# Presentation: 092093

## FDA CGMP China Training ProgramDecember 5-7, 2005Ying Jie Convention CenterBeijing University Beijing

**Solid Oral Dosage Forms**
**Nicholas Buhay**
**Deputy Director**
- Division of Manufacturing & Product Quality
- Office of Compliance, CDER, FDA

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Solid Oral Dosage Forms

- Discussion of Manufacturing Considerations and Current Good Manufacturing Practice

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## FORMS

- Powders
- Pills
- Troche
- Capsules
- Tablets

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Most Common Dosage Forms

- Convenient
- Relatively Stable
- Easily Administered
- Palatable
- Flexible

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Capsules

- Hard Gelatin
- Soft Gelatin

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Hard Gelatin Capsules

- Empty Capsule Storage
- Controlled temperature and humidity
- Too moist - capsules become tacky
- Too dry - capsules become brittle and change dimensions
- 30 to 45% R.M. ideal

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Operations

- Rectify the capsule
- Separate body from cap
- Fill the body
- Replace the cap

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Capsule Filling Machine

- Hand Operated
- Semi-automatic
- Fully automatic

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Slide 9

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## Slide 10

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## Process Variables

- Speed
- Humidity
- Bulk Powder Level
- Weight Variation
- Gelatin Moisture Content

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Compressed Tablet

- Un-coated
- Immediate Release

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Multiple Compressed

- Layered
- Tablet Within a Tablet
- Two Part
- Three Layer

- Compression Coated
- Function as Film/Sugar Coated

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Repeat-Action

- Active ingredient in the tablet core and in the coating.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Delayed-Action/Enteric Coated

- Coating protects core in the stomach
- Drug released in the upper GI tract after the stomach

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Film Coated

- Solvent Based
- Aqueous Based
- Alternative to Sugar Coated

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## INGREDIENTS

- Active
- Drug Substance

- Non-Active
- Diluents
- Binders
- Lubricants
- Disintegrants
- Coloring
- Flavoring
- Antiadherents
- Glidants

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Drug Substance

- Fully Characterized
- Physical  Specifications (Including Particle size distribution, density, isomerism and Morphology)

- Chemical Specifications (Including Impurity and Degradation Profile)

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## DILUENTS

- Lactose
- Starch
- Mannitol
- Calcium Sulfate
- Sorbitol

- Dicalcium Phosphate
- Kaolin
- Sodium Chloride
- Powdered Sugar
- Microcrystalline Cellulose

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## DISINTEGRANTS

- Starch
- Microcrystaline Cellulose
- Alginic Acid
- Gums
- Crospovidone

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Binders

- Starch Paste
- Glucose
- Gelatin Solution
- Acacia
- Sucrose
- Sodium Alginate

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## LUBRICANTS

- Magnesium Stearate
- Calcium Stearate
-  Talc
- Stearic Acid
- Sodium Lauryl Sulfate
- Sodium Acetate

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Observations

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -)    Testing standards for raw materials used in the manufacture of *****  40 mg tablets do not include specifications for physical characteristics.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -)     ***** raw material is not sufficiently characterized to determine its suitability for the manufacturing process. Various lots have passed all acceptance criteria, but have been identified as the causative factor in granulation and tableting deviations.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -)  .....The affect of particle size distribution, surface area and the particle morphology of the bulk drug substance, on the granulation process were not fully evaluated.....

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## There was a failure by QA to identify two separate lots of diluted Isosorbide Dinitrate bulk drug substance, received from the supplier in the same shipment...

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -)    The investigation into the acquisition and release of aluminum stearate of the wrong grade obtained from an unapproved source failed to identify that the wrong grade of material was ordered from the vendor. 

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## GRANULATING

- Wet Granulation
- Direct Compression
- Dry Granulation
- Slugging
- Roll Compaction

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Wet Granulation

- Advantages
- Improved Compressibility
- Improved uniformity
- Decreased segregation
- Flexibility

- Disadvantages
- Process complexity
- Cost
- Possible affect on drug substance

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Wet Granulation Manufacturing Steps 

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Wet Granulation

- Specific Manufacturing Instructions
- Amounts, Rates and Timing of Granulating Fluid Additions
- Mixer Speeds and Configuration
- Specified End Points - Motor Load, Appearance, Texture

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## FDA 483 Observation

- ...some granulation batches have required on the spot changes in established procedures for water addition and/or mix time to compensate for over and under granulation problems, the addition of a wet milling step or hand processing to break up lumps in over granulated batches, an additional drying step...

