Transcript 投影片 1 - 財團法人醫藥品查驗中心

Vaccine clinical trial
-Quality, include control of cell substrate
Ywan-Feng Li
Center for Drug Evaluation
4-7-2011
新醫藥品法規人才培訓課程（I）
The views expressed in this presentation are not necessary
those of Center for Drug Evaluation-Taiwan
本次內容僅代表查驗中心之觀點及
經驗分享
凡涉及政策方向及法規解釋適用，
應依衛生主管機關之指示為準
The views offered here do not necessarily reflect official positions
of TFDA
4-7-2011
2
Heterogenicity of the
biological/biotechnological products
Tissue engineering P.
Gene/cell therapy P.
Blood/plasma products
Peptides
(20-30 a,a,)
rDNA proteins
(Mab, fusion protein)
rDNA-derived vaccines
Allergens
4-7-2011
Traditional vaccines
3
Scope



Vaccine
Information from research stage
Clinical trial-IND




Cell substrate-Testing for adventitious agents
Quality, starts from phase 1
Quality, (almost) finalizes at phase 3 and continues
through product life span
Collaboration from all parties makes a trial
going
4-7-2011
4
Type of vaccine

Vaccines represent the most diverse type of
products
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4-7-2011
Attenuated or killed pathogens (bacteria, virus,
parasites) (~traditional vaccine)
Purified and recombinant protein
Synthetic peptides
Polysaccharide (free or conjugate to carrier)
DNA, viral vectors
(Cell-based product)
5
Preventive versus therapeutic
vaccines
In general:
Characteristic
Preventive
Therapeutic
Population
Healthy subject
Usually patient
Clinical outcome Decrease microbial
infection and/or
transmission
Cure or postpone disease
progression
(usually as a 2nd line
strategy)
Regimen
Low dose, episodic
Usually high dose, continual
(more like a drug)
Evaluations in
early trial
Safety, immunogenicity Safety, immunogenicity
4-7-2011
6
Preventive versus therapeutic
vaccines
Characteristic
Preventive
Therapeutic
Regulatory
evaluation
Emphasis on safety
Efficacy
Benefit/risk assessment
Efficacy
Public
expectation
Highly concern and
sensitive to the
potential risks
Less concern regarding the
potential risks
However, quality and assessment of the vaccine (Ag
and adjuvant) is the same for either type of vaccine
4-7-2011
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First licensed cancer therapeutic
vaccine-Provenge (FDA)
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Autologous dendritic cells, activated by prostatic acid
phosphatase (plus GM-CSF)
2010, approved by FDA to treat asymptomatic or minimally
symptomatic metastatic hormone-refractory prostate cancer
2011, FDA approved Dendreon's request to increase
production capacity
 FDA approved "36 additional workstations at the
company's New Jersey facility, adding to the 12 already
approved"
2011 (Mar.), US Medicare proposed to cover the cost of
$93,000/patient prostate cancer vaccine
4-7-2011
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Type of vaccine IND


New vaccines
 Include addition or change of adjuvant
Modification of original product

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Formulation (e.g., lyophilized vs. liquid)
Strength
Route of administration
Change in indication, age group, schedule, etc.
Concomitant administration with other vaccine
4-7-2011
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Vaccines in development/trial,
Taiwan, 2011
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4-7-2011
Ag type
 Virus vaccine
 Polysaccharide conjugate vaccine
 rDNA protein vaccine
Indication
 Infectious disease
 Cancer
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Reference
In general


Guideline on the requirements for quality documentation
concerning biological IMP in clinical trials, draft, EMA,
2010
Guideline on strategies to identify and mitigate risks for FIH
clinical trials with investigational medicinal products, EMA,
2007
Vaccines

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4-7-2011
WHO: Biologicals TRS
Japan NIID: Minimum requirements for biological products
Pharmacopeia: Ph. Eur, USP
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Quality of a product
(EMA)


