Safety and Quality Control of Pharmaceutical Excipients for Injection National Institutes for Food and Drug Control Song Xiaosong 2017-4-25 http://www.nicpbp.org.cn 01 03 02 Introduction Current status of excipients for injection in China Key points of quality control for injectable excipients 04 05 Examples of safety and quality control of the excipients for injection Summary
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Safety and Quality Control of Pharmaceutical Excipients for Injection
National Institutes for Food and Drug ControlSong Xiaosong
2017-4-25
http://www.nicpbp.org.cn
01
03
02
Introduction
Current status of excipients for injection in China
Key points of quality control for injectable excipients
04
05
Examples of safety and qualitycontrol of the excipients forinjection
Summary
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API Pharmaceutical
preparation
process
Pharmaceutical
container
Pharmaceutical
excipients
Pharmaceutical
products Quality control
1. Introduction
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• Functions of excipients
• 63 classifications of pharmaceutical excipients based on fuctions:pH adjusting agent, chelating agent, coating agent, coating agent, protective agent, humectant, disintegrating agent, surface
Pharmaceutical excipients have activities in vivo.The quality of excipients may significant effect on the
safety of drug products, especially of injections.
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2. Current status of excipients for injection in China
drug manufacturer
5%
food additive manufacturer
6%sugar
manufacturer21%
others1%
chemistry manufacturer
67%
Pharmaceutical excipient manufacturers in China
Only about 110 professional pharmaceutical excipient manufacturers in China
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Before Ch.P 2015 : over 140 excipients were used in injectionmanufacturing,but only 2 of them has injection level standards,others are common level or chemical level.
Safety requirements of excipients:should be based on their different applications
Excipients used in injection manufacturing in Chinapropylene glycol
sodium hydroxide
glycerinpolysorbate
80EDTA‐2Na ethanol
anhydrousethanol
PEG400sodium benzoate
sodium chloride
potassium chloride
Anhydrous sodium sulfite
ammonia sulfuric acidsodium
pyrosulfitecitric acid
calcium chloride
meglumine
sodium bicarbonate
chloroform mannitoldisodium hydrogen phosphate
cholesterolanhydrous sodium acetate
glycinesodium sulfate
sodium carboxymethylcellulose
polysorbate
20
sodium hydrogen sulfite
magnesium sulfate
sodium citrate
glutamic aciddipotassiumphosphate
lactic acid
phenollauryl sodium sulfate
methioninebenzyl alcohol
ethylenediamine soya bean
lecithin
lactosesodium
thiosulfatemalic acid
potassium hydroxide
diluted hydrochlori
c acid
Egg yolk lecithin
Merthiolate sucrosesodium
dihydrogenphosphate
sorbitol chloretonephosphoric acid
dextran soybean oil
2. Current status of excipients for injection in China
How to control the quality of excipients?
Improving the monograph of excipients in national pharmacopeia
Management of the excipients for injection by CFDA
excipients Use
1 2,6‐ditertbutyl‐4 methylphenol For injection、ophthalmic use
2 propylene glycol For Injection3 sodium hyaluronate For Injection、ophthalmic use4 poloxamer188 For Injection5 camellia oil(for injection) For Injection6 Soya Lecithin (for injection) For Injection7 Soybean Oil(for injection) For Injection8 Cholesterol For Injection9 egg yolk lecithin(for injection) For Injection
10 glycerin(for injection) For Injection11 refined corn oil For Injection12 Polysorbate 80 For Injection13 PEG 400 For Injection14 PEG 600 For Injection
Excipients under License Management
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15 PEG 200 For Injection16 PEG 300 For Injection17 Egg yolk lecithin(for injection) For Injection18 maltose For Injection19 gelatin20 Vacant Gelatin Capsules
21 Enteric Vacant Gelatin Capsules22 Hydroxypropyl Betadex(for injection) For Injection23 lactose For Injection, inhalation
24 Anhydrous lactose For Injection, inhalation
25 Anhydrous ethanol(for injection)For Injection26 PLGA(25:75)27 oleic acid For Injection28 sodium oleate For Injection
Management of the excipients for injection by CFDA
Excipients under License Management
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3. Key points of quality control for injectable excipients
Name
Chemical structure
Molecular fomulation
CAS No.
