In wet granulation, the Fluid Bed Dryer (FBD) is used to remove excess moisture from wet granules before milling and further processing.

One common problem observed during manufacturing is high LOD after FBD. The dryer cycle may be completed, but when the granules are tested, the LOD is still above the approved limit.

For example, suppose the approved LOD limit for a particular granulation is 1.5–3.0%, but the first sample shows 4.2%. The batch cannot simply be passed because the drying time has already been completed. The result has to be evaluated against the approved process, sampling procedure, analytical method, and product-specific requirements.

The important point is that FBD drying time alone does not prove that the granules have reached the required moisture level. The drying endpoint should be supported by appropriate process understanding and testing. ICH Q8 gives drying examples where moisture content is treated as an important process endpoint, and FDA inspection guidance also identifies moisture uniformity and drying endpoint as important considerations for wet granulation.

What Is LOD?

LOD means Loss on Drying.

It measures the amount of volatile material lost from a sample under specified test conditions. In many pharmaceutical materials, the major volatile component is water, but LOD is not automatically the same as specific water content. USP General Chapter <731> defines LOD as the amount of volatile matter driven off under the specified conditions.

Therefore:

LOD ≠ always pure water content.

If the manufacturing process requires specific measurement of water, a suitable water-specific method such as Karl Fischer may be more appropriate depending on the product and validated method. FDA guidance also notes that LOD can be suitable in some situations, while a specific water determination may be preferred in others.

What Does High LOD After FBD Mean?

High LOD after FBD generally means that the granules contain more volatile material than the approved or expected range.

For example:

Target LOD: 1.5–3.0%
Observed LOD: 4.1%

This indicates that the drying process may not have removed sufficient moisture, or that the result may not represent the actual condition of the whole batch.

Before immediately increasing the FBD temperature or extending the drying time, the reason should be understood.

Common Causes of High LOD After FBD

There is rarely one universal reason. The actual cause depends on the formulation, FBD design, loading quantity, process parameters and sampling method.

1. Insufficient Drying Time

The most straightforward reason is that the granules simply have not received enough effective drying.

For example:

• Wet granulation is completed.
• Wet granules are loaded into FBD.
• Drying is performed for 30 minutes.
• LOD is found to be 4.0%.
• The validated process normally requires moisture around 2%.

If the process parameters were otherwise normal, insufficient drying time may be one possible cause.

However, simply adding more time to every batch is not a proper permanent solution. The approved process and validated ranges must be considered.

2. Low Inlet Air Temperature

FBD drying depends strongly on the drying air conditions.

If the inlet temperature is lower than the approved operating range, the ability of the system to remove moisture may decrease.

For example, if the process was developed around an inlet temperature range of 50–60°C, but the actual temperature remains near the lower end or falls below the approved range, drying may take longer.

The exact temperature should always come from the product-specific BMR/BPR and validated process, not from a general industry number.

3. Low Airflow or Poor Fluidization

This is one of the most important practical causes.

The granules must be properly fluidized so that heated air can contact the material effectively.

If airflow is insufficient:

Poor fluidization → poor air-material contact → slow moisture removal → high LOD

A simple observation can sometimes provide an important clue.

If the product bed is not moving properly and parts of the material remain relatively stationary, drying may become non-uniform.

FDA inspection guidance specifically notes that moisture problems can occur in fluid-bed dryers when the granulation is not completely fluidized.

4. Excessive Batch Load

Suppose an FBD is designed and validated for a particular product load range.

If the quantity loaded is too high, the bed may become difficult to fluidize properly.

For example:

Validated load: 80–120 kg
Actual load: 130 kg

The larger quantity does not automatically mean that the batch will fail, but it can affect airflow, fluidization and drying behaviour if it is outside the approved operating range.

Therefore, batch loading should always be checked during investigation.

5. High Initial Moisture in Wet Granules

Sometimes the problem starts before the granules even enter the FBD.

If excess granulating liquid was added during wet granulation, the starting moisture load becomes higher.

For example:

Normal water addition → normal drying requirement

but

Excess water addition → greater moisture removal requirement

The investigation should therefore not stop at the FBD.

Check:

• Quantity of purified water/ granulating liquid added
• Actual versus theoretical quantity
• Addition time
• Granulation endpoint
• Mixing time
• Granulation parameters
• Wet granule condition before FBD

Research has demonstrated that both wet-granulation parameters and residual moisture after drying can affect granule and tablet properties.

6. Large or Dense Granules

Granule characteristics can affect drying.

Large or dense granules may release moisture more slowly than smaller, more porous granules.

This is why particle size and granule structure should not be ignored during an investigation.

A change in:

• impeller speed
• granulation time
• binder quantity
• binder concentration
• liquid addition
• wet massing
• screen size

can change the characteristics of the wet granules and consequently influence FBD drying.

