Session I: Manufacturing for Investigational Products ...thaitect.org/noppadol/thaitect_16th/04-08-2016/04082016-04-Kengo-… · Generally, the CMC department of a pharmaceutical

Your

happiness is

our aim

Session I:

Manufacturing for Investigational Products

Chemical Manufacturing Control for Submission


4th August, 2016, 16th ThaiTECT Annual Meeting 2016

Kengo Sonoda, Ph.D.,

Manager, R&D Department, KAKETSUKEN

2

Kaketsuken Introduction

The Chemo Sero Therapeutic Research Institute

Foundation Dec, 1945

In response to a proposal by Prof. Toyoichi Otawara of the Kumamoto Medical

College Kaketsuken was established based on the Institute of Experimental

Medicine, which was founded to produce and supply vaccines and antiserums.

Number of employees 1,927

Divisions 12

R&D, Vaccine, Blood Plasma, Animal Pharmaceuticals, Marketing, Production,

Quality, Clinical Laboratory. General Administration, Reliability Assurance, Legal &

Compliance, Corporate Planning

Kaketsuken Corporate Summary

Kaketsuken’s Mission

2011 Launched “ENCEVAC”

a Cell Culture (Vero) JE Vaccine in Japan

2012 Launched “QUATROVAC“

a DTaP-IPV (Sabin strain) in Japan

2013 "ENCEVAC" approved in Korea

2014 Approval of a Cell Culture (EB66) Pandemic Influenza Vaccine (H5N1)

2014 Approval of the first domestically produced bypassing product for

hemophilia patients with inhibitors

Current Activities

Products List of Each Japanese Manufacturer

KAKETSUKEN A B C D

Egg Derived Flu ● ● ● ― ●

CC Flu ● ― ― ● ―

DTaP-IPV ● ● ● ― ―

DTaP ● ● ● ― ―

DT ● ● ● ● ―

Tetanus ● ● ● ● ●

JE ● ● ― ― ―

Hep A ● ― ― ― ―

Hep B ● ― ― ― ―

Rabies ● ― ― ― ―

Smallpox ● ― ― ― ―

Measles & Rubella ― ● ● ● ―

Mumps ― ― ● ● ―

Varicella ― ● ― ― ―

Mamushi AT ● ― ― ― ―

Habu AT ● ― ― ― ―

Botulinus AT ● ― ― ― ―

Gas gangrene AT ● ― ― ― ―

Facilities

Facilities

Kumamoto

Prefecture

Amakusa

IslandsKumamotoCity

Kikuchi Research Center2,500,000 sq. ft.

(232,000 m2)Headquarters

1,550,000 sq. ft.

(144,000 m2)Aso Laboratories

1,270,000 sq. ft.(118,000 m2)

Airport

35 min. 30 min.

Japan

Tokyo Office

Fukuoka Office

Nagasaki Office

In Kumamoto

1) Headquarters

2) Kikuchi Research Center

3) Aso Laboratories

Mt. Aso

Kumamoto

Prefecture

Related Activities

Johnan Hospital

Kumamoto Health Science University (established in 2003)

On April 14 and 16, 2016, two large earthquakes hit the

Kumamoto area. Both earthquakes reached the maximum level

on the Japanese seismic scale

There have been over 2,000 aftershocks in the 3 months since

Our facility was closed for about 3 weeks. At present, all of our

activities have been restored except for some production lines.

2016 Kumamoto Earthquakes

9

Your

happiness is

our aim

Session I:

Manufacturing for Investigational products

Chemical Manufacturing Control

for Submission




What is “Chemical Manufacturing Control” (CMC)?

An example of CMC activities for our vaccine development

CMC related PMDA inquiries and responses from applicants

From review reports of vaccines licensed in Japan in this decade

Table of Contents

CMC is information on Chemistry, Manufacturing and Control of Drug Substance and

Drug Product in the document for a new drug application

In its broad sense, CMC includes R&D activities for manufacturing process

development and related quality evaluation.

CMC also includes the development of drug product formulation, manufacturing process

improvement activities, specification investigations, and test method development

Generally, the CMC department of a pharmaceutical company is responsible for

Conducting application activities to national regulatory authorities

Providing materials with appropriate quality for non-clinical and clinical

developments in a timely manner.

CMC is…..

