Frank Switzer, Larry Callahan, Yulia Borodina, Tyler Peryea

FDA/USP Substance Registration System (SRS)as an Informational Bridge

Between Chemistry and Biology

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To define all substances present in regulated products

To assign an identifier (a UNII) that is permanently associated with the substance (ingredient)

To support product listing activities for all FDA centers

Why SRS?

Approach to Substances

All substances will be defined independent of any name of the substance or proprietary code.

Substances will be defined independent of grade or level of purity.

Substances are defined based on what they are not how they are made or used

Substances ARISTOTLE (Metaphysics)...the generally

recognizable substances... are the sensible substances, and sensible substances all have matter..., and in another sense the formula or form..., and thirdly the complex of matter and form, which alone is generated and destroyed, and is, without qualification, capable of separate existence...

Early Chemists describe the first DIRT MOLECULE (The Far Side by Gary

Larson)

Substances Supramolecular interactions are excluded unless

they exist with defined (not necessarily small whole number ratios) stoichiometry (e.g. stable host-guest interactions and multi-chain holoenzymes)

Ambiguity should be limited◦ Vegetable oil NOT a substance◦ Stereochemistry should be defined

Microheterogeneity not captured◦ All Epoetin’s made in CHO CELLS are the same

substance (glycosylation type = mammal)

Substances A substance can be a single molecular entity or a

mixture of single entities that are either isolated together or the result of same synthetic or extractive process.

Mixtures are defined as combinations of single entities (proportions not captured).

Diverse material that is brought together to form a product is not defined as a substance.

Specified substances (not yet implemented) may be used to describe multi-substance materials.

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Which Ingredients are Substances? Materials that are combined from multiple sources to

form a product are NOT considered substances. Definable modifications to raw materials generate

unique substances - modifications must change the underlying chemical structure or mixture composition Oil Volatile oil Hydrogenation

Extracts not definable chemically are associated with their the source material

Is the Material a Substance?

Material

Substance Each Source Material is Substance

Reaction Product is Substance

Multiple Sources

Single Source

Source MaterialsReact Chemically

Source Materials Do Not React Chemically

Substances Five groups of elements are used to describe single

substances. ◦ Monodisperse

Chemicals Proteins Nucleic Acids

◦ Polydisperse Polymers (polysaccharides and synthetic polymers) Structurally Diverse Substances

Mixtures are comprised of combinations of single substances and source where relevant.

Monodisperse, Polydisperse or Mixture Substance Type?

Substance

Monodisperse Substance

Mixture Substance

Structurally Diverse

Substance

Single Molecular Entity

Multiple Molecular Entities

Limited Set (business rule) of Molecular Entities

Numerous/Unknown Molecular Entities

PolymerSubstance

Multiple Repeating Molecular Entities

Which Monodisperse Substance Type?

Structurable Molecule with Defined Formula

Structure Based on Linear Sequence of Amino Acids

Structure Based on Linear Sequence of NucleotidesProtein

SubstanceNucleic AcidSubstance

Monodisperse Substance

Chemical Substance

SRS Unique Identifier

The UNII consists of ten alphanumeric characters. 

Non-semantic non-chronological identifier The first nine alphanumeric characters are

randomly generated.  The tenth alphanumeric character is

determined through a mathematical algorithm, and is appended to the first nine.

369 = 1013 potential identifiers

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CDERCBERCVM

UNIIs Now Used ByUNIIs Now

Referenced By

USP DictionaryMartindaleWikipedia

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What is it? Is it new to SRS?

If so, a new UNII will be generated If not, it will be connected to an existing

UNIISRS is a vocabulary where each substance concept has an associated code

SRS Definitions

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How are Substance Definitions Developed?

FDA Office of the Chief Scientist 2011 Outstanding Service Award to Substance Registration System (SRS) Standard Team For sustained superior performance in

developing the Substance Registration System, an international standard for defining substances

SRS Review Board FDA center representatives USP, NLM, NCI, EMA

FDA, USP and EMA experts

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SRS Definitions

Chemical Structures XML Descriptive Elements

◦Stereochemistry◦Source Material◦Molecular weight measures◦Modifications

(2R,3R,4S,5S,6R)-2-[(2S,3S,4S,5R)-3,4-dihydroxy-2,5-bis(hydroxymethyl)tetrahydrofuran-2-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

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0 to many RNs for substances –not an identity standard

CAS has no consistent way to capture polydispersity

CAS RNs are copyrighted

What About CAS RNs?

