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Use of natural colors: experience and views in pharmaceutical and dietary supplement industries

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Use of natural colors: experience and views in pharmaceutical and dietary supplement industries

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USE OF NATURAL COLORS: EXPERIENCE AND VIEWS IN PHARMACEUTICAL
AND DIETARY SUPPLEMENT INDUSTRIES

by

Alexa E. Smith

A Dissertation Presented to the
FACULTY OF THE USC SCHOOL OF PHARMACY
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF REGULATORY SCIENCE

December 2020

Copyright 2020 Alexa E. Smith

ii
DEDICATION
This work is dedicated to my family, Don, Cadera and Lucy, who supported me through this
long journey and to my parents, Anthony and Carole Graffeo, who put me on this path from the
beginning.

iii
ACKNOWLEDGEMENTS
This dissertation is the result of many years of research and study that would not have been
possible without the assistance of the USC staff, my fellow students and my colleagues. I would
like to particularly thank my advisor, Dr. Frances Richmond, Ph.D., who steadfastly kept me on
course during the research and preparation of this dissertation. Her knowledge and guidance
were instrumental in the completion of this work and my own personal growth through the
process. I would also like to specifically thank my colleagues at IPEC Americas for their
participation in my focus group and who provided invaluable feedback on the survey. I would
like to acknowledge and thank my many colleagues at Colorcon who have provided guidance
and support throughout this process but I would like to give a special thanks to David Schoneker.
Dave has been a mentor and friend to me for many years and I credit him with sparking in me a
passion for regulatory affairs and supporting my career in a way that has eventually led to the
completion of this dissertation. Finally, I would like to thank my fellow cohort member, friend
and sometimes roommate, Catherine Sheehan, who always encouraged me to keep going.

iv
TABLE OF CONTENTS
DEDICATION .................................................................................................................... ii
ACKNOWLEDGEMENTS .............................................................................................. iii
LIST OF TABLES ......................................................................................................... viii
LIST OF FIGURES .......................................................................................................... ix
ABSTRACT ...................................................................................................................... xi
CHAPTER 1. OVERVIEW ........................................................................................ 1
1.1 Introduction .................................................................................................... 1
1.2 Statement of the Problem ............................................................................... 3
1.3 Purpose of the Study ...................................................................................... 4
1.4 Importance of the Study ................................................................................. 5
1.5 Limitation, Delimitations, Assumptions ........................................................ 6
1.6 Organization of Thesis ................................................................................... 7
CHAPTER 2. LITERATURE REVIEW .................................................................... 8
2.1 Evolution of Color for Pharmaceutical Purposes ........................................... 8
2.2 The Role and Regulation of Color ............................................................... 10
2.2.1 The Uses of Color ........................................................................... 10
2.2.2 Regulation of Color ........................................................................ 12
2.2.2.1 United States ...................................................................... 12
2.2.2.2 European Union ................................................................. 15
2.2.2.3 The Precautionary Principle .............................................. 16

v
2.2.3 Synthetic Colors and Behavioral Research ..................................... 19
2.2.4 Recent Legislative Developments .................................................. 21
2.2.5 Other Issues Related to the Use of Natural Colors ......................... 23
2.3 Framing the Study of the EU Regulations on Colors ................................... 27
2.4 Summary and Research Direction ................................................................ 30
CHAPTER 3. METHODOLOGY ............................................................................ 32
3.1 Introduction .................................................................................................. 32
3.2 Initial Survey Development ......................................................................... 32
3.3 Focus Group ................................................................................................. 33
3.4 Focus Group Results .................................................................................... 33
3.5 Selection of Respondents ............................................................................. 35
3.6 Survey Deployment ...................................................................................... 36
3.7 Data Analysis ............................................................................................... 36
CHAPTER 4. RESEARCH RESULTS .................................................................... 37
4.1 Analysis of Survey Results .......................................................................... 37
4.2 Respondent Characteristics .......................................................................... 37
4.3 Experience with Color Selection and Decision Making .............................. 40
4.4 Experience with Selection of Natural or Synthetic Colors .......................... 44
4.4.1 Natural Color Selection .................................................................. 44
4.4.2 Synthetic Color Selection ............................................................... 47
4.5 Impact of Southampton Study ...................................................................... 51

vi
4.6 Effectiveness and Utility of the Current Regulations .................................. 55
4.7 Views on Consumer Preference ................................................................... 60
4.8 Development of Regulations ........................................................................ 62
CHAPTER 5. DISCUSSION .................................................................................... 68
5.1 Overview ...................................................................................................... 68
5.2 Methodological Considerations ................................................................... 68
5.2.1 Limitations ...................................................................................... 68
5.2.1.1 Availability of Participants ................................................ 68
5.2.1.2 Survey Methodology ......................................................... 69
5.2.2 Delimitations .................................................................................. 71
5.3 Consideration of Results .............................................................................. 72
5.3.1 Protection of Human Health ........................................................... 72
5.3.2 Balancing Cost and Access ............................................................. 74
5.3.3 Establish Fair Trade Practices ........................................................ 78
5.4 Concluding Thoughts ................................................................................... 80
REFERENCES ................................................................................................................. 82
APPENDIX A ................................................................................................................... 93
APPENDIX B ................................................................................................................. 101
APPENDIX C ................................................................................................................. 107
APPENDIX D ................................................................................................................. 110
APPENDIX E ................................................................................................................. 113

vii
APPENDIX F.................................................................................................................. 116

viii
LIST OF TABLES
Table 1: Factors Limiting the Use of Natural Colors ........................................................43
Table 2: Use of Natural Colors Impact Rating Factor .......................................................46
Table 3: Comments on Changing Philosophy of Color Selection .....................................49
Table 4: Key Reasons for Color Decisions ........................................................................50
Table 5: Selected Comments Expanding on the Impact of EU Restrictions and
Legislation on the Pharmaceutical and Dietary Supplement Industries .............58
Table 6: Factor Criticality in Developing Regulations ......................................................67

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LIST OF FIGURES
Figure 1: Ramsey’s Model of the Objectives of Regulation ..............................................28
Figure 2: Key Areas of Assessment ...................................................................................30
Figure 3: Respondent’s Source of Experience with Color.................................................38
Figure 4: Occupational Category .......................................................................................38
Figure 5: Occupational Level .............................................................................................39
Figure 6: Operating Region ...............................................................................................39
Figure 7: Self-Rating of Regulatory Knowledge ...............................................................40
Figure 8: Respondent’s Source of Color Experience .........................................................41
Figure 9: Color Decision Influencers .................................................................................42
Figure 10: Influence of Natural Colors on Consumer Buying Behavior ...........................42
Figure 11: Reasons for Selecting Natural Colors ..............................................................45
Figure 12: Impact of the Use of Natural Colors ................................................................46
Figure 13:Primary Reason for Selecting Synthetic Colors ................................................47
Figure 14: Changing Philosophy on Color Selection ........................................................48
Figure 15: Validity of Southampton Study ........................................................................52
Figure 16: Increased Public Safety As A Result of Additional EU Labeling ....................53
Figure 17: Impact of Southampton Study on the Regulatory Environment ......................53
Figure 18: Should US Follow EU with Additional Labeling for Southampton Colors .....54
Figure 19: Influence of EU Actions on Other Countries ...................................................55
Figure 20: Do EU Regulatory Changes Support Consumer Interest? ...............................55
Figure 21: Impact of EU Regulatory Changes on Small Companies ................................56
Figure 22: Impact to Trade of Differing Regulations in the US and EU ...........................57

x
Figure 23: Impact of EU Measures on the Pharmaceutical Industry .................................58
Figure 24: Impact of EU Measures on the Dietary Supplement Industry ..........................58
Figure 25: Impact of EU Regulatory Changes on Consumer Safety .................................59
Figure 26: Views on Sufficiency of US Color Regulations to Protect the Public Health .60
Figure 27: Consumer Color Preference .............................................................................61
Figure 28: Safety of Natural Colors Versus Synthetic Colors ...........................................61
Figure 29: Consumer Preference as a Factor in the Development of Regulations for
Colors ..................................................................................................................62
Figure 30: Industry Impact as a Factor in Developing Regulations ..................................63
Figure 31: Impact on the Cost of Consumer Goods as a Factor in Developing
Regulations .........................................................................................................64
Figure 32: Impact of Challenging Regulations on the Health of the Industry ..................65
Figure 33: Should Regulators Encourage Manufacturers to Move Away from Synthetic
Colors? ................................................................................................................66
Figure 34: Impact of Switching to Natural Colors on Consumer Products .......................66

xi

ABSTRACT
Colors have been added to consumer products for most of recorded history, but that history has
been marked by problems with unsafe coloring agents that have driven remedial regulations.
The publication in 2007 of the “Southampton Study”, linking synthetic color additives to
behavioral changes in children, has been one of the most influential modern challenges to the
regulation of colors. Although the study was flawed scientifically, its conclusions were widely
disseminated to the public and drove regulatory changes in Europe. There, industry is now
required to label products with significant warnings for some synthetic colors and restrict the use
of others. The use of naturally derived colors has been advocated, but it can be difficult and
expensive to use naturally derived colors. Thus, it is unclear whether the regulatory
recommendations and requirements are achieving the identified goals of good regulatory policy,
including the goals of enhancing safety, protecting the interests of consumers and creating a level
playing field for manufacturers. In this study we explored the views and experience of the dietary
supplement and pharmaceutical industries about the appropriateness and impact of these
regulatory changes with the intent of helping to shape future color regulation and assist
companies in developing strategies and products that conform to the current regulatory
environment. The results of this study indicate almost all respondents share the view that safety
and science should be critical factors in developing regulations. Most expressed the view that
that certain EU color regulations, based upon the Southampton Study, do not improve safety or
enhance the public health. It appears from the results here that many companies are using
natural colors as a differentiating feature driven by consumer preference rather than regulation.
Many respondents felt that the impact of the restrictive EU regulations has been generally
negative, potentially increasing manufacturing costs and thus consumer prices. Many suggested

xii

that dissonance between the regulations in the EU and the US had a negative impact on the
industry overall.

1
CHAPTER 1. OVERVIEW
1.1 Introduction
Colors are used in drugs and dietary supplements for many reasons. They can make a tablet or
capsule easier to identify, reduce medication errors and increase patient compliance (Schoneker,
2005). They can also increase the visual appeal of a product. Product branding and brand
recognition rely heavily on the physical appearance of the product. Colors are used to
differentiate the product and to create subliminal messages related to value and function
(Moreton, 2018).
Most countries have regulations specifying which colorants can and cannot be used in food and
drug products. Their lists of approved colors include colors manufactured synthetically as well as
coloring substances derived from mineral, plant or animal sources. Regulatory agencies typically
perform an extensive review of available safety data before a colorant can be added to the list,
thus essentially endorsing the additives as safe. Nevertheless, the source of coloring agents has
been a matter of concern for much of the recent history of drug development. Researchers in the
1970s studied the effects of synthetic colors on the behavior of children. Perhaps the most
publicized of those studies was that carried out at the University of Southampton in 2007 that
examined the relationship between the consumption of synthetic colors and behavior in children.
The investigators in this large study claimed that a causal relationship was present between the
hyperactive behavior of children and the consumption of synthetic coloring agents (McCann et
al., 2007). The results caused concern amongst consumers and regulators when reported in the
media, and these concerns have continued to this day despite the fact that the validity of the
study has been challenged. For example, the Southampton Study was reviewed soon after its
publication by the European Food Safety Authority (EFSA) and found to be flawed in its design

2
and conclusions (EFSA, 2008). It was also reviewed, together with older studies making similar
claims, by the FDA in 2010. That Agency came to the same conclusion, that a causal
relationship could not be confirmed based on the existing data (FDA, 2010).
The fact that studies have been found by experts to be unconvincing has not allayed the
suspicions of many consumers that artificial colors might be harmful. In a 2011 Nielson poll,
92% of surveyed consumers had concerns about the use of artificial colors (Byrne, 2011). In
light of growing consumer concern, the European Union made a decision to ignore the EFSA
evaluation and require a warning about potential adverse effects on activity and attentiveness on
all foods containing the six colors studied in the Southampton Study. Additional legislation in
2012 also reduced the permissible levels of use for three synthetic colors in dietary supplements
(EU, 2012a) and the permissible levels of aluminum associated with aluminum lake colors in all
food categories (EU, 2012b), thereby increasing pressure on manufacturers to further reduce the
use of synthetic colors.
Not all colorants are synthetic. Colorants derived from minerals, plants or animals are often
identified as “natural” colors because of their organic sourcing. Naturally derived colors can be
an alternative to synthetic colors. However, natural colors are commonly less stable than
synthetic colors, and they can often be more susceptible to degradation from light, heat,
oxidation and pH (Chapman, 2001). This decreased stability can have little impact when the
natural color is used in a food that is consumed in a relatively short time frame or is sealed in a
container until use. When that product is used in a drug or dietary supplement, however,
problems of stability become more serious because these products are often stored for longer
periods, in containers designed to be opened frequently. Additionally, naturally derived colors

3
can also be much more expensive to produce and may be difficult to obtain if the raw materials
used in their manufacture are limited.
The term “natural” is not a statutory term; the US FDA has several times declined to define
“natural” in the context of food and color additives (Council for Responsible Nutrition, 2016).
Nevertheless, synthetic and natural colors are often treated differently by regulatory bodies. For
example, the UK Food Standards Agency (UK FSA) continues to encourage manufacturers to
replace synthetic colors with natural colors. The UK FSA has published a specific Guideline that
attempts to address how industry can deal with these concerns (Chapman, 2001).
1.2 Statement of the Problem
The concern about the use of synthetic colors in food and drug products has been debated for
many decades. More recent studies have caused consumer concern to rise. Regulators, in their
role of protecting the public health, have been quick to review the available data. While some
agencies have eschewed the recent studies as inconclusive, others have been quick to promulgate
regulations. Current consumer concerns about the use of synthetic colors, regulations calling for
negative labeling, limits on their use and regulatory guidance encouraging their replacement are
all factors that are driving manufacturers of both drugs and dietary supplements to evaluate
whether they should continue to use synthetic colors. Moving from synthetic colors to naturally
derived colors can have significant operational implications including increased manufacturing
costs, increased regulatory burden and decreased product stability. Not using colors at all can
also have negative results related to patient safety and compliance. How these outcomes will
ultimately impact the consumer is unknown. Considering the potential impact to industry and
the consumer, it is unclear if the regulations that have been put in place are achieving their

4
intended outcomes. These outcomes include not only protecting the public health but protecting
the interest of the consumers and establishing fair trade practices as well.
An important stakeholder in this debate is the industry that ultimately bears the added cost and
challenge of using natural colors. We know that changing to new ingredients such as these will
add costs and challenges to manufacturing operations that ultimately may impact the consumer.
However, it is not clear whether industry views the changes as appropriate and how great the
impact of these changes is seen to be. Given the issues on both sides of the adoption decision, it
is also not clear whether companies are making changes to new colors in light of the EU
regulations, and whether they are differentiating their approaches in different regions based on
regulatory differences or other factors.
1.3 Purpose of the Study
The purpose of this study was to examine, through a survey of industry professionals, the
industry point of view regarding the appropriateness of the regulatory changes impacting the use
of colors in dietary supplement and drug products that have occurred over the last decade.
Regulatory agencies have stated three goals of regulation that include not only an intention to
protect the public health but also to ensure innovation/efficiency in industry and provide
standards for fair trade. However, it is not clear if these often-competing goals have been fully
achieved. Thus the data collected in this study may provide better insight into the views of
industry on how effectively these goals are being met.
The development of the survey tool began with a draft that was juried by a focus group of select
industry experts. The focus group served to reduce bias in the construction of the survey
questions and assess the applicability of the questions in the survey to derive the necessary data

5
to make useful conclusions. The revised survey was then disseminated to participants from both
the pharmaceutical and dietary supplement industries. Because of the specific nature of the
research questions that reference often challenging concepts of regulatory requirements, the
inclusion criteria restricted the respondents to regulatory professionals who are positioned to
have the best knowledge of the color regulations in the US and Europe. However, also included
were respondents who understand the regulatory environment because of their job functions in
companies that formulate colored products for the European market.
1.4 Importance of the Study
Regulators have a duty to their constituents to evaluate the impact of regulations that they
impose. Without industry input, it is impossible for regulators to assess whether their regulatory
instruments are effective in achieving their intended outcomes. The results of this study
illuminate the position of industry in a way that will allow regulators to assess the views and
challenges of one major stakeholder, the industry that is directly affected by their initiatives. This
study provides data that may assist regulators in understanding the impact of the EU color
regulations on industry and ultimately on the consumer. Ideally, it brings attention to the
potential areas of concern and unintended consequences that may prevent the regulations from
meeting their stated purpose of protecting the interests of both consumers and industry alike. By
understanding how the regulations have shaped industry behavior not only in the EU but in other
markets, this study may contribute to the development of future regulations that may address any
areas of weakness.
The study also may have value to the industry by providing them insight into how the industry as
a whole is reacting to the current regulatory environment thus allowing companies to develop

6
strategies and products that address the regulatory and technical challenges to support successful
operations in the changing regulatory landscape.
1.5 Limitation, Delimitations, Assumptions
This study is delimited to the evaluation of the views of dietary supplement and drug product
manufacturers. Because a primary focus is on the appropriateness of regulations imposed in the
EU in the last decade, study participants were restricted to those manufacturers that are doing
business in Europe but not limited by geographic location. The study questions were limited in
number and focused only on the use of color additives and the corresponding regulations. It does
not consider the use or concerns related to other food additives, dietary ingredients, excipients or
drug substances.

Ideally, respondents were in a position in the company to speak to the effects the regulations
have had on their business. This requires not only a familiarity with the regulations in question
but a higher-level view of the company’s activities with regard to color replacement. These
requirements limited the pool of possible respondents. A small survey pool may limit the study’s
value in objectively representing the opinions of industry on this topic. Within the survey pool,
the level of experience of the respondent as well as the company’s current use of synthetic colors
or natural colors may affect the quality of their responses. Further, respondents may be limited
in their responses because they wish to assure confidentiality of company information, especially
information that they perceive to be key to the overall strategies of the company. To mitigate
this situation, respondents were assured of the confidentiality of their responses and the survey
questions were designed to avoid asking for confidential or proprietary information.