12

Items

CTD ModuleICH Guideline

(Biologicals)Drug

Substance

Drug

Product

Seed Development and

IND ManufacturingS2 P3 Q5, Q6B

Characterization S3 N/A Q6B

Quality Control and

TestingS4 P5 Q2, Q6B

Stability S7 P8 Q1A, Q1B, Q5C

CMC Related CTD Module and ICH Guideline

13

Seed development

Evaluation and selection of candidate seed for vaccine development

Preparation and characterization of seed lot system

An Example of CMC Activities for our

Vaccine Development

14

Manufacturing of investigational new drug (IND)

Preparation of pre-clinical testing material (preCTM)

Development of manufacturing process and production of Phase 1 clinical

trial material (CTM) based on preCTM quality profile.

Development of manufacturing process and production of Phase 2 CTM

based on Phase 1 CTM quality profile

Development of manufacturing process for Phase 3 CTM and commercial

products based on preCTM, Phase 1 CTM, and Phase 2 CTM quality

profiles.


Vaccine Development

15

Quality control and characterization

Development and improvement of testing methods

Validation activities depending on importance and development phase

Routine analysis

Stability

To assure quality of CTM

To obtain data for application

Others

Management of Contract Manufacturing Organization (CMO) / Contract Research

Organization (CRO)


Vaccine Development

16

Utilization of CMOs/CROs for Early Stage

17

QC

testing

dataCTM

by cGMP

Non

Clinical

Data

Clinical

Data

Capabilities based on expertise and experience

Time line management

Training system and records

Audit experiences by national authorities

Low turnover rate

Risk management

Back up power supply, emergency call system

Weather and natural disaster

Schedule and resources

To Choose an Appropriate CMO/CRO

18

PMDA Inquiries and Applicant Responses

in Reviewing CMC Issues

From review reports of recently

licensed vaccines

19

PMDA (Pharmaceuticals and Medical Devices Agency) is Japanese regulatory

agency, working together with Ministry of Health, Labour and Welfare.

Their obligation is to protect the public health by assuring safety, efficacy and

quality of pharmaceuticals and medical devices.

They conduct scientific reviews of marketing authorization application of

pharmaceuticals and medical devices, monitoring of their post-marketing

safety. We are also responsible for providing relief compensation for sufferers

from adverse drug reaction and infections by pharmaceuticals or biological

products.

https://www.pmda.go.jp/english/index.html

What is PMDA?

20

year Licensed vaccine (brand name, company)

2006 Pneumococcal vaccine (PnuemoVax NP, BANYU-Merk)

2007 Hib vaccine (ActHib),

Adsorbed influenza vaccine H5N1

2009 Cell culture Japanese encephalitis vaccine (JEBIK, Biken)

HPV vaccine (Cervarix, GSK)

Heptavalent pneumococcus vaccine for children

2011 Cell culture Japanese encephalitis vaccine (ENCEVAC, Kaketsuken)

Rota virus vaccine (Rotarix, GSK)

2012 Rota virus vaccine (Rota Teq)

IPV vaccine (IMOVAX POLIO, Salk Vaccine, Sanofi Pasteur)

DTaP-IPV vaccine (Quattrovac, Kaketsuken)

DTaP-IPV vaccine (Tetrabik, Biken)

2014 Tetravalent meningococcal vaccine (Menactra, Sanofi)

Vaccines Licensed in Japan

21

Regarding the specifications and test methods of drug product (final container), PMDA

asked the applicant to consider setting the insoluble particulate matter test for

injections, content uniformity test and osmotic pressure test.

The applicant answered that the insoluble particulate matter test for injections will be

included in the specifications and test methods by the end of December 2009, after

validating the test method, and that the content uniformity test will also be included in

the specifications and test methods. For osmotic pressure, the applicant presented the

results of 145 lots (monitoring of final container products), and explained that, because

consistent results were obtained, the osmotic pressure test will be handled as an in-

process control test rather than included in the specifications and test methods.

PMDA accepted the answer.

HPV Vaccine (Cervarix), GSK, 2009

22

Because the origin of the cytoplasmic cluster of particle-like structures in *********** cells observed

by electron microscopic analysis was unclear, PMDA asked the applicant to provide new findings, if

obtained after filing of the application.

(i) the frequency of appearance in the cytoplasm is low (<**%), but elimination by cloning is not

possible, (ii) appearance in the nucleus has never been detected so far, (iii) no increase is seen

even when cultured under stress, and no replicative capability is observed, (iv) there is no capacity

to infect mammal animal cells, insect cells or animal bodies, (v) since no pathogens such as insect

virus have been detected so far from the screening of the cell bank, it is unlikely to be insect virus

and (vi) the product safety is not affected when considering the virus clearance ability of the

manufacturing processes.