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SRS Preferred Substance Names Primary Name

When no official name is available Chemical name Code Brand name (last resort)

Synonyms Compiled from authoritative and other public sources Appropriately applied names May not always be substances themselves

Saline vs. salt (sodium chloride) Parenthesis

When an established name is incompletely defined (ambiguous)

Substance Model

Names

Codes

Reference Information

Simple Stoichiometric Substances Chemical substances defined based on the

molecular connectivity of the underlying substance. Salts or solvates are defined as independent

substances (different molecular formulas) Currently a single structural entity is associated

with a substance. Approach is somewhat affected by the software

used to store and retrieve chemical information

Unknown/Interconverting

Alkenes/Oximes/Semicarbazones◦ Rifampin

C H 3NN

NO H

O

OC H 3OO

CH 3

CH 3 O

C H 3O

CH 3 O H

CH 3

C H 3

C H 3

O

NHO HO HCH 3

O H

SS

R

S

R

R

R S S

E

E Z

Chiral

Salts

Amines other than ammonium salts and quaternary amines are not ionized.◦ Example

CODEINE HYDROCHLORIDE (USAN)

Defined as a dihydrate

Cl H

H O H

H

N

C H 3

OCH 3O

O H 22

R S

RR

S

Chiral

Salts Metal salts drawn as charged entities all equivalent

functional groups ionized when necessary charge balance achieved by addition hydrogen ions

TICARCILLIN MONOSODIUM ANHYDROUS

Na+

H+

NO

NH

S

O

O–

O

S

O O–

C H 3

C H 3

H

RR

R

S

Chiral

Mixtures

Currently used to describe related substances isolated together. ◦ Proportions are not captured

Variations in amounts can be great specification would be captured the specified substance level.

All single entities typically present in amounts greater than 1% either by weight or mole percent would be part of the mixture

Example: FUSAFINGINE - a mixture of four enniatin cyclohexadepsipeptides◦ Typically produced from Fusarium lateritium◦ Described as a chemical not a peptide/protein

Fusafungine

ENNIATIN A

O N

C H 3

CH 3

CH 3

OC H 3

CH 3

O

NCH 3 C H 3

C H 3OO

CH 3

C H 3O

N

C H 3

O

O

CH 3

CH 3

C H 3CH 3

HH

O

H

S

S

R

SS

RS

R

S

Chiral

Fusafungine

ENNIATIN A1

CH 3

CH 3

N

C H 3

OCH 3

CH 3O

O

C H 3

CH 3N

C H 3

OCH 3

C H 3

O O

C H 3

C H 3

H

NCH 3

O

C H 3

CH 3

O

O

H

S

S

R

SR

SS

R

Chiral

Fusafungine

ENNIATIN B

O N

C H 3

CH 3C H 3

OC H 3

CH 3

O

NCH 3 C H 3

C H 3OO

CH 3C H 3O

N

C H 3

O

O

CH 3

CH 3

C H 3

CH 3

O

SR

S

RS

R

Chiral

Fusafungine

ENNIATIN B1

O

O

N

H

ON

CH 3

C H 3

OCH 3

CH 3 N

C H 3

CH 3

C H 3

O

O

C H 3

O C H 3

CH 3

O C H 3

C H 3CH 3

O

CH 3

C H 3

R

S

RS

R

S

S

Chiral

Non-stoichiometric Substances

Non-stoichiometric

<CHEMICAL_SUBSTANCE> <STOICHIOMETRIC/><NON_STOICHIOMETRIC> <NUMBER_OF_MOIETIES>4</NUMBER_OF_MOIETIES> <MOIETY_AMOUNT_TYPE>MOLE RATIO</MOIETY_AMOUNT_TYPE>