7
Assumptions are made that the survey respondents were truthful and answered the questions to
the best of their ability based on their own knowledge. It was assumed that their views will
reasonably represent the experience and views of the company for which they are employed. It
is further assumed that respondents would not have agreed to participate if they lacked the
experience, knowledge or position to complete the survey or if they did not intend to complete it.
1.6 Organization of Thesis
This research contains three chapters. Chapter 1 introduces the issues and explains the purpose
of this research as well as the overall approach. Chapter 2 provides a detailed review of the
history of the use of colors and their regulation. Further, it summarizes the literature related to
the use of colors in dietary supplements and drug products, including its benefits, concerns and
recent studies related to behavior disorders linked to color use. A detailed discussion regarding
the operational difficulties associated with the use of natural colors is also provided. Finally, this
chapter contains a discussion of the general objectives of regulation and presents an evaluation
framework that is the basis for this research. Chapter 3 describes the research methodology that
will be used in conducting the research. Chapter 4 presents the data collected from the survey.
Chapter 5 is a discussion of the research results and conclusions as well as suggestions for future
research. The Appendices that are included in this thesis in include, Appendix A: Final Survey,
Appendix B: Original Draft Survey, Appendix C: Complete Respondent Comments On Factors
Limiting The Use Of Natural Colors, Appendix D: Complete Respondent Comments Change In
Philosophy On The Use Of Colors, Appendix E: Complete Respondent Comments On Key
Factors Impacting Color Decisions, Appendix F: Complete Respondent Comments On Impact
On Industry.

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CHAPTER 2. LITERATURE REVIEW
2.1 Evolution of Color for Pharmaceutical Purposes
The use of colors dates back more than 24,000 years (Ospitali et al., 2006). Paleolithic man used
natural pigments, often derived from minerals found in rocks, to paint on cave walls. The cave
paintings that remain visible in present times use black pigments from charcoal and animal
guano (Fernández et al., 2018). These types of stable colorants have been able to remain visible
despite thousands of years of environmental exposure. Prehistoric civilizations may have used
pigments from other natural sources such as animals and plants but these types of pigments are
highly sensitive to environmental factors such as light and heat that likely limited their visible
life.
As time progressed, man became more adept at creating lasting pigments. The Egyptians began
creating new more stable pigments, known as lakes, around 4000 BC by fixing dyes to a
transparent white base such as chalk or alum (Tamburini et al., 2019). This is a process similar
to the laking process used today. One of the most coveted colors in ancient times was Tyrian
purple. This reddish-purple dye was obtained from the mucosal secretions of freshly caught sea
snails in the Mediterranean (Plenderleith, 1950). Each snail yielded only a few drops of the
precious dye. Owing to its scarcity, this color came to represent wealth and is said to be the
source of the purple used in the robe worn by Caesar on the Ides of March (Plenderleith, 1950).
Over the years, various materials were used to create paint colors. Widely used even today are
pigments such as carmine lake made from cochineal beetles, carbon black from charcoal and iron
oxides and titanium dioxides from mineral sources. Until recently, however, pigments were

9
typically not used in pharmaceutical manufacturing. Oral dosage forms were typically white or
pastel until the 1960s (Khanal, 2014).
The “colorful” revolution exploded in the 70s, when attention to color as a marketing tool
encouraged the development of more than 80,000 color combinations, many based on older
technologies used for other purposes (Khanal, 2014). The first synthetic organic dye was
introduced in 1856 by William Henry Perkin (Zollinger, 1999). Early synthetic dyes were
manufactured from the by-products of coal processing and were given the common designation
of “coal-tar” colors, a designation that would stick with these products long after the coal by-
products were replaced by safer, petroleum-based chemicals. It was not long before artificial
colors had been added to most foods, drugs and cosmetics sold in the US. Colors were useful to
change or enhance the natural appearance of foods or to make up for color loss occurring from
exposure to environmental conditions such as light, air, moisture or temperature over the shelf
life of the product. These changes had important market value because the appearance of food
can affect the food choices of the consumer (Burrows, 2018).
In the latter part of the 19
th
century, the availability of synthetically prepared colors along with
industrialization of food processing was responsible for a rapid increase in the use of synthetic
colors to augment the color of foods (Hilts and Young, 2003). For example, the use of colors
was first allowed by the USDA in butter and cheese in 1881 (Hilts and Young, 2003). However,
those early coloring agents often contained high levels of toxic materials such as arsenic, lead
and mercury (Bailey et al., 2003). Thus, many were unsafe and were often used in ways intended
to defraud consumers by hiding spoilage. Canned green beans, for instance, were given a more
appealing shade of green by the addition of copper sulphate (Ensminger and Ensminger, 1993).
Toxic colors were also used to attract children to brightly colored candies. In 1880,

10
contamination of candy with toxic colors, and particularly with lead chromate, was prevalent in
the US; 46% of candy sampled in Boston was found to be contaminated with at least one toxic
colorant (Burrows, 2018). It is therefore not surprising that concerns about the use of colorants
soon drove a regulatory reaction.
The first Federal law to control the use of colors was the Food and Drugs Act of 1906. The Act
provided for a positive list of colors deemed safe that could be used in foods and established the
color certification program that is still in existence today. Enforcement of the 1906 Act was
originally under the jurisdiction of the USDA, but the FDA took over the responsibility for its
enforcement in 1927. However, the limited scope of the 1906 Act and associated difficulties
with its effective enforcement caused concern among consumer advocacy groups as well as the
FDA. Publications such as The American Chamber of Horrors, written by FDA employee, Ruth
DeForest Lamb, pointed out the limitations in the 1906 law that allowed dangerous adulterated
and misbranded products to remain on the market. Subsequently, the Federal Food, Drug and
Cosmetic Act (FD&C Act) of 1938 was crafted in part to address concerns about serious
incidents involving misbranded and adulterated consumer products containing toxic dyes; one
such product, Lash Lure eyebrow and eyelash dye, that contained paraphenylenediamine, caused
permanent blindness to hundreds of users (Hilts and Young, 2003). The 1938 Act extended
FDA’s authority over colors and spurred FDA to promulgate many regulations related to the use
of colors that are still in place today.
2.2 The Role and Regulation of Color
2.2.1 The Uses of Color
Today, color plays an important role in the way that products are presented to the consumer. The
most obvious use of color is to render otherwise drab products more esthetically pleasing.

11
However, specific colors often provoke instinctive, learned and preferential behaviors. Many
studies that have confirmed that patients and consumers can have strong reactions and
associations to colors (de Craen et al., 1996). For example, consumers may react instinctively to
colors such as blue, black and purple that they may associate with toxic or spoiled materials
(Burrows, 2018). They may also learn to identify foods by their colors. For example, most
consumers have learned that strawberries are red. The flavor of a strawberry candy will be
enhanced when consumers associate the red color of that candy with the fruit. Such
reinforcement is absent if a strawberry candy is colored green, and the flavor of that same candy
can then be difficult to judge (Gray, 2013). Preferential behavior is developed over the lifetime
of the consumer and causes groups of consumers to have color preferences associated with their
age group or culture (Cohen, 2014). For example, as noted in a study published in 1994,
children generally prefer brighter colors that are commonly associated with sweets (Boyatzis and
Varghese, 1994). Not only can colors create emotional reactions, they can also communicate
value and function (Moreton, 2018). For example, in Mexico, a country with a primarily
Catholic culture, the color blue is associated with religious icons such the Virgin Mary and
Heaven. Possibly because of these religious associations, blue in Mexico is often considered to
denote strong potency so its use may increase the perception that a product will have a strong
action (Stegemann, 2005).
Marketing professionals study the effects that colors suggest when designing the market image
for a product. Sometimes color is used simply to make a product immediately recognizable to
the consumer. For example, many consumers can readily identify Prilosec® and its follow-on
product Nexium® as the “purple pill.”

12
However, colors can also do more than appeal to the consumer from an aesthetic perspective.
They can play an important role in securing patient compliance and can help to reduce
medication errors particularly in geriatric populations (Stegemann, 2005). As patients age, the
number of different medications taken daily tends to increase at the same time as cognitive skills
and eyesight tend to degrade (Saljoughian, 2019). If patients cannot identify their medications
easily, the opportunities for errors increase (Lenahan et al., 2013). Colors provide a well-
established tool to recognize and distinguish between dosage forms. Tablet appearance,
including color, has also been shown in a recent study to affect patient compliance. A 2013
study by Fitzgerald (Fitzgerald, 2013) demonstrated that patients are 50% more likely to stop
taking their medications when the appearance of the medication changes from that to which they
were accustomed. When discussing the findings of his study, the principal investigator, Dr.
Aaron S. Kesselheim, stated, “We found that changes in pill color significantly increase the odds
that patients will stop taking their drugs as prescribed.” (Fitzgerald, 2013). Considering the
ubiquity of colors in today’s medications and foods, it is not surprising that they have been the
subject of much regulatory attention.
2.2.2 Regulation of Color
2.2.2.1 United States
In the United States, coloring agents are amongst the most strictly regulated of all constituents in
food and medicine. Regulations governing color additives require that all color additives be
approved by FDA through a color additive petition process prior to their use in foods or drugs
(Federal Food Drug and Cosmetic Act, 2018b). The petition process requires the petitioner to
demonstrate the safety and suitability of the color additive. Approval by the FDA is based on
several factors such as intended use and the associated exposure associated with that use, the
strength of the supporting safety data and the availability of appropriate methods to characterize

13
identity, purity and levels of impurities. Once the petition is reviewed favorably, FDA will
promulgate a regulation allowing for the use of the new colorant. This process includes an
opportunity for public comment prior to finalizing the proposed regulation (21 CFR, 1977a).
FDA can also delist colors if the colors prove to cause significant public health concerns such as
FD&C Red #2 that was delisted in 1976 due to uncertainties related to safety and data suggesting
carcinogenicity (National Archive and Records Administration, 1976).
In the U.S. two positive lists of colors can be used in foods and drugs respectively. These lists
are codified in 21 CFR, Parts 73, 74 and 82. The colors in these lists are further separated into
two groups that either do (Certified Colors) or do not (Exempt Colors) require batch certification
from the FDA prior to use. Batch Certification of synthetic colors, initially a voluntary program
for the color additive listed in the Food and Drugs Act of 1906, was later made mandatory in the
Federal Food, Drug, and Cosmetic Act of 1938 in an effort to control the quality of colors that
were being used in consumer products (Bailey et al., 2003). More than one hundred years later,
the rules continue to exist, even though the US is the only country in the world to have such a
certification program for colors, now funded completely by user fees.
Part 74 addresses colors that require batch certification by FDA. Products in this group are
synthetically manufactured colors whose primary source is from petroleum products. To use
colors listed in Part 74, manufacturers are required to submit a sample from every batch of color
that they manufacture to FDA’s Color Certification Branch for testing against the specifications
prescribed by the regulations (21 CFR, 1977b). This includes an evaluation of each sample by
testing such parameters as purity, residual salts, unreacted intermediates, impurities, heavy
metals and other tests as relevant to each color, as outlined in the regulations. Batches that meet
the critical quality and safety attributes related to composition and purity are issued an FDA lot

14
number and then can bear the nomenclature FD&C (Food, Drug and Cosmetic) or D&C (Drug
and Cosmetic), as appropriate. Through this certification process, FDA, and ultimately
consumers, can be assured of the quality of every batch of colors subject to this certification
process that are used in foods, drugs and cosmetics in the US.
Colors exempt from certification are listed in Part 73 and include colorants obtained from
mineral, plant or animal or other sources. Even though these colorants are derived from some
material in nature, they are still “artificial” colors insofar as they undergo significant processing
to achieve their final form. These colorants do not require FDA batch certification under the
law, but the regulations still require the manufacturer to assure that each batch of colorant meets
the compositional and purity requirements provided in the regulations for each color. Examples
of these requirements include identity, impurities and heavy metals. Manufacturers are required
under the regulations to maintain records demonstrating compliance with testing requirements
for each batch. The compositional and purity requirements for colors exempt from certification
are specific to each colorant and can be found in Part 73 of the regulations.
Part 82 of 21 CFR lists colors that are considered provisionally listed. Following the 1960’s
Color Additives Amendment to the FD&C Act, colors that were currently in use in the US but
that had not been proven to be safe and suitable under this amendment were put into the
provisional list while their safety was evaluated and they were either added to the permanent lists
in Part 73 or 74 or their listing was terminated. Originally some 200 colors were on the
provisional list but over time most have been either delisted or moved to permanent status
leaving only a small number of colors still on the provisional list in Part 82 (Bailey et al., 2003).
Colors listed in Part 82 continue to be legally permitted for use in food, drugs or cosmetics as
listed.

15
Certain colors permitted for use in drugs may also have specific requirements for additional
labeling. For example, 21 CFR §201.20 requires drug products containing FD&C Yellow No. 5
to have the following warning in the Precautions section of the labeling:
This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-
type reactions (including bronchial asthma) in certain susceptible persons. Although
the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general
population is low, it is frequently seen in patients who also have aspirin
hypersensitivity. (1994)

This warning statement was added to the regulations in 1980 based on studies from the mid-70s
that linked sensitivities to salicylic acid to co-sensitivities to FD&C Yellow No. 5 (National
Archive and Records Administration, 1980).

2.2.2.2 European Union
Rules for color additives in the EU are similar to those in the US. Approval of color additives
for foods and pharmaceutical products are not handled differently from other food additives.
Under EU legislation all food additives must be authorized by the European Commission before
they can be used (EU, 2008). To obtain permission to use a color additive, an application dossier
must be developed that contains information on the proposed use, exposure levels anticipated by
that use, and safety of the material. The dossier is submitted to the European Commission,
which refers it for an independent technical review by the European Food Safety Authority
(EFSA). The assessment of EFSA is used by European Commission to decide whether to
authorize an additive. The European Commission then proposes regulations for such
authorization to be adopted by the Parliament and Council. Authorizations can be revoked by
the Commission in light of new information or reevaluations conducted by EFSA so that
additives can be removed from the market if they are found later to pose hazards.

16
The EU, like the US, has a positive list for colors that can be used in foods. Authorized colors
are listed in Regulation EC No 1333/2008 of the European Parliament and of the Council of 16
December 2008 on food additives, Annex II. Annex II is presented as a database rather than an
actual list in the Regulation. The database is open to public access on the Europa website
(Directorate-General for Health and Food Safety, 2018). The positive list for foods contains both
synthetic colors and colors derived from natural sources. No separate positive list has been
developed for colors that can be used in medicinal products. Directive 2009/35/EC of the
European Parliament and of the Council of 23 April 2009 on the “Colouring Matters Which May
be Added to Medicinal Products” refers back to the positive list for foods. Any color that is
authorized for general use in foods can be used to color medicinal products as well, but colors
that are restricted for specified uses cannot be added to medicinal products (EU, 2009).
In all cases, manufacturers are responsible for assuring that color additives meet the
specifications listed in the regulations. These specifications are known commonly as purity
criteria and are listed in Commission Regulation (EU) No 231/2012 of 9 March 2012, “Laying
Down Specifications for Food Additives Listed in Annexes II and III”. The purity criteria
include tests and limits to ensure the purity of the color additive. Each colorant has its own set of
purity criteria and it includes a description of the colorant and tests of identity and purity specific
to that material. As in the U.S., additional labeling may have to be placed on some colors that
are permitted for use in medicinal products in the EU. For example, several synthetic colors
such as tartrazine and sunset yellow FCF are required to bear the statement, “May cause allergic
reaction” (EMA, 2018).
2.2.2.3 The Precautionary Principle

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A key concern for regulators in all constituencies has been the safety of additives, especially
additives that play a minimal role in providing a therapeutic or nutritional benefit (FDA, 2011b).
Regulators often invoke the “precautionary principle” when assessing whether the additive
should be approved. This principle is based on the premise that regulators have a social
responsibility to protect the public from harm. Under the precautionary principle, regulators
should make conservative discretionary decisions that favor the prevention of harm until
scientific data can clarify the acceptability of the risk. In the EU, the precautionary principle has
been a general tenet in the development of legislation and has been integrated extensively into
policy and statutory decisions.
The precautionary principle has influenced the design of color legislation in both the US and the
EU. Regulators have applied the principle in determining which colors will be permitted, and, if
permitted, whether restrictions will be placed on their use and labeling. Thus, the responsibility
to prove safety is placed on the proponents of a particular action. In the case of color additives,
that burden is borne by the manufacturer seeking approval of a particular color. Once a
restriction has been put in place by legislation, additional data and scientific consensus are
required to change the legislation.
In the US, this principle has influenced certain aspects of color legislation. In particular, it
greatly influenced approaches to additives that might be suspected of producing cancer, as a
result of legislative interventions that were put into place as part of the Food Additives
Amendment of 1958. Under this Amendment, food additives were required to undergo testing
and be found compliant with the “Delaney Clause”. The Delaney Clause was a zero-risk
provision in the Act that prohibited FDA from approving “any chemical additive found to induce
cancer in man, or after tests, found to induce cancer in animals” (Federal Food Drug and