7. FBD Filter or Airflow-Related Problems

The condition of the FBD should also be checked.

Possible issues include:

• Filter bags not functioning properly
• Filter choking
• Incorrect filter shaking
• Damaged filter
• Airflow restriction
• Exhaust-related problems
• Instrument malfunction
• Improper damper position
• Air handling system problem

The machine may show a temperature value that looks normal while actual fluidization or airflow is not satisfactory.

Therefore, temperature alone should not be used to judge FBD performance.

8. Improper Sampling of Granules

This is a very important point that is sometimes overlooked.

Imagine the batch contains 100 kg of granules.

A sample is collected from only one location and gives:

LOD = 4.5%

But another location may contain much drier granules.

This raises the question:

Is the entire batch wet, or was the sample not representative?

Sampling location, sample quantity, sample handling and timing should therefore be reviewed.

FDA guidance highlights moisture uniformity as an important consideration in drying operations.

A high LOD result should not automatically be treated as a complete-batch condition without following the approved sampling and investigation procedure.

9. Delay Between Sampling and Testing

Moisture can change after drying.

If granules are exposed to the environment for an extended period before testing, they may absorb moisture depending on their formulation and environmental conditions.

For example:

FBD completed → sample collected → sample left open for a long period → LOD tested

This can potentially influence the result.

During an investigation, review:

• Sampling time
• Testing time
• Sample container
• Container closure
• Sample transportation
• Exposure to room conditions
• Laboratory handling

10. LOD Analytical Error

Manufacturing should not always be blamed for an unexpected LOD result.

The laboratory side also needs to be checked.

Possible factors include:

• Incorrect sample preparation
• Incorrect test temperature
• Incorrect weighing
• Instrument issue
• Balance problem
• Moisture analyser issue
• Incorrect test program
• Method deviation
• Analyst error
• Improper sample handling

The approved analytical method and laboratory SOP should be followed.

USP <731> specifies that LOD is determined under defined conditions, which is why the test conditions themselves matter.

Practical Example of High LOD After FBD

Consider a tablet batch manufactured by wet granulation.

The approved process has an LOD range of:

1.5–3.0%

After FBD drying, the first sample gives:

LOD = 4.2%

Step 1 — Inform QA

The result is immediately communicated to the responsible QA and relevant production/laboratory personnel according to site procedure.

The batch should remain under appropriate status until the result is evaluated.

Step 2 — Check the LOD Result

Review:

• Sample identification
• Test method
• Calculation
• Analyst details
• Instrument status
• Standard/reference requirements
• Any laboratory abnormality

Step 3 — Check FBD Parameters

Review the complete drying cycle:

• Inlet temperature
• Outlet temperature
• Airflow
• Product temperature, where applicable
• Drying time
• Filter shaking
• Pressure/differential pressure, where applicable
• Alarm history
• Actual versus set values

Step 4 — Check Wet Granulation

The investigation should move backward.

Check:

• Granulating liquid quantity
• Binder preparation
• Addition rate
• Granulation time
• Impeller/chopper parameters
• Wet mass appearance
• Any process interruption

Step 5 — Review Loading

Confirm whether the quantity loaded into the FBD was within the approved range.

Step 6 — Evaluate Sampling

Check whether the sample was collected according to the approved procedure and whether the location was representative.

Step 7 — Identify the Root Cause

Suppose the investigation shows that:

• Water addition was within limit.
• Wet granulation parameters were normal.
• FBD temperature was normal.
• Drying time was normal.
• But airflow was below the approved range due to an equipment-related problem.

In this case, poor fluidization caused inadequate drying.

The root cause is therefore much stronger than simply writing:

“Drying time was insufficient.”

A good investigation should explain why the granules remained wet.

Related Articles

Want to understand the complete granulation and drying process? Read these related Pharma GMP Guide articles:

• Wet Granulation in Pharmaceutical Manufacturing – Learn the complete wet granulation process, important parameters, and common problems.
• Over Drying vs Under Drying in Pharmaceutical Granules – Understand how excessive or insufficient drying can affect granule and tablet quality.
• Fluid Bed Dryer (FBD) in Pharma – Learn the working principle, process steps, critical parameters, and precautions of FBD.
• Common Tablet Defects in Pharmaceutical Manufacturing – Learn how granule moisture and other process variables can contribute to tablet defects.
• LOD in Pharmaceutical Manufacturing – Understand Loss on Drying, its importance, testing, and interpretation in pharmaceutical manufacturing.

Can We Simply Increase FBD Drying Time?

Not automatically.

This is one of the most common mistakes in handling high LOD.

For example:

“LOD high, so run FBD for another 20 minutes.”

