:
:
:
:
11000
: 0-2590-1628 : 0-2590-1634
http://www.phdb.moph.go.th
1 : 2553
: 1,500
3 Biosimilar 10 2 21 17 4 3
... ... ... . .
25532553
1
((BBiioollooggiiccaall PPrroodduuccttss // BBiioollooggiiccss)
4
Biosimilar 5
(Biopharmaceuticals) 5
6
Recombinant-DNA (rDNA) Technology 7
Recombinant Protein 8
Prokaryotic Cell 9
Eukaryotic Cell 10
11
11
12
12
13
/ 13
14
(Identity) 14
16
(Binding Analyses) 23
(Biological Activity) 23
24
28
29
((BBiiooeeqquuiivvaalleennccee))
31
31
32
33
33
34
BBiioossiimmiillaarr 36
BBiioollooggiiccaall pprroodduuccttss
Albumin human.....% injection 37
Enoxaparin sodium......mg /......ml injection 40
Erythropoietin alpha......iu injection or for injection 43
Factor VIIa.....mg injection 46
Factor VIII.....iu injection ( plasma derived) 49
Filgrastim.....mcg injection 52
Immunoglobulin G.....% intravenous injection or for injection 55
Insulin aspart.....iu/ml.....ml injection 58
Insulin glargine.....iu/ml.....ml injection 61
Insulin human.....iu/ml.....ml injection 64
Isophane insulin human.....iu/ml.....ml injection 67
Insulin lispro.....iu/ml.....ml injection 70
Interferon alpha 2.....iu injection 73
Interferon beta 1.....mcg/.....ml injection 76
Peginterferon alpha 2.....mcg /.....ml injection 79
Octreotide.....mg/ml injection 82
Rabies vaccine 85
CChheemmiiccaall ddrruuggss
Cefoperazone sodium.....mg and Sulbactam sodium.....mg for injection 88
Imipenem.....mg and Cilastatin.....mg for injection 91
Meropenem.....g for injection 94
Piperacillin.....g and Tazobactam.....mg for injection 97
101
1
.2543
(Guidelines) (Pattern Specification)
(Specification) 4
1. (Generic Name) ( Dosage Form)
2. (Appearance)
- : ,,,
- :
()
- :
2
- : Labeling
(Expired Date) , (Manufacturing
Date)
3.
general requirements
4.
(Certificate of Analysis )
(Finished Product )
(Specification)
Identification, Label amount, (weigh/unit), Uniformity of dosage
units, Weight variation, Content uniformity, Disintegration time, Dissolution, Related Substances,
Particulate matter, pH, Pyrogens (in vivo) Bacterial endotoxins (in vitro), Leak test, Sterility
test, Microbial limit test, Deliverable volume ,Minimum fill, Water content & Loss on drying,
Chromatographic purity
. 2548
(http://phdb.moph.go.th)
(http://dmsic.moph.go.th)
)Customer enforcement)
(Pattern Specification)
(Specification)
82
3
1.
1.1
1.2
2. Finished product specification (FPS) and Certificate of analysis (COA)
3. Certificate of a Pharmaceutical Product (WHO)
4. BA/BE
5. Specific Rotation / Optical Rotation
6.
7.
8.
9.
2 () .2549
.2552
amino acids
//
22555533
4
((BBiioollooggiiccaall PPrroodduuccttss // BBiioollooggiiccss))
......
/ (Biological Products)
ASEAN HARMONIZATION ? @
? (allergens) (antigens) (vaccines) (hormones)
(cytokines) (enzymes) (stem cells)
(tissues) (human whole blood and plasma
derivatives) (immune sera) (immunoglobulin)
(monoclonal antibodies)
1. (eukaryotic cells)
2. [extraction of substances from
biological tissues including human, animal and plant tissue (allergen)]
3. (recombinant-DNA or rDNA techniques)
4. (hybridoma technique)
5. (propagation of microorganisms in embryo or
animals)
6.
(purity) (potency) (composition) (chemical) (physiochemical) @
(Biopharmaceuticals) (Biological
5
Products) Biologics Biological Products
Biosimilar
Biosimilar ? Follow-on Biologics @
follow-on biologics
impurity
(European Union)
generics
?Similar Biological Medicinal Products@
?comparability@ European
Medicines Agency (EMEA) guidelines
biosimilar
(Biopharmaceuticals)
( biocompatibility )
(identity) (
(primary, secondary, tertiary and quaternary structure)
6
(post-translational modification) (subunit
structure) (purity) (impurity) (quantity) (potency)
(physicochemical properties)
(glycosylation)
rDNA technology, hybridoma technology transformed
continuous cell lines
homogeneity
low molecular weight reference standard
validated
rDNA
7
technology monoclonal technology
transgenic animals transgenic plants, gene therapy
antisense DNA
rDNA technology monoclonal antibody
Recombinant-DNA (rDNA) Technology
Recombinant-DNA (rDNA) technology
(plasmid)
recombinant-DNA (rDNA)
prokaryotes ( ) eukaryotes (
)
E. coli
eukaryotes rDNA prokaryotes
eukaryotes prokaryotes
post-translational modification (glycosylation)
eukaryotes
8
()
rDNA
E.coli E.coli
Recombinant Protein recombinant protein 3
1. Upstream processing
bioreactor
2. Downstream processing
final bulk product
3. Formulation
(finish product)
9
Recombinant Protein
Prokaryotic Cell eukaryotes
E. coli folding
E.coli methionyl derivatives
protease endotoxin
(genetic stability)
DNA restriction mapping
peptide mapping
E.coli yield conformation
potency
(Chromatographic
purification)
upstream downstream upstream downstream formulation
upstream downstream
(Chromatographic
Purification)
/ (Precipitation/
Centrifugation)
(Concentration)
/ (Fermentation)
(Cell Harvest)
10
Eukaryotic Cell eukaryotes
rDNA E.coli
glycoprotein
folding
Chinese Hamster Ovary (CHO) cells
immortal cell lines
