COMPLIANCE CASE STUDIES

White Spots on Tablets—

Compliance Case Study #8
Paul L. Pluta

“Compliance Case Studies” discusses compliance situations useful to practitioners

in compliance and validation. Each case presented deals with a specific compli-
ance problem, elements of which are described to demonstrate strategy to solve
compliance problems. We intend this column to be a useful resource for daily work
applications. The main objective of this column: Useful and practical information.
Reader comments, questions, and suggestions are needed to help us fulfill our
objective for this column. Case studies illustrating compliance issues submitted by
readers are most welcome. Please send your comments and suggestions to journal
coordinating editor Susan Haigney at [email protected].
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KEY POINTS DISCUSSED

The following key points are discussed:
• A case study involving unexpected white spots on a previously prob-
lem-free blue tablet product is described.
• Initial speculation was that the white-spot problem was either grease
spots or microbial growth.
• FD&C Blue #2 was the colorant in the tablet formulation.
• Chemical change (chemical reduction in alkaline pH) of the blue dye
was determined to be the source of the white spots.
• Manufacturing personnel indicated that there was potential for incor-
rectly assembled milling equipment causing materials to
not be milled.
• Comparative testing of control tablets and experimental tablets under
accelerated temperature conditions indicated that the unmilled excipi-
ent was the cause of the distinct white spots in the tablets. FD&C
Blue #2 was chemically incompatible with the alkaline excipient.
• A new milling equipment assembly procedure and a new milling pro-
cess was developed.
• Training of manufacturing personnel was conducted.
• Process validation was completed.
• All investigations, analyses, and conclusions were documented to
close the corrective action and preventive action (CAPA). All investi-
gation documentation was reviewed by US Food and Drug Adminis-
tration investigators.

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• Additional monitoring of manufacturing was con- aqueous binder solution containing a

ducted to confirm successful corrective action. polymeric binder.
• This case study further demonstrated highly unlike- • Wet granulation was dried using a fluidized
ly causes of a serious compliance problem—an bed dryer.
inactive excipient and incorrect equipment setup. • Dried granules were sized using a sifting appa-
• Compliance personnel must keep an open mind ratus. Oversized granules were milled using an
without preconceived beliefs when investigating impact mill.
problem situations. • Remaining formulation ingredients were milled
using an impact mill. This included FD&C Blue
INTRODUCTION #2 as colorant in the formulation.
This case study was provided to the Journal of GXP Com- • All ingredients were mixed in a twin-
pliance by a reader who requested anonymity. The event shell blender.
described is an actual occurrence. • Tablets were compressed.
A small molecule pharmaceutical company had pro-
duced an uncoated blue tablet product for many years. A COMPLIANCE EVENT
large number of product complaints were unexpectedly A small molecule pharmaceutical company had
received from customers. Complaints described distinct produced an uncoated blue tablet product for many
white spots on the blue tablet product. The cause of the years. The product was a relatively large volume Rx
problem was not easily determined. Speculation ranged product. Product attributes and process perfor-
from grease spots to microbial growth. mance were reliable and reproducible. Annual
This discussion provides: product reviews and process monitoring for several
• Process description background. The manufactur- years indicated no ongoing problems or process
ing process for the tablet product is briefly described. trends. A large number of product complaints were
• Compliance event. A description of the event, the unexpectedly received from customers. Complaints
key issues to be addressed, and applicable current described easily visible distinct white spots on the
good manufacturing practice (CGMP) requirements. tablet product. Complaints were received on several
• Investigation. Interviews and actions conducted to different batches of product, but not all lots had
investigate the event. complaints. Manufacturing personnel speculated
• Discussion. Key information, activities, the cause to be grease spots from the compressing
and analysis. process, a problem occasionally observed in the
• Corrective action and preventive action (CAPA). past. Samples of problem tablets were received.
Actions and improvements implemented. Speculation from the appearance of the spots was
• Post CAPA. Lessons learned. Maintaining validation that microbial growth was occurring on tablets. No
and performance. instances of microbial growth had previously been
reported for this or any other products at the site.
PROCESS DESCRIPTION BACKGROUND
The manufacturing process in this case study involved What are the Issues?
manufacture of an uncoated blue tablet product. The There were several critical issues to be investigated
manufacturing process for the product comprised a as follows:
typical wet-granulation process. The following de- • What was the composition of the white spots?
scribes the manufacturing process: • What was the source of the white spots?
• The active pharmaceutical ingredient (API) and • Why were white spots not detected in
other inactive excipients were milled using an tablet inspection?
impact mill. • Why did the white spot complaints
• Wet granulation was performed using an suddenly occur?

