EF15April29 2 MaryMurry Amway
EF15April29 2 MaryMurry Amway
EF15April29 2 MaryMurry Amway
Excipients in Nutraceuticals and Dietary
Supplements
‐ Global View From a Formulation
Perspective
Mary A. Murray PhD
Senior Principal Research Scientist
Amway/Nutrilite Health Institute
28 ‐29 April 2015 San Juan, Puerto Rico
Introduction
• Solid dosage formulation and process design for drug
products and nutrition products is similar.
• Purpose and regulatory requirements may differ..
• Desire for a safe and effective dosage form is the
same.
• Desire for most cost effective formulation and process
is the same
• Excipients are a key factor to success!
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Formulation Goals for Nutrition
• Build in total quality
• Build in cost control
• Tablets preferred over capsules
• Direct compression first choice
• Smaller and fewer tablets per dose
• Global formula when possible
• Meet all internal quality and manufacturing process standards
• Meet global regulatory requirements for stability, ingredient
acceptability and substantiation
Formulation Challenges– What does it mean
to work with plant concentrates?
• Generally large dose per daily serving
• Multiple “active ingredients” versus one or two for drug
product
• Significant variation in active ingredient compression and
flow characteristics within one dosage form
• Large variation in heat and moisture sensitivity of ingredients
within one formula
• Significant stability challenges with multiple interaction
opportunities
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Natural Bioactive Compounds
Plant Concentrates:
Preparations of a single plant that have greater
levels of macronutrients, micronutrients or
phytochemicals than the feedstock
◦ Herbal Concentrates
◦ Fruit, Vegetable & Specialty Concentrates
Other Natural Bioactive Concentrates:
• Fungal and microbial materials are included as
feedstock that can produce concentrates. ( Bio‐
fermentation process)
• B12, digestive enzymes, hyaluronic acid
• Concentrates may include excipients used in
production (e.g., spray drying carriers)
Aspergillus Niger
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Common
Processes
Extraction Valerian
Extract
Valerian
Granulation
Retrieval of phytochemicals and essential plant
phytonutrients by extraction with water/alcohol
followed by spray drying with or without an inert
carrier
• Powder Characteristics: Often produces
hygroscopic powders with a fine particle size
• Tableting Challenges: Poorly flowing powders
◦ Cause sticking during tableting
Dehydration
Removal of water followed by milling to reduce particle
size
Powder Characteristics:
◦ Often results in materials that are fibrous, bulky, or spongy
Tableting Challenges:
Generally non‐compressible
powders
◦ Difficult to incorporate into tablets at a high dose
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Excipient Assessment
for Nutrition
* Formulator must assess properties of the active ingredients alone
and in combination with all other active ingredient and excipients
• Assessment is based on the requirements of the dosage form and
manufacturing processes applied.
• For Nutrition, the final formula must be robust to accommodate the
varied and variable physical characteristics of natural ingredients in a
complex formula.
Key Drivers in Excipient Selection For Global
Nutrition Formulations
1) Meets dosage form/ process functionality requirements
2) Regulatory Compliance
• Must meet applicable compendial requirements
• Must meet regional requirements or restrictions
• Materials and manufacturer must meet internal quality and safety,
specifications and performance requirements
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“One formulation’s functionality can be
another formulation’s dysfunctionality” *
• Excipient functionality can only be properly assessed in the context of
a particular formulation and manufacturing process
• Excipient functionality is linked inextricably to the formulation and
process, and all formulations are different, functionality is determined
by the excipient user and supplier
• It would be impossible to establish a widely accepted standard for a
particular excipient’s functionality in a pharmacopeia monograph.
