GMP級細胞因子-產(chǎn)品及質(zhì)量管理體系

GMP級細胞因子北京義翹神州科技股份有限公司01GMP級細胞因子細胞療法作為一種前沿醫(yī)學(xué)技術(shù)，主要分為免疫細胞治療和干細胞治療兩大類。以TIL、TCR-T、CAR-T、NK等為代表的免疫細胞治療，在實體瘤、血液瘤等方面已顯示出良好的治療效果。以iPSC、MSC等為代表的干細胞療法針對糖尿病、帕金森、阿爾茲海默癥和淋巴瘤等疾病有著良好的醫(yī)學(xué)治療效果，同時為治愈癌癥提供了可能性。在生產(chǎn)干細胞或免疫細胞治療產(chǎn)品過程中，EGF、FGF、IL-7、IL-15和IL-21等細胞因子是促進細胞增殖分化的主要試劑，也是細胞治療藥物生產(chǎn)的關(guān)鍵原材料。國內(nèi)外相關(guān)政策、法規(guī)均指出應(yīng)優(yōu)先選擇低風險級別原材料，GMP級細胞因子風險較低，在質(zhì)量、安全性、臨床研究和治療應(yīng)用、監(jiān)管合規(guī)性方面具有突出優(yōu)勢。義翹神州致力于開發(fā)高質(zhì)量的用于細胞治療研究及臨床的相關(guān)試劑，在擁有GMP質(zhì)量管理體系基礎(chǔ)上，以更完善的質(zhì)量管理和放行檢測標準，成功開發(fā)一系列更高質(zhì)量的GMP級細胞因子?；趯蛻魬?yīng)用的理解，我們從質(zhì)量管理、質(zhì)量保證、質(zhì)量控制和產(chǎn)品安全性等方面對產(chǎn)品進行了更嚴格的控制和管理。具體內(nèi)容如下：符合《藥品生產(chǎn)質(zhì)量管理規(guī)范》ISO9001：

2015質(zhì)量管理體系ISO13485：2016質(zhì)量管理體系符合《藥品生產(chǎn)質(zhì)量管理規(guī)范》附錄3生物制品符合《藥品生產(chǎn)質(zhì)量管理規(guī)范》附錄1無菌藥品FDA

DMF備案中完整的監(jiān)管支持文件（RSF）符合《中華人民共和國藥典》2020年版三部通則：生物制品生產(chǎn)用原材料及輔料質(zhì)量控制 符合USP<1043>Ancillary

Materials

For

Cell,

Gene,and

Tissue-engineered

Products質(zhì)量檢測依據(jù)《中華人民共和國藥典》2020年版高純度高活性高批間一致性高穩(wěn)定性現(xiàn)貨供應(yīng)專人負責管理人員培訓(xùn)體系建立和運行設(shè)備維護和校準程序供應(yīng)商管理體系和原材料管理體系文件體系和記錄管理完全滿足GMP規(guī)范要求完整的批生產(chǎn)記錄、批檢驗記錄、分裝記錄質(zhì)量文件/記錄經(jīng)QA審核和批準產(chǎn)品屬性GMP級細胞因子產(chǎn)品質(zhì)量管理體系質(zhì)量保證管理質(zhì)量控制產(chǎn)品特點細菌內(nèi)毒素＜5-10

EU/mg宿主蛋白殘留檢測＜0.5

μg/m（500ppm）宿主DNA殘留檢測＜100

pg/mg支原體檢測無菌檢測人源病毒檢測異常毒性檢測產(chǎn)品安全性北京義翹神州科技股份有限公司02GMP級細胞因子OOS控制程序儀器校驗/維護分析方法驗證 規(guī)范的菌種、培養(yǎng)基、樣品、檢測報告管理規(guī)范的檢驗記錄符合生產(chǎn)要求潔凈廠房各系統(tǒng)和設(shè)備驗證/維護/保養(yǎng)清潔、消毒、滅菌及效期驗證潔凈環(huán)境的日常監(jiān)測蟲害有效控制產(chǎn)品標簽信息核對產(chǎn)品包裝驗收供應(yīng)商審核準入入庫驗收物料檢查放行規(guī)范庫房管理不合格品管理出庫/效期管理規(guī)范的工藝規(guī)程和批生產(chǎn)記錄關(guān)鍵質(zhì)量屬性（CQA）關(guān)鍵工藝參數(shù)（CPP）工藝驗證無菌操作、無菌工藝模擬灌裝生產(chǎn)偏差分析、評估；生產(chǎn)變更控制；清潔、消毒、滅菌及效期驗證資質(zhì)證書GMP質(zhì)量管理體系ISO

