigations;
    the final class i.e., 5 is not acceptable, because the probability of detecting the decomposition in plant scale is negligible.

    Let's suppose if the onset of decomposition is found to be nearby the MTSR, then it is required to perform ARC test, because ARC will be of high accurate when compared with DSC.

    Basically DSC will be performed in a Heat flux DSC and Power compensated DSC. The temperature raise will be in range of 3 - 5 ℃/min, whereas ARC will be performed in a bomb calorimeter with ~9 thermocouples connected to control the temperature raise. And the raise will be 0.001 ℃/min, which attributes high accuracy.

    For more about DSC Visit here: Perform and Evaluate DSC

    d. Decomposition study (DSC / ARC) for second reaction

    The second reaction is condensation with compound C for 6 hours at 70 - 80℃. So the subject reaction is a batch reaction where there is no dosing applicable.

    So there is no requirement for RC, but as we are performing maintenance for prolonged hours i.e., 6 hours, it is required to understand the thermal behaviour of reaction mass, hence it is required to perform DSC / ARC.

    Lets say we have performed DSC and below is the detailing,

    Two exotherms are observed,
    1st exotherm onset 160 - 187℃; enthalpy: 120 J/g;
    2nd exotherm onset 210 - 287℃; enthalpy: 48 J/g;

    We don't have the MTSR but still we need to judge the risk associated, so there comes the 100 K rule,
    Our operating temperature is 70 - 80℃, and as per 100 K rule the medium rated exotherm shouldn't lie within next 100℃ i.e., 80 + 100 = 180℃.

    In our case, there is an exotherm starting at 160 ℃ with an enthalpy of 120 J/g, so we are in moderate risk zone. So, we should make ready our mitigation plans like controlling the heat supply source temperature, ensuring coolants in place etc.

    Let's say if the same exotherm is observed at some 100℃, then it violates our 100K rule and also the risk is too high, now to confirm the onset once again we need to get ARC test performed. The ARC will give accurate onset, based on that the mitigation plans can be provided.

    e. Decomposition study (DSC / ARC / TSU) for dry residue after distillation,

    If there is any dry distillations in the process, then it is required to study the thermal behaviour of end residue as the scope for temperature raise will be high due to lack of solvent.

    Similar to previous section, the 100K rule should be verified for the dry distillation too. If not, then we have another option like reducing the operating temperature, as the solvents will easily boil at relatively lower temperatures under vacuum.

    Read more about lowering of boiling point here: Boiling point varies with reduced pressure

    f. Decomposition study (DSC / ARC / TSU), Bulk resistivity, Burning test, Minimum ignition temperature, Dust explosion test, Fall hammer test, MIE for final dry material.

    Burning Test:
    Initially sample shall be dried under vacuum and sieved and a strip will be formed with material over a ceramic plate. A heated coil shall be placed at one end of strip for 5 seconds. The behaviour shall be observed and burning class shall be given. Below is the classification:

    No ignition
    No spreading of fire
    Brief ignition, Rapid extinction
    Glows without flame
    Glowing without sparks
    Fire spreads
    Slow quite burning with flames
    Very rapid combustion

    Upto class 3 the risk is low, upon increase of risk above 3, mitigation plans to be evaluated, Class 6 materials are quite rare, if any then those to be avoided or to be handled under supervision using atmos bags.

    Minimum Ignition Temperature:
    Sample shall be dried under vacuum and sieved. A BAM oven is heated to 500. Switched off the heater and allowed the temperature to fall. Sample is blown in to the oven at interval of 10 and ignition of dust is observed. The lowest temperature at which ignition observed is reported as Minimum Ignition Temperature of airborne dust. 

    Dust explosion test using hartmann apparatus:
    Sample is dried under vacuum and sieved. Weighed amount of product is charged into a modified Hartmann tube of 1.2 L volume. The product is converted into a dust cloud in glass cylindrical tube with compressed air and electrodes with continuous spark is used as ignition source to ignite this dust cloud. Based on dust fire or extent of opening of the hinged cover rating 0, 1 or 2 are assigned. Test is repeated with varied weights of the sample.

    St 0H
    No fire or explosion
    St 1H
    Dust fire or mild explosion
    St 2H
    Violent explosion

    Most of the cases, materials shall be reported with St 2H class.

    Bulk resistivity :
    Sample is dried under vacuum. The sample is filled in the test cell to form a layer of 10 mm thickness. A current is passed through the sample at 100volts. The resistance of the sample is directly measured on megohmmeter.

    Observation (Resistivity)
    < 10^8 ohm-m
    Moderately Conductive
    10^8 – 10^10 ohm-m
    > 10^10 ohm-m

    Most of the materials will fall into resistive. Relaxation periods, Earthing continuity, usage of conductive materials for handling shall be employed to mitigate the risk.

    Minimum Ignition Energy:
    Sample is dried under vacuum and sieved. The product is converted into a dust cloud in glass cylindrical tube with compressed air. The spark for ignition is provided with moving electrodes assembly at different energy levels from 1mJ to 1000mJ. The energy just sufficient to ignite the dust under investigation is determined. This ignition energy is then successively halved with variation of the dust concentration and the ignition delay time in a series of tests until no ignition takes place in at least 10 successive experiments. The minimum ignition energy MIE lies between the lowest energy value at which ignition occurred and at the energy value at which no ignition observed for 10 successive experiments.

    As the MIE value increases, the risk of handling will reduce. To mitigate the risks, systems like multi channelling earth monitoring are employed.

    Fall hammer test:
    Sample is dried under vacuum and sieved. Fall Hammer weight of 5Kg is dropped from a height of 80cm corresponding to an Impact energy of 39.2 Nm onto a weighed sample of 100mg in Aluminium wraper. This is repeated for ten times. If detonation, sparks or heavy smoke is observed even once then it is considered as positive.

    If a process involves milling or micronization, then the test is performed to understand the impact. If it is negative then there is no risk involved. Else its better to avoid such operations.

    That's it ......!!!!

    This is the basic detailing of process safety in API industries, many more tests are there to further evaluate the manufacturing process.

    If any queries feel free to comment / reach me.

    Comments are most appreciated.....!!!

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    About The Author

    Hi! I am Ajay Kumar Kalva, Currently serving as the CEO of this site, a tech geek by passion, and a chemical process engineer by profession, i'm interested in writing articles regarding technology, hacking and pharma technology.
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