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Dry Granulation

- Useful when ingredients are sensitive to moisture or heat
- Blended ingredients are either compressed into “slugs” or roll compacted into “sticks” or sheets
- Slugs or sticks are screened/milled
- Granulation is blended with lubricant and disintegrants then compressed

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Roller Compactor

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

**Notes:**
The Roller Compactor is a versatile densification and dry granulation machine that produces uniform compacted sheets with consistent hardness and increased density by compacting powdered material between two uniquely designed patented rolls. Free flowing granules for automatic packaging, compact granules for reduced packing sizes, and granules for high speed tableting or encapsulation are produced with consistent dust free purity and size. 
A tapered screw feeder inside the hopper precompacts and deaerates the powder for optimum product feeding. The screw feeder delivers deareated powder into the roll nip area and seal system. Roll seal system consists of top seal and side seals to confine powder to the roll nip area, and to minimize leakage of uncompacted powder.
Three types of rolls provide maximum versatility for the particular material to be compacted. The DP and DPS series feature concave-convex roll surfaces with an outer rim, assuring even material feed and pressure distribution on the roll surface.
The compacted sheets are milled to produce granules of the desired mesh size.

## Direct Compression

- Ingredients are milled and/or screened, then mixed, then compressed into tablets.
- Few Manufacturing steps
- Greater potential for segregation

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Mixers & Blenders

- Pony/Planetary Mixer
- High Shear Mixer
- Ribbon Blender
- Screw Blender
- Tumble Blenders
- Twin Shell
- Double Cone
- Drums
- Other

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Mixing Process Validation

- Validation of the reliability of mixing operations is a very significant control expected
- Sample from the blender (if possible)
- 10 individual assays
- Sample size
- Approximate unit dose

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Planetary Mixer

- Good horizontal mixing
- Cross contamination risk
- Poor vertical mixing

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Slide 40

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## Slide 41

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## Ribbon Blender

- Horizontal and vertical mixing
- Dead zones
- Cleaning issues

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Slide 43

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## Slide 44

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## Slide 45

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Screw Blenders

- Three Distinct Intermixing Action
- Screw produces lifting action
- Orbiting screw moves material from the walls of the blender into the center of the vessel
- Material lifted by the screw gravitates downward
- No picture

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Tumble Blenders

- Shell blenders
- Twin Shell and Double Cone
- Low energy mixing
- clumping and segregation
- Working capacity
- Cleaning
- Liquid Dispersion Granulation

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Slide 48

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## Slide 49

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## Slide 50

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## Slide 51

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## High Shear Mixers

- Very efficient
- Ideal for wet granulation
- Amount and addition rate of granulating fluid must be strictly controlled
- End points can be measured

- Single pot production
- Heat
- Cleaning

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Slide 53

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## Slide 54

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## OTHER BLENDERS

- Drum
- Bags

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Inspection Observations

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## d) there were no blend time studies conducted to assure uniformity of granulation for the pre-blend or final blend steps...In addition, production batch records do not specify a finite time for blend steps.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## b) one of six granulation samples obtained from the blender, at final blend step, assayed below specification.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -) Content uniformity of the preservative was not included in the validation study for ***.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -)    During the processing of  *** 500mg tablet batch ***, an operator was observed inverting a drum of granulation several times prior to placing it above the tablet press granulation hopper.  This step is not part of the established process, but is reportedly common practice.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -)    *******  40 mg tablets are not manufactured in accordance with the approved filed process.  The current manufacturing process includes an additional 5 minutes of blending with intensifier bar prior to the granulation step, an additional 3 minute blending step (drum mix) during the tableting operation, and pre-compression and dissolution evaluation steps, none of which are represented in the filed process.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## DRYING

- Fluid Bed
- Tray
- Vacuum

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Fluid Bed Drying

- Efficient
- Uniform drying
- Process Variables
- Temperature
- Air velocity
- Filter pore size

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Fluid Bed Granulating

- Process Variables
- Droplet size and spray rate
- Inlet air temperature, humidity and velocity
- Location of spay nozzle

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Oven/Tray Drying

- Drying is less uniform than with fluid bed
- End point determination
- Cross contamination issues
- Cleaning

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Vacuum Drying

- Jacketed tumble dryer
- Heat applied to vessel walls
- Vacuum draws off moisture/solvent

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Slide 67

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Slide 68

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Milling

- Process Variables
- Feed rate
- Inlet feed throat design
- Blade type
- Rotor speed
- Screen type
- (Overhead)

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Transfer & Storage

- Post blending segregation
- Floor vibration
- Chutes and collars
- Equipment Vibration
- Segregation ????