9001:2015認證2024年值得關(guān)注的生長因子供應(yīng)商ISO

13485:2016認證GMP認證ISO

17025:2017證書FDA

DMF備案DEPARTMENT

OF

HEALTH

AND

HUMAN

SERVICESFoodandDrugAdministration

SilverSpring,

MD

20993DMF

035978DMF

ACKNOWLEDGEMENTSINO

BIOLOGICAL,

INC.Attention:

ZHIQIANG

ZHANBUILDING

9,

JING

DONGHEI

TECHNOLOGY

PARKNO.

18

KECHUANG

10TH

ST,

BDA,

BEIJING,

100176,

CHINADear

Zhiqiang

Zhan,The

Food

and

Drug

Administration

acknowledges

receipt

of

the

following

Drug

Master

File

(DMF)

submission:DMF

NUMBER

ASSIGNED:

035978DATE

OF

SUBMISSION:

MAY

27,

2021DMF

TYPE:

IISUBJECT

(TITLE):

SUPERNUCLEASEHOLDER:

SINO

BIOLOGICAL,

INC.SUBMITTED

BY:

SINO

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控制系統(tǒng)物料系統(tǒng)廠房設(shè)施和設(shè)備系統(tǒng)包裝與

標簽系統(tǒng)生產(chǎn)系統(tǒng)質(zhì)量系統(tǒng)03GMP級細胞因子特色產(chǎn)品高純度高活性高批間一致性高穩(wěn)定性18.414.4Human

Interleukin-21

/

IL-21

ProteinCat#:

GMP-10584-HNAEkDa

M

11666.245.035.025.0020mAU

10080604018.414.4Human

IL7

/

interleukin

7

ProteinCat#:

GMP-11821-HNAEkDa

M

11666.245.035.025.05

10

15

20

25

min

5

10

15

20

25

minPurity

≥

95%

(SDS-PAGE

&

SEC-HPLC)

Purity

≥

95%

(SDS-PAGE

&

SEC-HPLC)mAU

706050403020100Induced

Interferon

gamma

secretion

by

humannatural

killer

lymphoma

NK-92

cells120010008006004002000-200Human

Interleukin-21

/

IL-21

ProteinCat#:

GMP-10584-HNAE1400Conc

of

Secretion

IFN-γ.(pg/mL)1E-3

0.01

0.1

1

10

100Human

IL-21

Conc.

(ng/mL)50ED

=0.4-2

ng/mLHuman

IL7

/

interleukin

7

ProteinCat#:

GMP-11821-HNAECellproliferation

assay

using

anti-CD3antibodyactivatedhumanperipheral

blood

mononuclear

cell

(PBMC).

The

speci?c

activity

ofRecombinant

Human

IL-7

is

>100，000

units/μg,whichis

calibratedagainst

the

human

IL-7

reference

standard

(NIBSC

code:

90/530)0.01

0.1

1

10 100

100080060040020001000Proliferation

%Human

IL-7

Conc.

(ng/mL)ED50

=0.5-8

ng/mL-1007006005004003002001000Proliferation,%Human

IL-4

ProteinCat#:

GMP-11846-HNAE800Batch

1Batch

29008007006005004003002001000Human

IL7

/

interleukin

7

ProteinCat#:

GMP-11821-HNAE1000Proliferation,%Batch

1Batch

21E-5

1E-4

1E-3

0.01

0.1

1 10

100

0.1

1

10

100Human

IL-4

Conc.

(ng/mL)

Human

IL-7

Conc.