*R. Christian Moreton “ Excipient Functionality”Pharmaceutical Technology MAY 2004
Desired Formulation Functionalities For Filler
Binders
• Direct Compression excipients preferred
• Good Flowability of excipient and final powder blend is required
• Good compressibility is required for satisfactory tableting
• the tablet must remain in the compact form once the compression force is removed
Good Dilution (or carrying) potential ‐defined as the amount of an active
ingredient that can be satisfactorily compressed into tablets
• remain unchanged chemically and physically upon compression or other
processing
Should not exhibit any physical or chemical change on ageing
• Should be stable to air, moisture and heat
• The particle size distribution should be consistent from batch to batch
It should be relatively cost effective
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Desired Formulation Functionalities For Filler
Binders
It should not interfere with the disintegration or dissolution
should not accelerate the chemical and/or physical degradation of the
active components
• It should not interfere with the biological availability of active ingredient
• It should show low lubricant sensitivity.
It should be compatible with all other excipients (disintegrants, lubricants,
binders ,glidants etc.) present in the formulation.
• It should be physiologically inert
Globally acceptable as both a nutritional and pharmaceutical excipient
Be Alert: Excipients Can Influence Solid State Stability
Especially when formulating with multiple plant
concentrates ..by
• Acting as surface catalysts,
• Acting as a source of extra moisture,
• Physical state of excipient can influence mobility of water
molecules within the tablet components
• Undergoing direct chemical reactions with the
extract/active components,
• Active/ excipient ratio Excipients may have
• Physical mixing vs. granulation, different stability
influences within different
• Granules vs compacts manufacturing processes
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Excipient Functionality
• For natural product formulation, excipient functionality in a
particular formula is heavily influenced by the complex
combination of multiple active ingredient characteristics
• Occasionally seemingly equivalent excipients are not
equivalent in functionality
Excipient Functionality vs Compendial Danger
Will
Requirements Robinson
The official pharmacopoeias define quality tests for the analytical
characterization of the individual excipients
Pharmacopoeial standards do not take into account particle
characteristics, powder characteristics or manufacturing processes that
often determine functionality of excipients
Excipient compliance with pharmacopoeial standards does not
guarantee appropriate functionality for your formula
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Case in Point: What happens when you make
a “one to one” excipient change?
• Excipients may have multiple functions in a product.. or a different
function in several products.
• If produced by batch process there is a possibility of batch‐to‐batch
variation from the same manufacturer.
• Excipients obtained from different sources that satisfy a monograph
may not have identical properties with respect to use in a specific
formulation.
Formulators must determine excipient equivalency either in final
formula or before use.
Case Study: Excipient Functionality
• Challenge– herbal formula capping in production trials
• Noted Change: new dextrose to meet GMO free requirements
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Are the two dextrose products equivalent?
• Both meet internal specification requirements
• Both meet compendial requirements
• New dextrose meets additional regional requirements and
restrictions
BUT ‐ Negative effect on functionality and
manufacturability for the herbal formula ‐ WHY?
Assessment of Excipient Properties
TECHNOLOGICAL FACTORS
Particle size/Micronization
Surface area
Porosity
Crystal structure
Powder flowability
Compressibility
Plastic/brittle fracture
ANALYTICAL FACTORS
Moisture content
Chemical Analysis
Impurities/Contamination STABILITY FACTORS
Structural Analysis Solid State Stability
SEM Images Degradation Forces
X‐ray Diffraction pH stability
Thermo analysis (DSC/ TGA) Moisture Activity
NMR Microbial bio burden
FTIR
Optimized Choice
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Purity
Test Results: Equivalent purity
and compression performance
A B
Equivalent
Particle Size
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A B
Equivalent Crystal Structure
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Dextrose Lot B
Dextrose Lot A
Dextrose B
Dextrose A
Dextrose Lot A
Dextrose Lot B
Morphology Differs
Case Study Outcomes – Dextrose
Functionality
• Modified blending process was used to accommodate the different
morphology of the Dextrose A and solve capping problem in the
herbal formula
• The flow improvement from Dextrose A was realized in other
formulas resulting in several improved run rates and related cost
savings
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Co‐processed excipients
IPEC‐Americas, Co‐processed Excipients Workshop April 29th 2013
Potential of Functional‐
Aka (co‐processed) Excipients
Dosage Formulators perspective:
• Excipient that may positively influence the physical characteristics of a powder
blend containing active ingredients and /or the characteristics of the resulting
finished tablets or capsules.