The applicant intends to continue the investigation and appropriately provide the information on

characterization results if any effective approach for the structural analysis is identified in the

future.

HPV Vaccine (Cervarix), GSK, 2009

23

PMDA inquiry

Describe the necessity of setting the specification test to assure attenuation of the

drug product

Applicant's response

No animal model to assure attenuation profile. So specification tests to assure

attenuation of the vaccine strain are impossible.

There is no need to set an attenuation test since the vaccine strain is genetically

stable

PMDA response

Agreed, but re-investigation is necessary to set specification tests to assure

attenuation of drug product, if attenuation markers are found

Rota Virus Vaccine (Rotarix), GSK, 2011

24

The candidate vaccine is an insoluble protein vaccine and its active ingredients are adsorbed onto

aluminum gel and characteristically, the homogeneous dispersion easily becomes unstable, e.g.

when the vaccine is allowed to stand, its active ingredients are precipitated. PMDA asked the

applicant to explain the consistency of the vaccine filling process and the degree of uniformity in

the amount of each active ingredient among dosage units.

As the uniformity of dosage unit tests, test for protein content and test for aluminum content will be

included in the drug product specifications to check the content uniformity of individual dosage

units.

The test for protein content was chosen because it has a higher precision than the test for

antigen content and the active ingredients as a whole can be measured.

The test for aluminum content was selected to evaluate the uniformity of dosage units,

considering that aluminum gel is the component most difficult to be dispersed

homogeneously by agitation, during the filling process.

DTaP-sIPV (Quattrovac), Kaketsuken, 2012

25

The country of origin of casamino acids could not be identified,

It is likely that casamino acids were not sourced from the UK or Portugal, a risk

assessment for TSE was performed in accordance with the notification. As a

result, the total risk assessment score was −21, which was lower than－3,

which is the threshold to provide a certain degree of safety assurance.

Therefore, the risk of TSE infection from the candidate DPT-sIPV vaccine is

considered very low. Raw materials will be replaced with appropriate ones

when a new MS is prepared.

Attachment to the joint notification of the Evaluation and Licensing Division and

the Safety Division, Pharmaceutical and Food Safety Bureau, MHLW (PFSB/ELD-

SD Notification No. 0801001, dated August 1, 2003).

DTaP-sIPV (Tetrabik), BIKEN, 2012

26

To set specification testing according to the Japanese Pharmacopeia

(latest version) and “Minimum Requirements for Biological Products”

To evaluate and show the safety of bio-derived materials according to the

“Standard for Bio-derived Materials”

To set acceptance criteria based on actual data from batches or lots

using non-clinical and clinical studies

Trends of PMDA’s inquiry

27

Review Reports: Drugs

http://www.pmda.go.jp/english/review-services/reviews/approved-

information/drugs/0001.html

References

28

Your

happiness is

our aim

Session I:


Manufacturing for Investigational

Products




Manufacturing scale and specifications in each development

phase

Case study: early stage live attenuated dengue vaccine

Table of Contents

Sponsors/developers have a responsibility to secure the quality of

investigational new drugs

Quality is based on test procedures and acceptance criteria

Requirements for investigational new drugs

To protect volunteers through quality assurance

To ensure the reliability of clinical trial results by assuring uniformity “lot to

lot” and “in-lot”

To show consistency in quality in the early clinical phase and to show

equivalency in quality in later clinical phases and the commercial phase

Quality Policy by the GMP for Investigational

Products (Japan)

Acceptance criteria are set in line with testing procedures to ensure the quality of

investigational new drugs

Acceptance criteria are not set to ensure high purity

They are set to ensure quality to meet the efficacy aimed for in clinical trials

To ensure quality to protect volunteers (impurities, sterility, endotoxins, etc)

Acceptance criteria that ensure consistency in quality at the early clinical phase

and equivalency in quality from the late clinical phase to the commercial phase

Acceptance criteria should be kept the same or tightened as development

progresses

Basic Policy for Acceptance Criteria

32

Phase1 trials are usually small trials and performed to investigate the safety profile and

pharmacodynamics

Phase1 CTM is manufactured at a small scale or laboratory scale for one lot

Provisional test procedures and acceptance criteria are applied for Phase 1 CTM

Tests to confirming contents are important (antigen ELISA, potency, etc)

Acceptance criteria for impurities are established based on the results from non clinical

lots used in safety studies (HC-DNA, HCP, adventitious agents, etc)

