Cost Reduction by Minimizing Solvent Losses in API Manufacturing

1. Cost Reduction by
Minimizing Solvent Losses In
API Manufacturing
Dr.Gangadhar Akkinapalli

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Efficient solvent recovery is a challenging task in the API / Pharmaceutical
industry. Whether it is a boon or bane depends on the approach of the industry and by the
attitude of the management towards solvent recovery. If the industry and its management
takes corrective and preventive steps to arrest solvent losses and is committed to efficient
solvent recovery then it is a boon for that industry. Conversely, it is a bane. If the industry
and its management do not take corrective measures, then it fails to compete in the
domestic as well as in the international markets.
In many an industrialist’s perspective, the corrective measures involve a lot of
investment, resulting in fixed cost increase as it requires provision of additional facilities.
But it is a false notion. When solvent losses are arrested, the variable cost shall come down
drastically, which, in turn, boosts the profitability of industry and the fixed costs spent on
the facilities for solvent recovery shall be paid back in a reasonable period, depending on
the cost contribution of the solvent.
Many industries who are in regulatory markets assume that usage of recovered
solvents in API manufacturing is unacceptable to regulatory agencies. This is not true.
Most regulatory inspectors (or) auditors consider this as one of the critical areas and they
are only interested in the process of recovery and the purity of recovered solvents.

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They are not against the usage of recovered solvents in the API manufacturing
process. The fact is that one should ensure that the recovery method is effective and should
provide a high purity solvent, without any cross-contamination and without any
problematic impurities in it.
If solvents are not recovered efficiently, the disadvantages are four-fold:
 It leads to high cost of production;
 The industry becomes globally uncompetitive;
 It results in financial losses, making the firm sick; and
 It also increases pollution loads due to VOC increase
Most of the times, the variable cost increase in manufacturing is due to poor
recovery of various solvents used in the manufacturing process. Many an industry has now
realized the importance of recovery of solvents in the manufacturing process to make their
firms globally competitive. However, there are no standardized techniques available for
identifying the losses of solvents during manufacture.
I would like to share with the pharma industry a modus operandi adopted by me
in various API industries for improving recovery of solvents. I am not sure whether this is a
complete remedy for all the solvents or not. However, I would like to present the steps taken
for efficient solvent recovery as a guidance tool.