18
Cosmetic Act, 2018a). Thus, any animal data showing cancer risk, regardless of level with
respect to anticipated use, became a cause to delist a color additive. For example, certain uses of
FD&C Red 3 were restricted based on study that showed a cancer risk in animals but at levels far
exceeding relevant human exposure. As time passed, new analytic methods capable of detecting
minute levels of chemicals in a color made the Delaney clause harder and harder to satisfy. In
1986, FDA began to base its approvals or restrictions of color additives on a “negligible risk”
standard (Picut and Parker, 1992). This standard was formally introduced into federal legislation
in 1996 as part of the Food Quality Protection Act in conjunction with pesticide regulations.
This new standard was later endorsed for food additives as well. However, in 2018 FDA had to
concede that the negligible risk standard, allowed for pesticides in the 1996 amendments, did not
apply to food additives. In 2018, a Petition for Writ of Mandamus was filed in an appeals court
by a coalition of environmental and consumer advocacy groups forcing FDA to take action on
food additive petitions submitted in 2016 requesting to delist seven flavoring ingredients (Center
for Food Safety, 2018). In spite of FDA’s conclusions that “they do not pose a risk to public
health under the conditions of their intended use”, FDA agreed to accept the petitions and revoke
the flavors as the petitioners provided evidence that these substances can cause cancer in animals
at high doses and as such had to be removed from the food additive regulations under the 60 year
old Delaney clause in the FD&C Act (FDA, 2018).
Although the precautionary principle is widely accepted, opponents criticize the principle
because it lacks a threshold for the level of scientific certainty needed to avoid the application of
precautions (Recuerda, 2008). If any level of risk can trigger the principle, unnecessary
precautions may be put into place. Warnings and limitations based on limited scientific data can
cause consumers to become concerned and confused. In the EU particularly, some have argued

19
that there is “dangerous tendency to take measures without clear evidence of risk, or even against
the scientific opinions of its scientific bodies” (Recuerda, 2008), even in the face of contrary
opinions. One example of the use of the precautionary principle in broadly limiting the use of
synthetic colors based on fear rather than evidence appears to be that linking synthetic colors
with behavioral problems.
2.2.3 Synthetic Colors and Behavioral Research
The public is commonly suspicious of additives in food, and these concerns have fueled much
research, good and bad, into potential links between additives and adverse health effects (Hilts
and Young, 2003). For color additives, the emphasis has focused particularly on the possible
links between synthetic additives and hyperactivity in children. An early publication to propose
such a linkage was Feingold’s Why Your Child Is Hyperactive, published by Random House in
1975 (Feingold, 1975a). Feingold hypothesized in his book that artificial colors, artificial flavors
and foods naturally containing salicylates were a primary factor in hyperkinesis and learning
disabilities in children. His treatment included elimination diets that excluded these items from
the patient’s diet. Feingold stated in a 1975 paper on the subject that the mechanism by which
these substances cause this effect is unknown but it was not considered to be allergenic in nature
(Feingold, 1975b). Feingold’s largely unscientific book created public anxiety that served as a
driver for several studies in the late 70s and early 80s to investigate the effects of food additives
on the behavior of children. Some of these studies focused on color additives. Results of the
investigations were conflicting and controversial. Although some studies weakly supported
Feingold’s assertions, some had contradictory findings. An analysis of the studies available
during this time was published in March of 1982 in the Journal of the American Academy of

20
Child Psychiatry by Dr. Bernard Weiss (Weiss, 1982). The relatively unconvincing data from
these early studies was not sufficient to shift the legislation of these substances (Weiss, 2012).
In 2007, concern about the use of synthetic colors surfaced again, when a large study conducted
at the University of Southampton concluded a causal relationship between the consumption of
synthetic colors and increased hyperactivity in children (Scotter, 2011). In that study, children
were given two types of “cocktails” based on six different colors (tartrazine, quinolone yellow,
sunset yellow, carmoisine, ponceau 4R, allura red AC) and sodium benzoate, a preservative. The
study was conducted as a randomized, double blinded, placebo-controlled, three-armed crossover
trial in which 153 3-year-old and 144 8-9-year-old children participated. The main measure was
based on a global hyperactivity aggregate that was comprised of behavioral observations made
by parents and teachers as well as a computer-based assessment in the case of the 8-9-year-old
group. The first mixture (A) of color additives was intended to replicate a mixture used in a
previous similar study and the second (B) was intended to match the current daily consumption
of these food additives in the general population of the relevant age group. The dosages for each
age group were normalized to take into account differences in body mass between the children in
the two age groups. All the mixtures were consumed mixed with fruit juice (McCann et al.,
2007). The results of the study were purported to reveal an increase in the mean level of
hyperactivity in both age groups when they were administered mixture B, supporting a
conclusion that hyperactive behaviors were exacerbated by consumption of these colors and
preservative (McCann et al., 2007). The study had wide media attention that increased the level
of consumer concern over the safety of the color additives. In the US, for example, a citizen’s
petition was lodged to ban the eight then-approved synthetic colors (FDA, 2010).

21
In response to consumer outcry, a number of regulatory agencies reviewed the available data to
investigate whether the Southampton Study findings were correct and meaningful. A 2008
assessment by EFSA questioned the clinical significance of the findings and the methodology
which limited the ability to determine which of the substances might have actually produced the
observed effect. In its Scientific Opinion, “the Panel concluded that the findings of the
McCann et al study could not be used as a basis for altering the ADI of the respective food
colours or sodium benzoate” (EFSA, 2008). FDA also reviewed the Southampton Study
findings in 2010 during their preparations for a Food Advisory Committee meeting held in 2011.
FDA concluded that “a causal relationship between exposure to color additives and hyperactivity in
children in the general population has not been established.” (FDA, 2010). The subsequent Food
Advisory Committee agreed (79% in favor) with FDA’s evaluation (FDA, 2011a).
Other regulatory agencies also evaluated the Southampton Study and found issues with the
conclusions. The Norwegian Scientific Committee for Food Safety concluded in 2008 that “the
study provides a limited support to an increase in hyperactive behaviour from mixtures of artificial
food colours and sodium benzoate” but “cannot clarify whether the reported effects are caused by
single compounds or mixtures of these” and further had no relevance in Norway (Norwegian
Scientific Committee for Food Safety, 2008). A study commissioned by the Irish Department of
Agriculture, Food and Fisheries similarly concluded that the Southampton Study also was not
relevant in Irish children because the “levels of exposure to food additives rarely, if ever, reach the
levels used in the Southampton Study.” (Connolly et al., 2009).
2.2.4 Recent Legislative Developments
Often the impact of scientific assessment can be modest when public sentiment has been
aroused. Although EFSA’s evaluation of the Southampton Study did not support legislative

22
change, the European Commission nonetheless included a requirement that all foods (except
alcoholic beverages) containing the six colors evaluated in the Southampton Study bear the
statement “may have an adverse effect on activity and attention in children.” This addition,
published in an Annex to Regulation 1333/2008, became effective on 20 January 2010 (EU,
2008).
Since that time, the EU Commission has requested a review of the ADIs (acceptable daily intake)
for all food colors currently permitted in the EU by EFSA. The review began with the colors in
the Southampton Study and progressed through all currently approved colors from both synthetic
and naturally derived sources. These new evaluations led the Commission to reduce the
maximum permitted levels of three synthetic colors, sunset yellow, quinoline yellow and
ponceau 4R, in dietary supplements. Following the EFSA review of aluminum, the EU
Commission in 2012 proposed legislative amendments to reduce the amount of aluminum from
aluminum lakes included in dietary supplements (EU, 2012b). Aluminum lakes are a commonly
used form of synthetic colorant, so this new restriction reduced further the extent to which
synthetic colors in the lake form could be used in dietary supplements. In 2013, based on the
review of a new in vivo comet assay in mice that suggested possible genotoxicity of allura red
AC, EFSA recommended that new studies be conducted to investigate the potential genotoxicity
of six currently authorized and structurally related sulphonated mono- azo- dyes (EFSA, 2013).
To date, these legislative changes to control the use of synthetic color additives have been
directed to foods, including dietary supplements, where exposure is likely to be higher than it
would be for medications. It is unclear whether the legislative changes will have a subsequent
effect on the use of synthetic color additives for medicinal products sold in the EU.

23
2.2.5 Other Issues Related to the Use of Natural Colors
It seems increasingly clear that consumers are concerned about consuming synthetic colors. A
2011 Nielson poll surveyed 5,000 respondents from 10 countries and found that 92% had
concerns about synthetic colors and 78% were willing to pay higher product prices for products
using naturally derived colors (Byrne, 2011). Manufacturers wishing to sell their products in
retail stores that promote healthy offerings such as Whole Foods and Trader Joe’s, grocery
chains, must meet strict requirements that include the use of colors derived from natural sources.
This preference seems to stem from an overall trend to favor food additives that are perceived to
be healthier alternatives (Byrne, 2011). This trend has not been lost on industry but such change
can be challenging.
It is not a trivial matter for companies to replace synthetic colors in pharmaceutical and dietary
supplement products. One of the most significant technical challenges relates to chemical
stability. Naturally derived colors are generally less stable than synthetic colors and are subject
to degradation or fading when exposed to extremes of heat, light, oxygen or pH (Chapman,
2001). Most food products spoil easily so are preserved in sealed containers; once opened the
food is usually consumed in a relatively short period of time. However, drugs and dietary
supplements have more stringent requirements. Not only must they have a longer product shelf
life, but they are commonly subject to greater environmental extremes of temperature and are
held in containers that must be opened frequently. All of these assaults on stability can affect the
quality of the color. The Guideline produced by the UK Food Standards Agency provides
detailed information on the stability of common natural colors under a variety of conditions to
assist manufacturers in the reformulation of food products (Chapman, 2001).

24
Most natural colors also lack the color intensity of synthetic colors. Thus it is difficult to match
the bright, intense colors that synthetic additives can achieve. Many initially vibrant natural
colors oxidize and fade very quickly so they are difficult to use as colorants for consumer
products (Matulka, 2016). For example, when General Mills decided to replace the synthetic
colors in Trix cereal in 2015, one of their cereal developers, Kate Gallager, stated, “We haven’t
been able to get that same vibrant color.” (Houck, 2015). Another journalist compared the old
and new Trix, by saying that “The effect is akin to putting a watercolor of a desert landscape
next to an Andy Warhol print: Nature’s colors are more muted, gentle.” (Wollan, 2016). The
color blue is particularly difficult to replicate. A true blue is rare in nature, a challenge to which
the Wrigley division of Mars can attest. Mars has been searching for a naturally derived blue to
replace the synthetic blue used in M&M candy. Neil Willcocks, vice president of global
research for Mars stated, “This is the most complex technical undertaking that any of us have
ever seen in the history of the company.” (Wollan, 2016). The industry as a whole is expending
significant resources to develop highly saturated natural colors. However, some methods of using
existing approved natural colors require that the color be processed thorough manufacturing
steps that change the ingredient in a way that no longer allows it to meet the regulatory definition
of the initial starting color, such as encapsulation where the color particles are sealed by another
material to improve stability. It thus becomes a new color additive that must go through safety
testing and a regulatory approval process before it can be used (Matulka, 2016).
In addition to technical difficulties, naturally sourced colors also are on average five times more
expensive than their synthetic counterparts (Crane, 2015), and have supply chains more prone to
disruption. Because most natural colors come from plants or animals, their supply can be
affected by weather or other environmental conditions, and this can affect the availability and

25
price as well as the quality or consistency of the color. The use of red dye from cochineal beetles
is a useful example of this problem. Cochineal beetles grow on the prickly pear cactus and for
centuries has been a source of red dye. Primarily sourced from Peru, these small insects are
harvested by hand from the plant and crushed to make a few drops of dye that is used for
carmine, a deep red aluminum lake made from the extract. Because it is difficult to obtain
cochineal, even in good harvest years it is expensive compared to synthetic alternatives. In 2010,
the availability of cochineal was extremely limited due to climate conditions and limited
cochineal production at a time when the demand was increasing. As a result, the price increased
6 to 8-fold in one year (Heller, 2010).
Another example is spirulina. Spirulina extract, approved as a colorant by FDA in 2013, is made
from microscopic algae, Arthrospira platensis. Over 90% of the world’s supply of spirulina is
produced by one Chinese company with only two manufacturing locations (Wollan, 2016).
Unfortunately, as the demand grows the availability has become limited and the price has risen.
It is predicted that the demand will increase by 10-fold over the next few years. Mars, who filed
the initial color additive petition with FDA, estimates that they would need twice the current
global supply of the material just to convert the blue in M&M candies to spirulina (Wollan,
2016).
Industry views also support the difficulties associated with the use of natural colors. In response
to a petition filed by the Center for Science in the Public Interest (CSPI) asking for a ban on
currently approved synthetic colors and asking for interim additionally labeling related to
hyperactivity, FDA held a Food Advisory Committee meeting in 2011 to discuss the labeling
request. Industry and public comments were also solicited to be reviewed by the Advisory
Committee. The Safe Color Coalition provided industry views to the Committee. The Safe

26
Color Coalition included trade associations as well as individual companies with an interest in
the use of colors in the US. In the Coalition comments, they supported the concerns presented in
the literature surrounding the difficulties of replacing synthetic colors with natural colors citing
shelf life issues, limited supply and natural batch to batch variability as significant concerns
(Safe Color Coalition, 2011). Nutritional Outlook, a journal focused on the nutraceutical
industry, reported in 2013 that a recent industry survey of technologists working with natural
colors stated that pH stability was their number one concern when working with natural colors
(Nutritional Outlook, 2013). In a more recent article, two large color manufacturers that produce
both synthetic and natural were interviewed and concur on the difficulties presented by natural
colors. Roland Beck of Sensient Food Colors stated that there is nothing better than synthetic
colors for stability. FMC’s natural colors applications manager, Andrew Kent, commented
“Moving from a synthetic colour that is stable and works anywhere to natural colours that all
have their own characteristics is a fascinating challenge.” (Houlton, 2016).
In summary, the desire to move toward natural color use seems strong amongst some consumers
and regulators. However, the challenges and resources needed for such a move and its impact on
final product price are largely invisible to those stakeholders because they are not involved in the
actual implementation of such changes. Examples show that conversion to natural colors can be
difficult and costly for industry. However, little systematic information is available to gain
insight into whether industry shares the view that a switch to natural colors is appropriate and is
on target to achieve the goals of regulations in general. It was therefore a goal of this
dissertation to investigate the appropriateness of the regulatory changes that have occurred over
the last decade as seen through the eyes of individuals in the pharmaceutical and dietary
supplement industries. To do this in a systematic manner, I adopted a commonly used framework

27
that assists in exploring the results of new regulatory interventions in terms of their effectiveness
in achieving the aims of regulation, described below.
2.3 Framing the Study of the EU Regulations on Colors
Regulations are public policy instruments that impose restrictions on private enterprise for the
purposes of attaining specified goals set by the governing body for the benefit of the governed
population (Ratanawijitrasin and Wondemagegegnehu, 2002). One central goal of
pharmaceutical regulations across all countries is that of protecting public health by assuring the
safety and effectiveness of medical products. Indeed, this goal is so important to the FDA that it
appears numerous times in statements regarding the raison d’etre of the Agency, as shown, for
example, in its most recent overview of strategic priorities:
A key priority for FDA is improving the safety and effectiveness of medical products,
both through rigorous review of clinical studies and manufacturing process
information before products are approved as well as through monitoring actual
patient experiences and manufacturing quality once they are on the market (FDA,
2011b).

However, this goal taken in isolation can have negative consequences for other important aspects
of the industry and healthcare system. Two additional goals of regulation were identified in a
recent study by Ramsey in her work on the “Impact of Incomplete Monographs on the OTC
Drug Industry”. Ramsey maintained that regulatory agencies have additional goals that may be
stated in somewhat different ways but can be collected into two additional areas as shown in
Figure 1 (Ramsey, 2013).

28
Figure 1: Ramsey’s Model of the Objectives of Regulation

The two additional goals in Figure 1 concern the impact that the regulations can have on the
health, not specifically of patients, but on the industry producing the drugs and devices upon
which those patients depend. One of the stated goals is to facilitate efficiencies that will assure
to long-term viability of the industry as an innovative force for assuring public health and disease
management. The pharmaceutical industry is a key asset in the US and European economy
(European Federation Pharmaceutical Industry Association, 2017). Likewise, the economic
impact of the dietary supplement industry in the US reached $122 billion-in 2016 (Council for
Responsible Nutrition, 2016) and in Europe is expected to reach 7.9 billion Euros in 2020 (Gray,
2015). Therefore regulators must consider how regulations that apply restrictions, especially
difficult to satisfy or expensive restrictions, may have unintended consequences for the health
and competitiveness of these industries and thus on the availability and affordability of
medicines and dietary supplements. In this context, they must determine if regulatory restrictions
are justified and what resources are needed to ensure they are effectively achieved
(Ratanawijitrasin and Wondemagegegnehu, 2002). Otherwise, onerous or misdirected regulation

29
can cause the unnecessary diversion of scarce resources that could otherwise be directed into
more valuable activities. That regulators appreciate this requirement is reflected in the goals of
the European Directorate General (DG) of Health and Food Safety, which is responsible for
pharmaceutical and dietary supplement regulation in the EU. The primary stated goal of the DG
is to protect and improve public health in the EU but in doing so, to consider trade and
competitive issues as well as the protection of the environment. Some key challenges they have
set for themselves from 2016 – 2020 is to foster greater cost-effectiveness and competitiveness
through evidence-based policy making (Directorate-General for Health and Food Safety, 2016).
Additionally, in any assessment of regulation, it is important to review the stated goals of the
specific piece of legislation. In the case of the European Regulation related to the use of colors,
1333/2008, the stated goals are directed at ensuring effective functioning of the internal EU
market while providing protection of human health and consumer interests.
The third goal of the regulatory framework in Figure 1 is the requirement to equalize impact of
the regulations across the industry. In the European regulation 1333/2008, this additional goal
could be identified in its stated intention of the regulation to create fair practices in the food
trade. FDA’s Stodart and Lal also addressed this concern in the FDA Voice, in a discussion titled
“FDA: Helping Small Businesses Get Big Results”:
For many years, to help level the playing field, FDA has been assisting small
pharmaceutical companies to maximize their opportunities for success…At a time
when quality manufacturing and the safety and effectiveness of drugs in development
is as important as ever, CDER understands that providing support to small
businesses through education and resources is vital to advancing innovation and
protecting public health. (Stodart and Lal, 2017).

The framework described above helps to broaden considerations of regulatory impact. It has the
premise that regulators must balance public health considerations with the need to protect
innovation in the pharmaceutical industry to meet the demands of patients seeking treatment.