NDA, to ensure a consistent, state-of-the art quality
of a product
IMP, quality attributes related to safety aspects

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Nature of product, clinical phase, patient population,
nature/severity of illness, duration of trial.
IMP documentation, M3 of CTD
“IMP should be produced in accordance with the
principles and the detailed guidelines of GMP…..”
4-7-2011
12
A clinical trial
Starts with the quality/control of the test drug

Quality of a biological/biotechnological product



Include safety issues, e.g., impurity, adventitious agent
(e.g., bacteria/fungi, mycoplasma, virus)
Test drug used in animal toxicity studies be
representative of the material for human study
So as to support a phase 1 study with end points of
safety and preliminary immunogenicity
4-7-2011
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Characterization
-Ag vs. therapeutic drug


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For Ag, immunogenicity is the desired effect, therefore,
concept of certain characteristics is different (e.g.,
product-related impurity, which would otherwise cause
undesired immunogenicity for protein drug)
In general, extent of characterization is less for an Ag
(e.g., product-related impurity)
Thus, “Process = quality” is more likely to be the case
for Ag. Therefore, the approach to establish a “design
space” or platform technology is less likely to apply to
vaccine product
4-7-2011
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Scope




Vaccine
Information from research stage
Clinical trial-IND
Collaboration from all parties makes a trial
going
4-7-2011
15
Information from research stage

Science

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
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A vast amount of information has generated from basic
research
However, most information is yet to be interpreted and thus
transferable to development
Provide rationale based on disease pathogenesis, and
identify Ag candidate
Control of materials
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4-7-2011
Raw materials, starting materials, solvents, reagents,
catalysts, e.g.,
 Source, history of the cell substrate
 History of construction of the expression plasmid
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Information from research stage
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Safety information
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Plan to obtain and document relevant safety data
from research studies even they are designed to
assess biologic effects.
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4-7-2011
This is an effective approach to lunch preclinical safety
evaluation
Extent and design of toxicity studies could depend on
how much prior info exist
Especially for vaccine product
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Control of materials

Documents, starting from research stage
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Establishment of a cell bank or virus bank

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~GMP
Storage, inventory, identification, handling, GMP
Qualification of cell and virus bank
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4-7-2011
Origin, lineage
History of passage, testing
Media component, e.g., FBS, trypsin
All of the documents be transferable to R& D stage
Contract lab
GLP/GMP status
18
History of a virus strain
Example (FDA, Review of Vero cell banks for Rotarix, 2008)
 The Serotype G1 HRV strain (genotype P[8]) which GSK used
to make vaccine product is designated RIX4414. It was
derived from strain 89-12, initially developed by Avant
Therapeutics, Inc. ---------------. The virus was isolated in ------------ from a child in Cincinnati with a natural case of
rotavirus with mild diarrhea. This original isolate was
passaged 26 times in primary African Green monkey kidney
cells (AGMK) by Avant for use as seed material. The P26
virus was ------- passaged by -- --------------- AVANT, -------,
which passaged the seed virus an additional 7 passages to P33.
This was the material that was clinically tested ---------------.
The additional 7 passages were performed in an AGMK cell
line that ------- characterized in --------.
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Raw material of animal source
COA of FBS (partially shown)
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Raw material of animal source
COA of porcine trypsin
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Scope



Vaccine
Information from research stage
Clinical trial-IND




Cell substrate-Testing for adventitious agents
Quality, starts from phase 1
Quality, (almost) finalizes at phase 3 and continues
through product life span
Collaboration from all parties makes a trial
going
4-7-2011
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Biosafety control
Combination of testings (starting material, UPB,
intermediates..) and demonstrating production process to
remove a wide variety of potential infectious viruses
Research
stage
Contract lab
Contract lab
Cell/virus seed & raw material
Cell/virus bank
and unprocessed bulk
Viral
clearance steps
Purified bulk
(Calculation of estimated
particles/dose)
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CMC
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Control of materials (before phase 1)