Saccharomyces cerevisiae
E.coli
glycoprotein monoclonal antibody
genetic stability , yield
adventitious organism eukaryotes
oncogenic DNA/RNA
E. coli
peptide mapping resolution sensitivity adventitious organisms
mycoplasmas adventitious viruses degree glycosylation
glycoprotein degree
(half-life) (potency)
(antigenicity)
11
(fermentation)
(cell culture) chromatofocusing ,
reversed-phase chromatography , hydrophobic interaction chromatography , charge-transfer
chromatography , size-exclusion chromatography ( molecular sizing ) , ion-exchange
chromatography , affinity chromatography
E. coli protease
protease
monograph European Pharmacopoeia
(EP) British Pharmacopoeia (BP)
intermediary compounds
immunogenicity
current GMP
upstream
( bulk concentrated material) downstream (
purified raw material) intermediate
product
12
prokaryotic cells eukaryotic cells
prokaryotes , ,
karyology, phenotyping
(DNA restriction mapping ) ,
mRNA / plasmid DNA eukaryotes
master cell bank working cell bank adventitious
organisms, karyology, eukaryotic
( ) retroviruses, retroviral activity markers tumorigenicity
stabilizer
solubilizing buffer
lyophylization
deamidation,
aggregation, oxidation proteolysis protease
stabilizer
- (tonicity)
proteins, polyhydric alcohols, amino acids, carbohydrates, bulking agents,
inorganic salts nonionic surfactants lyophilized
monograph
(accelerated stability studies)
(shelf life) protein
conformation Arrhenius
13
(reference standard)
USP, WHO, NIH FDA
(activity units)
(calibrate secondary standard)
/
(numerical limits) (range)
intermediate
Certificate of Analysis (COA)
(physicochemical properties) (biological activity)
(immunochemistry analysis) (purity) (impurities and contaminants)
(quantitative analysis)
International Conference on Harmonization (ICH ; technical guidelines )
(appearance; )
(, circular dichroism (CD), DSC, EPR, MS, IE focusing, isoform
14
pattern, native electrophoresis, NIR, NMR, peptide mapping, 2D electrophoresis, X-ray
diffraction), ( receptor)
() (capillary
electrophoresis, ELISA-HCP, HPIEC, RP-HPLC, HPSEC, LAL test, PCR),
(Kjeldahl analysis, UV absorbance), sterility, pH, osmolarity
COA
monomer multimers
chromatography, electrophoresis
(primary structure)
(comparability)
(Identity)
, post-translational modifications
,
, , , , X-ray
diffraction , NMR
recombinant protein
molecular weight, isoelectric point, ,post-translational modification,
liquid chromatography patterns biomolecular interaction
15
post-translational
modification ( glycosylation, phosphorylation acylation pattern)
immunogenic
allergic
molecular weight electrospray mass
spectrophometry, MALDI-TOF, HPSEC ultrafiltration
isoelectric point (pI) isoelectric focusing (IEF)
polyacrylamide gel capillary electrophoresis (CE-IEF) pI pH
N (N-terminal sequencing) Edman
degradation, C (C-terminal analysis)
(peptide mapping)
RP-HPLC mass spectrophotoscopy
matrix-assisted laser desorption/ionization time-of-
flight (MALDI-TOF)
Fourier transform-infrared/Raman far-UV circular dichroism
near-UV circular dichroism
nuclear magnetic resonance spectroscopy (NMR)
dynamic light scattering
X-ray crystallography
Post-translational modification side group
methionine,
16
deamidation asparagines glutamine, phosphorylation, glycosylation, fatty acid
acylation, farnesylation, sialic acid capping, N-methylation acetylation
modification
RP-HPLC , HPIEC mass spectroscopy
glycosylation
recombinant protein eukaryotic cell lines
glycosyltransferases
(neutral sugars; D-galactose, D-mannose L-fucose), amino sugars (N-acetylglucosamine
N-acetylgalactosamine) acidic sugar sialic acid
oligosaccharides
Protein Sequencing
Protein sequencing
N C
recombinant DNA protein
homogeneity
Peptide Mapping by HPLC
peptide mapping
genetic stability
peptide mapping
endoprotease
Purity
(specific biological activity)
specific biological activity
17
recombinant technology
adventitious
agents specific impurities
Impurities
Contaminants
heterogenous
form form
aggregation
electrophoresis column chromatography (
HPLC)
impurities contaminants
impurities impurities
scrambled form
in-vitro folding
impurities
impurities
impurities
impurities host cell recombinant protein
18
apoptosis lysis impurities endotoxins, viruses, prions, nucleic acid, host
cell lipids, proteins proteolytic enzymes
impurities upstream,
downstream impurities bacteria, yeast, fungi, mycoplasma,
viruses, prions, endotoxins,
impurities des-amido
forms, oxidized forms, scrambled forms, glycosylated forms, cleaved forms, carbamylated
forms, acylated forms polymeric forms
polymeric forms immunogenicity
impurities
Des-Amido Forms amido-
glutamine asparagines amido-
Oxidixed Forms Met, Cys, His, Trp
Tyr oxidation cystinyl
Carbamylated Forms primary amino, sulfhydryl,
carboxyl, phenolic hydroxyl, imidazole phosphate group cyanate
urea
des-Amido forms, oxidixed forms carbamylated forms
HPIEC, RP-HPLC , native PAGE, IEF, MS CE
Aggregates () hydrophobic interaction
aggregates