30
The key areas of Ramsey’s model are well-aligned with the stated goals of both the EU DG for
Health and Food Safety as well as the stated goals of the current EU regulations. Therefore, it
appeared reasonable to use a similar model in the assessment of the effectiveness and impact of
the current regulations imposing restrictions on the use of colors in foods and pharmaceutical
products in the EU. Thus, for the research presented here, the framework shown in Figure 2 is
used as a basis for evaluation.

Figure 2: Key Areas of Assessment

2.4 Summary and Research Direction
In the review of the existing literature elaborated in this chapter, it is clear that the long history
over which colors have been regulated has been paralleled by a similarly long history of reported
health-related issues related to synthetic colors in ingested products. Regardless of whether the
health-related issues are based on sound science, European regulators have been motivated to
take decisive action in promulgating regulations limiting the use of certain synthetic colors. The

31
actions of one regulatory agency often have ripple effects. They can encourage the development
of matching regulations in other countries. Even without such regulations elsewhere, global
companies will often try to develop uniform specifications for globally marketed products that
meet the requirements of the most stringent or restrictive market in order to simplify
manufacturing and distribution. Thus it is critical to understand the views of all stakeholders
when trying to evaluate the degree to which the regulations are meeting their stated goals. In this
study, a survey of industry provided the basis for exploring these topics.

32
CHAPTER 3. METHODOLOGY
3.1 Introduction
The research that is the basis for this study has two parts. Part one is a detailed literature review
that is presented in Chapter 2 and not discussed further here. Part two is an exploratory research
survey. This study employed an on-line survey as the primary means of collecting industry
views regarding the appropriateness of the color regulations implemented in the last decade. The
survey tool was developed and then critiqued by a focus group prior to deployment. The
targeted survey population included industry personnel working for companies engaged in the
manufacture of dietary supplements or drug products doing business in the EU. Mid-level and
senior level employees working in the field of regulatory affairs or product formulation who are
familiar with the European regulations were the main target for the research survey. These
individuals are the most likely to be able to represent the views of their company with respect to
the topic.
3.2 Initial Survey Development
The survey was developed using Qualtrics web-based survey software (www.qualtrics.com).
The initial draft of the survey included 31 questions of varying formats including multiple
choice, yes/no, scaled and open-ended options. The development of the draft survey questions
was guided by the literature review summarized in Chapter 2 and discussions with individuals
known to the researcher and knowledgeable in the area of color regulations and the use of colors
in the EU. Questions were selected to cover the following areas: demographics of the
respondents, respondent’s view of the impact of color regulations on color decisions in
respondent’s business and the respondent’s opinions on the suitability of existing color
regulations to fulfill the key areas of assessment outlined in Figure 2. The key areas of

33
assessment for the purposes of this research are protection of public health, protection of
consumer interests, and establishment of fair trade practices.
3.3 Focus Group
A focus group (FG) of 7 people was convened to review the draft survey and critique the
questions. The focus group included individuals from academia, industry (color manufacturing
and pharmaceutical manufacturing) and professional trade associations competent in the areas of
EU regulations. The FG was provided a paper copy of the draft survey in advance and met in
person and by on-line web conferencing for approximately 90 minutes to discuss and optimize
the proposed questions. I moderated the meeting which began with introductions and an
overview of the proposed research. The group reviewed each question and considered its
relevance to the research as well as the layout of the question. During the FG meeting, the
proposed selection method for survey participants was also reviewed.
Prior to deployment, the final survey was also sent to six administrative reviewers to test the
functionality of the electronic survey.
3.4 Focus Group Results
Before the Focus Group convened, the participants were provided Chapter 1of this paper and a
draft copy of the survey instrument to review. A meeting of the focus group, described in
Chapter 3, was attended in person by four participants, and through the internet conferencing
session, Webex, by three participants. After a brief introduction, the participants provided
feedback on the structure and wording of the questions.
In the section exploring the backgrounds of the respondent, focus group participants suggested
that demographic questions focus on when and where the respondents obtained their color

34
experience rather than where they are currently employed. Because the question to explore the
level of knowledge held by the respondents was pivotal in the survey, the focus group discussed
at length the best language to use as multiple choice selections to minimize any tendency of
some individuals to overestimate their level of expertise. The focus group suggested that
respondents working in a company using colors in the last 5 years might have had different
experiences that those who had been away from that sector of activity for a long time. Those
respondents without recent experience were not presented with some questions that would rely
on recent regulations or activities.
The second block of questions addressing impactful elements that affected industry use of colors
were also critiqued to improve the wording and consistency of response choices presented in
questions pertaining to natural colors relative to those pertaining to synthetic colors. Some
additional response choices were also suggested by the focus group. As noted in Chapter 2, the
Southampton Study has held substantial influence of public thinking. Thus, the focus group felt
that a question should be added to ascertain whether the respondent knew about this study. Only
those participants with prior knowledge of this study would be presented with follow-on
questions relating to the impact of the study.
The final section of the survey was focused on the impact and adequacy of the current
regulations and views on how regulations should be developed or revised. Focus group
participants suggested that some questions be split to focus only the dietary supplement industry
and parallel questions be developed to address those in the pharmaceutical industry.
Additionally, the focus group suggested that a few simpler yes or no questions be introduced to
allow respondents in to express definitive positions.

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After reviewing the survey instrument, the FG discussed potential groups that could potentially
provide qualified survey participants from amongst their members. It was suggested that
members from IACM (International Association of Color Manufacturers), CRN (Council for
Responsible Nutrition), CHPA (Consumer Health Products Association), NPA (Natural Products
Association) and NATCOL (Natural Food Colours Association) may all be possible sources
from which appropriate participants could be recruited.
Following the conclusion of the meeting, the survey instrument was revised to address the
suggestions of the FG participants. Copies of the final survey and the original draft survey are
included in Appendix A and Appendix B, respectively
3.5 Selection of Respondents
The participants targeted for this research were individuals that are employed or were recently
employed in the dietary supplement or pharmaceutical industry or with a company that supplies
colors to these industries. Ideally participants had positions in regulatory affairs, product
formulation or specific knowledge of these areas by virtue of their experience as former
employees, industry consultants or industry trade-association staff. Participants were identified
using personal referrals, social networking platforms, professional association membership and
attendance at industry meetings. The majority of potential participants were recruited in person
at industry meetings and agreed to participate at the time of the initial conversation. Other
participants were contacted by email to determine their willingness to participate. Finally, some
participants were recruited through professional association chat boards. Participants were also
encouraged to nominate others to participate, using the snowball technique to further expand the
pool of potential participants.

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3.6 Survey Deployment
The final survey was disseminated electronically via Qualtrics. The target population for this
survey was 75 participants. The survey remained open for 45 days and was sent via direct email
to 74 individuals and posted on one professional chat board resulting in an additional 7
participants. Participants were assured of anonymity and offered a copy of the survey results
upon request. The survey recipients were also asked to nominate other individuals who they felt
were qualified by experience and position to participate. Surveys where the respondent provided
responses for at least 80% of the questions were considered complete and included in the results.
In addition to the survey, an invitation message, reminder notes and a thank you notes were
created in the Qualtrics software and used in the deployment of the survey. Reminders were sent
at the one and two week marks as well as in the final week of the survey period to invitees who
had not completed the survey. An electronic thank you note was sent to all participants that
completed the survey.
3.7 Data Analysis
The results of the surveys were collected and stored electronically. Statistical data was
calculated by Qualtrics for all questions that were not open-ended and is included in Chapter 4.
The open-ended questions were evaluated by the researcher for trends and commonality. Those
details are also provided in Chapter 4. In the evaluation of one question, an impact index was
used to determine which attribute had the most impact based on the respondent’s selections.
Each selection was weighted using a multiplier. The selection “strongly impacted” was given a
weighting factor of 3, “somewhat impacted” was given a 2 and “did not impacted” was given a
factor of 1. The weighted total for each attribute was divided by the number of responses
received for this attribute to determine the impact rating for that element.

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CHAPTER 4. RESEARCH RESULTS
4.1 Analysis of Survey Results
The final survey was sent by email invitation to 74 individuals who had previously agreed to
participate in the survey. Of the 74 persons receiving an individual link to the survey, 48 persons
opened the survey and 46 people completed the survey. In addition, a general link to the survey
posted on a RAPS (Regulatory Affairs Professional Society) discussion board was effective in
securing the participation of an additional five respondents who completed the survey. Thus,
participants started 53 surveys and completed 51 surveys, yielding a response rate after two
reminders of 72%. The completion rate of those starting the survey was 96%. Only the results
of the respondents who completed a majority of questions were included in the final data set and
analysis. A single respondent was excluded because he/she completed less than 50% of the
survey.
4.2 Respondent Characteristics
Demographic data revealed that 79% (41/52) of respondents gained at least some of their color
expertise in the pharmaceutical industry whereas 73% (38/52) of respondents gained that
experience in part in the dietary supplement industry. Other respondents gained experience with
coloring agents in other industries (23%, 12/52), most commonly the traditional food industry.
More respondents were employed at some point by suppliers to either pharmaceutical or dietary
supplement companies (58%, 30/52; 58%, 30/52, respectively) than by manufacturers of
pharmaceutical or dietary supplement products (21%, 11/52; 15%, 8/52, respectively) (Figure 3).

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Figure 3: Respondent’s Source of Experience with Color
About two-thirds of respondents were employed in either Marketing/Sales (31%, 16/52) or
Regulatory Affairs (31%, 16/52). Most of the remaining respondents were employed in
Research and Development (19%, 10/52) and Product Development (12%, 6/52) (Figure 4). A
few respondents selected Quality Assurance or another category not offered as a choice.

Figure 4: Occupational Category

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The majority of respondents (78%, 43/52) identified that they were in positions at or above the
manager level (Figure 5). Most commonly, the respondents were team leaders/managers (38%,
20/52) or directors (25%, 13/52), and a few were members of the executive team at or above the
VP level. Only 17% (9/52) of respondents self-identified as individual contributors.

Figure 5: Occupational Level

Additionally, respondents worked for companies that had business interests in varying regions
around the world (Figure 6). At least 85% of respondents identified that their companies were
present in all of the continents listed as choices.

Figure 6: Operating Region

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Respondents were asked to rate their level of familiarity with color regulations. Of the 53
respondents starting the survey, 94% (51) of respondents ranked their levels as intermediate or
above and were prompted to complete the survey (Figure 7). The remaining 2 were directed to
the end of the survey.

Figure 7: Self-Rating of Regulatory Knowledge

4.3 Experience with Color Selection and Decision Making
Respondents with a self-affirmed intermediate or expert knowledge of color regulations were
then asked a series of questions designed to establish their experiences with color selection
during the previous five-year period. Respondents were asked about their employment during
the previous five-year period to determine if they had recent experience in a company that either
used or sold colors for consumer products. The 82% of respondents (41/50) who had experience
in such companies were asked additional questions about their experiences related to color
selection and decision making.
Respondents proceeding to this section were first categorized according to the activities that had
informed their experience. The results indicated that 39% (16/41) of respondents participated in

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activities involving the use of colors in consumer products whereas 60% (25/41) participated in
activities involving the sale of colors to industry (Figure 8). The respondents were further
categorized to identify those with experiences with natural colors versus synthetic colors. The
groups had about an equal representation of natural versus synthetic color experience, 19%
(7/41) and 20% (8/41) amongst those who used colors for products and 28% (12/41) and 32%
(13/41) amongst those selling the colors to industry (Figure 8).

Figure 8: Respondent’s Source of Color Experience

Respondents were asked to indicate whether regulatory requirements or consumer preference had
been most influential when making color decisions in their company. Most respondents, 63%
(26/41), felt that consumer preference was most influential whereas 34% (14/41) felt that
regulatory requirements were most influential (Figure 9). Only one respondent felt that neither
was influential.

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Figure 9: Color Decision Influencers

Respondents were further asked if these influences actually caused synthetic colors to be
removed from their consumer products. Regulatory requirements were reported to drive the
removal of synthetic colors by 34% (13/38) of respondents, whereas consumer preference was
indicated as cause of removal of synthetic colors by 56% (20/36). Most respondents (73%,
30/41) believed that the use of natural colors had an impact on consumer buying behavior. Only
a few (10%, 4/41) felt that it did not affect buying behavior and a modest number were unsure
(17%, 7/41) (Figure 10).

Figure 10: Influence of Natural Colors on Consumer Buying Behavior

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In an open-ended question, respondents were asked to describe factors that they felt had limited
their company’s use of natural colors. In 34 individual comments provided, 74% (25) mentioned
the stability of natural colors as a key impediment to their use. Other comments cited regulatory
concerns (24%, 8), performance (24%, 8) and cost (21%, 7) as barriers to the adoption of natural
colors. A selection of comments on these top factors are presented in Table 1. A complete list
of comments can be found in Appendix C.

Table 1: Factors Limiting the Use of Natural Colors
What barriers, if any, do you feel may limit your company’s use of natural colors?
Stability
Stability of the natural colors and difficulty in color matching.
Natural colors have limitations including stability, all around 'general purpose' limitations (use is
particular is not as straight forward as FD&C synthetic.
Stability concerns.
Reduced stability profiles when compared to synthetic colorants.
Regulatory Concerns
The lack of a classification for Coloring foodstuffs in many countries, this type of colours are also not
permitted in pharmaceuticals in Europe.
Also a general lack of regulatory acceptance globally impacts natural colors and natural color suppliers
try to avoid regulations by promoting colouring foodstuffs.
With multinational companies - regulatory nuances between countries sometimes prevents developing
common global formulas.
Regulatory approvals in certain countries.
Performance
Not able to achieve the colours required by customers when using natural compared to synthetic.
Limited color palate.
Poor Color Strength.
Color and its shade as pharma and dietary manufacturers always demand exact shade matches for their
products.
Cost
The cost is higher.
Natural colors are much more expensive than synthetic and have much shorter shelf life.
It’s depend of the color, some barriers are few supplier sources and price, stability.
Price, stability especially to heat and pH, vibrancy.

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4.4 Experience with Selection of Natural or Synthetic Colors
The survey then explored specific experiences of the respondents regarding natural or synthetic
color selection, and how these choices had impacted their choices and their consumer products.
Respondents were first asked if their company had chosen either natural colors or synthetic
colors for a project in the last five years. Only respondents with an affirmative response were
presented with the questions on the nature and impact of the decision.
When asked about selection of natural colors for projects in the last five years, 40 responses were
received. Of the those responding, 90% or 36 had participated in a project in which a natural
color was selected. Only these 36 respondents were asked additional questions about the
selection of natural colors, detailed below in section 4.4.1.
In the case of selection of synthetic colors, 38 responses were recorded. Of the 38 respondents,
82% or 31 respondents had selected synthetic colors for a project in the last five years. These 31
respondents were asked additional questions about the selection of synthetic colors, detailed
below in section 4.4.2.
4.4.1 Natural Color Selection
The key reasons for the selection of natural colors for new projects are listed in Figure 11.
Respondents could select multiple responses. In a large majority (89%, 31/35) of those
responses, “consumer preference” was identified as a primary reason for selecting natural colors
(Figure 11). About two-thirds of respondents (63%, 22/35) selected “marketing reasons”.
“Regulatory status” was selected as a reason in 40% (14/35) of responses and a few (9%, 3/35)
also chose “regulatory filing implications”. “Stability of the color” was chosen by 26% (9/35) of
the respondents. The remaining reasons selected related to availability, 20% (7/35); cost, 9%

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(3/35); ability to match color, 17% (6/35); and complexity of development, 3% (1/35). Safety
concerns also accounted for 17% (6/35) of responses (Figure 11).
Figure 11: Reasons for Selecting Natural Colors

When respondents were asked to indicate how the selection of natural colors impacted their
consumer product, at least some respondents indicated that the selection affected all of the
attributes with which they were presented (Figure 12). In order to determine which attribute
appeared to be most affected, selections were weighted and averaged to produce an impact index
(Table 2), as discussed in the methods. The highest overall impact was attributed to the ability to
match color, which had an impact rating of 2.5 (Table 2). Nearly as important was its effect on
the product’s shelf life (2.4) and cost to manufacture the product (2.3) (Table 2). To a lesser
degree, complexity of product development and the cost of the retail product were also was cited
by respondents as impacted with overall impact ratings of 2.2 and 2.1, respectively (Table 2).