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 Paul L. Pluta

• Did manufacturing operators follow batch record in the past. The manufacturing staff comprised experi-
directions properly? enced operators and some newly trained operators. All
processes were considered to be well established and
CGMP Requirements problem-free. There were no training issues or varia-
Relevant CGMP (1) requirements potentially applicable tion in performance thought to be associated with the
to the above event are listed as follows: manufacturing procedure.
• Subpart D–Equipment.
• 211.63. Equipment Design, Size, QA Personnel Interviews
and Location. QA personnel reviewed inspection records from
• 211.65. Equipment Construction. problem lots. Tablet inspection occurred periodically
• Subpart F–Production and Process Controls. throughout the compressing process. Laboratory per-
• 211.110. Sampling and Testing of In-process sonnel conducted a final tablet inspection of a com-
Materials and Drug Products. posite sample in the analytical laboratories—different
• 211.113. Control of people in different areas inspected the tablets. All
Microbiological Contamination. tablet inspection records were acceptable. No instances
• 211.134. Drug Product Inspection. of white spots on tablets were reported.
• Subpart J–Records and Reports.
• 211.180. General Requirements. Technical Personnel Investigation
• 211.188. Batch Production and Technical personnel conducted parallel investigations
Control Records. addressing possible causes of the white spot problem.
• 211.192. Production Record Review. These included microbiological testing, elemental
analysis, changes in formulation materials, and FD&C
INVESTIGATION Blue #2 chemistry. As investigations indicated poten-
Investigation and ultimate resolution of this event tial causes for the problem, leads would be pursued.
required involvement of several groups. These included Microbiological testing. White spots were removed
personnel involved in the incident (manufacturing and from the tablet surface and submitted for microbiologi-
quality assurance [QA]) and technical personnel respon- cal testing. No microbial growth was observed. The
sible for the manufacturing formulation and process. moisture content of the tablets would not support
There were many details that needed to be investigated microbial growth. Microbial growth was eliminated as
or confirmed. Personnel from all groups were inter- a cause of the problem.
viewed and interacted to address the above issues. Elemental analysis. White spots were removed
from the tablet surface and submitted for microscopic
Product Testing elemental analysis. Samples of greases used in the
Products with white spots were submitted for analyti- tablet compressing process were also submitted for
cal testing for all product attributes. All test results comparison. No evidence of contamination by grease
were acceptable. Products were fully potent regarding was observed. The elemental composition of the
active drug. Dissolution test data were acceptable and white spots was identical to the tablet formulation
showed no slowing of the product dissolution perfor- components. Grease spots were eliminated as a cause
mance. Despite the white spots, there did not seem to of the problem.
be any adverse effects on the other product attributes. Changes in formulation materials. The purchasing
history of all product ingredients was reviewed. There
Manufacturing Personnel Interviews were no changes in materials. There were no changes
Manufacturing personnel affirmed that all batch record in suppliers of formulation materials. All materials and
directions were performed as specified. Manufacturing suppliers had a good quality history. Material changes
operators had manufactured this product many times were not a cause of the problem.