ALUMINUM SESQUICHLOROHYDRATE

A 3-A

B

UNDEFINED

Cl– O H

–

Al3+

O H 2

ALUMINUM SESQUICHLOROHYDRATE <MOIETY_GROUP>  <MOIETY_NAME>ALUMINUM CATION</MOIETY_NAME>  <MOIETY_ID>3XHB1D032B</MOIETY_ID> <AMOUNT>  <AVERAGE>1</AVERAGE>  <LOW_LIMIT/>  <HIGH_LIMIT/>  <UNIT/>  <NON_NUMERIC_VALUE/>  </AMOUNT>  </MOIETY_GROUP> <MOIETY_GROUP>  <MOIETY_NAME>CHLORIDE ION</MOIETY_NAME>  <MOIETY_ID>Q32ZN48698</MOIETY_ID> <AMOUNT>  <AVERAGE/>  <LOW_LIMIT>1.26</LOW_LIMIT>  <HIGH_LIMIT>1.90</HIGH_LIMIT>  <UNIT/>  <NON_NUMERIC_VALUE/>  </AMOUNT>  </MOIETY_GROUP>

<MOIETY_GROUP>  <MOIETY_NAME>HYDROXIDE ION</MOIETY_NAME>  <MOIETY_ID>9159UV381P</MOIETY_ID> <AMOUNT>  <AVERAGE/>  <LOW_LIMIT>1.1</LOW_LIMIT>  <HIGH_LIMIT>1.74</HIGH_LIMIT>  <UNIT/>  <NON_NUMERIC_VALUE/>  </AMOUNT>  </MOIETY_GROUP> <MOIETY_GROUP>  <MOIETY_NAME>WATER</MOIETY_NAME>  <MOIETY_ID>059QF0KO0R</MOIETY_ID> <AMOUNT>  <AVERAGE/>  <LOW_LIMIT/>  <HIGH_LIMIT/>  <UNIT/>  <NON_NUMERIC_VALUE>UNDEFINED</NON_NUMERIC_VALUE>  </AMOUNT>  </MOIETY_GROUP>

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Hypromellose

USP 33: Hypromellose is a methyl and hydroxypropyl mixed ether of cellulose. It contains, calculated on the dried basis, methoxy (–OCH3: 31.03) and hydroxypropoxy (–OC3H6OH: 75.09) groups conforming to the limits for the types of Hypromellose (hydroxypropyl methylcellulose) set forth in the accompanying table.

Methoxy (percent) Hydroxypropoxy (percent)

Substitution Type Min. Max. Min. Max. 1828 16.5 20.0 23.0 32.0 2208 19.0 24.0 4.0 12.0 2906 27.0 30.0 4.0 7.5 2910 28.0 30.0 7.0 12.0

(Polydisperse) Polymers

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Hypromellose

USP 33: Labeling—Label it to indicate its substitution type and its nominal viscosity value in milli-Pascal per second (mPa·s).

Hypromellose is the INN and BAN

CAS 9004-65-3

(Polydisperse) Polymers

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Hypromellose

OH

CH3

CH 3H

H

O

O

OO

OR

Chiral

R1

R2

<POLYMER_TYPE>HOMOPOLYMER<NUMBER_OF_SRU>1<ORIENTATION_OF_POLYMERIZATION>HEAD-TAIL <R_ID>R1 <LIMIT_TYPE>WEIGHT<AVERAGE>10<LOW_LIMIT>7<HIGH_LIMIT>12<R_ID>R2<LIMIT_TYPE>WEIGHT<AVERAGE>29<LOW_LIMIT>28<HIGH_LIMIT>30<TYPE_MW>NUMBER <MW_AVERAGE>8000 <LOW_LIMIT_MW/> <HIGH_LIMIT_MW/><PHYSICAL_PROPERTY_TYPE>VISCOSITY <AVERAGE>3 <LOW_LIMIT>2.4 <HIGH_LIMIT>3.6 <UNITS>MPA.S

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HypromelloseHYPROMELLOSE 2910 (3 MPA.S) 0VUT3PMY82HYPROMELLOSE 2910 (5 MPA.S) R75537T0T4 HYPROMELLOSE 2910 (6 MPA.S) 0WZ8WG20P6HYPROMELLOSE 2910 (15 MPA.S) 36SFW2JZ0WHYPROMELLOSE 2910 (50 MPA.S) 1IVH67816NHYPROMELLOSE 2910 (4000 MPA.S) RN3152OP35

HYPROMELLOSE 2910 (15000 MPA.S) 288VBX44JCHYPROMELLOSE 2906 (50 MPA.S) 612E703ZUQHYPROMELLOSE 2906 (4000 MPA.S) 5EYA69XGATHYPROMELLOSE 2208 (3 MPA.S) 9H4L916OBUHYPROMELLOSE 2208 (100 MPA.S) B1QE5P712K

