In wet granulation, drying is an important step because the granules must reach the required moisture level before milling, lubrication and tablet compression.

A common problem is low LOD after drying. The FBD cycle may have been completed as planned, but the tested granules show an LOD below the approved range.

For example, suppose the approved LOD range for a product is 1.5–3.0%, but the dried granules show an LOD of 0.7%.

This does not simply mean that the batch is “very dry and therefore better.”

The objective is to achieve the product-specific moisture range required for consistent processing and product quality.

What Is Low LOD After Drying?

LOD means Loss on Drying.

When the LOD result after drying is below the approved or established range, it may indicate that the granules have been dried excessively.

For example:

Approved LOD: 1.5–3.0%
Observed LOD: 0.7%

This result should be evaluated according to the approved specification, process documentation and investigation procedure.

There is no universal LOD value that is suitable for every pharmaceutical product. The appropriate moisture range depends on formulation, development data, and the manufacturing process.

FDA guidance also notes that LOD may be suitable for water determination in some products, while a more specific method such as Karl Fischer may be preferable in certain cases.

Why Is Very Low LOD a Problem?

It is easy to assume:

Less moisture = better drying = better granules

But pharmaceutical granules do not always behave that way.

Moisture can influence:

• Granule strength
• Granule porosity
• Compressibility
• Compactibility
• Tablet strength
• Disintegration
• Dissolution
• Lubrication behaviour
• Powder flow
• Downstream processing

The actual effect depends heavily on the formulation.

Research on wet-granulated pharmaceutical material has shown that residual moisture after drying can significantly affect tablet crushing strength.

Another study found that granule moisture and liquid-to-solid ratio affected tablet tensile strength and compressibility in continuous manufacturing.

So, the correct target is not minimum moisture.

It is controlled and reproducible moisture.

7 Common Causes of Low LOD After FBD

1. Excessive Drying Time

This is one of the most obvious causes.

Suppose the validated drying process normally reaches the required LOD within a defined time, but the batch continues drying significantly longer.

The additional drying can remove more moisture than intended.

For example:

Expected drying: 35 minutes
Actual drying: 55 minutes

If the process is sensitive to drying time, this additional exposure may contribute to an unnecessarily low moisture level.

However, the exact impact must be assessed against the product’s validated process.

2. High FBD Inlet Temperature

Higher drying temperature can increase the rate of moisture removal.

For example, if a process is designed around an approved temperature range and the actual inlet temperature is consistently higher than intended, the granules may lose moisture faster.

The investigation should compare:

• Set temperature
• Actual temperature
• Temperature trend
• Product temperature, where applicable
• Approved operating range
• Alarm history

Do not assume that a higher temperature automatically means better drying.

ICH Q8 uses drying as an example of a process where parameters such as initial moisture, temperature and particle size can interact and affect product behaviour.

3. Excessive Airflow

Airflow is necessary for fluidization and drying.

However, an inappropriate airflow condition can change the drying behaviour of the granules.

During investigation, review:

• Airflow setting
• Actual airflow
• Differential pressure
• Fluidization behaviour
• Filter condition
• Damper position
• Equipment alarms

The objective is not simply to maximize airflow.

The dryer should operate within the established process range.

FDA inspection guidance specifically identifies moisture uniformity as an important consideration in drying and notes that moisture problems can occur in FBD operations when granulation is not completely fluidized.

4. Low Initial Moisture Before FBD

The problem can sometimes begin during wet granulation.

Suppose the granulation process normally produces wet granules with a particular moisture condition, but the actual wet mass contains less liquid than expected.

The FBD then starts with less moisture to remove.

If the normal drying cycle is continued without considering the changed starting condition, the final granules may become excessively dry.

Therefore, investigation should include:

• Granulating liquid quantity
• Binder solution quantity
• Addition rate
• Granulation time
• Wet massing
• Granulation endpoint
• Wet granule condition

ICH Q8 specifically illustrates the interaction of initial moisture content with other drying parameters, demonstrating why drying should be understood as a complete process rather than as an isolated temperature/time operation.