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FD&C Blue #2 chemistry. Technical personnel in- • Control tablets. Product tablets were manufac-
vestigated the chemical properties of FD&C Blue #2, tured with correctly milled material.
the blue colorant used in the formulation. Chemical • Problem tablets. Product tablets were manufac-
change (chemical reduction in alkaline pH) of the tured with improperly milled material.
blue dye was determined to be the source of the white
spots. FD&C Blue #2 is a widely used synthetic blue Comparative testing of control tablets and experi-
dye and is used in the dying of blue jeans. FD&C mental tablets under accelerated temperature condi-
Blue #2 is also known as Indigotin, Indigo dye, and tions was then conducted. Samples of respective tablets
E132 in Europe. In alkaline pH, this dye is chemi- were also stored under refrigeration. Tablets manu-
cally reduced to indigo white or leuco-indico, which factured with the improperly milled material stored
is white in color. The formulation of the blue tablet at high temperature developed distinctly visible white
product contained excipients that maintained an spots. It was concluded that the large particle-size ex-
alkaline pH in the tablet. This pH was necessary for cipient was the cause of the distinct white spots in the
API product stability. The alkaline pH of the tablet tablets. Comparison of tablets stored under accelerated
core caused reduction of the blue dye to indigo-white, conditions to the refrigerated tablets indicated that the
which in turn caused white sports. However, because refrigerated tablets were slightly darker in color than
of the sudden change in the appearance of the tablet the heated tablets. This result indicated that the FD&C
when there had been no changes in the formulation, Blue #2 was chemically incompatible with the alkaline
materials, or manufacturing process was unknown. excipient. However, as long as the alkaline excipient
Manufacturing equipment. When problems with was finely milled, color change was slow, diffuse, and
the blue dye were identified, manufacturing manage- generally unnoticeable to the naked or untrained eye.
ment further probed FD&C #2 handling and process-
ing. Discussions with manufacturing operators indi- DISCUSSION
cated that there was potential for improperly assembled Information obtained through interviews and subse-
milling equipment. It was possible that the milling quent experimental work enabled good understanding
screens were not correctly installed. If this occurred, of the problem, determination of the root cause, and
unmilled particles would escape the milling chamber ultimate corrective and preventive action. Original
and would not be milled. Correct equipment setup was speculation as to potential causes of the problem were
necessary for good milling. tested and disproven. Investigative and experimental
Experimental trails were designed to test this hy- work by the technical group conclusively determined
pothesis, as follows: the root cause of the white spot problem. FD&C Blue
• Control milling. The impact mill was assembled #2 dye in the formulation was chemically reduced to
properly. Alkaline excipient was successfully indigo white, a white substance. Large particles of
milled. Sieve analysis was conducted to character- alkaline excipient, which had not been milled, caused
ize the milled material. the localized chemical reaction resulting in the forma-
• Problem milling. The impact mill was assem- tion of the distinct white spots. The alkaline excipient
bled incorrectly. Alkaline excipient was milled. in the formulation was not milled because the milling
Unmilled powder was observed escaping the screens were incorrectly installed in the impact mill.
milling chamber. Sieve analysis was conducted Comparative testing conclusively proved that the im-
to characterize the milled material. Data indi- properly milled alkaline excipient was the cause of the
cated that a small percentage of particles were not white spot problem. Comparison of heated tablets to
milled, resulting in relatively large alkaline par- refrigerated tablets confirmed the susceptibility of the
ticles in the tablet core. It was hypothesized that FD&C Blue #2 to alkaline chemical reduction. As long
these large particles reacted with blue dye to cause as the alkaline excipient was finely milled, lightening of
white spots in the blue tablets. the blue tablets was not noticeable. The importance of

68   Journal of GXP Compliance

 Paul L. Pluta

the milling process, and especially of correct installation Training

of screens in the impact mill, was clearly demonstrated. All personnel were trained on the new equipment
assembly procedure and milling process procedure.
CORRECTIVE AND PREVENTIVE ACTIONS The importance of the milling process in manufac-
The following CAPA and associated activities turing this product and the correlation of improper
were conducted: milling to the white spot problem were well commu-
• New milling equipment assembly procedure nicated. Training on proper setup of milling equip-
• New milling process ment was applicable to all products manufactured at
• Process validation the site. Essentially all products included milling as
• Training part of their manufacturing process.
• Documentation
• Communication to other sites Documentation
• Other similar products manufactured at the site. All work associated with the original validation was
completed. All investigations, analyses, and conclu-
New Milling Equipment Assembly Procedure sions were documented to close the CAPA. Develop-
The importance of equipment assembly in the ment of the new manufacturing process including
milling process indicated that greater control was trial runs was documented and filed in the validation
required. A new and more detailed assembly pro- library as supporting information for the validation
cedure was implemented. Also, the manufacturing process qualification (PQ) runs. US Food and Drug
supervisor checked and approved (signature) the Administration investigators visited the manufacturing
assembly of the mill by the manufacturing operator. site in response to customer complaints. All investiga-
Signoff by the supervisor was added to the manufac- tion documentation was reviewed by FDA investiga-
turing batch record. tors. No FDA 483 observations were issued.