Raw materials, starting materials, solvents,
reagents, catalysts
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Source, history, and generating of cell substrate
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Expression construct
Cell banking system, characterization, and testing
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4-7-2011
Biologically-sourced materials, TSE concern
Non-viral agent
Endogenous and adventitious viruses
Tumorigenicity, case dependent
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A reference
- Ancillary materials (AMs) for cell-based product

Reagent and materials that are NOT intended to be
present in the final product, e.g., FBS, digestion
enzymes, GF, cytokines, antibiotics, media
Vendor qualification

(cGMP), audit/inspection record
 Quality control testing program
 Documentation
 Grade, traceability, or country of origin/source
( animal-derived AMs)
 Batch analytical results
Stability assessment during use
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Risk classification of AMs
USP<1043>
Risk tier 1

Low-risk, highly qualified materials with intended use
as therapeutic drug or biologic, medical device, or
implantable material
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

Therapeutic grade
 E.g, HSA, insulin, IL-12, antibiotics
Certificate of analysis (COA)
Assess removal from final product
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Risk classification of AMs
USP<1043>
Risk tier 2
 Low-risk, well-characterized materials with
intended use as AMs, produced in compliance with
GMPs
 For use in drug, biologic, or medical device
manufacture, e.g., growth factor, proteolytic enzymes,
density gradient media (Exclude most animal-derived
materials)

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4-7-2011
COA
Assess removal from final product
Vendor audit
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Risk classification of AMs
USP<1043>
Risk tier 3
 Moderate-risk materials not intended for use as AMs


For in vitro diagnostic use or reagent grade materials, e.g,
growth factors, culture media, chemicals
COA

Confirm critical test result shown in COA

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Develop internal specifications, eventually
Assess removal from final product
Vendor audit
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Risk classification of AMs
USP<1043>
Risk tier 4
 High-risk materials

Toxin, most animal-derived materials
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COA

Confirm critical test result shown in COA
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Feeder cells, ascites-derived Ab, cholera toxin, animal-derived
additives (e.g., FBS)
Develop internal specifications, eventually
Assess removal from final product
Vendor audit
Source animal, country of origin, adventitious agent
testing
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Recent guidance
- Cell substrate


Guidance for industry: Characterization and
qualification of cell substrates and other biological
starting materials used in the production of viral
vaccines for the prevention and treatment of
infectious disease, FDA, 2010
Recommendations for the evaluation of animal cell
cultures as substrates for the manufacture of
biological medicinal products and for the
characterization of cell banks, draft, WHO, 2010
4-7-2011
30
Ideal substrate to produce
biological/biotechnological products
WHO Technical report series, No. 878, 1998
 Permanent/continuous cell line



MCB, WCB
Quality controlled
Serum-free and/or protein-free media
Nature Reviews, June 2010, vol.10, p.441 Cell line identification


4-7-2011
Incidence of misidentification in 1977 was 16%, 1999 was 18%
ATCC working group ASN-0002 (BOX), currently developing a
standard for human cell line authentication
31
Cell substrate
From embryonic egg for Flu vaccine
Inoculation: into allantoic
cavity, manually or automated
system
4-7-2011
Harvest: allantoic fluid, manual or
automated systems
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Cell lines for the production of
vaccines
Licensed vaccine

Cell substrate
Vaccine
Type
Origin
Live attenuated
Inactivated
Primary tissues or
cells
Calf lymph, mouse
brain, chicken egg,
chicken embryo cell
Small pox, Influenza,
Measles, Mumps
JEV, Influenza,
Rabies
Diploid cells
Human (MRC-5, WI-38) Rubella,
Varicella/Zoster
Poliovirus, HAV,
Rabies
Continuous cells
(Non-tumorigenic)
Monkey (Vero)
Small pox, Rotavirus
Poliovirus, JEV,
Rabies
Continuous cells
(Tumorigenic ±)
Canine (MDCK)
-
Influenza
Non-mammalian
cells
Yeast (S. cerevisiae)
Insect (Hi-5)
-
HBV, HPV
(rDNA product)
4-7-2011
33
Qualification of the cell bank
-Biosafety tests
Non-viral agent
 Sterility, Mycoplasma, (Mycobacteria,
Spiroplasma)
 Adventitious or endogenous viruses
 General (in vitro and in vivo test, retrovirus)
 Specific (cell line dependent)
 Tumorigenicity, case dependent