(ng/mL)Cell

proliferation

assay

using

TF-1

Cell

proliferation

assay

using

anti-CD3

antibody

activatedhuman

erythroleukemic

cells.

human

peripheral

blood

mononuclear

cell

(PBMC)Conc

of

Secretion

IFN-γ.(pg/ml)凍融穩(wěn)定性1600

凍融0次1400

凍融3次1200

凍融5次10008006004002000-2002000180016001400120010008006004002000Conc

of

Secretion

IFN-γ.(pg/ml)25℃加速穩(wěn)定性數(shù)據(jù)25℃

0

day25℃

16

day25℃

24

day25℃

48

dayHuman

Interleukin-21

/

IL-21

Protein

Cat#:

GMP-10584-HNAE1E-3

0.01

0.1

1

10

100

1E-3

0.01

0.1

1

10

100Human

IL-21

Conc.

(ng/mL)

Human

IL-21

Conc.(ng/mL)Induced

Interferon

gamma

secretion

by

human

natural

killer

lymphoma

NK-92cells北京義翹神州科技股份有限公司04GMP級細胞因子其他細胞因子產(chǎn)品和國際知名品牌產(chǎn)品比較數(shù)據(jù)Human

IL-1

beta

/

IL1B

ProteinCat#:

GMP-10139-HNAEInduce

Interferon

gamma

secretion

byhuman

natural

killerlymphomaNK-92

cells.

The

speci?c

activity

of

recombinanthuman

IL-1

beta

is

>60,

000

IU/μg,

which

is

calibratedagainst

the

human

IL-1

beta

WHO

InternationalStandard(NIBSC

code:

86/680)Purity

≥

95%

(SDS-PAGE)kDa

M

11666.245.035.025.018.414.4min510

15

20Purity

≥

95%

(SEC-HPLC)25mAU

1601401201008060402001E-4

1E-3

0.01

0.1

1

10

100120010008006004002000-200Conc

of

Secretion

IFN-γ.(pg/mL)Human

IL-1

betaConc.

(ng/mL)50ED

=0.2-2

ng/mLMeasured

in

a

cell

proliferation

assayusing

TF-1

humanerythroleukemic

cells.

Thespeci?c

activity

of

recombinant

humanIL-6is

>100,

000

IU/μg,

which

is

calibratedagainst

human

IL-6WHOInternational

Standard

(NIBSC

code:

89/548)Purity

≥

95%

(SDS-PAGE)18.414.4kDa

M11666.245.035.025.0-1005004003002001000Human

IL6

/

Interleukin-6Protein

Cat#:

GMP-10395-HNAE600Proliferation,%1E-5

1E-4

1E-3

0.01

0.1

1 10

100HumanIL-6

beta

Conc.

(ng/mL)50ED

=0.1-0.8

ng/mL9008007006005004003002001000Proliferation,%0.1

1

10

100Human

IL-7

Conc.

(ng/mL)Competitor

RSinobiologicalHuman

IL7

/

interleukin

7

Protein

Cat#:

GMP-11821-HNAE1000

ED50

=0.5-8

ng/mLHuman

Interleukin-21

/

IL-21

Protein

Cat#:

GMP-10584-HNAE1E-3

0.01

0.1

1

10

100120010008006004002000Conc

of

Secretion

IFN-γ.(pg/ml)501400

Competitor

R1600

ED

=0.4-2

ng/mLSinobiologicalCell

proliferationassayusing

anti-CD3

antibodyactivatedhuman

peripheral

bloodmononuclearcellHuman

IL-21

Conc.

(ng/mL)Induced

Interferon

gamma

secretion

byhuman

natural

killer

lymphomaNK-92

cellsHuman

TNF-alpha

/

TNFA

ProteinCat#:

GMP-10602-HNAE100806040200-20Cytotoxicity,%1E-3

0.01

0.1

1

10

100

1000

10000Human

TNF-alpha

Conc.

(ng/mL)ED50

=3-30

pg/mLSinobiologicalCompetitor

R-100Proliferation,%1E-5

1E-4

1E-3

0.01

0.1

1 10

100Human

IL-4

Conc.