4. For better recovery of solvent, we need to identify the potential areas first where
the solvent loses would be possible. To identify the major causes, we can use a simple Cause
– Effect diagram / Fish bone analysis. This technique was devised by Professor Ishikawa of
Tokyo University, Japan and has been widely used in industries for:
 Improving quality of products;
 Lowering of production costs;
 Increasing productivity;
 Elimination of accidents;
 Minimizing delays in delivery;
 Arresting machine breakdowns;
 Reducing pollution load; and
 Controlling attrition rate (turnover of workers)
This technique enables clear understanding of the linkage between the various
causes and the end result. This chart is also known as ‘Ishikawa Diagram’ or ‘Fish bone
chart’based on its shape
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5. In cause-effect diagram, the ‘Effect’ means the result of work (here the effect is
solvent loss) and the ‘Cause’ means an element or factor which may influence the effect
(Here the cause is the area where solvent loss is possible or the factor that is responsible for
loss). This influence could be either direct or indirect.
The leader should consider the following points while making a ‘cause and effect
diagram.’
*Use of 4 M’s and/or 7 factors as an aid to find causes (various reasons
contributing for solvent loss);
*‘4M’ stands for Man, Machine, Material and Method and 7 factors stand for
Man, Machine, Material, Method, Measurement, Jig and Transportation
*Should not consider only the views of an expert while making cause effect
diagram. An expert in a field sometimes is too confident of his knowledge about his job and
may commit mistake in the belief that there is no fact other than what he knows. This results
in charting of only his knowledge.
*Involving all the people concerned with the problem to identify the causes.
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6. How to make a Cause and Effect Diagram?
The leader should arrange a meeting comprising a group of people (an
appropriate size of the group should be 5 to 10) concerned with the problem and follow the
steps given below to prepare a Cause - Effect Diagram
Step 1: Define and clarify the problem
The leader should define and clarify the problem (Here it is solvent loss) to find
out the causes and effects of the problem in the production process. The problem /subject
can not merely be quality such as % defective, strength variation, etc., but also economic
characteristics such as yield, energy consumption, production rate, efficiency etc., The
problem must be stated precise. Bad quality is not a good way of expressing a problem. It
should be like ‘Variation in weight’or ‘deviation in pH value’etc.
Step 2: Gather Members for Discussion
After choosing the people who have knowledge and experience about the problem,
gather them in a meeting hall.
Step 3: Brainstorming
‘Brainstorming’ is a common method to bring forth ideas from the members who
are all involved with the problem. The leader should ensure that the people who are familiar
with the brainstorming join the discussion. To get effective ideas from these people, the
following method is recommended:
 Present the title of the problem, which is to be taken for discussion on the black-
board on the wall of the meeting room, in large letters for everybody’s view.
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7.  The leader should give a few sheets of white paper to every member and ask them
to write down as many causes as they can think of. (Usually 15 to 20 minutes is enough to
write down the ideas)
 The leader then should ask each member to present his ideas. When this process is
going on, the leader should write all ideas presented by members on the blackboard for
everybody’s view. By looking at the ideas presented on the blackboard, the members also
develop new associated ideas. It may take several rounds to finish the presentation of ideas
Step 4: Draw the Cause and Effect Chart
The leader should classify the causes obtained through brainstorming into several
large groups. Then he should make sub-groups of causes in the large group.
He should prepare the chart on a sheet of paper in the presence of the members. Then he
should ensure that: (a) sub- causes have been properly classified so that practical steps can
be taken to solve the problem; and (b) are there any items which have no effect on the
problem?
Step 5: Determine importance of Significance of Causes
The leader should determine the significance of the causes written on the chart
through discussion. It is preferable to express the significance in terms of amount of money.
If it is not possible, he should classify the causes into three groups: A, B and C, in
accordance with significance to the effect.
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8. For example, in case of solvent loss (Effect), the leader should classify the areas
(Causes) similar to that of ABC analysis used in inventory management, in accordance
with significance to the effect.
Where solvent losses are expected to be more – A (Most significant)
Where solvent losses are expected to be medium – B (Medium significant)
Where solvent losses are expected to be negligible – C (Non-significant)
The classification of areas (Causes) differs from industry to industry, depending on the
facilities available
Step 6: Final step
Ensure that all the causes are included in the chart. When you are convinced that
the relationship between cause and effect has been expressed in a remarkable manner,
mount the chart at a place accessible to everybody
Step 7: Corrective actions
After identification and segregation of causes (areas), plan for corrective
measures by evaluating the investments required based on the cost-benefit analysis (CBA).
The areas (causes) where one should concentrate are most significant & medium significant
areas. In case of solvent loss (Effect), one should concentrate on A and B areas to maximize
the recovery. Once it is achieved, one should also concentrate on non-significant areas to
reduce VOC (Pollution load).
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9. Step 8: Preventive actions
Take preventive actions also, if possible, wherever necessary and wherever some
kinds of losses are expected / possible.
Advantages of efficient solvent recovery
Reduction of variable cost leading to a low cost product;
Low pollution due to reduction in evaporation loss;
VOC reduction resulting in a better pollution control;
Enabling the firm to increase its profit margin; and
Enabling the firm to be globally competitive.
A list of causes i.e., areas (common to most of the solvents and most of the
industries) are identified and segregated. Refer to the typical fish bone diagram for solvent
loss. The causes and sub-causes are listed along with corrective and preventive actions
(CAPA) in Table-1. This gives an outline on the subject and it is a bird’s eye view.
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Sub-cause
Mode of storage:
The storage of solvents is
normally done either in
tanks or in drums
Improper storage of drums
CAPA
Drum storage vs. tank storage:
Drum storage
Drums Occupy more space. Unsafe. Loss of solvent due to
damage of drum. Evaporation loss. Handling Loss
Tank storage (Tank farm)
Occupies less space
Safe
Minimum loss
Less evaporation (can be arrested using water sprinklers).
Hence, storage of solvent(s) in tanks is advisable for better
control over storage loss.
Till the solvent is consumed in manufacturing, the drums
must be stored in a shed. They must not be stored under the
sun. If solvent drums are not stored properly, drums may
get damaged due to bulging. Sometimes this leads to
damage at the bottom, resulting in leakage of solvent.
After some time, to your surprise, the drum will be empty.
Table 1a: Causes for solvent loss during storage & CAPA