Source and manufacture
Appearance and solubility
Identification
Specific test
Assay
Classification
Packaging and storage
specific items for injectable excipients Items of quality specification
Source and manufacture
Endotoxin and Sterility
allergic impurities
Substances cause Haemolysis oragglutination
undue toxicity
Substances cause hypertension orhypotension
stimulating substance …
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ingredients %
PC 73.0%PE 15.0%SPM 2.5%
PI 0.9%
LPC 5.8%
LPE 2.1%
OTHERS 0.9%
ingredients %
PC 57.8%PE 13.3%PI 2.2%
LPC 3.2%
LPE 0.6%
OTHERS 22.9%
Lecithin
The difference in composition and content would effect on thefunction and safety of excipients, and effect on the efficiency andsafety of injection.
The source of excipients for injection needs to be noticed.
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Egg yolk lecithin for injection
Endotoxin
Sterility
For the process of preparations without terminal sterilization
May cause fever or other side effect
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Allergic impurities in excipients for injection
Proteins in lactoseSource: whey fermented from milk
Allergen: residual protein in whey
residual protein in lactose %
α-Lactalbumin 19.7%
β-Lactoglbulin 43.6%
BSA 4.7%
免疫球蛋白(Ig) 3%
Other proteins 29%
The residual proteins may induce immune response and allergy, causing serious safety issue.
•LPC/LPE: hydrolysis from PC/PE•During producing process;•During sterilization process of emulsion
Substances cause Haemolysis or agglutinationlysophosphatide in lecithin
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PC LPC
棘皮红细胞显微镜图
棘皮细胞
Compared with phospholipids, the hydrophilic and hydrophobic property of lysophospholipids are more equivalent, which accelerate the exchange between cell membrane and cytoplasm. Red blood cells become to echinoderms cells. When the concentration of lysophospholipids reaches 2×10-4M, haemolysis occurs.
Substances cause Haemolysis or agglutination——lysophosphatide in
Fatty acids composition is an important function and safety parameter of polysorbate 80 for injection.More oleic acid in polysorbate 80, the more colorless and transparent.
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impurities
qualitypurity
Illegal additive hydrogen peroxide
Polysorbate 80 is a mixture
colorless and transparent
component separation structure confirmation
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Hydrogen peroxide test
hydrogen peroxide
ceriometry
iodometry
permanganate titration
Color of titration end-point is not
obvious
Iodine
淀粉
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A
50 mL water+sample37
5minAdd 30 mL of sulfuric acid (3 mol·L-1)
Add 200 uL of phenanthroline indicator
Cerium sulfate titrant(0.001 mol·L-1)
hydrogen peroxide and other reducing
substances
B50 mL water+sample+
0.1% catalase
37
5minAdd 30 mL of sulfuric acid (3 mol·L-1)
Add 200 uL of phenanthroline indicator
Cerium sulfate titrant(0.001 mol·L-1)
other reducing substances
Hydrogen peroxide test
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Hydrogen peroxide test
Result based on 10 batches of polysorbate 80
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Component separation and structure confirmation
Theoretical structure of polysorbate 80
Complex ingredient :different in
①parent nucleus(sorbitan、isosorbide)
②fatty acids(oleic acid, linoleic acid, palmitic
acid , Stearic acid, etc.)
③esterification of oleic acid (monoeaster,
diester, triester, tetraester)
④polymerization of ethylene oxide
X+Y+Z=20
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optimization
Polysorbate 80
Chromatographic systemColumn:Agilent SB-C8 (250x4.6mm,5um)Mobile phase A:2% formic acid in waterMobile phase B:2% formic acid in isopropanol
A C
B
D
E
F
G
Column:Aiglent Eclipse XDB-C18(4.6x150mm, 5μm) ; temperature : 30 ; Detector : AlltechELSD; Mobile phase:A= methanol B=THF;Gradient elute:0~4.9min:100%B过渡到90%B;5.0~18.9min:90%B过渡到20%B;19~19.1:20%B过渡到100%B。