HYPROMELLOSE 2208 (4000 MPA.S) 39J80LT57T

HYPROMELLOSE 2208 (15000 MPA.S) Z78RG6M2N2

HYPROMELLOSE 2208 (100000 MPA.S) VM7F0B23ZI

Diphtheria Toxoid <SUBSTANCE_NAME> CORYNEBACTERIUM DIPHTHERIAE TOXOID ANTIGEN

(FORMALDEHYDE INACTIVATED) <SUBSTANCE_ID> IRH51QN26H <SEQUENCE_TYPE> COMPLETE <SUBUNIT_NUMBER> 1 <SUBUNIT_ID> 1 <LENGTH>567</LENGTH>

<SEQUENCE>MLVRGYVVSRKLFASILIGALLGIGAPPSAHAGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNKYDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVGTEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMYEYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVSEEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEKTTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYNFVESIINLFQVVHNSYNRPAYSPGHKTQPFLHDGYAVSWNTVEDSIIRTGFQGESGHDIKITAENTPLPIAGVLLPTIPGKLDVNKSKTHISVNGRKIRMRCRAIDGDVTFCRPKSPVYVGNGVHANLHVAFHRSSSEKIHSNEISSDSIGVLGYQKTVDHTKVNSKLSLFFEIKS</SEQUENCE>

Diphtheria Toxoid

<DISULFIDE_LINKAGE> 1_218-1_233;1_493-1_503 <MODIFICATION_TYPE> AGENT <AGENT> FORMALDEHYDE <AGENT_ID> 1HG84L3525

Reference Information <MW_AVERAGE>61601</MW_AVERAGE> <PROTEIN_TYPE> ANTIGEN <PROTEIN_SUBTYPE>DIPTHERIA TOXIN <PARENT_ORGANISM>CORYNEBACTERIUM DIPHTHERIAE <LIGAND>ELONGATION FACTOR 2 ADP RIBOSYLATION EC:2.4.2.36

Tuberculosis

<SUBSTANCE_NAME> BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN

<SUBSTANCE_ID> 2XQ558L16Z <SOURCE_TYPE> BACTERIUM <FAMILY> MYCOBACTERIACEAE <GENUS> MYCOBACTERIUM <SPECIES> BOVIS <STRAIN> BCG SUBSTRAIN TICE <PART> WHOLE

Influenza A <SUBSTANCE_NAME> INFLUENZA A VIRUS A/CALIFORNIA/7/2009 X-

179A (H1N1) HEMAGGLUTININ ANTIGEN (FORMALDEHYDE INACTIVATED)

<SUBSTANCE_ID> C8E791RO82 <SOURCE_TYPE> VIRUS <FAMILY> ORTHOMYXOVIRIDAE <GENUS> INFLUENZAVIRUS A <SPECIES> INFLUENZA A VIRUS <STRAIN> A/CALIFORNIA/7/2009 X-179A (H1N1) <PART> ENVELOPE <FRACTION_TYPE> GLYCOPROTEIN <FRACTION> HEMAGGLUTININ <MODIFICATION_TYPE> AGENT <MODIFICATION> INACTIVATION <AGENT> FORMALDEHYDE <AGENT_ID> 1HG84L3525

Influenza A <SUBSTANCE_NAME> INFLUENZA A VIRUS A/CALIFORNIA/7/2009 X-179A

(H1N1) NEURAMINIDASE ANTIGEN (FORMALDEHYDE INACTIVATED) <SUBSTANCE_ID> 460J8Y21CE <SOURCE_TYPE> VIRUS <FAMILY> ORTHOMYXOVIRIDAE <GENUS> INFLUENZAVIRUS A <SPECIES> INFLUENZA A VIRUS <STRAIN> A/CALIFORNIA/7/2009 X-179A (H1N1) <PART> ENVELOPE <FRACTION_TYPE> GLYCOPROTEIN <FRACTION> NEURAMINIDASE <MODIFICATION_TYPE> AGENT <MODIFICATION> INACTIVATION <AGENT> FORMALDEHYDE <AGENT_ID> 1HG84L3525