• Powder Bed: powder flow Tablet: content uniformity
hygroscopicity hardness
compressibility friability
loading capacity
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Functional (co‐processed) Excipients for
Nutrition
• Formed by combining two or more established excipients using an
appropriate process (co‐processing)
• Goal is formation of excipients with superior properties compared to
the simple physical mixtures of their components
• Main aim of co‐processing is to obtain a product with added value
related to the ratio of its functionality/price
• Regulatory: Globally – for Nutrition categories, there is no uniform
regulatory criteria for approval of use. Can often list co‐processed
material as two separate ingredients if the “intimate mixture” has no
chemical change
Examples of Co‐processed Functional Excipients
TRADE NAME ADJUVANTS MANUFACTURER
Cellactose MCC,Lactose Meggle,Germany
Starlac Lactose, Maize Starch Roquette,France
Avicel CE 15 MCC, Guar gum FMC, USA
Prosolv MCC, Colloidal Silica Penwest, USA
(JRS Rettenmaier , Germany)
Key Considerations:
• Fixed ratio of components might not be suitable for all
formulations
• Most are intimate mixtures in a fixed ration – not a new
chemical entity
• Many functional excipients do not yet have a specific USP
Monograph but rely on monographs for the individual
adjuvants.
• IPEC is drafting a guideline to facilitate development and
adoption of co‐processed excipients
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Regulatory Considerations in
Excipient choice
Regulatory Guidances for Global
Nutrition ‐ just a few that must be considered
• WHO • Australia TGA ( Therapeutic
• British Pharmacopoeia Goods Administration)
• US Pharmacopoeia • Japan Pharmacopoeia
• European Pharmacopoeia
• China Pharmacopoeia • Codex Alimentarius
• China GB National • ICH
standards
• Canada Health‐ Natural • Korea HFF Codex
and Non‐prescription • Japan Positive list for use in
Health Products foods (not a drug ingredient)
Directorate (NNHPD)
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Registration Certifications May Be required
Certification requirements often apply to excipients as
well as active ingredients
• GMO Free
• Halal
• Kosher
• WADA Compliance
• (World Anti Doping Agency) country and product specific
More Challenges for Global
Formulation
• Registration category/classification
• According to claims and ingredients the formula may fit into different
categories by country
• Registration complexity varies by category and country, dossier
requirements vary greatly
• Testing requirements for finished products, as well as ingredients and
excipients are not uniform
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• Dietary Supplement • Food Supplement
• Food • Traditional Medicine
• NHP‐ Compendial • Complimentary Medicine
• NHP‐ Non Compendial • Functional Food
• Health Functional Food • Novel Food
• Tablet Food • Phytotherapeutic
• Health Food • Food complement
• General food • Natural product
• Drug • Natural Products, Drug
• Traditional Chinese Medicine • Herbals
• OTC • Nutrient Supplement
• Food for Specified Health Uses
Nutrition Classifications (not
comprehensive)
Example: Malaysia
• Four nutrition categories‐ Functional Foods, Traditional Medicine,
OTC, Health Supplement.
• Many Products fall into the Food Drug Interface (FDI)
• Depending on characteristics and ingredients, they may be regulated
by the National Pharmaceutical Control Bureau (NPCB) or the Food
Safety and Quality Division (FSQD) of the Ministry of Health
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Content close to Substances or Content close to Herbs & spices that Mixtures of food
100% active ingredients that are 100% herbs (singly are traditionally used ingredients with
ingredients (singly or used for therapeutic or in combination) in food preparations active ingredients
in combination) purposes shall not that are not and/or herbs
be added to food traditionally used as
food and have
medicinal property
For example: For example: For example: For example: > 20% active ≤ 20% of active
ingredients with ingredients or natural
Amino Acids & Gypsum Alfalfa Aloe Black cumin pharmacological/ ingredients with
Peptides vera (Habbatus therapeutic pharmacological and/or
fibrosum
Collagen Barleygrass sauda) properties, singly or
Pearl Powder therapeutic properties.