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Figure 12: Impact of the Use of Natural Colors

Table 2: Use of Natural Colors Impact Rating Factor

Strongly Impacted
(Response Count X3)
Somewhat Impacted
(Response Count X2)
No Impact
(Response Count X1)
# of Responses
Overall
Impact
Factor
Cost 33 38 2 32 2.3
Retail Cost 21 30 4 26 2.1
Shelf Life 54 20 5 33 2.4
Complexity 36 28 5 31 2.2
Match Color 54 24 2 32 2.5

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The same respondents who were asked the questions above were also asked if synthetic colors
were considered as an alternative option for those projects. Responses to this question were
almost evenly split (52%, “No”; 48%, “Yes”).
4.4.2 Synthetic Color Selection
Respondents who had chosen synthetic colors for a project in the last 5 years were then offered
similar questions about the implications of that experience. First, they were asked about the
reasons why synthetic colors were selected from a set of offered choices. Respondents could
select more than one choice. The responses of the 29 respondents to this question are shown in
Figure 13. Leading reasons selected by respondents were: the ability to match color (83%,
24/29), stability (83%, 24/29) and regulatory status (76%, 22/29). Also significant to
respondents were the availability (52%, 15/29) or cost (45%, 13/29) of those colors. In the case
of synthetic colors, consumer preference (28%, 8/29) and marketing reasons (24%, 7/29) were
much less influential than for natural colors. The remaining less frequently chosen responses
included: complexity of development (21%, 6/29); regulatory filing implications (17%, 5/29);
and safety concerns (10%, 3/29).
Figure 13:Primary Reason for Selecting Synthetic Colors

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Respondents were asked if natural colors were also considered in the projects in which synthetic
colors were selected. Of the responses to this question, 64% (16/25) indicated that natural colors
were considered but synthetic colors were ultimately selected. Respondents were also asked, in
separate questions, if synthetic colors were replaced as a result of regulatory concerns or
consumer preference. Only 34% (13/38) stated that they had replaced or removed synthetic
colors for regulatory reasons. However, 56% (20/36) indicated that they had replaced or
removed synthetic colors for reasons of consumer preference.
Respondents were asked if their companies had changed their philosophy regarding color choice
in the last five years. Responses from 35 respondents were divided 40% (14/35) indicating that
they had changed their philosophy and 60% (28/35) who had not (Figure 14). Those that
responded to this question were invited to elaborate on their response. Comments were provided
by 34 respondents. A selection of the comments representing both those who indicated a change
in philosophy and those that did not is presented in Table 3. The full list of comments is
provided in Appendix D.
Figure 14: Changing Philosophy on Color Selection

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Table 3: Comments on Changing Philosophy of Color Selection
Comments on Changed Philosophy
We have added new product lines to specifically target the dietary supplement (and potentially
pharma) customers who desire to utilize natural colors and avoid synthetic colors. We have not moved
in this direction though due to ANY concern about the safety of synthetic colors because we believe
these colors to be inherently safe and that this has been demonstrated by many high quality studies
over the years. In fact, there is significantly more information available demonstrating the safety of the
synthetic colors than there is for natural colors. We are only responding to what some of our
customers would like to see developed for their purposes.
We sell b2b so our customers have started to select natural colours for DS applications, this is driven
by consumer preference. As a result we have made more natural colours available.
Needing to keep up with consumer preference
We adapt to the customer demands which has always been our philosophy
we have decidedly chosen more natural source colors over synthetics
The market trends and consumer preference to natural colors has changed the company philosophy
strongly.
Comments on Related to Unchanged Philosophy
color selection has been the same
We have not considered moving into the natural color market because our expertise has historically
been the synthesis and purification of synthetic colors and pigments.
We manufacture synthetic colors and don't currently have a path forward to "make"/extract natural
colors. We are aware of the increase in requests for natural colors, but I haven't seen an overall
philosophy change in how we are approaching our supply.
In the pharma sector our philosophy has not changed, however in the supplement sector the vast
majority of products developed recently contain natural colors based purely on consumer
opinion/perception. We have invested strongly in the qualification of a range of natural colors used to
pigment our product offering.
We select the color that provides the best blend of value, technical effect, customer delight, and
usability in the manufacturing process. Whether or not the pigment or dye is derived from natural
sources is not significant for nearly all of our customers. Natural is not synonymous with safe.
We use synthetic colors within the regulatory requirements of various global regulations. there have
been issues involved with use of synthetic colors but based on scientific justifications of USFDA we
are using colors for our products and so are our customers. We have not changed our thinking on use
of colors

In the final question in this section of the survey, respondents were asked to comment on the key
factors impacting color selection over the last five years. Thirty-three responses were submitted.

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The primary reasons listed were consumer preference (16/33) and regulatory concerns (15/33).
Other significant reasons were: stability (4/33); cost (3/33); and ability to match colors (3/33).
Availability (2/33), ease to market (1/33) and marketing reasons (1/33) were also mentioned. A
sample of the comments in each of the primary categories is listed in Table 4. A complete list of
comments is provided in Appendix E.
Table 4: Key Reasons for Color Decisions
In the last 5 years, what are the key factors that have impacted color decisions for your products?

Consumer Preference
Consumer demand and regulatory acceptance.
Consumer preference, and regulatory issues
Consumer preferences and negative news about synthetic.
For us, it is our customer's preference. We do see a preference for natural colorants.
Customer Demand
Again the key factor has been consumer preference, over regulatory changes. However in Europe it could be said
that public opinion has itself driven regulatory changes, eg quantitative limits on certain colors.
The key factor has been the consumer preferences which affected finished dosage product manufacturers (i.e. our
customers), who request for naturally derived, clean label ingredients to be used in film coating systems.
The elimination of ingredients that are not recognizable to consumers and undesirable to consumers.
requirements from customers who will specify if they want non synthetic pigments
Customer preferences & regulatory factors
Regulatory Concerns
The Southampton Study and the ensuing political decision by the European Parliament to require a warning label
for these synthetic colors essentially created a situation in Europe for foods and food supplements where none of
the finished product manufacturers want to use synthetic colors in their products due to consumer perception of a
problem and the need to put this warning label on their products. Additionally, the current situation in France
where they are planning to suspend use of TiO2 E171 for food applications is driving the need for TiO2-Free
formulations. Again, this concern in France is not based on good science but rather a political situation driven by
one poorly run study in France on E171 that is not credible.
Regulation for global markets.
Regulatory approvals
Regulatory& consumer preference toward clean labeling

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Sometimes use of colorants in Europe for paediatric use is a concern. Many azo colors are not usable in such
formulations and its a concern to Pharma users when they have to distinguish between various strengths or doses
of their products. sometimes even after using a right permissible colorants the regulatory agencies ask for
removal of the colorant or justification on safety . Regulatory agencies in Europe are very sensitive to use of
colorants in drugs especially paediatric.
negative regulatory changes in the EU, Russia etc inappropriately requiring a warning label about attention in
kids. This inappropriately-assigned legislation against synthetic colourants and lack of understanding of science
under the guise of safety is negatively impactful to all except the natural colour companies. Sadly this lack of
science gets pushed to the common people and leaders of companies that natural colours must be "better" than
synthetic colours. there is room for both synthetic colors and natural colors in the world. but the natural color
industry is pushing only for natural colors, going against science /synthetic colors under the guise of safety when
in actuality it is to increase their profits. This is unethical, and I am not sure how these natural color companies
live with themselves. they are totally gaming the system.
Stability
stability, availability and market regulations
Stability, ability to match the colour
Cost
Price- if company cannot afford natural colors, must use synthetic Stability- if natural color does not provide the
needed stability including vibrancy, need to use synthetic colors
Ability to Match Color
Mainly our customers preference combined with regulatory considerations, ability to match color, stability and
cost.
Availability
availability, cost natural vs synthetic, % usage in formula
4.5 Impact of Southampton Study
The next section of the survey asked respondents about their opinion of the Southampton Study
and their views on the impact of the study on the regulation of colors. Before proceeding,
respondents were asked if they were aware of the Southampton Study. There were 48 responses
to this question with 83% (40/48) of respondents indicating that they were aware of the
Southampton Study. Eight respondents (17%) were not aware of the study. The 8 respondents
that were not aware of the study were not presented with the next question about the validity of
the study.

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The 40 respondents that were familiar with the Southampton Study were asked if they felt it was
scientifically valid. The majority of respondents, 74% (29/39), indicated that they did not feel
the Southampton Study was scientifically valid (Figure 15). Another 8 respondents (21%) were
not sure and only 2 of the 39 respondents (5%) felt the Southampton Study was a scientifically
valid study (Figure 15).
Figure 15: Validity of Southampton Study

Additional questions about the Southampton Study’s impact on color regulation were posed later
in the survey. One question probed the respondent’s views on impact of the regulations that
resulted from the Southampton Study on public safety. Respondents were asked if they felt that
the additional labeling regulations for colors used in the Southampton Study has resulted in an
increase in public safety in Europe. Out of 47 responses, 38 (81%) disagreed to some extent that
this additional labeling has increased the safety of the public (Figure 16). Alternatively, 5
respondents (11%) felt that these measures have increased the safety of the EU citizens (Figure
16). There were 4 respondents that indicated they could not comment on this topic (Figure 16).

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Figure 16: Increased Public Safety As A Result of Additional EU Labeling

The next question sought to capture the respondent’s views on how the Southampton Study
impacted the regulatory environment for colors in general. Out of 47 respondents, 42 (89%) did
not feel that the study had a positive impact on the regulatory environment for colors (Figure 17).
Only 4 respondents (8%) had the opposing opinion that the study had a positive impact (Figure
17). One respondent did not feel able to comment on this topic.
Figure 17: Impact of Southampton Study on the Regulatory Environment

Respondents were asked if they felt the United States should follow the EU in requiring
additional labeling for colors that were the subject of the Southampton Study. A majority, 60%

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(28/47), disagreed with this point of view (Figure 18). A smaller group, 23% (11/47), were
neutral on this statement and 15% (7/47) agreed that the US should have similar labeling
requirements (Figure 18). One respondent did not feel they could comment on this topic.
Figure 18: Should US Follow EU with Additional Labeling for Southampton Colors
In the final question about the Southampton Study, respondents were asked their opinion as to
the influence of the actions of the EU following the study on legislation in other countries. Of
the 47 respondents answering this question, 60% (28/47) felt that to some extent the legislative
actions of the EU in response to the Southampton Study influenced legislation in other countries
(Figure 19). A smaller number, 19% (9/47), were neutral on this topic with 17% (8/47) not able
to comment (Figure 19). Only 4% (2/47) did not think there was any influence on other
countries (Figure 19).

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Figure 19: Influence of EU Actions on Other Countries

4.6 Effectiveness and Utility of the Current Regulations
The next set of questions in the survey sought to establish the views of the respondents on the
effectiveness and utility of the current regulations. The first questions related to this topic focus
on the impact of regulatory changes in the EU related to the use of synthetic colors. Respondents
were asked if they felt the regulatory changes in the EU supported the interests of the consumers.
Of the 47 respondents, 25 (53%) agreed or strongly agreed that the regulatory changes were
supportive of the consumer’s interests while 16 (34%) disagreed with this assertion (Figure 20).
Five respondents (11%) were neutral on this topic and 1 respondent could not comment (Figure
20).
Figure 20: Do EU Regulatory Changes Support Consumer Interest?

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Next, respondents were probed on their views of how the EU regulatory changes impacted small
companies. The majority of the 46 respondents, 74% (34/46) agreed or strongly agreed that
these regulatory changes make the regulatory environment more challenging for small
companies (Figure 21). Alternatively, 9% (4/46) of respondents held the opinion that the
regulatory changes did not make it more challenging for small companies (Figure 21). There
were 11% (5/46) that were neutral on this topic and 7% (3/46) that felt they could not comment
on this topic (Figure 21).
Figure 21: Impact of EU Regulatory Changes on Small Companies

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Respondents were also asked whether differing regulations in the EU and US had an impact on
trade. A majority of respondents, 68% (31/46), agreed or strongly agreed that differing
regulations do have an impact on trade (Figure 22). However, another 9% (4/46) of respondents
disagreed with this assertion (Figure 22). Of the respondents, 17% (8/46) were neutral on this
topic and 7% (3/46) did not feel they could comment on this question (Figure 22).

Figure 22: Impact to Trade of Differing Regulations in the US and EU

The next questions probed the respondents on their thoughts regarding the impact of limitations
and additional labeling imposed in the EU on the use of synthetic colors by the pharmaceutical
and dietary supplement industries. In the case of the pharmaceutical industry, only 2% (1/47) of
respondents felt these measures had a positive impact on the industry (Figure 23). Of the 47
respondents, 40% (19/47) had the view that these measures had a negative impact on the industry
and 34% (16/47) had the view that these measures had no impact (Figure 23). Twenty-three
percent (11/47) of respondents were unsure of the impact (Figure 23). In the case of the dietary
supplement industry, 11% (5/47) of respondents felt these measures had a positive impact on the
dietary supplement industry (Figure 24). In contrast, 53% (25/47) of the respondents felt the
measures had a negative impact on the industry and 11% (5/47) had the view that the measures

58
had no impact (Figure 24). A further 23% (12/47) were unsure of the impact of the measures
(Figure 24). Respondents were asked to elaborate on their responses regarding impact to these
industries. A selection of the comments is provided in Table 5. The full list of comments is
provided in Appendix F.
Figure 23: Impact of EU Measures on the Pharmaceutical Industry

Figure 24: Impact of EU Measures on the Dietary Supplement Industry

Table 5: Selected Comments Expanding on the Impact of EU Restrictions and Legislation
on the Pharmaceutical and Dietary Supplement Industries
Conflicting regulations between regions presents significant challenges for suppliers.
Reformulations due to regulatory changes causes unnecessary work with no benefit to the
consumer and higher cost for all.

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Eliminating potentially superior products (colors) based on a false categorization of the
entire class of those products into "synthetic" or "natural", is not a good way to make
regulation. Each individual product whether natural or synthetic should be evaluated
objectively for safety and other performance characteristics. Restricting colors on the basis
of their natural or synthetic origin will have a negative impact on industry and the consumer
by possibly eliminating availability of the best colors for certain applications.
The warning label requirement in the EU is primarily for foods and food supplements, not for
pharmaceuticals. Therefore, while most food and food supplement manufacturers are
avoiding synthetic colors in Europe, this is not the case yet with many pharmaceutical
companies. Many of them are still using synthetic colors. However, some are now starting to
think about possible removal of synthetic colors. However, the stability of natural colors is
typically not good enough for the shelf life needs of many pharmaceuticals so natural colors
are many times not good alternatives.
In my opinion, media coverage, suggesting negative safety issues, leads to the biggest
impact on consumer preference.
Regulatory decisions in the food industry for color additives eventually negatively impacts
the dietary supplement and pharmaceutical industry. A similar example may be the
increased use of gluten-free claims in food labeling is now negatively impacting the dietary
supplement and pharmaceutical industry.

Respondents were asked to provide their views as to the impact of the recent regulatory changes
on consumer safety. A majority of respondents, 68% (32/47) indicated that they did not think
that the recent regulatory changes were improving consumer safety (Figure 25). A smaller
number, 9% (4/47), had an opposing view and indicated that they felt these regulatory changes
did improved consumer safety (Figure 25). There were also 23% (11/47) who were unsure if
there was an impact to consumer safety (Figure 25).
Figure 25: Impact of EU Regulatory Changes on Consumer Safety

The last question in this section explored respondent views on current United States color
regulations. A majority of respondents, 68% (32/47), agreed or strongly agreed that the current

60
US regulations were sufficient to protect the health of the citizens in the US (Figure 26).
Another 13% (6/47) were neutral on this topic and a smaller number, 10% (5/47), had an
opposing view and either disagreed or disagreed strongly that US color regulations were
sufficient to protect the public health (Figure 26). There were 9% (4/47) of respondents that did
not feel that they could comment on this topic (Figure 26).
Figure 26: Views on Sufficiency of US Color Regulations to Protect the Public Health

4.7 Views on Consumer Preference
In the next set of questions, respondents were asked to provide their views on how consumers
feel about colors. Specifically, respondents were asked if they think consumers prefer natural
colors over synthetic ones. Most respondents, 64% (30/47), agreed or strongly agreed that
consumers prefer natural colors (Figure 27). A smaller number, 19% (10/47), were neutral on
this topic (Figure 27). In contrast, 13% (6/47) of respondents disagreed or strongly disagreed
that consumers prefer natural colors (Figure 27). One respondent could not comment on the
question (Figure 27).

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Figure 27: Consumer Color Preference

Respondents were asked directly to provide their views about the safety of colors. Responses
were divided across all potential choices. Of the 47 respondents, 47% (22/47) disagreed or
strongly disagreed that natural colors were safer than synthetic colors (Figure 28). Another 28%
(13/47) were neutral on this point (Figure 28). With an opposing viewpoint, 17% (8/47) of
respondents did feel natural colors were safer than synthetic colors (Figure 28). A small number,
9% (4/47), could not comment on this question (Figure 28).
Figure 28: Safety of Natural Colors Versus Synthetic Colors

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4.8 Development of Regulations
The final set of questions in the survey focused on collecting respondent views on the
development of regulation and the factors that should be considered by regulators when
developing new regulations on the use of colors. The first question focused on the role of
consumer preference in the drafting of regulations. Respondents were asked their view on
whether regulators should consider consumer preferences or opinions when drafting regulations.
In response to this question, the majority of respondents, 66% (31/47), indicated that consumer
preference should never be considered by regulators and that all regulations should be based only
on science (Figure 29). Alternatively, 30% (14/47) of respondents indicated that they felt
regulators should consider consumer preference sometimes, depending on the circumstance
(Figure 29). A smaller number of respondents, 4% (2/47), felt that regulators should always
consider consumer preference when drafting regulations (Figure 29).
Figure 29: Consumer Preference as a Factor in the Development of Regulations for Colors

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Another factor that might be considered in developing regulations is the impact on industry.
Respondents were asked if regulators should consider the impact of a regulation on industry
when they develop regulations. Half of respondents, 50% (23/46), agreed or strongly agreed that
regulators should not consider industry impact when developing regulations and should only
focus on public health (Figure 30). Alternatively, 41% (19/46) of respondents disagreed or
strongly disagreed and felt that industry impact should be considered by regulators (Figure 30).
Additionally, 15% (7/46) of respondents were neutral on this topic (Figure 30).
Figure 30: Industry Impact as a Factor in Developing Regulations

Another potential consideration for regulators is the potential impact on the cost of consumer
goods such as pharmaceuticals and dietary supplements. Survey respondents were asked their
views about whether regulators should consider the potential impact to the cost of consumer
goods when developing regulations. Over half of respondents, 53% (24/46), agreed or strongly
agreed that the potential impact on consumer good prices should not influence regulators in

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promulgating regulations (Figure 31). Alternatively, 33% (15/46) of respondents disagreed or
strongly disagreed with the statement presented and felt that regulators should consider the
potential impact to the cost of consumer goods when developing regulations (Figure 31).
Another 15% (7/46) were had a neutral position on this topic (Figure 31).
Figure 31: Impact on the Cost of Consumer Goods as a Factor in Developing Regulations

Respondents were asked their views on regulations that challenge the marketing capabilities of
companies; specifically, if regulations are challenging for companies, does this negatively impact
the health of the industry? Of the 46 respondents, 42% (19/46) indicated that they agreed or
strongly agreed that these types of regulations have a negatively impact the health of the industry
(Figure 32). Another 17% (8/46) had an opposing view and disagreed or strongly disagreed that
these types of regulations negatively impact industry (Figure 32). Twenty-eight percent (13/46)
of respondents that had a neutral position on this topic and another 13% (6/46) did not feel they
could comment on this question (Figure 32).