4-7-2011
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Qualification of the cell bank
-Virus tests
MCB
Tests for Retroviruses and Other Endogenous Viruses
Infectivity
+
WCB
EPC
+
Electron microscopy
+
+
Reverse transcriptase
Case dependent
Case dependent
Other virus-specific tests
Case dependent
Case dependent
Tests for Nonendogenous or Adventitious Viruses
In vitro Assays
+
In vivo Assays
+
Antibody production tests
Case dependent
(e.g., MAP, RAP, HAP—for
rodent cell lines)
Other virus-specific tests
Case dependent
Case dependent
Case dependent
+
+
Case dependent
Case dependent
Specific tests for :
Cell lines derived from human, NHP, or other cell lines as appropriate.
Culture media using animal-derived components ( e.g., bovine or porcine)
USP, Ph. Eur.
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Tumorigenicity



Tumorigenicity (when not known, test on EPC)
 Cells form tumor in animal (nude mice), Hela as + control,
medium/2n cells as – control, 12 wks, ≧4 months
Oncogenicity (when T+ and for product of prophylactic use)
 Agents (e.g., virus, DNA) induce host cell to form tumor
(newborn animal), negative control, ≧4 months
Cell substrate w/ or w/o tumorigenicity (in trial or licensed)
4-7-2011
Traditional vaccine
rDNA protein product
(drug or vaccine)
T- O-
Yes (inactivated, attenuated)
Yes
T+ O-
Yes (Inactivated)
Yes
T+ (O+)
e.g., rodent cells
No
Yes
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PCV

Porcine circovirus types 1 and 2 are both small
sscDNA viruses and common in pigs.


Detecting PCV1 DNA in Rotarix and PCV1/PCV2
DNA in RotaTeq vaccine products


Neither PCV1 nor PCV2 are known to infect or cause
illness in humans, however PCV2 may cause illness in pigs.
Viruses derived from Vero MCB and carried through
manufacture process to products
PCV1 DNA is present in poliovirus harvests, but not
in final bulk or container (due to inactivation step)
Source: FDA vaccine advisor committee meeting (May 7, ’10)
4-7-2011
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PCV

RotaTeq (Merck)


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A live, oral pentavalent vaccine that contains 5 live
reassortant rotaviruses, parent strains were isolated from
human and bovine hosts
Package insert (Sep. 2010)
Rotarix

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4-7-2011
A live, oral vaccine derived from human 89-12 strain
(G1P[8] type)
Package insert (2010)
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FDA actions
Additional testings are required

FDA (Dec., 2010) requested information regarding

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4-7-2011
Plans that the manufacturers may have to implement
additional adventitious agent testing methods as part of
their manufacturing process as these methods become
available including, but not limited to, screening for PCV
and PCV DNA, and
Any additional in-process testing for adventitious agents
that they may have recently added, but not reported to
FDA.
39
Validation of viral clearance steps

For rDNA vaccine produced from
mammalian/insect cell lines, why virus
testing alone is not enough?