aggregate aggregates
non reducing agents, 1D-SDS-PAGE, HPSEC, MS CE
hydrophobic aggregates HPSEC
19
Scrambled Forms in-vitro folding HPIEC, RP-HPLC, CE
peptide mapping
Glycosylated Forms glycosylation
HPIEC, RP-HPLC, native PAGE, IEF, MS, peptide mapping CE
Cleaved Forms proteolysis N- C-
HPIEC, RP-HPLC, native PAGE, IEF, MS, peptide mapping CE
Residual Host Cell DNA/Protein
Host Cell DNA/RNA Residual host cell DNA
DNA recovery
DNA DNA
DNA RNA RNA/DNA
RNA retrovirus
Center of Biologics Evaluation and Research (CBER)
10 pg 100 pg
DNA hybridization (dot blot analysis)
DNA
biosensor polymerase chain reaction
(PCR) DNA RNA realtime PCR
20
Host cell protein Host cell protein host
expression system
impurities
process validation finished product
SDS-PAGE, 2D-electrophoresis, western blot immunoassay
Host cell protein generic specific test
generic assays
pattern impurities
specific test assays
host cell protein host cell protein
mammalian cell culture
master seed bank
working cell banks ,,
, ,
pH
Prions transmissible spongiform encephalopathies (TSE)
scrapie , chronic wasting disease , bovine spongiform
21
encephalopathy (BSE) Kuru Creutzfeldt-Jakob disease (CJD)
recombinant protein
prions
( trypsin, serum, transferin, bovine/human serum
albumin, protein supplements, peptones)
semiquantitative assay western blot, capillary immunoelectrophoresis, conformation-
dependent immunoassay dissociation-enhanced,time-resolved fluoroimmunoassay
Microbial agents
Mycoplasma GMP
mycoplasma mycoplasm
Endotoxins endotoxins
(Raw Materials) impurities
prions
(stabilizers)
22
Impurities Contaminants
Impurities Contaminants Impurities Endotoxin Bacterial Endotoxins Test, Pyrogen Test
Host cell proteins SDS-PAGE, Immunoassays
Other protein impurities (media) SDS-PAGE, HPLC, Immunoassays
DNA DNA hybridization, UV spectrophotometry,
Protein binding
Protein mutants Peptide mapping, HPLC, IEF, MS
Formyl methionine Peptide mapping, HPLC, MS
Oxidized methionines Peptide mapping, Amino acid analysis, HPLC,
Edman degradation analysis, MS
Proteolytic Cleavage IEF, SDS-PAGE (reduced), HPLC,
Edman degradation analysis
Aggregated proteins SDS-PAGE, HPSEC
Deamidation IEF, HPLC, MS, Edman degradation analysis
Monoclonal antibodies SDS-PAGE, Immunoassays
Amino acid substitutions Amino acid analysis, Peptide mapping, MS,
Edman degradation analysis
Contaminants
Microbial (bacteria, yeast, fungi) Microbial Limit Tests, Sterility Tests,
Microbiological testing
Mycoplasma DNA-binding Fluorochrome
Viruses (endogenous and adventitious) Cytopathic effect and Hemadsorption (exogenous
virus only), Reverse transcriptase activity,
Murine antibody production
23
(Binding Analyses) binding assay
binding assay
1. ligand** ligand analog binding assay
enzyme-linked immunosorbent assay (ELISA)
epitope
ligand
2. monoclonal antibody binding assay
(Biological Activity)
/ (potency; )
Biomimetic assays animal model assays, cell
culture-based bioassays in-vitro (physicochemical) assays
Animal Model Assays animal facilities , ,
( ) ,
** ligand
24
cell culture-based bioassays in-vitro assay
human growth hormone (somatrem and somatropin)
rat
Cell Culture-Based Bioassays , ( 1-3
),
antiviral activity human -interferon human diploid foreskin cell line
human lung carcinoma cell line (A549)
In-vitro (Physicochemical) Assays (potency test)
(in-vivo)
(in-vitro)
in-vitro in-vivo
in-vitro potency test
,, tissue-type
plasminogen activator (alteplase) in-vitro clot lysis assay
antibody antigen ligand
monoclonal antibody
Protein Content
protein content
protein content
UV spectrophotometry Kjeldahl
reference standards Lowry protein,
biuret, protein content
25
potency
protein content
protein content
UV absorptivity
aromatic amino acid tyrosine, tryptophan phenylalanine
total protein content
des-amido forms, oxidized forms polymeric forms
high performance chromatography
UV
bioassay amino acid
analysis, Kjeldahl analysis, ultraviolet spectrometry high-performance chromatography
Total Protein
total protein
UV spectrophotometry, Kjeldahl assay, bicinchoninic acid (BCA)
assay, biuret assay, Bradford assay, Lowry assay
(total protein)
amino acid analysis, Kjeldahl UV absorbance
ELISA
Immunoassays
Immunoassays
host cell protein
immunoassay
E.coli CHO protein
immunoassays potency monoclonal antibodies
26
immunoassays
radioimmunoassay (RIA) enzyme-linked immunosorbent assays
(ELISAs) ELISA impurity sandwich
ELISA
ELISA (Enzyme Linked Immunosorbent Assay) microtitration plate
Electrophoresis Electrophoretic Assays
homogeneity
denaturation, aggregation, oxidation, deamidation electrophoresis
sodium dodecyl sulfate polyacrylamide gel
electrophoresis (SDS-PAGE) isoelectric focusing (IEF)
Polyacrylamide Gel Electrophoresis (PAGE)
polyacrylamide gel
sodium dodecyl
sulfate (SDS)
polyacrylamide gel Sodium Dodecyl Sulfate
Polyacrylamide Gel Electrophoresis (SDS-PAGE) anionic detergent SDS
denature
27
polyacrylamide
aggregation (
non-denature) denature
sodium dodecyl sulfate (SDS)