5. Small or More Porous Granules

Granule size and structure can influence drying.

Smaller or more porous granules may dry differently from larger or denser granules.

Changes in:

• Impeller speed
• Chopper speed
• Granulation time
• Binder quantity
• Liquid addition
• Wet massing
• Screen size
• Milling conditions

can alter granule characteristics.

Research using pharmaceutical granules after fluid-bed drying has shown that granule size is an important factor in the drying process.

Therefore, if low LOD suddenly appears after a process or material change, granule characteristics should be reviewed.

6. Incorrect Drying Endpoint

Another possible cause is relying only on a fixed drying time.

For example:

“The FBD cycle is programmed for 40 minutes, so the batch is always dried for 40 minutes.”

This approach may not adequately account for variation in starting moisture or material characteristics.

Modern pharmaceutical process understanding increasingly considers property-based endpoint determination, including moisture measurement approaches such as NIR. Recent research has also evaluated moisture sensors and NIR for determining drying endpoints in commercial-scale FBD operations.

The approved process, however, should always be followed.

7. LOD Sampling or Analytical Issues

Not every unexpected low LOD result is necessarily caused by the FBD.

The laboratory and sampling process should also be reviewed.

Check:

• Sample identification
• Sample quantity
• Sampling location
• Sample container
• Sample handling
• Test method
• Instrument status
• Balance calibration/status
• Analyst activity
• Test temperature
• Test duration
• Calculation

A representative sample is particularly important because moisture may not be distributed perfectly throughout a batch.

FDA guidance emphasizes the importance of moisture uniformity at the drying endpoint.

Related Articles

Practical Example: Low LOD After FBD

Consider a wet-granulated tablet batch.

The approved moisture range is:

1.5–3.0% LOD

After completion of the FBD cycle, the laboratory reports:

LOD = 0.8%

The first reaction should not be:

“The granules are dry, so continue with compression.”

The result should be evaluated according to the site’s approved procedure.

Step 1 — Inform QA

The result is communicated to QA and the relevant Production and QC personnel according to the site’s procedure.

The batch remains under the appropriate status until the result is evaluated.

Step 2 — Verify the Laboratory Result

Review:

• Sample identity
• Test method
• Calculation
• Instrument status
• Analyst activity
• Any laboratory abnormality

If a genuine analytical error is identified, it should be handled through the approved laboratory investigation process.

Step 3 — Review FBD Parameters

Check the complete drying record.

Review:

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

Look for abnormal trends rather than checking only the final values.

Step 4 — Review Wet Granulation Parameters

Move backward in the process.

Check:

• Quantity of granulating liquid
• Binder quantity
• Addition rate
• Granulation time
• Impeller speed
• Chopper speed
• Wet massing time
• Granulation endpoint

The question should be:

Did the granules enter the FBD with less moisture than expected?

Step 5 — Check Granule Characteristics

Review:

• Granule size
• Bulk density
• Granule appearance
• Milling condition
• Fines
• Any change in granulation behaviour

If the granules were smaller or more porous than usual, this could have influenced drying behaviour.

What Problems Can Low LOD Cause During Compression?

The exact effect depends on the formulation, so it is incorrect to say that low LOD will always cause one particular tablet defect.

However, moisture can influence the way granules deform and compact.

Possible observations may include:

Poor Tablet Strength

Changes in granule moisture can affect tablet crushing or tensile strength. Experimental studies have demonstrated significant effects of dried granule moisture on tablet strength.

Increased Friability

If the formulation requires a particular moisture level for good bonding during compression, excessive drying may contribute to weaker tablets.

But this should be confirmed with product-specific data rather than assumed.

Changes in Disintegration

Granule porosity and moisture can influence tablet structure and water penetration.

Dissolution Variation

Changes in granule properties can influence tablet performance, including dissolution.

FDA guidance notes that particle size and granulation characteristics can affect tablet pore structure and dissolution.

Compression Behaviour Changes

The compression machine may require different force or may show changes in tablet hardness when granule moisture changes.