Due to limitations of testing methods


Sampling of test material

4-7-2011
Sensitivity, susceptibility (indicator cell, animal
model)
Reference: “Validation of Biopharmaceutical
purification processes for virus clearance evaluation”,
Allan Darling, Mol. Biotec. Vol. 21, 2002
40
Allan Darling,
Molecular Biotechnology, vol. 21, 2002

Besides DL of test method, ability to detect low
concentrations of virus is also limited by statistical
sampling


If V>>v, above equation be simplified by Poisson
distribution


Probability that a sample v does not contain virus is
p(0) = ((V-v)/V)n
p(0) = e-cv, c = (In p)/-v
If v=1 mL, c=10-1000 virus particles/L
Probability of 1 mL will not contain a virus particle
c
10
100 1000
p(0) 0.99 0.90
0.37

4-7-2011
41
Scope



Vaccine
Information from research stage
Clinical trial-IND




Cell substrate-Testing for adventitious agents
Quality, starts from phase 1
Quality, (almost) finalizes at phase 3 and continues
through product life span
Collaboration from all parties makes a trial
going
4-7-2011
42
A clinical trial
-IND dossier

Biological/biotechnological products



4-7-2011
Poorly characterized, e.g., virus vaccine, cell-based vaccine
Well-characterized, e.g., rDNA protein vaccine, DNA vaccine
Technical related document

Clinical study proposal

Investigator brochure

CMC

Pharmacology and toxicology

(PK, when appropriate)

Clinical
43
CMC

A summary report with supporting documents,
e.g., batch analysis, stability data
A valid description which reveals all necessary
components to demonstrate the quality and control of
the test drug
 Present data in tabular form with brief narrative
highlighting the main points
CTD format is a valid reference to organize the dossier
After phase 1, any change such as cell line, process,
manufacture site, will require comparability



4-7-2011
44
CTD M3 (partially shown)

3.2.S DRUG SUBSTANCE (原料藥)

3.2.S.1 General Information (一般資料)




3.2.S.2.Manufacture (製造)

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4-7-2011
3.2.S.1.1 Nomenclature (命名)
3.2.S.1.2 Structure (結構式)
3.2.S.1.3 General Properties (一般性質)
3.2.S.2.1 Manufacturer(s) (製造者)
3.2.S.2.2 Description of manufacturing process and process controls
(製程敍述及製程管制)
3.2.S.2.3 Control of materials (物質管制)
3.2.S.2.4 Controls of critical steps and intermediates (關鍵步驟及中間
體管制)
3.2.S.2.5 Process validation and/or evaluation (製程確效及/或評估)
3.2.S.2.6 Manufacturing process development (製造程序的發展)
3.2.S.3 Characterization (特性)
45
舉
例
(
)
原
料
藥
部
分
3.2.S.2.Manufacture
3.2.S.2.2
流程圖並簡要敘述製程及製程管控關鍵步驟，包括批量大小、物料
Description of
、起始物、試劑 (來源及供應商)等。
manufacturing
process and
process controls
 表列製程所使用的物料，例如培養基，酵素等。
 如果抗原的生產來自細胞及/或病毒種批系統：
 說明種細胞或病毒的來源、分離、識別、及培養過程、特性。
 細胞庫（Cell bank）及病毒種批（Virus seed lot）系統的建立
過程及管控
3.2.S.2.3 Control of
 細胞庫或病毒種批系統的identity、viability、purity及培
materials
養過程中的基因穩定性`。
 病源的檢測。
 Unprocessed bulk的病源檢測。
 如果是基因重組製造的抗原，提供expression construct 相關的資料
3.2.S.2.4 Controls
of critical steps and
intermediates
3.2.S.2.5 Process
validation and/or
evaluation
4-7-2011
簡要敘述安全性相關的步驟及管控，例如DNA/蛋白質清除步
驟、不活化反應、嵌合反應(conjugation)、無菌過濾等。
敘述安全性相關步驟的評估數據/結果，例如無菌過濾、不活化、病毒
清除、減毒、凍乾等步驟。
46
CMC summary
-Phase 1

Manufacturer ad manufacturing process


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

4-7-2011
Flow diagram and description, batch size
Controls which relate to product safety
For rDNA products derived from cell lines of
human or animal origin, validation of the viral
clearance procedure
For inactivated vaccines, a validation of the
inactivation process
For live vaccines, a demonstration of the
attenuating characteristics
47
CMC summary
-Phase 1