immunoblotting
Isoelectric Focusing (IEF) electrophoresis
isoelectric point (pI)
pI phosphorylated forms glycosylated forms
pH
Isoelectric pH (pI) pH
gradient isoelectric pH
homogeneity
pI
protein deamidation pI IEF
glycosylation
sialic acid IEF gel SDS-PAGE
2D-electrophoresis isoelectric focusing
SDS-PAGE pI
isoelectric focusing SDS-PAGE
Capillary Electrophoresis (CE) Capillary Zone Electrophoresis (CZE) capillary polyacrylamide, agarose ampholyte
( isoelectric points)
electro-osmotic flow electrophoresis
(1 10 pL)
28
High-performance Liquid Chromatography (HPLC)
electrophoresis
high-
performance ion-exchange chromatography (HPIEC) , reversed-phase high-
performance liquid chromatography (RP-HPLC) hydrophobicity high-performance
size-exclusion chromatography (HPSEC)
recombinant
hydrophobicity
recombinant protein RP-HPLC, HPIEC, HPSEC
HIC impurities
degradation product
High-performance Ion-exchange Chromatography (HPIEC) impurities oxidized (
methionine) deamidation ( glutamine asparagine)
High-performance Size-exclusion Chromatography (HPSEC)
aggregation fragmentation
Hydrophobic Interaction Chromatography (HIC)
hydrophobicity hydrophobic proteins
29
Prekallikrein Activator (PKA)
human albumin immunoglobulin
prekallilrein activator Blood coagulation factor XIIa fragments
PKA final product
Immunochemical Properties
Efficacy
Efficacy
Potency
(Room Temperature)
?@ 18L25C
(Sensitivity) Limit of detection
(Specificity)
false-positives
30
Sialic acid
Silalic acid N-linked O-linked-Neuraminic acid derivatives
sialic acid
in-process control glycosylation
Normocythemic mice/Polycythemic mice
hematocrit ( normocythemia) hematocrit
(polycythemia)
erythropoietin
1. Crommelin, D.J.A., R.D. Sindelar, and B. Meibohm, Pharmaceutical biotechnology :
fundamentals and applications. 3rd ed. 2008, New York: Informa Healthcare. xiv, 466 p.
2. Gad, S.C., Handbook of pharmaceutical biotechnology. 2007, Hoboken, N.J.: Wiley-
Interscience. xix, 1659 p.
3. Niazi, S., Handbook of biogeneric theraupetic proteins : regulatory, manufacturing, testing,
and patent issues. 2005, Boca Raton: Taylor & Francis. 554 p.
4. Rathore, A.S., R. Mhatre, and Wiley InterScience (Online service), Quality by design for
biopharmaceuticals principles and case studies. 2009, Wiley: Hoboken, N.J. p. xvi, 288 p.,
[16] p. of plates.
5. Walsh, G., Pharmaceutical biotechnology : concepts and applications. 2007, Chichester,
England ; Hoboken, NJ: John Wiley & Sons. xviii, 480 p.
6. Wu-Pong, S. and Y. Rojanasakul, Biopharmaceutical drug design and development. 2nd
ed. 2008, Totowa, N.J.: Humana Press. x, 375 p.
7. The United States Pharmacopoeia XXXIII.
8. The European Pharmacopoeia 6th edition.
31
((BBiiooeeqquuiivvaalleennccee))
......
Bioequivalence
.. 2535
(new chemical entity)
Bioequivalence (BE)
(pharmaceutical equivalence) pharmaceutical alternative
(same molar dose)
(same route of administration) bioavailability
(pharmaceutical equivalence)
chlordiazepoxide
hydrochloride 5 mg capsule
/ /
tetracycline hydrochloride 250 mg capsule
32
pharmaceutical alternative tetracycline phosphate 250 mg capsule quinidine sulfate
200 mg tablet pharmaceutical alternative quinidine sulfate 200 mg capsule
Bioavailability (BA)
100%
100%
100%
(therapeutic equivalence)
Orange Book 30th
edition ) . .2553)
section 505 of the Federal Food, Drug, and Cosmetic Act
1. 2.
3.
4. 5. (good manufacturing practice, GMP)
ASEAN Guidelines for
the Conduct of Bioavailability and Bioequivalence Studies
ASEAN Harmonization 1 2552
33
1 2553
GLP ISO/IEC 17025
pharmaceutical alternative
) ( 12 )
20%
18-24 (
(Cmax , maximal plasma concentration) (AUCt or , area under the
plasma concentration-time curve from administration to last observed concentration at time t or
to infinite time) Cmax AUCt or
log (logarithmic transformation) ANOVA
) ( formulation, period, sequence subject (within sequence) 90%
confidence interval Cmax AUCt or
90% confidence interval
Cmax AUCt or 0.80-1.25
90% confidence interval 0.75 - 1.33
1.
(low therapeutic index/ narrow safety margin)
(therapeutic inequivalence)
2.
34
3. (modified release dosage form)
(transdermal dosage form)
4. (fixed combination products)
5. 6.
1.
(high solubility) (high permeability)
Biopharmaceutical Classification System (BCS) 1 )
( (low therapeutic
index/ narrow safety margin) (rapid
dissolving) (very rapidly dissolving)
(polymorphism)
2. elixir, syrup, tincture reconstituted powder
for oral solution
3.
35
4.
5. (inhalation)
6. preservative, buffer, tonicity
/ 7.
8. /
1. . :
, .. 2552.
2. Drug Control Division, Food and Drug Administration. Guidelines for the conduct of
bioavailability and bioequivalence studies adopted from ASEAN Guidelines for the Conduct
of Bioavailability and Bioequivalence Studies. Nonthaburi; Food and Drug Administration,
2009.
3. US Department of Health and Human Services, Food and Drug Administration, Center for
Drug Evaluation and Research, Office of Pharmaceutical Science, Office of Generic Drugs.