Dukung Anak
Coral calcium Gamat Garlic in combination. However, if a product
2 Kacip Fatimah
Dietary Fibre Manjakani
Ginger contains specific active
Enzymes Mas Cotek Misai Pegaga ingredients which
Fatty Acids Kucing Noni Traditional possess high
Live micro Extract Royal Chinese Raw pharmacological or
organism
3, 4
Jelly Spirulina Herbs therapeutic potencies,
Minerals Plant Tongkat Ali Turmeric the product may be
Stanol/ Sterol Tunjuk Langit regulated by NPCB
& Esters Wheatgrass even if these active
Psyllium ingredients are present
(≥3.5g/day)
Husk(≥3.5g/day) in less than 20%
Vitamins
Several Countries have their own testing requirements
or “positive list” that impact excipient choices
• Global Markets do not always reciprocate the USP standards for
excipients
• China‐ CHP, MOH, GB Guobiao, or “National Standard”
• Korea, HFF (Health Function Food Code) and MFDS (Ministry of Food and
Drug Safety) re‐org March 2013
• Japan, JFHA‐ Japan Health Food Association (positive list for food additives)
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Towards Global Harmonization
Reference:
Allowance of Ingredients
Must comply to regulations and
process for new ingredients
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ASEAN (Association of Southeast Asian
10 Member States
Nations) Approx 520 million population
ASEAN HARMONIZATION
of Traditional Medicine Health Supplement (TMHS)
REGULATIONS
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ASEAN Proposal: Global List of Restricted
Additives & Excipients
• Currently many countries and regions maintain “positive lists”
• ASEAN Guiding principles for entry of additives and excipients into
ASEAN List of Restricted Additives and Excipients
• Development stage
• Not listed in CODEX or any international reference
Regulatory trends: Global Formulation
(Nutrition)
• Regulatory scrutiny is increasing, but with regional differences
• Increased focus on substantiation of health claims through clinical
studies
• Food safety issues will result in more restrictions
• Some regions heading towards globally harmonized rules (EU, ASEAN)
• *However, regulatory harmonization delayed in some regions due to
local interests
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Nutrition – Food Products In Market Registration timing
(Powders, Drinks and Bars)
Notification or No Registration Market
Registration Market (low/med complexity 0 – 6 mo)
Registration Market (med/high complexity 6+ mo ‐ years )
Nutrition: Categories Excluding Food Products – In Market
Registration Timing (Health Supplements, TCM’s, Health Foods and
items considered “Drugs/Medicines”)
Notification or No Registration Market
Registration Market (low/med complexity 0‐ 6 mo )
Registration Market (med/high complexity 6+ mo )
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Conclusions: Global Formulation
• Correct choice of excipients can be a key driver in formulation and
economic success –
• Excipients have a very broad influence on tablet performance:
including both physical and physiological characteristics
• If regulatory issues can be addressed, functional excipients will have a
significant positive impact on formulation and process development
(QbD)
• Globally, guidance for finished product specifications are not uniform.
• Globally excipient monographs and specifications are not uniform
• Globally excipient acceptability and use restrictions are not uniform
Thanks for your Contributions to This
Presentation!
• Kaela Napolitano‐ Formulation Scientist (NBS)
• Mark A. Smith and Haywood Ware – Analytical Scientists‐ Forensic
Analysis Laboratory
• Michele Stout ‐ Senior Principal Regulatory Policy Coordinator ( RPI
Group)
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Thank you!
Mary A. Murray PhD
Senior Principal Research Scientist
Amway/Nutrilite Health Institute
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