Control of materials

Raw materials, starting materials, solvents, reagents,
catalysts


Source, history, and generating of cell substrate and
viral/bacterial seed


Expression construct
Cell/virus/bacteria banking system, characterization,
and testing



4-7-2011
Biologically-sourced materials, TSE concern
Non-viral agent
Adventitious and endogenous viruses
Tumorigenicity, case dependent
48
CMC summary
-Phase 1

Analytical method


Pharmacopeia
Non pharmacopeia

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4-7-2011
A brief description
Qualification of safety related method
 E.g., HCP, host cell DNA, residual reagent
49
CMC summary
-Phase 1

Drug substance (Ag, adjuvant, novel excipient)



Characterization
Specification (preliminary), e.g., identity, strength,
potency, and purity (& impurity)
 E.g., HCP, DNA, residual reagents
Drug product



4-7-2011
Adjuvant, excipients, diluents
Dosage form, composition
 Premix, on-site mix (adjuvant, dilution, reconstitution)
Specification (preliminary)
50
CMC summary
Phase 1

Stability



At least cover the duration of trial
In-use stability information, e.g., after mixing, dilution,
reconstitution, multiple withdrawing
Batch analytical result, DS and DP

4-7-2011
Batch for animal and clinical studies
 Same batch/formulation is recommended for vaccine
products
 If not, describe (to compare)
 CMC
 Animal study might be useful
51
Phase-in of validation


Validation of manufacturing processes and analytical
methods goes along with the clinical development
In phase 1, safety related method requires certain
extent of validation



4-7-2011
E.g., Host cell DNA, protein, viral test (e.g., PCR)
“Limit” - specificity and LOD
“Quantitation”- more extensive validation
52
Potency assay


Correlation to in-vivo biological activity should
be justified
Potency should be in the stability study, even it is
not proven to be stability-indicating in the early
trial
4-7-2011
53
Phase-in of validation
Bioassay (potency)


No need for LOD, LOQ
At phase 1/2
 Specificity
 Precision

Repeatability, e.g.,



4-7-2011
Samples from several independent preparations of the same
stock
Same sample, well to well, %CV<15-20%
(Linearity/range/accuracy)
54
Phase-in of validation
Bioassay (potency)

At phase 3 and NDA
 Precision

Intermediate precision, e.g.,




4-7-2011
Reproducibility, inter-laboratory
Robustness


plate to plate, day to day, analyst to analyst
Apply changes that probably will not happen (e.g.,
increase in Rx time, temperature change)
Pushing the system
Linearity/range/accuracy
55
USP<1226> Verification of
compendial procedures

Users of compendial analytical procedures are not
required to validate procedure, but documented
evidence of “suitability” should be established under
actual conditions of use


Not for microbiological procedures
Some of the analytical performance characteristics for
“validation” study, may be used for verification
process

E.g., “specificity” is a key parameter, potential interference
from


4-7-2011
Drug substance from different suppliers may have different
impurity profiles
Drug product contains different excipients, additives
56
Pre-clinical preparation

Ag (and adjuvant)


Analytical methods, to characterize Ag/adjuvant,
specification set up, and stability indicating
Formulation, delay optimization until beyond phase 1 and
achieves proof of concept



Bioanalytical assays, to monitor immune response in vivo


4-7-2011
To maintain stability during trial
Enable use in animal Tox and FIH study
Vaccine-specific parameters
Identify infections
57
After Phase 1




Formulation for next clinical studies
Develop/optimize manufacturing processes
Optimize analytical test methods
Update CMC section of IND
4-7-2011
58
Phase 2






4-7-2011
Update clinical supplies
Identify critical process parameters
Optimize manufacturing process
Select doses for phase 3 studies
Establish formulation and container/closure
Update phase 2 package
59
Phase 3