New Milling Process Communication to Other Sites

A new milling procedure and control test was also The incident described herein was communicated to
implemented for this product. The alkaline ex- other global sites licensed to manufacture this product.
cipient that was determined to be the cause of the
white spot problem was milled twice through the Other Similar Products Manufactured At The Site
impact mill. After milling, the milled material was The milling problem described was unique to the
sampled and tested for passage through an appro- specific product. Other products did not contain
priate screen. Any unmilled particles would not the same colorants or formulation containing the
pass through the screen. If unmilled particles were alkaline excipient.
observed, the process was stopped and a supervisor
was immediately notified. POST CAPA MONITORING
Additional monitoring of manufacturing was con-
Process Validation ducted to confirm successful corrective action. A final
Product manufactured using the new milling pro- report summarizing all monitoring data was prepared
cess was validated. The amount of alkaline excipient after three months (many lots) of manufacturing. No
comprised a very low percent of the formulation. instances of improper machine set up were observed.
The amount of potentially smaller particle size No milling difficulties were reported. No customer
of this ingredient did not impact the particle size complaints on product lots that were manufactured
distribution in the blended granulation and did not after the process changes were received. Corrective
affect the flow properties or compressing process for action was successful.
the product.

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COMPLIANCE CASE STUDIES

CONCLUSIONS same product. No other products manufactured at

A case study describing a compliance event in which the site were susceptible to this problem. Additional
a large number of product complaints involving dis- monitoring of manufacturing was conducted. No
tinct white spots on a tablet product was discussed. instances of improper machine set up were ob-
The cause of the problem was not easily determined. served. No milling difficulties were reported. No
Speculation on the problem source ranged from complaints on product lots that were manufactured
grease spots to microbial growth. The product had after the process changes were received. Corrective
been successfully manufactured for many years action was successful.
without any incidence of this type of complaint. This case study demonstrated highly unlikely causes
Technical personnel conducted parallel investiga- of a serious compliance problem. Chemical proper-
tions addressing possible causes of the white spot ties of inactive ingredients are not a typical cause of
problem. These included microbiological testing, el- problems. The milling process is also not considered
emental analysis, changes in formulation materials, to be a problematic manufacturing process. These
and chemistry of FD&C Blue #2, the colorant in the two unlikely causes combined to cause a very signifi-
formulation. Chemical change (chemical reduction cant problem. Compliance personnel must be aware
in alkaline pH) of the blue dye was determined to that all ingredients in the formulation, not just the
be the source of the white spots. All other potential active drug, may have significant negative effects on
problem causes were disproven. the product. Compliance personnel must not assume
Manufacturing personnel determined that there simple manufacturing processes to be problem free.
was potential for improperly assembled milling The inactive ingredients are important components
equipment causing material that was not milled. of products. The performance of even presumably
This in turn caused formation of the white spots. mundane processes such as milling must be seriously
Experimental trials confirmed this hypothesis. This considered. Compliance personnel must keep an open
work also indicated that the FD&C Blue #2 was mind without preconceived beliefs when investigating
chemically incompatible with the alkaline excipient. problem situations.
However, as long as the alkaline excipient was finely
milled, color change was slow, diffuse, and generally REFERENCE
unnoticeable. The importance of the milling pro- FDA, Code of Federal Regulations, Title 21, Food and Drugs, Part
cess, and especially of correct installation of screens 211, Current Good Manufacturing Practice for Finished Phar-
in the impact mill, was clearly demonstrated. maceuticals, 43 Federal Register 45077, Sept. 29, 1978. GXP
CAPA and associated activities conducted in-
cluded a new milling equipment assembly procedure
ABOUT THE AUTHOR
to prevent improper equipment setup, a new milling Paul L. Pluta, Ph.D., is a pharmaceutical scientist with extensive
process, process validation of the new process, train- technical and management experience in the pharmaceutical
ing of manufacturing personnel, and documenta- industry. He is editor in chief of the Journal of GXP Compliance and
tion of all activities. The documentation was almost the Journal of Validation Technology. Dr. Pluta is also adjunct associ-
ate professor at the University of Illinois College of Pharmacy in
immediately useful when FDA audited the site in
Chicago, Illinois USA. He is the editor of and contributed chapters
response to customer complaints to the Agency. to Cleaning and Cleaning Validation, published by PDA and Davis
This event and its corrective actions were commu- Healthcare International in 2009. He may be reached by e-mail at
nicated to other corporate sites manufacturing the [email protected].

70   Journal of GXP Compliance