Orange book, 30th edition.(2010). Available at: www.fda.gov/Drugs/DevelopmentApproval
Process/ucm079068.htm (access date: 9 April 2010)
36
BBiioossiimmiillaarr**
1. Enoxaparin sodium ??.. mg / ........ ml injection
2. Erythropoietin alpha ..??.. iu injection or for injection
3. Filgrastim ??.. mcg injection
4. Insulin aspart ??..iu/ml ??.. ml injection
5. Insulin glargine??.. Units /ml ??.. ml injection
6. Insulin human ??.. iu/ml ??.. ml injection
7. Isophane insulin human ??.. iu/ml ??.. ml injection
8. Insulin lispro??..iu/ml ??..ml injection
9. Interferon alpha 2???.. iu injection
10. Interferon beta 1???..mcg/??...ml injection
** Biosimilar EMEA
37
AAllbbuummiinn hhuummaann
.... %% iinnjjeeccttiioonn
Albumin human
.. % injection
1. colloid
2. albumin human ....... g .. ml
3.
4. -
- Sodium
-
1. Identification
- Immunoelectrophoresis
- Ouchterlony test (Double immunodiffusion)
2. pH finished product specification
3. Total protein 94 - 106 %
4. Albumin albumin 95%
5. Haem content finished product specification
6. Prekallikrein activator [PKA] finished product specification
7. Sodium 160 mmol/l 95 -105 %
sodium
8. Sterility sterile
9. Pyrogens finished product specification
10. Aluminium finished product specification
11. Potassium finished product specification
38
12. Heat stabilizers finished product specification
N-acetyl-DL-tryptophan,
caprylic acid /caprylate
heat stabilizer
heat stabilizer heat stabilizer
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- Anti-HIV-1 , Anti-HIV-2 ,
Hepatitis B Surface antigen, Anti-HCV ( Antibody against Hepatitis C Virus)
39
3.4 NIBSC (National
Institute for Biological Standards and Control), AABB(American Association Blood
bank), PPTA (Plasma Protein Therapeutic Association),
4.
4.1 ..........
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
6.2 (Lot Release)
7.
Administration set membrane filter
40
EEnnooxxaappaarriinn ssooddiiuumm
.... mmgg // ................ mmll iinnjjeeccttiioonn
Enoxaparin sodium
.. mg / ........ ml injection
1.
2. enoxaparin sodium ... mg/ml ( iu anti-Xa / ml )
3.
4.
1. Identification finished product specification
2.
Anti -Xa activity 90.0 - 110.0 %
3. Anti - IIa activity 20 - 35 iu /mg
4. Ratio of Anti-Xa/Anti-IIa 3.3 - 5.3
5. pH 5.5 -7.5
6. Bacterial endotoxins 0.01 endotoxin units/anti-factor Xa iu
7. Volume in container finished product specification
8. Sterility sterile
9. Particulate matter finished product specification
41
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- molecular weight
- free sulfate content 0.12%
4.
4.1 ..........
42
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
6.
6.1 Long Term Stability
43
EErryytthhrrooppooiieettiinn aallpphhaa....
.... iiuu iinnjjeeccttiioonn oorr ffoorr iinnjjeeccttiioonn
Erythropoietin alpha ..
.. iu injection or for injection
1. solution
lyophilized form
2. recombinant erythropoietin alpha .. iu
3. (pre-filled syringe)
4. -
- erythropoietin alpha
1. Erythropoietin identity 1 5 (
) - CZE IEF
- PAGE + immunoblotting
- Peptide mapping / LC
- N-terminal sequence analysis
- HPLC
2. Assay
-Biological assay (Potency) Biological assay
1 3
- In polycythaemic mice (in vivo)
- In normocythaemic mice (in vivo)
- Immunoassay (in vitro)
potency 80 - 125%
44
- HPLC () HPLC erythropoietin
finished product specification
3. pH finished product specification
4. Bacterial endotoxins/ Pyrogens finished product specification
5. Sterility sterile
6. Particulate matter finished product specification
7. Extractable volume ( solution) finished product specification
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
45
3.3 - residual host cell DNA residual host cell protein
- sialic acid
- dimer / related substances of higher molecular mass
SEC (Size-Exclusion Chromatography) HPSEC 2%
4.
4.1 ..........
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
46
FFaaccttoorr VVIIIIaa
.. mmgg iinnjjeeccttiioonn
Factor VIIa
. mg injection
1.
2. human coagulation factor VIIa . mg
3.
4.
1. Potency 15 iu of factor VII 1 ml
2. Solubility 10
3. Assay of human coagulation factor VII 80 -125% of the stated potency
4. pH 6.5 - 7.5
5. Heparin ( heparin) heparin
0.5 iu heparin/ iu factor VII
6. Coagulation test ( heparin) coagulation 30
thrombin
7. Water content finished product specification
8. Sterility sterile
9. Pyrogens finished product specification
10. Residual host cell protein/DNA
11. Protein identification
47
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3 - Factor II Not more than 125% of the stated content. The confidence limits
(P=0.95) are not less than 90% and not more than 111% of the
estimated potency
- Factor IX Not more than 125% of the stated content. The confidence limits
(P=0.95) are not less than 80 % and not more than 125% of the
estimated potency
- Factor X Not more than 125% of the stated content. The confidence limits
(P=0.95) are not less than 90% and not more than 111% of the
estimated potency
48
- Anti-HIV-1 , Anti-HIV-2 ,
Hepatitis B Surface antigen , Anti-HCV (Antibody against Hepatitis C Virus)
- recombinant-human factor VII residual host
cell DNA residual host cell protein
4.
4.1 ..........
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
6.2 (Clinical Trial) Route of Administration
49
FFaaccttoorr VVIIIIII
.. iiuu iinnjjeeccttiioonn (( ppllaassmmaa ddeerriivveedd))
Factor VIII
.. iu injection
1.
2. human coagulation factor VIII .. iu human plasma
3.
4. -
- human derived factor VIII
1. Specific activity 1 iu AFU factor VIII
(1AFU=1 iu)
2. Factor VIII activity 80 - 160% of stated potency
3. Solubility 10
4. pH 6.5 - 7.5
5. Sterility sterile
6. Anti-A haemagglutinins 1 to 64 dilutions do not show agglutination
7. Anti-B haemagglutinins 1 to 64 dilutions do not show agglutination
8. Pyrogens finished product specification
9. Stabilizer finished product specification
50
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- Anti-HIV-1, Anti-HIV-2 , Hepatitis B Surface antigen , Anti-HCV
( Antibody against Hepatitis C Virus)
4.