Influenza A <SUBSTANCE_NAME> INFLUENZA A VIRUS A/CALIFORNIA/7/2009 X-

179A (H1N1) ANTIGEN (FORMALDEHYDE INACTIVATED <SUBSTANCE_ID> XQO8062U6R <MIXTURE_TYPE> ALL OF <CONSTITUENT_NAME> INFLUENZA A VIRUS A/CALIFORNIA/7/2009 X-

179A (H1N1) HEMAGGLUTININ ANTIGEN (FORMALDEHYDE INACTIVATED)

<CONSTITUENT_ID> C8E791RO82 <CONSTITUENT_REQUIREMENT> ALWAYS PRESENT <CONSTITUENT_NAME> INFLUENZA A VIRUS A/CALIFORNIA/7/2009 X-

179A (H1N1) NEURAMINIDASE ANTIGEN (FORMALDEHYDE INACTIVATED)

<CONSTITUENT_ID> 460J8Y21CE <CONSTITUENT_REQUIREMENT> ALWAYS PRESENT

Immunoglobulins

Can be a single protein entity or a complex mixture defined using structurally diverse elements

Monoclonal antibodies are defined using protein elements and polyclonal antibodies defined using structurally diverse elements

Modifications either resulting in a non-reversible change in molecular structure or a change in the overall specificity of polyclonal will result in a different substance.

Monoclonal Antibodies

Described as proteins Each subunit’s sequence is captured along

with disulfide bonds, sites of glycosylation and glycosylation type

Modifications captured as agent, fragment or moiety along with a molecular structure of the fragment or moiety.

Polyclonal Immunoglobulins Differences in xenogenic (source), allogenic or

autologous origins result in a different substance ID.

Donor or size of donor pool does not effect the substance ID.

Would not distinguish between immunoglobulins prepared from natural exposure or from immunization with the targeted antigen at the substance level.

Process used to purify immunoglobulins is not explicitly captured but subtype that resulted from the purification is captured (i.e. protein A, IgG)

Immunoglobulins of a predominate isotype are distinguished (IgG from IgM).

Organism/Part Substances

Whole Organisms Parts of Organisms Oils (liquid fats and/or terpenes) Butters (semi-solid plant derived fats) Animal Fats (solids) Waters (steam distilled) Seedcakes

Sugar Kelp<SUBSTANCE_ID> 68CMP2MB55• Source Type – brown alga• Kingdom - Chromista• Phylum - Ochrophyta• Class - Phaeophyceae• Order - Laminariales • Family - Laminariaceae Genus - Saccharina Species – Latissima Part - Thallus Taxon Author - (L.) C.E. Lane, C. Mayes,

Druehl & G.W. SaundersSynonym – Laminaria saccharina (L.) J.V. Lamour.

Lemon Oils• Source Type – Plant• Kingdom - Plantae• Phylum - Magnoliophyta• Class - Magnoliopsida• Order - Sapindales • Family - Rutaceae Genus - Citrus Species – Limon Part – Fruit Rind (peel) Taxon Author - (L.) Burm. f. Common Name – lemon peel

Lemon Oils<SUBSTANCE_ID> I9GRO824LL<NAME>LEMON OIL

<SUBSTANCE_ID> ET5GD00TRP<NAME>LEMON OIL, DISTILLED

Food Chemicals Codex (FCC) Monographs Lemon Oil, Cold-pressed I9GRO824LL Lemon Oil, Desert Type, Cold-pressed I9GRO824LL Lemon Oil, Distilled ET5GD00TRP

LEMON OIL CONSTITUENTScompound Oil %

α-pinene 2 

sabinene 3

β-pinene 15 

myrcene 2 

limonene 63 

γ-terpinene 9

perillaldeyde 2 

neryl acetate 1 

Specified Substance

A single set of elements◦Components of multi-substance

materials (includes proportions)◦Detailed information about substances

Specified Substance

A specified substance can contain different levels of detailed information depending on the:◦the region it is implemented ◦the use in the description of the product

◦the actual material

Specified Substance Group 1

Specified Substance Group 2

Specified Substance Group 3

Specified Substance Group 4

Current SRS System

Two step business process - one person enters the data and another approves

Contains records for about 50,000 substances about 31,000 of which have a public UNII

Basic information is public for most UNIIs but investigational substances can also receive UNIIs

Very little information on relationships between substances (Specified Substance).

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http://fdasis.nlm.nih.gov/srs/srs.jsp

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