(ng/mL)700

Sinobiological600

Competitor

R5004003002001000Human

IL4

/

Interleukin-4Protein

Cat#:

GMP-11846-HNAE800

ED

=

0.05-0.25

ng/mL50Cytotoxicity

assayusingL929

mouse?brosarcomacells

Cell

proliferationassayusing

TF-1

humanin

the

presence

of

the

metabolic

inhibitor

actinomycin

D

erythroleukemic

cells北京義翹神州科技股份有限公司北京義翹神州科技股份有限公司05GMP級細胞因子貨號產(chǎn)品名稱應(yīng)用GMP-10605-HNAEHuman

EGF/

Epidermal

Growth

Factor

Protein

(ECD)ESC/iPSC,

NSC,

MSCGMP-10014-HNAEHuman

FGF2

ProteinESC/iPSC,

NSC,

MSC,

TGMP-10210-HNAE-LHuman

KGF/

FGF-7

ProteinESC/iPSCGMP-10015-HNAHHuman

GM-CSF/

CSF2

ProteinHSC,

Mono/Mac,

DC,GranGMP-11725-HNAEHuman

IFN-gamma/

IFNG

ProteinHSC,

B,

DC,

Mono/Mac,

NK,

TGMP-10139-HNAEHuman

IL-1

beta/

IL1B

ProteinT,Mono/Mac,

DCGMP-11848-HNAEHumanInterleukin-2/

IL-2

ProteinHSC,

T,

NK,

BGMP-11858-HNAEHuman

IL3

ProteinESC/iPSC,

Gran,

DC,

Mono/Mac,

NKGMP-11846-HNAEHuman

IL4/

Interleukin-4ProteinHSC,T,

Mono/Mac,

DC,BGMP-11846-HNAE-LHuman

IL4/

Interleukin-4ProteinHSC,T,

Mono/Mac,

DC,BGMP-10395-HNAEHuman

IL6/

Interleukin-6

ProteinESC/iPSC,

MSC,HSC,

T,

Mono/Mac,

DC,GranGMP-11821-HNAEHumanIL7/

interleukin

7

ProteinHSC,

T,

NK,

BGMP-11821-HNAE-LHumanIL7/

interleukin

7

ProteinHSC,

T,

NK,

BGMP-CT011-H08HHuman

IL-12

(IL12A

&

IL12B

Heterodimer)

ProteinHSC,

T,

NKGMP-10360-HNCEHuman

IL-15/

IL15/

Interleukin

15

ProteinHSC,

T,

NKGMP-10360-HNAEHuman

IL-15

ProteinHSC,

T,

NKGMP-10584-HNAEHuman

Interleukin-21/

IL-21

ProteinHSC,

T,

NK,

BGMP-10452-HNAHHuman

Oncostatin

M/

OSM

ProteinMSCGMP-10602-HNAEHuman

TNF-alpha/

TNFA

ProteinT,

DCGMP-10602-HNAE-LHuman

TNF-alpha/

TNFA

ProteinT,

DCGMP-10429-HNAHHuman/

Mouse/Rat/

Cynomolgus/

Rhesus

Inhibinbeta

A/

Activin

A

ProteinESC/iPSCGMP-10451-HNAE1-L-AFHuman

SCF

ProteinESC/iPSC,

HSC,

T,

NK,

Mono/Mac,

DC,GranGMP-10315-HNAE1-L-AFHuman

Flt3

Ligand/FLT3LG

ProteinESC/iPSC,

HSC,

T,

NK,

DC,

BGMP-10584-HNAE1-L-AFHuman

IL-21

ProteinHSC,

T,

NK,

B產(chǎn)品列表縮略詞:DMF備案無動物源細胞因子ESC/iPSC胚胎/誘導(dǎo)多能干細胞NSC神經(jīng)干細胞MSC間充質(zhì)干細胞HSC造血干細胞TT細胞BB細胞NK自然殺傷細胞Mono/Mac單核/巨噬細胞DC樹突狀細胞Gran粒細胞北京義翹神州科技股份有限公司06GMP級細胞因子A01你們的產(chǎn)品是如何保證分裝精度，需要檢測幾支的實際含量才符合相關(guān)標準？A02在購買產(chǎn)品之前，我們是否可以先了解一下產(chǎn)品的穩(wěn)定性?A04你們的原材料是否有進廠驗收？A03有效期是從什么時候開始計算的呢？A05你們產(chǎn)品做過安全方面的評價嗎？06你們產(chǎn)品分裝是在什么環(huán)境下進行的？A

我們終產(chǎn)品分裝是在B+A級潔凈環(huán)境下進行的，分裝全過程進行了動態(tài)監(jiān)測。Q&A發(fā)表文