4.1 ..........
51
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
52
FFiillggrraassttiimm
.... mmccgg iinnjjeeccttiioonn
Filgrastim
... mcg injection
1.
2. filgrastim ... mcg (... iu) .. ml
3. 4.
1. Identification 1 5
- CZE IEF
- PAGE + immunoblotting
- Peptide mapping / LC
- N-terminal sequence analysis
- HPLC
2. Potency 80 - 125%
3. Sterility sterile
4. Bacterial endotoxins 2.5 endotoxin units/mg
5. pH 3.8 - 4.2
6. Extractable volume finished product specification
7. Particulate matter visible particle practically free from particles
Spec.
- stabilizer
53
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- Anti-HIV-1 , Anti-HIV-2 ,
Hepatitis B Surface antigen, Anti-HCV ( Antibody against Hepatitis C Virus)
- purity : 95% main peak
- impurities with higher molecular masses : 2%
4.
4.1 ..........
54
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
55
IImmmmuunnoogglloobbuulliinn GG
..%% iinnttrraavveennoouuss iinnjjeeccttiioonn oorr ffoorr iinnjjeeccttiioonn
Immunoglobulin G
..% intravenous injection or for injection
1. 1 (slightly opalescent)
2
2. 1 immunoglobulin Gg .ml ....... ml
2 immunoglobulin Gg ml ....... ml
3.
4. -
-
1. Identification
- Immunoelectrophoresis
- Immunodiffusion
2. Anticomplimentary activity 50% (1 CH50 /mg immunoglobulin)
3. Prekallikrein activator [PKA] 35 iu/ml (30g/l immunoglobulin)
4. Anti-A and Anti-B Haemagglutinins 1 to 64 dilutions do not show agglutination
5. Anti-HBsAg 0.5 iu/g immunoglobulin
6. Osmolality 240 mOsmol/kg
7. pH finished product specification
8. Anti D antibodies finished product specification
9. Total protein 30 g/l 90-110%
10. Molecular distribution finished product specification
(Monomer + Dimer)
56
11. Protein composition Electrophoresis : Not more than 5% of
protein has a mobility different from that of the
principle band
12. Water ( lyophilized powder) finished product specification
13. Sterility sterile
14. Pyrogens finished product specification
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- Anti-HIV-1, Anti-HIV-2 , Hepatitis B Surface antigen , Anti-HCV
(Antibody against Hepatitis C Virus)
- anti-D Antibodies
57
3.4 NIBSC (National
Institute for Biological Standards and Control), AABB(American Association Blood
bank), PPTA (Plasma Protein Therapeutic Association),
4.
4.1 ..........
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
6.2 (Lot Release)
7.
Administration set membrane filter
58
IInnssuulliinn aassppaarrtt
....iiuu//mmll
....mmll iinnjjeeccttiioonn
Insulin aspart
..iu/ml
.. ml injection
1.
2. insulin aspartiu/ml ....... ml
3.
4. -
- - (avoid freezing)
1. Identification finished product specification
2. 90.0-110.0% of labeled amount of insulin aspart
3. pH 7.2 - 7.6
4. Limit of high molecular weight proteins 1.5%
5. Related proteins B28isoAsp insulin aspart 2.5%
5%
6. Total Impurities 3.5%
7. Zinc content 16.3 - 24.5 mcg/ml
8. Preservative finished product specification
9. Sterility sterile
10. Bacterial endotoxins 80 endotoxin units/100 insulin aspart units
59
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- recombinant-human insulin residual host cell
DNA residual host cell protein
4.
4.1 ..........
60
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
61
IInnssuulliinn ggllaarrggiinnee
.. iiuu//mmll
....mmll iinnjjeeccttiioonn
Insuline glargine
.. iiuu//mmll
.. ml injection
1.
2. Insulin glargine .. iu /ml ........ ml
3.
4. -
- - (avoid freezing)
1. Identification finished product specification
2. 95.0 -105.0 % of labeled amount of insulin glargine
3. pH 3.5 - 4.5
4. Limit of high molecular weight proteins 0.3%
5. Related proteins
Largest 0.5%
Sum 2.0%
6. Particulate matter finished product specification
7. Preservative finished product specification
8. Zinc content finished product specification
9. Sterility sterile
10.Bacterial endotoxins 80 endotoxin units/100 insulin glargine units
62
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- recombinant-human insulin residual host cell
DNA residual host cell protein
4.
4.1 ..........
63
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
64
IInnssuulliinn hhuummaann
.... iiuu//mmll
.... mmll iinnjjeeccttiioonn
Insulin human
.. iu/ml
.. ml injection
1.
2. insulin human recombinant DNA
insulin mono-component .. iu/ml ........ ml
3.
4. -
- - (avoid freezing)
1. Identification finished product specification
2. 90.0 - 110.0 % of labeled amount of insulin human
3. pH finished product specification
4. Sterility sterile
5. Zinc content finished product specification
6. Bacterial endotoxins 80 endotoxin units/ 100 insulin human units
7. Limit of high molecular weight proteins finished product specification
8. Particulate matter finished product specification
9. Extractable volume finished product specification
65
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- recombinant-human insulin residual host cell
DNA residual host cell protein
4.
4.1 ..........
66
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
67
IIssoopphhaannee iinnssuulliinn hhuummaann
.... iiuu//mmll
.... mmll iinnjjeeccttiioonn
Isophane insulin human
.. iu/ml
.. ml injection
1.
2. zinc insulin human protamine sulfate buffered water for injection
.. iu/ml ........ ml
3.