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Compression

- Start up tablets
- In process testing
- hardness
- friability
- size
- shape
- disintegration
- thickness

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Tablet Presses

- Single Punch
- Rotary Press
- High Speed Rotary Press
- Multi-layer Rotary Press

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Slide 73

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Tooling

- Quality Control
- Accountability
- unique identifier
- security

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Slide 75

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## Slide 76

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Problems

- Sticking and Picking
- granulation moisture
- lubricant
- punch face

- Capping
- Fines
- Air
- punch-die clearance

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Problems

- Lamination
- Tooling
- granulation procedure
- formulation
- increase binder
- lubricant

- Chipping & Cracking
- tooling
- granulation
- fines
- granule size

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Common controls

- Hardness
- Force required to break a tablet

- Friability
- Ability to withstand abrasion and trauma without crumbling

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Common controls

- Disintegration
- The time it takes for a tablet to disintegrate in an aqueous medium

- Dissolution
- How the formulation releases the drug

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Inspection Observations

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## The investigations into a capping problem associated with seven production batches of XXX Tablets identified by MDIR's for one year are incomplete, in that;  there was no evaluation of the granulation nor of the raw materials used. 

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## The manufacturing process for XXX Extended Release Tablets is not validated in that :a) the 45 station Stokes BB2 rotary tablet press (firm's ID # xxx ) was not qualified to assure the capability and controls for this piece of equipment were suitable to meet requirements established for manufacture of this product.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## MDIR's were not generated, nor investigations conducted to determine cause, identity of content, and quantity of "chunks" of granulation  which had to be occasionally removed from the tablet press screen during compression of xxx, batch xxx, nor  of "lumpy" granulation observed in the hopper of the press during granulation of xxx, batch xxx. 

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -)   Development history supports an in-process disintegration limit lower than the current value of < 15 min.  An unusual dissolution profile in a development batch was associated with in-process disintegration times > 9min.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -)    The ***** 40mg tablet manufacturing process is not validated in that: a) Tableting parameters are set batch to batch based on pre-compression dissolution test results.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## b) Critical physical characteristics of raw materials have not been identified.c) Validation lots did not include specifications for the physical characteristics of blends and granulations.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## d) Final blend samples taken for physical characteristics analysis were composite.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -)    The agency was not notified, in accordance with NDA Field Alert reporting requirements, when it was determined that lot **** failed dissolution testing at the 1 month stability station. 

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -) The operating speed for the Perry Powder Filler when filling XXX is listed as 95 bottles per minute (BPM) in the Line Set-up Standard Sheet, which is outside the 80 to 90 BPM range used in the validation batches.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## COATING

- Protect drug from the environment
- Mask taste
- Improve appearance
- Separate ingredients
- Provide multiple release  profiles

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Equipment

- Standard coating pan
- Perforated coating pan
- Fluidized bed

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Standard Pans

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Slide 94

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Perforated Pans

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Fluid Bed

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Types

- Film
- Enteric
- Sugar

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Film Coating Materials

- Polymers - 	Hydroxypropyl methylcellulos 				Povidone         						Polyethyleneglycol
- Enteric Materials -	Cellulose acetate phthalate

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Sugar Coating Materials

- Sealant - Shellac
- Sugar - Syrup and color

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Process Variables

- Pan design
- Pan speed & load
- Air quality
- Temperature

- Airflow rate
- Spray rate
- Spray pattern
- Nozzle to bed distance

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## There are no written SOP's  for conducting batch record reviews to assure consistency and completeness of those reviews...

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## d. A sticky note, attached to the official lab report, both dated with the same day, contained unacceptable test results of an individual tablet relative to a dissolution profile test conducted during the initial validation batch xxx, for product XXX. The values for this tablet were not included on the final lab report.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -)    80% of the Aluminum Stearate used in the formula for ***** lot ***** was an unapproved grade obtained from an unapproved source.  This lot has been distributed.  The following two lots, ***** & *****, which were manufactured using 100% of the unapproved material were rejected for failing to meet specification.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## -)  There  was no investigation conducted following the rejection of86 kg of XXX 40mg tablets from lot *****  (a post validation lot) when the 2 hour compression trial sample failed dissolution testing; there was also no QA Management evaluation of the incident or its impact on the validation status of the process.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## The local Quality Unit review has failed to assure the accuracy and completeness of validation reports, manufacturing documents, and analytical reports. For example:...