Select commercial manufacturing and
packaging sites
Prepare pharmaceutical development report
Scale up
Process validation
Establish stability studies
Prepare CMC section of NDA
4-7-2011
60
Lot release, in general
Marion Gruber, FDA-vaccine review , 2008
4-7-2011
61
Tests after mixing, an example
Marie-Chantal Uwamwezi, GSK-malaria vaccine, 2010
4-7-2011
62
Product development
-a reference to check

US National Institute of Allergy and Infectious
Diseases-Vaccines



Instruction and advise to HIV vaccine researchers
Information regarding (HIV) vaccines in all aspects
Preclinical master contract (HIV vaccines)



4-7-2011
Manufacture GMP pilot lots of vaccine for testing in humans, or
lots for testing in nonhuman primates
Perform tests for safety, immunogenicity and other preclinical
testing of vaccine candidates
Preparation of FDA submissions leading up to human trials
63
Overview of
product
development
of a vaccine
Source: US NIAID
4-7-2011
64
Thank you!
4-7-2011
65
SPARE SLIDES
4-7-2011
66
Phase 2 & 3
- incremental requirement






PC characterization, to more detail
 Character(s) affected by manufacture process
Batch information
 Comparability due to changes such as process, scale
Stability data, update
Manufacturing and controls, update
Specification, update
Phase-in validation
 Process validation (phase 3 or NDA)
 Analytical method validation (phase 3 or NDA)
4-7-2011
67
Phase 1
3
- incremental requirement
Paul-Ehrlich-Institut
4-7-2011
68
Phase 1
3
- incremental requirement
Paul-Ehrlich-Institut
4-7-2011
69
Phase 1
3
- incremental requirement
Paul-Ehrlich-Institut
4-7-2011
70
Different role and thus
point of view
Scientist
Contract
manufacturer
Sponsor
Regulatory
agency
Concentration of test drug
Scientist
If only the purified protein is potent, as expected.
Concentration is not a major issue.
Sponsor

Contract
manufacturer

Concentration affects injection volume, either for animal
study or clinical trial.
Volume/dose for sc, id, im is less than iv, thus more
concentrate formulation is required for route other than iv.
Concentration affects the vaccine formulation, if
adjuvant is to be used.
Concentration be clarified before agreement.
It depends on the capacity of the production.
Process improvement or modification
Timeline, cost

Regulation
4-7-2011
If only the stability of product is demonstrated,
concentration is not a major issue.
72
Lot and quantity of the test material
Regulation
Different lots can be used for animal and clinical study, if only
they are comparable
Sponsor

4-7-2011
Same or different lot for toxicity and clinical study
Timeline, contract, cost
Quantity for pharmacology studies (may be research grade)
Quantity for toxicity studies
Overage of 15-20%, plus consideration of formulation and
vialing (e.g., 10 dose/vial, last 2 doses will use 1 vial)
(Quantity for specification and stability testings, retention
samples)
Quantity for clinical trial
73
On site mixing
-Ag and adjuvant come from different manufacturer
Regulation
In-use stability
At least potency and sterility tests are required….
Robustness of the method of on-site mixing
During trial, if no change in the CMC (manufacture,
specification…..), tests are done on one representative lot.
Sponsor

4-7-2011
Design the method of mixing
What are the test items required at this condition
Who/where would be able to perform the in-use stability
tests
74
Estimate cost of the test materials
Examples
Manufacturer

Sponsor

4-7-2011
If there is no DMF already in place, additional cost is
needed to prepare document
Any test/study by contract lab (e.g., viral clearance, cell
bank qualification) is at additional cost
~10% overage for each filling/mixing step or each
component.
Usually 30-40% of the total quantity are used for clinical
trial, the rest of the products are used in animal studies (e.g.,
immunogenicity, toxicity) and tests (e.g, in-use stability)
Final quantity ordered need to take all experiments, tests,
and reserve samples into consideration
75
Thank you