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Figure 32: Impact of Challenging Regulations on the Health of the Industry

In addition to restrictions and additional labeling requirements for synthetic colors in the EU, the
EU and other regulatory agencies in Europe have encouraged manufacturers of consumer goods
to switch from synthetic colors to natural colors. Survey respondents were asked if regulators
should be influencing companies to move away from synthetic colors since these colors continue
to be legally permitted for use in consumer products. A majority of respondents, 77% (36/47),
indicated that they do not think regulators should be involved in this type of activity (Figure 33).
A smaller number, 17% (8/47), were not sure if they agree with this practice and a few
respondents, 6% (3/47), felt regulators should be encouraging this type of activity (Figure 33).
Respondents were also asked if they felt switching to natural colors would negatively impact
consumer products. Of the 46 responses to this question, 37% (17/46) disagree or strongly
disagree that a switch to natural colors would negatively impact consumer products (Figure 34).
Alternatively, 33%, (14/46) of respondents agree or strongly agree that switching to natural
colors would negatively impact consumer products (Figure 34). A smaller number, 28% (13/46),

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had a neutral opinion on this topic and a few, 4% (2/46), could not comment on this question
(Figure 34).
Figure 33: Should Regulators Encourage Manufacturers to Move Away from Synthetic
Colors?

Figure 34: Impact of Switching to Natural Colors on Consumer Products

The last question listed various factors that may influence the development of regulations.
Respondents were asked to rate these factors as “Critical”, “Major” and “Minor” regarding their
views as to the importance of each factor in developing regulations. The results of these ratings
are shown in Table 6. Assessing the highest rated factors in each category, the following factors

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were the two highest rated in the “Critical” category: impact on safety at 91% (43/47); impact on
quality at 57% (27/47) (Table 6). In the category of “Major”, the two highest rated factors were
the following: impact on availability of products at 64% (30/47); ability of industry to comply at
51% (24/47) (Table 6). In the category of “Minor”, the two highest rated factors were the
following: consumer views at 66% (31/47); impact on price of products at 49% (23/47) (Table
6).
Table 6: Factor Criticality in Developing Regulations

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CHAPTER 5. DISCUSSION
5.1 Overview
Although colors have been used for centuries in various types of consumer products, how they
should be regulated has been a subject of debate. Many controversial studies on the safety of
colors have been carried out during the last few decades but none has been more impactful than
the study conducted at the University of Southampton that concluded a causal relationship
between the consumption of synthetic colors and increased hyperactivity in children (Scotter,
2011). Although many scientific bodies and regulators have criticized the scientific validity of
that study, it nonetheless formed the basis for legislative changes in the EU. The research results
presented here examine these regulations in the context of the intended goals of regulation by
exploring the views of industry on this topic.
5.2 Methodological Considerations
5.2.1 Limitations
5.2.1.1 Availability of Participants
One of the potential limitations identified at the outset of this study was the availability of
suitable, willing participants with appropriate experience and credentials. A small survey sample
can limit the value of a study to represent the opinions of the larger industry population.
However, for this study, inclusion criteria were deliberately strict. Targeted participants were
required to have more than a basic understanding of color regulation; they needed to have
enough experience in their respective companies to be knowledgeable about the impact of the
regulations on their business. This narrowed pool of respondents already represents a fraction of
regulatory professionals. It is limited further to those individuals willing to participate in a

69
survey. Survey fatigue is a common reason that otherwise qualified participants may decline to
participate (Karlberg, 2015).
Other factors that can limit sampling are associated with the logistics of recruitment activities.
Using diverse strategies for recruitment can improve the likelihood that the response will reflect
the views of the population of interest (Ponto, 2015). Thus, multiple methods of recruitment,
from personalized approaches with known experts, to attendance at trade association meetings
and appeals in targeted on-line chat groups, were used in this study to assure an adequate sample
size. Even with these efforts, it is likely that more participants could have been recruited if it
were possible to attend all related trade association meetings. However, it seems as though the
recruitment effort was quite effective, based on the high percentages of respondents with suitable
backgrounds in color regulations and strong experience to comment on the impact of regulations
for their companies. The response rate of 72%, seen here, is considered above average. In an
examination of surveys done by Baruch and Holtom (2008), the reported health care industry
average survey response in the health care industry was 53.8% with an average of 50% across
multiple industries. Other studies place the response rate much lower. One retrospective review
of 35 e-mail surveys across found an average response rate of only 33% (Shih and Fan, 2009).
5.2.1.2 Survey Methodology
Survey research is a common method to collect data on a substantial pool of widely distributed
participants, in order to assure appropriate representation of views from a larger population. In
this study, the survey instrument was distributed electronically to allow the applicants to
participate easily from a range of geographic locations. Surveys inherently have certain
limitations, but some of these can be managed to some extent through careful survey design.
Sources of possible serious limitations include sampling errors, measurement errors and non-

70
response challenges (Ponto, 2015). A sampling error is the inclusion of individuals that do not
represent the population of interest. Sampling errors are reduced by clearly defining the
population of interest (Ponto, 2015) and by controlling the distribution through selecting the
participants through channels in which the target population is typically concentrated.
Measurement errors are more diverse and include survey questions that are off topic or are
worded in ways that are confusing or lead to inaccurate responses. It was therefore important to
construct the survey in a manner that minimized the potential for participants either knowingly or
unknowingly to provide inaccurate information or abandon the survey. There are several reasons
that respondents may provide inaccurate information; for example, they may fear social pressure
or failures of anonymity. They may also have insufficient or outdated knowledge so that they
provide inaccurate feedback, or they simply may not understand a badly worded question (Sue
and Ritter, 2012). To minimize the likelihood that questions were misinterpreted, a focus group
was employed to evaluate the questions for its appropriateness to the research objectives and the
survey audience.
Non-response challenges can be difficult to manage and require careful organization of the
survey look, feel and length. Respondents can become disinterested or bored by surveys that are
too long or complicated (Ponto, 2015). Additionally, selected respondents can become fatigued
from receiving too many surveys and refuse to participate (Baruch and Holton, 2008). In this
study, the survey instrument was limited to 35 questions that were worded carefully to reduce
unnecessary complexity. To address first time non-responders, reminders were sent to invitees
who had not completed the survey. However, the reminders yielded only a few more
participants, perhaps because the response rate was high initially.

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5.2.2 Delimitations
This study evaluated the views of manufacturers supplying colors to the dietary supplement and
pharmaceutical industries as well as manufacturers of dietary supplements and medicinal
products. These products are specialized from a regulatory point of view because they fall under
a more rigorous regulatory system in most countries than might be typical for other ingredients
(EU, 2008). A primary focus of the study was on the appropriateness of color regulations,
particularly those in the EU. The study did not consider the use or concerns related to other food
additives, dietary ingredients, excipients or drug substances. Further, the participants were
restricted to those with at least an intermediate knowledge of color regulations. Thus, it does not
include the views of other potential stakeholders, like consumers or health care professionals,
who are known to have different views. For example, consumers often develop their views on
regulatory issues based on information provided in public media rather than a fully informed
knowledge of the science or other factors driving the regulatory environment (McCluskey et al.,
2016). Consumers are also generally focused on their own consumption of consumer products
and may have little knowledge of impact of regulations on the industries being regulated. Thus
any survey to understand their views and level of knowledge would have to be structured
differently. Restricting the study only to industry opinions while excluding other stakeholders
may result in a bias that would be otherwise be counterbalanced by exploring the views of other
stakeholder groups.
Regulations and the regulatory environment also change over time therefore the results of this
survey may have limited usefulness in the future even in the relatively mature markets in the US
and EU. Color regulations can differ or even be absent in other countries, and particularly
emerging economies. Consequently, the present research did not study the views and experience

72
of those countries. However, regulations in these countries are undergoing review, and the
results of this work may inform the changes that they might consider. As the regulatory
environment evolves in these countries, the global regulatory climate for colors will change over
time in ways that cannot be predicted.
5.3 Consideration of Results
This study used a three-part model modified from the framework recently published by Ramsey
(Ramsey, 2013) to evaluate color regulations and their impact. The first element of the
framework, to protect the public health, is a common priority across regulatory agencies around
the world, including the US FDA (FDA, 2011b). The second and third elements of the
framework, that deal with consumer protection and fair trade practices, are also important
priorities for regulatory agencies (Directorate-General for Health and Food Safety, 2016). These
three priorities can be challenging to balance and can involve tradeoffs, as consumer and
business interests are weighed against public and patient health. Viewing the study results in the
context of this triadic framework may give some perspective on the success of color regulation in
achieving a sensible balance, from the view of two major stakeholders, the medical products and
dietary supplement industries.
5.3.1 Protection of Human Health
The DG Sante is responsible for health and food safety in the EU, including the oversight of food
additives, as well as color additives. As stated in the Strategic Plan 2016-2020, it has as a goal to
“create a solid framework based on scientific facts” and to assure that its policy making is “built
on a scientific evidence base”. It seems clear from the results of this survey that almost all
industry respondents share the same view- that safety and science should be critical factors in
developing regulations. Should that mean that color regulations should be ruled by a

73
“precautionary principle” (Recuerda, 2008) in which the product is assumed to be dangerous
until well-proven otherwise? Such an approach might seem to abdicate responsibility to make a
benefit-assessment based on emerging science in favor of perceptions held by consumers that
can be based on media distortions. In this regard, most respondents appeared to feel that that the
Southampton Study, upon which certain color regulations in the EU are based, is not valid
scientifically and the regulations put into place because of that study does not improve safety or
enhance the public health. This is consistent with the views of many regulatory agencies outside
of the EU including the US FDA (FDA, 2010). Even the EU agency, EFSA, has reviewed the
study and found it to be flawed (EFSA, 2008). Therefore, it could be concluded that certain EU
regulations are not consistent with the stated goals of the DG SANTE, at least through the eyes
of the industry respondents here.
In addition to specific regulations imposing additional labeling or restrictions on synthetic colors,
European regulators have encouraged manufacturers to replace synthetic colors with natural
colors (Chapman, 2001). Their guidance does not appear to be consistent with any of the
published goals established by DG SANTE. It is well understood that natural colors have their
own problems with stability, availability and cost. Further, less than 20% of respondents in this
study regarded natural colors as safer than synthetic colors. This and other responses appear to
convey the broader opinion in industry that the choice of colors under current rules will not
change the safety profile of the currently available products. Their views are consistent with
evidence that both synthetic and natural colors have a long history of safe use (Federal Food
Drug and Cosmetic Act, 2018b). Agencies, including EFSA, that have recently reviewed the
safety of synthetic colors continue to maintain that they are safe for use and they both remain
legally permitted for use in food and drugs even in the EU. Additionally, colorants contribute

74
only a small part, usually less than 1%, to the volume of a medicinal or dietary supplement
product, so that the considerations often based on food use may have little relevance when the
amounts of color in the tablet or capsule are orders of magnitude lower than might be the case in
a food or beverage. Most respondents instead appeared to believe that that US color regulations,
which have not been modified to favor natural colors, are sufficient to protect the health of the
US public. This view matches the opinions of the 2011 Food Advisory Committee, which
declined to recommend additional regulatory changes as a result of the Southampton Study (FDA,
2011a).
What does appear to happen however, is that consumers make their own decisions when an issue like
color regulations is publicly debated. Many consumers are highly sensitive to any suggestion that a
medicinal or food product can damage the health of their families (Byrne, 2011). A similar
sensitivity is seen in other situations, such as that underlying the resistance to childhood vaccinations
(Ruiz and Bell, 2014). In these cases, “perception is reality” (Nyilasy et al., 2016). The results of
the study show that some companies appear to be using natural colors as a differentiating feature
driven by consumer preference and thus sales considerations rather than regulations related to public
health. In fact it would appear that most companies that have changed their approaches to color
selection in the last five years have used consumer related factors, not safety, as the primary
driver for natural color use.
5.3.2 Balancing Cost and Access
Protection of public health is just one type of concern that governments consider when they try to
protect consumers. Regulators also need to consider the cost of product to consumers as an
important factor in assessing a risk-benefit relationship. Chambers, Collins and Krause theorize
that regulators may sometimes seek to maximize their political influence by implementing

75
regulations that will win them favor with influential groups rather than respond to scientific or
risk-based assessments. When costly regulations are implemented to address low-probability
risks, consumers can be negatively impacted by the higher price of the affected consumer goods
(Thomas, 2019). More specifically, consumers who face higher prices for items like necessary
medicines have less money to spend on other goods including goods that might be more
impactful to reduce risk in their lives (Thomas, 2019) or they may not obtain a needed
medication because of cost concerns. In addition, regulations that increase the cost or restrict the
availability of ingredients or components of a product may affect the willingness or ability of the
manufacturer to produce that product under the restrictive rules. This in turn can decrease the
availability of the product or reduce its competitiveness with respect to other cheaper but less
effective products.
In considerations of the more stringent rules in the EU, one might ask whether products with
natural colors produced for the EU market will suffer unnecessarily when they are exported to
the US where synthetic colors are widely used. A definitive answer to this question will lie
beyond this dissertation and will depend on the relative change in cost or availability of
comparable natural and synthetic colors. If the natural color is readily available and its cost
differential is small (given the small amount of color needed for the small number of tablets in a
typical consumer package), then the effect of switching from one type of color to another may
not change product access or price significantly. If, however, the natural product is hard to
obtain, has a short shelf-life and can only be purchased at a high cost, then damaging effects on
consumer access should be much more important to consider.
Respondents in this study identified that a switch to natural colors does in fact increase
manufacturing costs, as might be predicted, and that these costs would have to be passed onto the

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consumers through the pricing of retail products. A senior vice president of sales and marketing
at a large color manufacturer reported that natural colors cost on average about five times more
than synthetic colors. This could increase the cost of manufacturing in some confectionery
applications by 20 fold over the use of synthetic colors (Crane, 2015). However, this research did
not make clear whether the added costs in dietary supplements and medicinal products were high
enough to affect prices in a significant way. Further, it was clear that some natural colors were
in short supply (Wollan, 2016) but it was not clear whether this restriction caused any product
shortages. The respondents in this study were largely drawn from regulatory job functions, so it
may be necessary to conduct additional research with the sales and marketing departments of
these companies to understand more fully the impact of moving from synthetic to natural colors
on the cost and accessibility of different products.
It may even be possible that the use of natural colors sold at a premium price might be seen as
having a beneficial outcome for sales and reputation. Based on the findings of this study, the use
of natural colors is seen to affect consumer preference. Several studies have supported this view
by showing that consumers often equate “healthy” with “more expensive” (Haws et al., 2017).
For example, in a food and beverage study of 1,600 consumers conducted by L.E.K. Consulting,
over 70% of consumers who self-identified as committed to healthy eating indicated that they are
willing to pay a premium for products with natural ingredients (Steingoltz et al., 2018). A
different study of 1,009 American consumers sponsored by the International Food Information
Council and conducted by Greenwald & Associates in 2018 reported that 4 in 10 respondents
who prefer natural ingredients would be willing to pay up to 50% more for a product with no
artificial ingredients (International Food Information Council Foundation, 2018). Thus,
companies that move to natural colors may find that they can offset the increased manufacturing

77
costs by charging more for their product. That additional price could be well in excess of the
production cost differential and could actually increase the sales revenue of the company relative
to that when using synthetic colors.
Despite the potential for companies to use natural colors as a marketing feature in a way that
could increase profitability, many respondents felt that the impact of the restrictive EU
regulations has been negative. One comment stated,
Regulatory decisions in the food industry for color additives eventually
negatively impacts the dietary supplement and pharmaceutical industry. A
similar example may be the increased use of gluten-free claims in food labeling
is now negatively impacting the dietary supplement and pharmaceutical
industry.
The literature describes other cases in which EU legislation promulgated to protect the public
health has had negative effects on the food and drug industry. For example, the EU has had
more restrictive regulations related to biotechnology and functional foods. EU regulators have
created a complex process requiring pre-approval for novel genetically modified products that
differs from not only other food categories in the EU but also from the regulatory scheme in the
US, which requires no preapproval for these types of products (Menrad and Blind, 2006).
Functional foods have also suffered a complicated start in the EU. Lack of EU-wide regulations
for many years left the industry behind the US in regulating these types of products.
As a result of the more cautious regulatory environment in the EU, some evidence suggests that
innovation in the EU’s food industry has been handicapped in comparison to that in other regions
with less restrictive regulations. Regulations that impose additional and perhaps unnecessary
bureaucratic activities increase costs. The effect of these regulations was discussed by Menrad
and Blind in their publication, The Impact of Regulation on the Development of New Products in
the Food Industry (2006). In this publication, they describe the results of a survey that explored

78
the views of EU food manufacturing firms regarding the effect of the EU regulatory framework
on innovation activities in the food industry. Their survey revealed a widely held view that the
regulations in the EU had more negative than positive effects on innovation and new product
development. This same opinion seems to be reflected by the comments made by industry
respondents in the present study. For example, one comment stated that the distinction of a color
additive only on a binary choice of “natural” or “synthetic”, is overly simplistic and restrictive.
Eliminating potentially superior products (colors) based on a false categorization of the
entire class of those products into "synthetic" or "natural", is not a good way to make
regulation. Each individual product whether natural or synthetic should be evaluated
objectively for safety and other performance characteristics. Restricting colors on the
basis of their natural or synthetic origin will have a negative impact on industry and the
consumer by possibly eliminating availability of the best colors for certain applications.
5.3.3 Establish Fair Trade Practices
A third area of interest explored in this research was the effect of different color regulations on
fair trade practices. In the EU, the strategic plan of the DG SANTE clearly states that its
regulations must not only protect public health but also support trade. One of the stated missions
of the organization is to “contribute to a well-functioning and fair internal market in food, feed,
agricultural and medical” (Directorate-General for Health and Food Safety, 2016). It aspires to
fulfill this mission by developing a regulatory framework that “supports growth, investment and
competitiveness within these sectors (health and food safety)” (Directorate-General for Health
and Food Safety, 2016). It is unclear what metrics are used by the Directorate to determine if
this goal is achieved.
The US FDA has a narrower mandate, as expressed in their Foods and Veterinary Medicine
Program Strategic Plan for the period 2016–2025. A guiding principle of their plan is that
“public health is the first priority” (FDA, 2016). FDA objectives do not typically speak to topics
related to industry competitiveness and the need for a level playing field in the area of food