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Sub-cause:
Improper handling
of drums
Improper storage of
wet cakes during
manufacture
Spillage due to
improper handling
CAPA:
When solvent is stored in drums, handling poses a problem. They
have to be transported to the usage place very carefully in a drum
trolley using manpower. If the solvent is stored in a tank,
manpower requirement is negligible and it can be transferred using
dedicated lines to specified receiver.
During manufacture, many intermediates are isolated as wet
cakes and stored in drums/carboys. If they are not stored
properly, or if wet cakes are exposed to open atmosphere, the
solvent present in wet cakes gets evaporated and the wet cakes
get dried. This results in loss of solvent. Poses pollution
problem
Improper handling of drums also results in loss of solvent due to
spillages
Table 1a: Causes for solvent loss during storage & CAPA

13. 13
Sub-cause
Vacuum transfer
Wrong selection of
transfer pump/
poorly designed
pump
Transfer pump gland
leakage
Poor pipeline design
/Pipeline leakage
Incompatibility of
MOC of pump and
pipeline with the
solvent(s)
CAPA
Do not use vacuum for transfer of solvents. Use pumps for
transfer. During vacuum transfer, the solvent loss is more
Use suitable centrifugal pumps with proper design
Transfer pump / circulation pump must be leak-proof. Use
mechanical sealed pump to prevent loss of solvent
Design the pipeline accordingly. While designing the pump,
carefully calculate the head and discharge. The pipeline should be
capable of discharging the required quantity of solvent
See the compatibility of pump and pipeline MOC with that of
solvent for whose transfer it is being used.
Table 1b: Causes for solvent loss during transfer & CAPA

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Sub-cause
Loss during transfer
of solvent with loose
hose pipes
Improper sucking /
pumping
Jacketed vacuum
trap to vacuum
pump
CAPA
Do not use loose hose pipes with binding wire etc., for transfer of
solvent. Transfer through permanent pipelines
Solvent loss is possible if sucking/pumping is not done properly,
while transferring solvent from drums to receiver / reactor. Take
precautions while sucking/pumping
Arrangement of jacketed vacuum trap with chilled water helps to
collect the solvent vapors during vacuum transfer
Table 1b: Causes for solvent loss during transfer & CAPA

15. 15
Sub-cause
Use of open
crystallizers
pH adjustment keeping
reactor manhole open
CAPA
Do not use open crystallizers. In most of the small scale
industries, use of open crystallizers for crystallization of
products is a common phenomenon. In such cases the solvent
is exposed to open atmosphere. This is an unsafe operation and
also leads to solvent loss during operations. Better to avoid
open crystallizers while doing crystallization of products in a
solvent. In case of water there is no problem. However,
contamination is possible. Not acceptable as per cGMP.
Exposure of reaction mass to open atmosphere during pH
adjustment leads to solvent loss due to evaporation.
Contamination is possible and not acceptable as per cGMP.
Table 1c: Causes for solvent loss during process & CAPA

16. 16
Sub-cause
Hold up in leaf filters
Solvent loss during
centrifuging
Loss of solvent
during layer
separation
CAPA
In most of the carbon treatment operations, the hold ups in leaf
filters are neglected. This is an important area where the
operator has to concentrate. If the hold ups are not collected
properly, the company loses not only the solvent, but also the
product present in it in dissolved form. One can go for most
advanced filters instead of leaf filters where losses are minimal.
No. of centrifuge lots: Reduce centrifuge lots by increasing the
capacity of centrifuge, if required or utilize the maximum
capacity of centrifuge. When no. of lots increases, no. of
washings with solvent increases and hence loss increases.
Loss during cake washings: Do not wash the cakes by keeping
centrifuges open. Use spray nozzles provided for washing the
cakes. It requires less solvent for uniform cake washing.
Wherever possible go for closed filtration using ANF (Agitated
Nutsche Filter).
Solvent loss along with product is possible during separation of
layers (organic layer, a mixture of solvent & product, and
aqueous layer resulting in a product’s manufacture), if organic
layer is not separated properly.
Table 1c: Causes for solvent loss during process & CAPA