4. -
- insulin
-
- (avoid freezing)
- (shake carefully before use)
1. Identification finished product specification
2. 90.0 - 110.0 % of labeled amount of insulin human
3. pH 6.9 - 7.8
4. Sterility sterile
5. Zinc content 0.021- 0.04 mg/100 insulin human units
6. Bacterial endotoxins 80 endotoxin units/ 100 insulin human units
7. Limit of high molecular weight proteins 3.0%
8. Preservative finished product specification
9. Related substances
A21 desamido insulin finished product specification
Others finished product specification
10. Insulin in the supernatant 2.5% of total insulin content
68
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- recombinant-human insulin residual host cell
DNA residual host cell protein
4.
4.1 ..........
69
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
70
IInnssuulliinn lliisspprroo
....iiuu//mmll
....mmll iinnjjeeccttiioonn
Insulin lispro
..iu/ml
..ml injection
1.
2. Insulin lispro iu/ml ....... ml
3.
4. -
- - (avoid freezing)
1. Identification
2. 90.0 - 110.0% of labeled amount of insulin lispro
3. pH 7.0 - 7.8
4. Particulate matter finished product specification
5. Limit of high molecular weight proteins 1.50%
6. Preservative finished product specification
7. Zinc content 14 - 35 mcg/100 USP unit of insulin
8. Sterility sterile
9. Bacterial endotoxins 80 endotoxin units/100 insulin lispro units
10 Related substances
A21 desamido insulin finished product specification
Others finished product specification
71
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- recombinant-human insulin residual host cell
DNA residual host cell protein
4.
4.1 ..........
72
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
73
IInntteerrffeerroonn aallpphhaa 22
.... iiuu iinnjjeeccttiioonn
Interferon alpha 2
.. iu injection
1.
2. interferon alpha 2 . iu
3.
4. -
- interferon alpha 2a 2b
1. Appearance of the solution finished product specification
2. Identification 1 5
- CZE IEF
- PAGE / immunoblotting
- Peptide mapping / LC
- Anti viral activity
- HPLC
3. pH finished product specification
4. Osmolality finished product specification
5. Sterility sterile
6. Bacterial endotoxins 100 endotoxin units / of interferon
finished product specification
7. 84.0 - 116.0% of labeled amount of interferon
74
8. Purity HPIEC HPSEC finished product specification
/ Impurities oxidised forms, dimers
and high molecular weight substances
9. Anti Viral Assay 80 - 125 % of the stated potency
10. preservative
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- recombinant-human interferon residual host
cell DNA residual host cell protein
75
4.
4.1 ..........
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
76
IInntteerrffeerroonn bbeettaa 11
..mmccgg//..
....mmll iinnjjeeccttiioonn
Interferon beta 1
..mcg/
...ml injection
1.
2. interferon beta 1..mcg ........ml
3.
4. -
- interferon beta 1a 1b
1. Appearance of the solution finished product specification
2. Identification 1 5
- CZE IEF
- PAGE / immunoblotting
- Peptide mapping / LC
- Anti viral activity
- HPLC
3. pH finished product specification
4. Osmolality finished product specification
5. Sterility sterile
6. Bacterial endotoxins 100 endotoxin units / mg of interferon
7. 84.0 - 116.0% of labeled amount of interferon
8. Purity HPIEC HPSEC finished product specification
/ Impurities oxidised forms, dimers
and high molecular weight substances
77
9. Anti Viral Assay 80 - 125 % of the stated potency
10. Moisture / Water () 3%
11. preservative
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- recombinant-human interferon residual host
cell DNA residual host cell protein
4.
4.1 ..........
78
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
79
PPeeggiinntteerrffeerroonn aallpphhaa 22
..
.... mmccgg //
.... mmll iinnjjeeccttiioonn
Peginterferon alpha 2... mcg /
.. ml injection
1.
2. peginterferon alpha 2. mcg ....... ml
3.
4. -
- peginterferon alpha 2a 2b
1. Appearance of the solution finished product specification
2. Identification 1 5
- CZE IEF
- PAGE / immunoblotting
- Peptide mapping / LC
- Anti viral activity
- HPLC
3. pH finished product specification
4. Osmolality finished product specification
5. Sterility sterile
6. Bacterial endotoxins 100 endotoxin units/mg of peginterferon
7. 84.0 - 116.0% of labeled amount of peginterferon
8. Purity HPIEC HPSEC finished product specification
/ Impurities oxidised forms , dimers
and high molecular weight substances
80
9. Anti Viral Assay 50 - 150% of the stated potency.
10. preservative
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- recombinant-human peginterferon residual
host cell DNA residual host cell protein
4.
4.1 ..........
81
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
82
OOccttrreeoottiiddee
.... mmgg//mmll iinnjjeeccttiioonn
Octreotide
.. mg/ml injection
1.
2. octreotide .. mg ........ ml
3.
4.
1. Identification finished product specification
2. 90.0 -110.0% of labeled amount of octreotide
3. pH 3.9 - 4.5
4. Volume in container finished product specification
5. Sterility sterile
6. Particulate matter finished product specification
7. Bacterial endotoxins 100 endotoxin units/mg of octreotide
8. Total degradation products 2.0%
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
83
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3 - recombinant-human octreotide residual host
cell DNA residual host cell protein
4.
4.1 ..........
5.
5.1 .......... ( / )
5.2
5.3
/
84
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
85
RRaabbiieess vvaacccciinnee
Rabies vaccine
1.
2. inactivated vaccine (vero cells primary chick/duck
embryo fibroblast cells human diploid cell) rabies antigen 2.5 iu
3.
4. -
- 2 - 8
1. Potency 2.5 iu/dose
2. Water content finished product specification
3. Sterility sterile
4. pH 7.0 - 7.8
5. Bovine serum albumin 50 ng/dose
6. Pyrogens
Bacterial endotoxins 25 endotoxin units/dose
7. Safety
Spec.