That action may or may not be acceptable depending on the approved process and investigation procedure.

Over-drying can also create problems. ICH Q8 provides an example where operating outside the drying design space can create excessive impurity formation at one extreme and excessive particle attrition at the other.

Therefore, the target should not be:

“Make the granules as dry as possible.”

The target should be:

“Achieve the product-specific moisture range that provides the required quality.”

High LOD vs Low LOD After FBD

Both conditions can create problems.

The actual effect depends on the formulation.

Studies have shown that dried-granule moisture can influence tablet properties such as crushing strength and other performance attributes.

Another pharmaceutical study notes that excessive moisture can contribute to sticking/picking, while very low moisture may contribute to problems such as lamination or friability, with some products having a relatively narrow acceptable moisture range.

How to Prevent High LOD After FBD

Prevention starts with controlling the complete process rather than focusing only on the dryer.

During Wet Granulation

• Maintain accurate granulating liquid quantity.
• Control addition rate.
• Follow approved granulation parameters.
• Avoid unnecessary variation in wet massing.
• Maintain consistent binder preparation.
• Monitor the granulation endpoint.

During FBD Loading

• Maintain the approved batch load.
• Avoid overloading the bowl/container.
• Ensure proper product distribution.
• Confirm equipment readiness before starting.

During Drying

• Maintain approved inlet temperature.
• Maintain appropriate airflow.
• Confirm proper fluidization.
• Monitor relevant temperature and pressure parameters.
• Follow the validated drying cycle.
• Perform LOD/moisture checks according to the approved procedure.

During Sampling

• Follow the approved sampling plan.
• Collect representative samples.
• Minimize unnecessary exposure of granules to the environment.
• Send samples to the laboratory promptly.

What Should Be Checked During a High LOD Investigation?

A practical investigation can be divided into four areas:

1. Material

• Raw materials
• Binder
• Granulating liquid
• Initial moisture
• Granule size/density

2. Machine

• FBD condition
• Airflow
• Filters
• Temperature sensors
• Pressure
• Exhaust system
• Equipment alarms

3. Method

• Granulation parameters
• Drying parameters
• Sampling procedure
• LOD test method

4. People

• Operator activity
• Parameter recording
• Sampling practice
• Analyst activity
• Any procedural deviation

This approach helps prevent the investigation from becoming a simple “machine problem.”

Important GMP Point: Do Not Guess the LOD Limit

There is no universal FBD LOD limit such as 2% or 3% that applies to every pharmaceutical product.

One product may have an acceptable range of 1–3%, while another may require a different range.

The limit should come from the approved product/process documentation, development data, validated process, specification or applicable procedure.

ICH Q8 emphasizes understanding the relationship between process parameters and critical quality attributes rather than relying on arbitrary operating numbers.

Conclusion

When LOD is high after FBD, the first reaction should not be:

“Increase drying time.”

Instead, ask:

Why did the granules retain excess moisture?

Check the complete chain:

Wet granulation → initial moisture → FBD loading → airflow → fluidization → temperature → drying time → sampling → laboratory testing

This approach gives a much stronger GMP investigation.

A good pharmaceutical manufacturing process does not depend only on achieving a particular drying time. It depends on understanding the relationship between drying conditions, granule properties, moisture content, and final product performance.

High LOD after FBD is therefore not just a laboratory number. It can be an indication of variation somewhere in the manufacturing or testing process, and the investigation should identify the actual cause before corrective action is taken.

Reference & GMP Resources

FDA – Oral Solid Dosage Forms: Pre/Post Approval Issues

FDA guidance covering oral solid dosage manufacturing, granulation, in-process moisture testing, process validation, manufacturing procedures, and equipment controls.

ICH Q8(R2) – Pharmaceutical Development

ICH guidance explaining pharmaceutical development, critical process parameters, critical quality attributes, design space, and process understanding.

FDA – Q6A: Specifications, Test Procedures and Acceptance Criteria

Useful reference for understanding pharmaceutical specifications, test procedures, and acceptance criteria.

USP <731> – Loss on Drying

Official USP reference for the Loss on Drying test and the specified conditions used for determining loss on drying.

Saurabh Saini

Saurabh Saini is a pharmaceutical warehouse professional with over 3 years of hands-on experience in GMP-regulated manufacturing. He currently works as a Junior Officer – Warehouse at Abbott Healthcare and previously served as an Assistant Officer at Mankind Pharma. His expertise includes Raw Material Receipt, Raw Material Dispensing, Warehouse Operations, Inventory Management, GMP documentation, and SOP implementation. Through Pharma GMP Guide, he shares practical GMP knowledge, SOPs, regulatory guidance, and pharmaceutical best practices to help students and industry professionals.