79
additives including color additives. Instead, effects on the “level playing field” have more
commonly been of great interest to the Federal Trade Commission, that oversees competitive
practice and polices anticompetitive practices, especially in the areas of over-the counter drugs
and dietary supplements.
Overall results of this survey presented a mixed picture regarding the views of industry
regulatory personnel when asked about how much impact the dissonant regulations in the US and
EU will have on slanting the playing field between companies of different sizes and origins.
While this research did not indicate that the regulations in the EU have created a trade imbalance
amongst consumer product manufacturers in the EU, respondents did express the view that
dissonance between the regulations in the EU and the US had a negative impact on the industry
overall. For example, one respondent states:
“Conflicting regulations between regions presents significant challenges for
suppliers. Reformulations due to regulatory changes causes unnecessary work with
no benefit to the consumer and higher cost for all.”
It is difficult to know from this study whether it is more difficult for manufacturers outside of the
EU to enter the EU market because of the added requirements and how larger companies with a
multinational footprint are handling the dissonant requirements. Some may potentially produce
certain products for the EU market that differ from those sold in the US, but it can be more
expensive to maintain two products instead of one (Song and Chen, 2010).
From the perspective of those involved in the sale or use of synthetic colors, the EU’s position to
require additional labeling for these products puts them at a disadvantage compared to
companies that sell or use natural colors. The potential inequity is further widened by
recommendations from some EU regulatory agencies that manufacturers should move away from
synthetic colors even though they remain legal and safe. As noted previously, the division of

80
colors into synthetic and natural categories creates a false separation that puts natural colors and
synthetic colors on opposing sides. While this research cannot quantify the financial impact to
the synthetic color industry, this is an area that could be explored in future studies. However,
business analysts do predict that the growth of natural colors will outpace that of synthetic
colors, with one analyst predicting a compounded annual growth rate of 6.8% CAGR versus only
3.6% for synthetics (Prasad, 2016).
5.4 Concluding Thoughts
This study collected a representative view of industry professionals on the impact of newer EU
color regulations on the pharmaceutical and dietary supplement industries. As such it represents
only one stakeholder group’s opinions. It was clear from the responses provided by these
professionals that these color regulations are not seen to have a strong basis in science and have
been influenced to a large extent by consumer perception. This is supported by the opinions of
other regulatory agencies and remarks in the existing literature suggesting that these perceptions
have been swayed not by science but rather by the extensive media coverage of a few poorly
designed studies. The study results presented here point to concerns amongst industry
professionals that future regulation should be based instead on sound scientific studies that
support safety.
While it was not possible to quantify the impact to consumers in this study, the survey did reveal
strong feelings among most industry professionals that the impact is negative in several areas,
including cost and shelf-life. The EU color regulations apply to all food types including dietary
supplements and, by associated regulation, medicinal products, but no distinction is made in the
regulations that take into account the relatively small quantities of colors consumed from these
types of products as compared to traditional foods. Nor does there seem to be any consideration

81
in these regulations of the challenges faced by manufacturers when using natural colors in
products that could otherwise enjoy an extended shelf-life. It is hoped that this study will
provide some insight to regulators and assist them in developing science-based regulations that
protect the public health in a meaningful way. To support such policy evaluations, the results
point to the value of additional study to determine the safety risk of a low level of color, whether
synthetic or natural, when consumed in the form of tablets or capsules. Furthermore, future work
to quantify the impact of the color regulations on the entry and pricing of products into and out
of the EU and the US.

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APPENDIX A
FINAL SURVEY

The following survey seeks to explore views and experiences of individuals familiar with the use of colors
particularly in the dietary supplement and pharmaceutical industries. It is intended to investigate the
appropriateness and impact of recent regulatory changes regarding the use of synthetic colors. This survey
should take approximately 15-20 minutes. It is part of research associated with the Doctor of Regulatory Science
degree at the University of Southern California. Participation in this survey is completely voluntary. Candid
answers are important to the success of the study and responses will be kept anonymous in any published
results. Results of the survey are available on request once the survey is closed. Thank you for your
participation in this research.

NOTE: In the context of this survey, the term "natural color" is intended to represent colors derived from
natural substances such as plants, animals and minerals.

In which industry did you obtain your experience working with colors? Please select all that apply.
Manufacturer of pharmaceutical products
Manufacturer of dietary supplements
Supplier to the pharmaceutical industry

Supplier to the dietary supplement industry
Other

What occupational category best describes your most recent role in the industries selected in the previous question?
Regulatory Affairs
Research and Development
Product Formulation
Quality Control/Quality Assurance
Marketing/Commercial Sales
Other

Which job level best describes your position in the occupational category selected in the previous question?
Individual Contributor
Group/Team Leader, Manager
Director
CEO/Vice President/President
Other

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In what regions does your company do business?

Rate your knowledge of color regulations.
Expert
Intermediate
None

The following set of questions relates to your recent experience with the use of colors. Have you been employed
with a company in the last 5 years that used or sold colors?
Yes
No

Which best describes your experience with the use of colors? Please select all that apply.
Use synthetic colors for coloring consumer products
Use natural colors for coloring consumer products
Sell synthetic colors for use in coloring consumer products
Sell natural colors for use in coloring consumer products
Other

How have regulatory changes impacted how your company has selected colors in the last 5 years? Please select
all that apply.
It has not impacted color selection for new products
More natural colors have been selected
Fewer natural colors have been selected
More synthetic colors have been selected
Fewer synthetic colors have been selected
More white or clear coatings have been selected
Fewer white or clear coatings have been selected

Yes No Unsure
North America
Latin America
Europe
Africa/Middle East
Asia
Australia/New Zealand

95

Which of the following has been the MOST influential in color decisions for your company?
Consumer preference
Regulatory requirements
Neither has impacted color decisions
Not sure

Has your company replaced, removed or discontinued the use of synthetic colors in any products or product lines due to
regulatory concerns?
Yes
No
Not Sure

Has your company replaced, removed or discontinued the use of synthetic colors in any products or product lines due
to consumer preference?
Yes
No
Not Sure

Do you feel that consumer buying behavior is influenced by the use of natural colors?
Yes
No
Not Sure

What barriers, if any, do you feel may limit your company’s use of natural colors?

Has your company selected natural colors for any new or existing products in the last 5 years?
Yes
No
Not Sure

96

How did the selection of natural colors impact the following?
Strongly impacted Somewhat impacted Did not impact Not Sure
Cost to manufacture the
product
Retail cost of the product
Shelf life of the product
Complexity of product
development
Ability to match color

In the projects where natural colors were selected, what were the primary reason(s) that natural colors were
selected? Please select all that apply.
Consumer preference
Regulatory status
Regulatory filing implications
Marketing reasons
Safety concerns
Cost of the color
Availability of the color
Stability of the color
Complexity of product development
Ability to match color
Other

In projects where natural colors were selected, were synthetic colors also considered for the project?
Yes
No
Not Sure

Has your company selected synthetic colors for any new or existing products in the last 5 years?
Yes
No
Not Sure

In projects where synthetic colors were selected, were natural colors also considered for the project?
Yes

97

In the projects where synthetic colors were selected, what were the primary reason(s) that synthetic colors were
selected? Please select all that apply.
Consumer preference
Regulatory status
Regulatory filing implications
Marketing reasons
Safety concerns
Cost of the color

Availability of the color
Stability of the color
Complexity of product development
Ability to match color
Other

Has your company changed their philosophy on the use of colors in the last 5 years?
Yes
No
Not Sure

Please elaborate on your answer above.

In the last 5 years, what are the key factors that have impacted color decisions for your products?

In 2007, a study in the UK, commonly known as the Southampton Study, concluded a causal relationship
between the consumption of a group of synthetic colors and hyperactivity in children. The US FDA determined
that this relationship could not be established based on this study and took no action to change color regulations.
The European Food Safety Authority questioned the clinical significance of the findings and the methodology
used in the study. However, the EU Commission enacted legislation to require warning labeling and other
restrictions on the colors used in this study.

Were you aware of the Southampton Study?
Yes

98

Do you believe the Southampton Study was scientifically valid?
Yes
No
Not Sure

Please indicate your level of agreement or disagreement with the following statements.
Neither
Strongly Agree or Strongly Cannot
Disagree Disagree Disagree Agree Agree Comment
This action in the EU of requiring additional labeling of the
colors used in the Southampton Study has increased the
safety of the public.
The recent regulatory changes imposed on the use of
synthetic colors in the EU support the interests of consumers.
FDA should follow the lead of the EU in requiring additional
labeling in the US for the colors studied in the Southampton
study.
Natural colors are safer than synthetic colors.
Consumers prefer natural colors over synthetic colors.
The Southampton Study has positively impacted the
regulatory environment for colors.
The current color regulations in the US are sufficient to
protect the health of the citizens in the United States.
The actions in the EU following the Southampton Study have
influenced legislation in other countries.

The European Union and other regulatory agencies in Europe have encouraged manufacturers to switch
synthetic colors in their products to natural colors. Natural colors are sometimes not readily available and are
more expensive than synthetic colors. Some believe that making this switch could raise the cost of consumer
goods.

Should regulators be encouraging companies to move away from synthetic colors when these colors continue to
be legally permitted for use in consumer products?
Yes
No
Not sure

Should consumer preferences/opinions regarding the use of natural versus synthetic colors be taken into account
by regulators when drafting regulations?
Always
Sometimes, depending on the circumstance.
Never, regulations should always be science based.
Not sure
No

99

Please indicate your level of agreement or disagreement with the following statements.

Neither
Strongly agree nor Strongly Cannot
Disagree Disagree Disagree Agree Agree Comment
Regulators should only be concerned with protecting the public
health and not the impact on industry when developing
regulation.
Regulators should NOT consider the increased cost of
consumer goods in their regulatory decision-making process.

Please rate these factors as to their level of importance in developing regulations.
Critical Major Minor
Consumer views
Impact on the quality of
products
Impact on the safety of products
Ability of industry to comply with
the regulation
Impact on the availability of
products
Impact on the price of products
Other

Do you think that recent limitations and labeling imposed on synthetic colors in the EU have had an impact on the
pharmaceutical industry?
Positive impact
Negative impact
No impact
Not Sure

Do you think that recent limitations and labeling imposed on synthetic colors in the EU have had an impact on the dietary
supplement industry?
Positive impact
Negative impact
No impact
Strongly
Neither
agree nor Strongly Cannot
Disagree Disagree disagree Agree agree Comment
Recent regulatory changes pertaining to synthetic colors in the
EU are more challenging for small companies.
Regulations that challenge the marketing capabilities of
companies negatively impact the health of the industry.
Switching from synthetic colors to natural colors will have a
negative impact on consumer products.
Differing regulations in the US and EU with regard to the use of
synthetic color impacts trade.
Not Sure

100

Please elaborate on your answers regarding the impact on the pharmaceutical or dietary industries.

Do you believe that recent regulatory changes in the EU impacting the use of synthetic colors are improving
consumer safety?
Yes
No
Not sure

Thank you for completing this survey. The usefulness of the results depends on the number of views collected. If
you know someone whose input would be valuable to this topic, please provide their email address below so they
can be invited to participate in this survey.

101
APPENDIX B
ORIGINAL DRAFT SURVEY

Q1. The following survey seeks to explore views and experiences of the dietary supplement and pharmaceutical
industries. It investigates the appropriateness and impact of recent regulatory changes regarding the use of
synthetic colors. This survey should take approximately 15-20 minutes. It is part of research associated with the
Doctor of Regulatory Science degree at the University of Southern California. Participation in this survey is
completely voluntary. Candid answers are important to the success of the study and all responses are completely
anonymous. Results of the survey are available on request once the survey is closed. Thank you for your
participation in this research.

Q2. Which industry best describes your most recent employer? Please select all that apply.
Manufacturer of pharmaceutical products
Manufacturer of dietary supplements
Supplier to the pharmaceutical industry

Supplier to the dietary supplement industry
Other

Q3. What occupational category best describes your most recent position?
Regulatory Affairs/Legal
Research and Development
Quality Control/Quality Assurance
Other

Q4. Which job level best describes your most recent position?
Associate, Specialist, Coordinator
Group/Team Leader, Manager
Director
CEO/Vice President/President
Other

Q5. In what regions does your company do business?
Yes No Unsure
North America/South America
Europe/Africa/Middle East
Asia
Australia

102

Q6. Rate your knowledge of color regulations.
Expert
Basic
None

Q7. Which best describes your company’s use of colors? Please select all that apply.
Use/sell synthetic colors
Use/sell natural colors
Don't use or sell any colors

Q8.
How have recent regulatory changes impacted how your company selects colors for new products? Please select
all that apply.
It has not impacted color selection for new products.
More natural colors have been selected.
Fewer natural colors have been selected.
More synthetic colors have been selected.
Fewer synthetic colors have been selected.
More white or clear coatings have been selected.
Fewer white or clear coatings have been selected.
My company does not use colors.

Q9. Which of the following has been the MOST influential in color decisions for your company?
Consumer preference
Regulatory requirements
Neither has impacted color decisions
Not sure

Q10. Has your company replaced or removed any synthetic colors in any products due to regulatory concerns?
Yes
No
Not Sure
Q11. Has your company replaced or removed any synthetic colors in any products due to consumer preference?
Yes
No
Not Sure

103
Q12. Do you feel that consumer buying choices are influenced by the use of natural colors in your products?
Yes
No
Not Sure

Q13. What barriers, if any, do you feel may limit your company’s use of natural colors?

Q14. Has your company selected natural colors for any new products in the last 3 years?
Yes
No
Not Sure

Q15. How did replacing synthetic colors with natural colors impact the following?
Somewhat Did not replace or
Strongly impacted impacted No impact Not Sure remove colors
Cost to manufacture the
product
Retail cost the product
Shelf life of the product

Q16. In the projects where natural colors were selected for a new product, were synthetic colors also considered for the
project?
Yes
No
Not Sure

Q17. In the projects where natural colors were selected for a new product, please rank the reason natural colors
were selected from most influential (1) to least influential (7).
Consumer preference

Regulatory status

Marketing reasons

Cost

104

Stability

Other

Q18. Has your company selected synthetic colors for any new products in the last 3 years?
Yes
No
Not Sure

Q19. In projects where synthetic colors were selected for the product, were natural colors also considered for the
project?
Yes
No
Not Sure

Q20. In projects where synthetic colors were selected for the product what was the primary reason synthetic colors were
selected? Please select all that apply.
Consumer preference
Performance
Regulatory restrictions
Cost
Availability
Stability
Other

Q21. Has your company changed their philosophy on the use of colors in the last 3 years?
Yes
No
Not Sure

Q22. Please elaborate on your answer above.

105
Q24. Have these factors been influenced by regulatory changes restricting the use of synthetic colors?
Strongly Agree
Agree
Neither Agree or Disagree
Disagree
Strongly Disagree
Not Sure

Q25. In 2007, a study in the UK, commonly known as the Southampton Study, concluded a causal relationship
between the consumption of a group of synthetic colors and hyperactivity in children. The US FDA determined
that this relationship could not be established based on this study and took no action to change color regulations
as a result. The European Food Safety Authority questioned the clinical significance of the findings and the
methodology used in the study. However, the EU Commission enacted legislation to require warning labeling and
other restrictions on the colors used in this study.

Neither
Strongly Agree or Strongly Not
Disagree Disagree Disagree Agree Agree sure
This action in the EU of restricting certain colors has
increased the safety of the public.
The recent regulatory changes imposed on the use of
synthetic colors in the EU support the interests of consumers.
FDA should follow the lead of the EU in restricting the colors
studied in the Southampton study.
Natural colors are safer than synthetic colors.
Consumers prefer natural colors over synthetic colors.
The Southampton Study has positively impacted the
regulatory environment for colors.
The current color regulations in the US are sufficient to
protect the health of the citizens in the United States.

Q26.
Should consumer preferences/opinions regarding the use of natural versus synthetic colors be taken into account
by regulators when drafting regulations?
Always
Sometimes, depending on the circumstance.
Never, regulations should always be science based.
Don’t know
The European Union and other regulatory agencies in Europe have encouraged manufacturers to switch
products that contain synthetic colors to natural colors. Natural colors are sometimes not readily
available and are more expensive than synthetic colors. This could raise the cost of consumer goods
making this switch.
Q27.

106

Neither
agree
Strongly nor Somewhat Strongly Not
Disagree Disagree Disagree Agree Agree Agree Sure
Regulators should NOT consider the increased cost of
consumer goods in their regulatory decision-making process.
Switching from synthetic colors to natural colors will not have a
negative impact on consumer products.
Recent regulatory changes pertaining to synthetic colors in the
EU are more challenging for small companies.
Regulators should only be concerned with protecting the public
health when developing regulation and not the impact on
industry.
Regulations that challenge the marketing capabilities of
companies negatively impact the health of the industry.
Differing regulations in the US and EU with regard to synthetic
color usage does not impact the availability of consumer
products in these regions.

Q28.
Please rate these factors as to their level of importance in developing regulations that support the interests of the
consumer.
Critical Major Minor
Impact of the regulation on the
price of consumer goods
Consumer preferences
Impact of the regulation on the
quality of the consumer goods
Ability of industry to comply with
the regulation
Impact of the regulation on the
availability of consumer goods
Other

Q29.
Do you think recent limitations and labeling imposed on synthetic colors in the EU have had an impact on the
pharmaceutical or dietary supplement industries?
Yes
No
Not Sure

Q30. Please elaborate on your answer above.
Q31. Thank you for completing the survey. The more data that is collected, the more insightful the results will be.
If you know someone who's input would be valuable to this topic, please provide their email address below so
they can be invited to participate in this survey.