- ID 0.7 iu/0.1 ml
- albumin albumin
86
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- tissue culture residual host cell DNA
residual host cell protein
4.
4.1 ..........
87
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
5.5 cold chain system
6.
6.1 Long Term Stability
88
CCeeffooppeerraazzoonnee ssooddiiuumm
mmgg aanndd SSuullbbaaccttaamm ssooddiiuumm
..mmgg ffoorr iinnjjeeccttiioonn
Cefoperazone sodium
mg and Sulbactam sodium
mg for injection
1.
2. cefoperazone sodium cefoperazone .. mg
sulbactam sodium sulbactam .. mg
3.
4.
1. Identification finished product specification
2.
Cefoperazone 95.0 - 105.0% of labeled amount of cefoperazone
Sulbactam 95.0 - 105.0% of labeled amount of sulbactam
3. pH 4.5 - 6.5
4. Uniformity of dosage units finished product specification
5. Particulate matter finished product specification
6. Bacterial endotoxins finished product specification
7. Sterility sterile
8. Constituted solution finished product specification
9. Water content 4.0 %
10.Related substances finished product specification
Chromatographic purity specific impurity
89
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3 - related substances cefoperazone sodium
any other impurities : 1.5 %
total impurities : 4.5 %
4.
4.1 ..........
90
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
6.
6.1 2 Long Term Stability
6.2
91
IImmiippeenneemm
.... mmgg aanndd CCiillaassttaattiinn
.. mmgg ffoorr iinnjjeeccttiioonn
Imipenem
. mg and Cilastatin
. mg for injection
1.
2. imipenem .. mg cilastatin sodium cilastatin.. mg
3.
4.
1. Identification
Imipenem finished product specification
Cilastatin finished product specification
2.
Imipenem 90.0 -115.0 % of labeled amount of imipenem
Cilastatin 90.0 -115.0 % of labeled amount of cilastatin
3. pH 6.5 - 8.5
4. Particulate matter finished product specification
5. Uniformity of dosage units finished product specification
6. Bacterial endotoxins 0.17 endotoxin units/mg of imipenem
0.17 endotoxin units/mg of cilastatin
7. Sterility sterile
8. Loss on drying 3.5%
92
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
Potency (Raw material)
Imipenem
imipenem : 98.0 J 101.0% of imipenem monohydrate
specific rotation : between +84 and +89
related substances
thienamycin : not more than 1.0%
any other impurities : not more than 0.3%
sum of impurities other than thienamycin : not more than 1.0%
93
Cilastatin
cilastatin : 98.0 -101.5% of cilastatin sodium, calculated on
the anhydrous and solvent free basis
specific rotation : between +41.5 and +44.5
4.
4.1 ..........
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
6.
6.1 2 Long Term Stability
6.2
94
MMeerrooppeenneemm
...... gg ffoorr iinnjjeeccttiioonn
Meropenem
.. g for injection
1.
2. meropenem trihydrate anhydrous meropenem
meropenem g sodium carbonate
3.
4.
1. Identification finished product specification
2. 90.0 -120.0% of labeled amount of meropenem
3. pH (1 in 20) 7.3 - 8.3
4. Uniformity of dosage units finished product specification
5. Bacterial endotoxins 0.125 endotoxin units/mg of meropenem
6. Sterility sterile
7. Constituted solution finished product specification
8. Chromatographic impurity
- Impurity with a retention time of about 0.8 %
0.45 relative to meropenem
- Impurity with a retention time of about 0.6 %
1.9 relative to meropenem
9. Loss on drying 9 - 12 %
10. Particulate matter finished product specification
11. Content of Sodium 80 - 120% of labeled amount of sodium
95
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3 - specific rotation: -17 and -21
- chromatographic purity
at relative RT about 0.45 : 0.3 %
at relative RT about 1.90 : 0.3 %
any other impurities : 0.1 %
sum of all other impurities : 0.3 %
- limit of acetone : 0.05 %
96
4.
4.1 ..........
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
6.
6.1 2 Long Term Stability
6.2
97
PPiippeerraacciilllliinn
.... gg aanndd TTaazzoobbaaccttaamm
.... mmgg ffoorr iinnjjeeccttiioonn
Piperacillin
.. g and Tazobactam
.. mg for injection
1.
2. piperacillin sodium piperacillin .. g tazobactam sodium
tazobactam.. mg
3.
4.
1. Identification
Piperacillin finished product specification
Tazobactam finished product specification
2.
Piperacillin 90.0 - 120.0 % of labeled amount of piperacillin
Tazobactam 90.0 - 115.0 % of labeled amount of tazobactam
3. pH finished product specification
4. Particulate matter finished product specification
5. Uniformity of dosage units finished product specification
6. Bacterial endotoxins 0.07 endotoxin units/mg of piperacillin
7. Sterility sterile
8. Constituted solution finished product specification
9. Water content finished product specification
10.Related compounds finished product specification
98
1. (declare)
1.1 (.2 .3 .4 )
1.1.1 ( .2)
1.1.2 ( .3)
1.1.3 ( .4)
1.2 . 1
(finished product specification)
finished product
specification
2.
(GMP)
Certificate of pharmaceutical
products
3.
3.1 (Certification of analysis)
3.2 (Raw material)
3.3
- specific rotation
: piperacillin : +155 +175
- related compounds
: piperacillin specific related substances
: tazobactam specific related substances
4.
4.1 ..........
99
5.
5.1 .......... ( / )
5.2
5.3
/
5.4
6.
6.1 2 Long Term Stability
6.2
100
101
()
99 /2552
----------------------------
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
102
-2-
17. 18. 19. 20. 21. 22. 23. 24.
1.
2. 3.
10 .. 2552
( )
( )
/
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Chemical drugsCefoperazone sodium mg and Sulbactam sodium mg for injectionImipenem . mg and Cilastatin . mg for injectionMeropenem .. g for injectionPiperacillin .. g and Tazobactam .. mg for injection