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Sub-cause
Loss of solvent in
aqueous layer
Loss during
exothermic reactions
Gasket leakage at
manhole
Reactor bottom
valve leakage
Gland leakage of
reactor
Improper insulation
to vapor line
CAPA
Solvent loss is possible in aqueous layer, depending on that
particular solvent’s solubility in water. This problem can be
solved by settling the aqueous layer for more time
Solvent loss is more during exothermic reactions, if they are not
controlled. One should design the equipment accordingly.
Use suitable gaskets, preferably made of Teflon which has
resistance to wear and tear, to arrest leakages.
Replace with efficient & effective bottom valve.
Do not use sub-standard make bottom valves
Ensure good gland packing with a preventive maintenance
schedule or use mechanical seals wherever possible
Vapor line insulation integrity has to be checked at a pre-defined
time interval
Table 1c: Causes for solvent loss during process & CAPA

18. 18
Sub-cause
Ineffective heat
exchanger/Poor
design/ Heat
Exchanger with
insufficient heating
surface area
Insufficient cooling
of Heat Exchanger/
Fouling of heat
exchanger
CAPA
Heat exchanger design plays an important role. The heat
exchanger has to be designed carefully. One should not oversize
the heat exchanger. It not only increases the capital cost, but also
increases the running cost by consuming more energy. At the
same time one should not go for undersized heat exchanger as it
again leads to solvent loss during distillation / processing /
manufacturing. Hence design heat exchangers with suitable
heating surface area. Use efficient heat exchangers like spiral
heat exchanger and plate heat exchanger, wherever necessary
The insufficient cooling of heat exchanger is normally due to
scaling. All of us know that the scale formation in a heat
exchanger will result in energy loss as well as solvent loss. Hence,
the heat exchanger should be cleaned as per the pre-determined
preventive maintenance schedule for better cooling capacity. One
should not forget that the cooling tower water parameters have to
be maintained strictly and also regularly to blow-down the
cooling tower water.
Table 1d: Causes for solvent loss during distillation & CAPA

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Sub-cause
Vapor loss from Vent
Improper/ Incomplete
distillation leading to
loss in residue
Overflow from
receivers (insufficient
capacity)
Non-jacketed receiver
CAPA
Vent condensers to be installed with chilled water facility for
collection of vapors. This will help us in increasing the recovery
of solvent
While recovering the solvent by distillation from corresponding
MLR, incomplete distillation leads to loss of solvent in the
residue. This operation has to be carried out meticulously.
This happens when solvent is collected more than the capacity
of receiver. This problem can be solved by arranging overflow
lines
A jacketed receiver should be kept while distilling solvent for
efficient recovery
Table 1d: Causes for solvent loss during distillation & CAPA

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Sub-cause
No proper control of
steam
More volume in the
reactor
No chiller
Insufficient cross
sectional area and
short length of vapor
line
Lack of frequent
hydraulic test
CAPA
Steam should be controlled during distillation. It means a
solvent has to be distilled in a controlled manner
Taking more volume in a distillation reactor (more than the
defined/designed capacity) will sometimes lead to bumping,
which, in turn, results in loss of solvent. This is also not a safe
operation
Absence of chiller leads to solvent loss. Addition of chiller to
heat exchanger shall arrest loss during distillation
Vapor line should be designed based on the capacity of the
reactor. There should not be any design problem. Over-batch
size is also a problem whenever vapor line is not as per the
standard requirements.
Hydraulic test should be done as per a pre-defined schedule to
prevent the leakages, which, in turn, lead to solvent loss
Table 1d: Causes for solvent loss during distillation & CAPA

21. GLOSSARY
1. ABC Analysis: This is popularly known as “Always Better Control”. It is an analytical method
of inventory control which aims at concentrating efforts in those areas where attention is required
most.
2. CBA (Cost-benefit analysis): The cost benefit analysis is a technique used for analyzing investment
and for rating the alternative investment opportunities, as well as for ranking such opportunities on
thebasis of therate of return to investment.
3. Fixed Cost: Cost on fixed factors is called fixed cost. Fixed cost includes costs on
capital, land and salaries of top managers who are permanent employees. Fixed cost
does not change with the change in production.
4. Variable Cost: Cost on variable factors is called Variable cost. Variable cost is the cost
which varies with the level of output. Variable cost includes cost of raw materials,
electricity charges, wages etc. Variable costs change with change in production.
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For further questions or clarifications, you may reach at
E: dragangadhar@rediffmail.com