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## The local QA unit failed to follow the procedure (***.*) to notify senior corporate officials of significant quality issues so that resources could be allocated to resolve problems...

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Laboratory procedures do not provide for the expeditious analysis of stability samples that require multi stage testing.  For example,  stage one  dissolution testing for stability sample *** was initiated on August 9, but stage three testing, indicating a stability failure, was not completed until  October 5.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Specifically, the manufacturing process for lots of  *** mg tablets manufactured between *** and *** was not validated in that approximately 9 of 39 lots were rejected due to dissolution failures. Changes made to the manufacturing process during this time did not resolve the dissolution failures. Approximately 21 lots manufactured during this time were released for commercial distribution.

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Summary

- Process Analysis
- Process Variables
- Process Controls

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Summary

- Evaluate material
- Evaluation of site for cross-contamination
- Consider operations (steps) in process
- Consider equipment for operations
- Determine process controls
- Demonstrate process reliability (validation)
- Commit to continuous monitoring of manufacturing experience

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## Inspection References

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURER'S - CGMP'S October, 1993

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT AND VALIDATIONJanuary, 1994 

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES May 1987

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## GUIDE TO INSPECTIONS OF PHARMACEUTICAL QUALITY CONTROL LABORATORIES July, 1993

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## EXPIRATION DATING AND STABILITY TESTING FOR HUMAN DRUG PRODUCTS 

**Inspection Technical guide 41 **
**(****http://www.fda.gov/ora/inspect_ref/itg/itg41.html)**

- Oral Solid Dosage Forms/Michael O'Meara/ 2004

## CGMP Guidance:  Answers to Frequently Asked Questions

**Notes**
- _[Human Drug CGMP Notes](http://www.fda.gov/cder/dmpq/cgmpnotes.htm)__ (3/1995-7/2000) _
- Human Drug CGMP Notes (1/1993-12/1994)
- [_[CNOTES vol. 1 no. 1 Feb 1993](http://www.fda.gov/cder/dmpq/CNOTES%20vol%201%20no%201%20feb%2093%20.pdf)__]  _
- [_[CNOTES vol. 1 no. 2 May 1993](http://www.fda.gov/cder/dmpq/CNOTES%20vol%201%20no%202%20may%2093.pdf)__]   _
- [_[CNOTES vol.1 no. 3 Sept 1993](http://www.fda.gov/cder/dmpq/CNOTES%20vol%201%20no%203%20sep%2093.pdf)__]   _
- [_[CNOTES vol.1 no. 4 Dec 1993](http://www.fda.gov/cder/dmpq/CNOTES%20vol%201%20no%204%20dec%2093.pdf)__]   _
- [_[CNOTES vol. 2 no. 1 Mar 1994](http://www.fda.gov/cder/dmpq/CNOTES%20vol%202%20no%201%20mar%2094.pdf)__]   _
- [_[CNOTES vol. 2 no. 2 Jun 1994](http://www.fda.gov/cder/dmpq/CNOTES%20vol%202%20no%202%20jun%2094.pdf)__]    _
- [_[CNOTES vol. 2 no. 3 Sep 1994](http://www.fda.gov/cder/dmpq/CNOTES%20vol%202%20no%203%20sep%2094.pdf)__]    _
- [_[CNOTES vol. 2 no. 4 Dec 1994](http://www.fda.gov/cder/dmpq/CNOTES%20vol%202%20no%204%20dec%2094.pdf)__] _
***►******TO FIND, GO TO WEBSITE:  ***_[http://www.fda.gov/cder/dmpq/index.htm](http://www.fda.gov/cder/dmpq/index.htm)_
**Other Resources**
- _[Guidance for Industry: CGMPs (Pharmaceutical CGMPs for the 21st Century) ](http://www.fda.gov/cder/guidance/guidance.htm#CGMPs)_
- _[Questions and Answers on Current Good Manufacturing Practices (cGMP) for Drugs](http://www.fda.gov/cder/guidance/cGMPs/default.htm)__ (Posted 8/4/2004) _
***►******TO FIND, GO TO WEBSITE:  ***_[http://www.fda.gov/cder/guidance/cGMPs/default.htm](http://www.fda.gov/cder/guidance/cGMPs/default.htm)_

## Good Luck!!

- Think soundly
- Operate under control

- Oral Solid Dosage Forms/Michael O'Meara/ 2004