This is why moisture should be treated as an important process attribute rather than simply a laboratory number.

Low LOD vs High LOD After Drying

Both conditions should be controlled.

The important point is that the acceptable range is product-specific.

A value that is acceptable for one formulation may not be appropriate for another.

Can We Simply Add Moisture Back?

Generally, this should not be treated as a routine manufacturing shortcut.

If a batch has been excessively dried, adding water or another material simply to increase the LOD is not automatically acceptable.

Any reprocessing, rewetting, conditioning or other recovery operation must be supported by the approved procedure and appropriate technical and quality evaluation.

The decision should consider:

• Product formulation
• Approved process
• Validation status
• Stability
• Microbiological considerations
• Chemical stability
• Blend uniformity
• Reprocessing procedure
• QA assessment

Never create an unofficial “water addition” step simply to bring an LOD result back into range.

How to Prevent Low LOD After FBD

During Wet Granulation

• Maintain the approved liquid quantity.
• Control liquid addition rate.
• Follow the established granulation endpoint.
• Maintain consistent granulation parameters.
• Monitor wet granule characteristics.

During FBD Operation

• Follow approved inlet temperature limits.
• Maintain appropriate airflow.
• Maintain proper fluidization.
• Follow the approved drying cycle.
• Monitor relevant process trends.
• Avoid unnecessary extension of drying time.

During Sampling

• Follow the approved sampling procedure.
• Use representative sampling locations.
• Protect samples from environmental exposure.
• Send samples for testing according to the approved procedure.

During Process Review

Trend LOD results batch-to-batch.

For example:

Even before a formal failure occurs, this downward trend may justify investigation or process review according to the site’s procedures.

Trending is better than waiting for a batch to fail.

What Should Be Checked During a Low LOD Investigation?

A simple investigation framework is:

Material

Check:

• Raw material characteristics
• Granulating liquid
• Binder
• Initial moisture
• Granule size
• Granule density

Machine

Check:

• FBD condition
• Temperature sensors
• Airflow
• Filters
• Pressure
• Exhaust
• Alarms

Method

Check:

• Granulation parameters
• Drying parameters
• Drying endpoint
• Sampling procedure
• LOD analytical method

People

Check:

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

This approach helps identify whether the variation came from material, equipment, process, measurement or human activity.

Important GMP Point

Do not write a deviation investigation simply as:

“LOD was low because the product was over-dried.”

That is a conclusion, not necessarily a root cause.

A stronger investigation asks:

Why was it over-dried?

For example:

Low LOD → excessive moisture removal → drying continued beyond approved endpoint → endpoint determination/process control issue

Or:

Low LOD → unusually low starting moisture → variation during wet granulation → drying cycle not adjusted/controlled according to the approved process

The actual root cause must be supported by evidence from batch records, equipment data, analytical results and process history.

Conclusion

Low LOD after drying should not automatically be considered a sign of good drying.

In pharmaceutical manufacturing, the goal is to achieve the right moisture level, not simply the lowest possible moisture.

A proper investigation should move through the complete process:

Wet Granulation → Initial Moisture → FBD Loading → Airflow → Temperature → Drying Time → Drying Endpoint → Sampling → LOD Testing → Compression Performance

When low LOD is observed, check the complete process before deciding on corrective action.

The most important question is:

“Did the granules reach the approved moisture range without creating downstream quality problems?”

That is the GMP-focused way to look at drying.

References

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

FDA guidance discusses fluid-bed drying, moisture uniformity, LOD/moisture testing and the importance of controlling the drying endpoint.

ICH Q8(R2) – Pharmaceutical Development

ICH Q8 provides examples showing how drying parameters such as initial moisture, temperature and particle size can interact and influence pharmaceutical development and product quality.

PubMed – Effect of Dried Granule Moisture on Tablet Quality

Research has demonstrated that residual moisture after granule drying can significantly affect tablet quality attributes, including tablet crushing strength.

PubMed – Granule Moisture and Compression Properties

Research on continuous manufacturing found that granule moisture content can influence compressibility and final tablet tensile strength.

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.