107
APPENDIX C
COMPLETE RESPONDENT COMMENTS ON FACTORS LIMITING THE USE OF
NATURAL COLORS
Question: What barriers, if any, do you feel may limit your company’s use of natural
colors?

Respondent Comments:
stability of the natural colors and difficulty in color matching
Our use of natural colors mainly comes from requests we might get from customers for
coatings or inks made with natural colors. That said, we recently have developed a series of
product lines which are designed to use natural colors since some customers seem to want
these types of products.
Performance of color
The lack of a classification for Coloring foodstuffs in many countries, this type of colours are
also not permitted in pharmaceuticals in Europe.
Stability.
Natural colors have limitations including stability, all around 'general purpose' limitations (use
is particular is not as straight forward as FD&C synthetic type colorants), refrigeration
limitations at factories, limitations due to the carriers that come along with juices, or that are
used to functionally assist natural colors (emulsifiers such as polysorbate 80, sucrose esters,
mono and di-glycerides, polyglycerol esters of fatty acids, etc). Let's face it, we need
preservatives in some colorants, and this is lacking for natural colorants. Shorter shelf lives of
natural colors negatively affect impact supply chain. Natural colors do not have the same
safety as synthetic colors--there are many natural color manufacturers that are not familiar
with color regulations (many consider it's natural so it must be reg approved), and also many
that do not understand regulations therefore it limits trust in the supply chain of natural colors.
Pesticides, higher usage rates, heavy metals, etc. Also a general lack of regulatory acceptance
globally impacts natural colors and natural color suppliers try to avoid regulations by
promoting colouring foodstuffs.
with multinational companies - regulatory nuances between countries sometimes prevents
developing common global formulas
Reduced stability profiles when compared to synthetic colorants.
Stability, cost
Stability / shorter shelf life
Color stability on storage and application on products. this indirectly influences the shelf life
allotted to our products. Batch to batch consistency in color and its shade as pharma and
dietary manufacturers always demand exact shade matches for their products

108
Main barriers are stability (shelf-life) and compatibility of the natural colorants.
The cost is higher. Synthetic colors have superior stability compared to natural colors.
STABILITY OF NATURAL COLORS
batch to batch color variation
Stability concerns
Poor Color Strength
heat and pH stability
Natural colors are much more expensive than synthetic and have much shorter shelf life. They
are also less stable, and many require refrigeration.
Supply consistency.
My experience is European, where synthetic colours were phased out more than 5 years ago.
In this market we see a move away from colour additives and to colouring foods (no selective
extraction/mostly fruit and vegetable juices). There has been no change in the actual
regulations, but the EU Guidance has made the status clear and so more regulatory-
conservative companies have begun to use them in formulations. The barriers are typically
about stability and dosage levels
Limited color palate. Change in color over time.
Regulatory approvals in certain countries
Our facility has historically focused on synthetic color manufacturing, and I am not sure if we
are equipped to manufacture natural colors.
Price, stability especially to heat and pH, vibrancy
Difficulty of Regulatory approvals
the market does not appear ready to grow / people won’t buy an appreciable amount more if
the natural colors are utilized
costs, poor stability, poor functionality
Availability, regulatory status
Regulatory restrictions and potential for impurities.
Regulatory acceptability Stability Cost Residual taste Odor
allergy purity
It’s depends of the color, some barriers are few supplier sources and price, stability.
The colors are not stable. The determination between if a natural color is a simple mixture or
co-processed excipient.
stability of natural colors over time sourcing - sometimes limited availability and difficult to
match colors across different suppliers

109
The most significant barrier is stability of the natural colour. Those which are sufficiently
stable gives a limited range of shades which can be offered. In many cases the natural color is
being used to replace a synthetic and the end user expects no shelf life reduction.
Color stability is all of the various products they are used in.
Heat stability and extractability / leachability
Not able to achieve the colours required by customers when using natural compared to
synthetic. Less stable than synthetic pigments - especially when in combinations. Finding
enough suitable colours for the pharma/dietary industry with good supply and good colour
stability.

110
APPENDIX D
COMPLETE RESPONDENT COMMENTS CHANGE IN PHILOSOPHY ON THE USE OF
COLORS

Question: Has your company changed their philosophy on the use of colors in the last 5
years? Please elaborate on your answer above.

Respondent Comments:
Different customers and different markets are the primary drivers for color selections.
We have added new product lines to specifically target the dietary supplement (and potentially
pharma) customers who desire to utilize natural colors and avoid synthetic colors. We have
not moved in this direction though due to ANY concern about the safety of synthetic colors
because we believe these colors to be inherently safe and that this has been demonstrated by
many high quality studies over the years. In fact, there is significantly more information
available demonstrating the safety of the synthetic colors than there is for natural colors. We
are only responding to what some of our customers would like to see developed for their
purposes.
Customer who have been using naturals have been using them for at least five years. There
have been some natural pigments that have been moved to the "no" list in that five years but
still using natural pigments.
We sell b2b so our customers have started to select natural colours for DS applications, this is
driven by consumer preference. As a result we have made more natural colours available.
We tend to focus on US/EU/JP colors for pharma products.
the SH6 study has been negatively impactful globally. The poor study design (and resulting
lack of conclusions) of this study and resulting European regulators implementing a warning
label about attention and activity of children was in effect a ban on these 6 colorants. The EU
regulators ignored their own independent body EFSA's review of the SH6 study. There is
serious lack of understanding in the regulators in the UE (their desire to allow colouring
foodstuffs, the warning label requirement for the 6 colourants used in the south hampton
study, lack of understanding of the importance of colour, lack of understanding of synthetic
colorant purity and resulting low usage levels in foods, etc). In the EU, the precautionary
principle is often mis used and so is the term "other legitimate factors"--that the regulators
have built into the EU regulations which effectively allow perpetuation of negative
misunderstandings of science across all ingredients, and especially synthetic colours to
negatively impact regulations. Also the EU regulators inappropriately believe that natural
must be better. unfortunately other countries globally look to the UE for regulatory guidance,
and the supplier of natural colorants (cha ching) have perpetuated this inappropriate negative
view of synthetic colorants.
Needing to keep up with consumer preference

111
We use synthetic colors within the regulatory requirements of various global regulations. there
have been issues involved with use of synthetic colors but based on scientific justifications of
USFDA we are using colors for our products and so are our customers. We have not changed
our thinking on use of colors
We have made significant investment to expand the use of stable colorants such as Sprulina
extracts & Iron Oxide in DS applications in NA through petitions to FDA, as well as
conducting stability and compatibility studies on naturally derived pigments.
Synthetic colors are undesirable to consumers.
We adapt to the customer demands which has always been our philosophy
The market trends and consumer preference to natural colors has changed the company
philosophy strongly.
The Colors we offer are generally considered safe.
There is a strong consumer preference for Natural Colors on top of some Regulatory issues for
synthetic colors. Cost and stability however are significant issues when dealing with Natural
Colors.
We are suppliers of colors, therefore, we adapt our offer including natural colors.
We offer both natural and synthetic colorants to our customers. We have seen more of a trend
towards natural colorants. Probably due to marketing concerns, that indicate consumers prefer
a cleaner or more natural colorant use.
color selection has been the same
We have not considered moving into the natural color market because our expertise has
historically been the synthesis and purification of synthetic colors and pigments.
Company's philosophy since inception in 1931 has always focused on natural ingredients,
including colors
we have decidedly chosen more natural source colors over synthetics
we are prepared to utilize them because the market appears to be requesting them but not
willing to pay for them
We manufacture synthetic colors and don't currently have a path forward to "make"/extract
natural colors. We are aware of the increase in requests for natural colors, but I haven't seen
an overall philosophy change in how we are approaching our supply.
We provide formulations with both synthetic and natural colorants to the pharmaceutical and
nutritional supplement industries. While we have seen some customers begin to change their
preference to natural colors, there is still significant demand for formulations with synthetic
colors. We will continue to provide formulations with both types of colorants for the
foreseeable future.
Colors are selected first by regulatory status. This is true GLOBALLY. That has to be the
starting point for all product classifications (foods, drugs, cosmetics; perhaps not so much for
devices). For products making "natural" or "no synthetic dyes" claims, the next criterion is the
biological origin of the colorant (plant, insect, fish), or synthetic organic vs. inorganic.
Use more non-synthetic colorants. More resources used to evaluate stability, alone and in
combination with other colorants

112
I think that the regulation is the most important point. The philosophy depends on it. The
regulation is not amended in Japan, recently.
My company are able for both, natural and synthetic color, it depend of the customer’s
requesting.
We use both synthetic and natural colors in our formulations.
X is a solution provider and therefore does not take a stance on any colorant type. Instead we
offer a variety of color options to meet all customer needs and requirements, be they related to
regulatory, consumer preference, stability, etc.
In the pharma sector our philosophy has not changed, however in the supplement sector the
vast majority of products developed recently contain natural colors based purely on consumer
opinion/perception. We have invested strongly in the qualification of a range of natural colors
used to pigment our product offering.
We started to use Natural colors in that timeframe, and we have continually developed
stability programs and products based on continued consumer preference.
We select the color that provides the best blend of value, technical effect, customer delight,
and usability in the manufacturing process. Whether or not the pigment or dye is derived from
natural sources is not significant for nearly all of our customers. Natural is not synonymous
with safe.
Impact of preference for no TiO2 in France and other EU countries is making colour matching
difficult. Limited colour palette for natural pigments but trying to meet customer
requirements. More natural colours are available in our systems than 10 years ago, but still do
not allow exact match to some synthetic colours.

113
APPENDIX E
COMPLETE RESPONDENT COMMENTS ON KEY FACTORS IMPACTING COLOR
DECISIONS
Question: In the last 5 years, what are the key factors that have impacted color decisions
for your products?

Respondent Comments:
Consumer Preference
Customer preferences & regulatory factors
Regulatory Concerns
The Southampton Study and the ensuing political decision by the European Parliament to
require a warning label for these synthetic colors essentially created a situation in Europe for
foods and food supplements where none of the finished product manufacturers want to use
synthetic colors in their products due to consumer perception of a problem and the need to put
this warning label on their products. Additionally, the current situation in France where they
are planning to suspend use of TiO2 E171 for food applications is driving the need for TiO2-
Free formulations. Again, this concern in France is not based on good science but rather a
political situation driven by one poorly run study in France on E171 that is not credible.
Regulation for global markets.
Consumer demand and regulatory acceptance.
Prop 65, Titanium Dioxide discussions.
negative regulatory changes in the EU, Russia etc inappropriately requiring a warning label
about attention in kids. This inappropriately-assigned legislation against synthetic colourants
and lack of understanding of science under the guise of safety is negatively impactful to all
except the natural colour companies. Sadly this lack of science gets pushed to the common
people and leaders of companies that natural colours must be "better" than synthetic colours.
there is room for both synthetic colors and natural colors in the world. but the natural color
industry is pushing only for natural colors, going against science /synthetic colors under the
guise of safety when in actuality it is to increase their profits. This is unethical, and I am not
sure how these natural color companies live with themselves. they are totally gaming the
system.
Stability
availability, cost natural vs synthetic, % usage in formula
Stability, ability to match the colour
Cost

114
Sometimes use of colorants in Europe for paediatric use is a concern. Many azo colors are not
usable in such formulations and its a concern to Pharma users when they have to distinguish
between various strengths or doses of their products. sometimes even after using a right
permissible colorants the regulatory agencies ask for removal of the colorant or justification
on safety. Regulatory agencies in Europe are very sensitive to use of colorants in drugs
especially paediatric.
The key factor has been the consumer preferences which affected finished dosage product
manufacturers (i.e. our customers), who request for naturally derived, clean label ingredients
to be used in film coating systems.
The elimination of ingredients that are not recognizable to consumers and undesirable to
consumers.
Consumer demand, availability regulatory compliance
Ability to Match Color
Regulatory& consumer preference toward clean labeling
Customer Demand
Availability
Consumer preference, and regulatory issues
Consumer preferences and negative news about synthetic.
For us, it is our customer's preference. We do see a preference for natural colorants.
Regulatory approvals
We are mostly at the mercy of what consumers want to buy, and we try to match the
shade/color of what they are looking for through the synthetic colors available to us.
Price- if company cannot afford natural colors, must use synthetic Stability- if natural color
does not provide the needed stability including vibrancy, need to use synthetic colors
ease of route to market and consumer perception
stability, availability and market regulations
Mainly our customers preference combined with regulatory considerations, ability to match
color, stability and cost.
1. regulatory status. 2. marketing claims 3. color matching
Studies that have linked use of specific synthetic colorants to hyperactivity in children
Increasing demand from manufacturers of dietary supplements for non-synthetic alternative
colorants
The regulation
N/A
i think color stability and whether or not the "natural" color is actual a simple mixture of
ingredients or a co-processed excipient.

115
Color decisions are made by the customer. Factors driving are consideration are meeting
consumer preferences and regulatory requirements. X is a leader in colored excipients for the
pharmaceutical and nutraceutical markets. As such we have been successful in extending
available options for the nutritional/dietary supplement market via FDA petitions for the use
of spirulina extract and synthetic iron oxides.
Again the key factor has been consumer preference, over regulatory changes. However in
Europe it could be said that public opinion has itself driven regulatory changes, eg quantitative
limits on certain colors.
Customers continually asking for more natural colors, and less use of Titanium Dioxide.
See above.
requirements from customers who will specify if they want non synthetic pigments

116
APPENDIX F
COMPLETE RESPONDENT COMMENTS ON IMPACT ON INDUSTRY
Question: Please elaborate on your answers regarding the impact on the
pharmaceutical or dietary supplement industries.

Respondent Comments:
Conflicting regulations between regions presents significant challenges for suppliers.
Reformulations due to regulatory changes causes unnecessary work with no benefit to the
consumer and higher cost for all.
Eliminating potentially superior products (colors) based on a false categorization of the
entire class of those products into "synthetic" or "natural", is not a good way to make
regulation. Each individual product whether natural or synthetic should be evaluated
objectively for safety and other performance characteristics. Restricting colors on the basis
of their natural or synthetic origin will have a negative impact on industry and the consumer
by possibly eliminating availability of the best colors for certain applications.
The warning label requirement in the EU is primarily for foods and food supplements, not
for pharmaceuticals. Therefore, while most food and food supplement manufacturers are
avoiding synthetic colors in Europe, this is not the case yet with many pharmaceutical
companies. Many of them are still using synthetic colors. However, some are now starting to
think about possible removal of synthetic colors. However, the stability of natural colors is
typically not good enough for the shelf life needs of many pharmaceuticals so natural colors
are many times not good alternatives.
These trends were already in place for DS industry before the study. The study was a "result"
of this trend in action.
The list of colours requiring a warning is different for the food regs compared to pharma
regs. Natural colours are viewed positively, but I doubt many consumers could recognise a
natural colour
I wish your survey was geared as well to the food industry.
Pharma products enjoy a high level of trust compared to Dietary Supplements because of
strong regulatory involvement in Pharma and perceived to actual weakness in Dietary
Supplements.
In my opinion, media coverage, suggesting negative safety issues, leads to the biggest impact
on consumer preference.
Pharma / dietary companies are extremely careful in choosing colorants while developing
product for EU market. even after choosing the right colorants they demand for safety data
and all different statements. due to these regulations some companies decide to drop the
projects and this impacts our business.
Regulatory decisions in the food industry for color additives eventually negatively impacts
the dietary supplement and pharmaceutical industry. A similar example may be the increased
use of gluten-free claims in food labeling is now negatively impacting the dietary
supplement and pharmaceutical industry.

Abstract (if available)

Abstract Colors have been added to consumer products for most of recorded history, but that history has been marked by problems with unsafe coloring agents that have driven remedial regulations. The publication in 2007 of the “Southampton Study”, linking synthetic color additives to behavioral changes in children, has been one of the most influential modern challenges to the regulation of colors. Although the study was flawed scientifically, its conclusions were widely disseminated to the public and drove regulatory changes in Europe. There, industry is now required to label products with significant warnings for some synthetic colors and restrict the use of others. The use of naturally derived colors has been advocated, but it can be difficult and expensive to use naturally derived colors. Thus, it is unclear whether the regulatory recommendations and requirements are achieving the identified goals of good regulatory policy, including the goals of enhancing safety, protecting the interests of consumers and creating a level playing field for manufacturers. In this study we explored the views and experience of the dietary supplement and pharmaceutical industries about the appropriateness and impact of these regulatory changes with the intent of helping to shape future color regulation and assist companies in developing strategies and products that conform to the current regulatory environment. The results of this study indicate almost all respondents share the view that safety and science should be critical factors in developing regulations. Most expressed the view that that certain EU color regulations, based upon the Southampton Study, do not improve safety or enhance the public health. It appears from the results here that many companies are using natural colors as a differentiating feature driven by consumer preference rather than regulation. Many respondents felt that the impact of the restrictive EU regulations has been generally negative, potentially increasing manufacturing costs and thus consumer prices. Many suggested that dissonance between the regulations in the EU and the US had a negative impact on the industry overall.

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Asset Metadata

Creator Smith, Alexa Elizabeth (author)

Core Title Use of natural colors: experience and views in pharmaceutical and dietary supplement industries

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Publication Date 10/23/2020

Defense Date 08/17/2020

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag colorants,colors,colours,drug manufacturing,dyes,excipients,hyperactivity,hypersensitivity,OAI-PMH Harvest,synthetic colors

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Richmond, Frances (committee chair), Clemens, Roger (committee member), Louie, Stan (committee member), Pacifici, Eunjoo (committee member)

Creator Email alexaesm@usc.edu,asmith@colorcon.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c89-385332

Unique identifier UC11666291

Identifier etd-SmithAlexa-9059.pdf (filename),usctheses-c89-385332 (legacy record id)

Legacy Identifier etd-SmithAlexa-9059.pdf

Dmrecord 385332

Document Type Dissertation

Rights Smith, Alexa Elizabeth

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

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