Points to consider for setting specifications

Impurity content of the dug substance used for safety or toxicity studies

Lot analysis data and stability profile of formulation study lot and Phase 1 lot

Phase 1 CTM

33

Phase 2 trials are performed to investigate safety profiles and efficacy (age de-

escalation, dose finding, etc)

Phase 2 CTMs are manufactured in small number at the pilot scale

Approximately the same test procedures and acceptance criteria as Phase 1

CTM are used, but developers should tighten the specifications as much

controllable for Phase 2 CTM


Phase 1 CTM test procedures and acceptance criteria

Phase 2 lot stability profile and lot analysis data

Phase 2 CTM

34

Phase 3 trials are pivotal studies and are performed to confirm efficacy and the safety

profile

Phase 3 CTMs are manufactured at the actual production scale validated by process

validation of at least 3 lots

Phase 3 trials can be conducted using CTMs produced at the pilot scale in Japan,

but GMP audits of actual production facilities and process validation data is strictly

conducted to confirm consistency between pilot and actual production

Validation of test procedures and finalization of acceptance criteria


Phase 2 CTM test procedures and acceptance criteria

Phase 3 lot stability profile and lot analysis data

Phase 3 CTM

35

Acceptance criteria should only be tightened

Broadening of acceptance criteria is not accepted unless

unavoidable

Developers need to show that there are no effects on quality.

Developers will be required to return to the previous step if they

cannot show this clearly.

Change Control

36

37

Development of

a Novel Dengue Vaccine

0

100

200

300

19

99

20

01

20

03

20

05

20

07

20

09

20

11

20

13

20

15

0

2

4

6

8

10

12

09ส.ค.

16ส.ค.

23ส.ค.

30ส.ค.

06ก.ย.

13ก.ย.

20ก.ย.

27ก.ย.

04ต.ค.

11ต.ค.

18ต.ค.

25ต.ค.

Imported cases in Japan

Yoyogi Tokyo Outbreak in 2014

162 cases

Live attenuated tetravalent dengue vaccine (KD-382)

Kaketsuken and Mahidol University entered into the MTA.

Dr. Sutee Yoksan, Centre for Vaccine Development, Mahidol University, Thailand

Primary dog kidney (PDK) cells were used for the attenuation of Dengue

virus serotypes 1-4 (Set II)

This vaccine candidate is not genetically modified

Temperature sensitivity, small or middle size plaque, low neurovirulence in

suckling mice

Development of a Novel Dengue Vaccine

by Kaketsuken and Mahidol University

38

Geometric Mean Titer of Nab in NHPs

(60 days after single administration, N=3)

39

DENV-1

DENV-2

DENV-3

DENV-4

5,5,5,5 5,3,5,3 5,3,3,3

Formulation (DENV1, 2, 3, 4, Log PFU/dose)

Long Lasting Nab Titers in NHPs After Single

Administration (N=6)

Bars show ±SD 40

Viral load (RT-qPCR) in NHPs after wild parental

virus challenge at 14 months p.i.

41

No.Challenge

virus*

Viral load after challenge measured by RT-qPCR(GE/mL)

Day 1 Day 2 Day 4 1 month

1

DENV1

<LLOQ <LLOQ <LLOQ <LLOQ

2 <LLOQ <LLOQ <LLOQ <LLOQ


4

DENV2




7

DENV3




10

DENV4




GE (Genome copies equivarent)

LLOQ (Lower Limit of Quantification) = 7143 GE/mL

IND Manufacturing Process

42

Cell culture( for each serotype)

Virus propagation

Harvesting

Ultrafiltration

Monovalent bulk

Tetravalent bulk

Filling

Freeze (< -65C)

Cell culture( for each serotype)

Virus propagation

Harvesting

Monovalent bulk

Tetravalent bulk

Filling

Lyophilize (2~8 C)

DNase treatment

Ultrafiltration

For non-clinical studies For clinical studies

Vero cells are used for virus culture. A cell bank system has been

established for GMP manufacturing

Fetal Bovine Serum (FBS) is used for the cell propagation step

Serum free medium is used for the virus propagation step

Kaketsuken uses ultrafiltration for the non-clinical drug as a

purification step. Kaketsuken added a DNase treatment step to

reduce host cell derived DNA for Phase 1 CTM

IND Manufacturing

43

Tests for bacteria, fungi, mycoplasmas, and mycobacteria

Tests for adventitious agents

[In vitro] Test in cell cultures for adventitious viruses relevant to the

passage history of the seed virus

[In vivo] Tested in animals that include guinea-pigs, adult mice, and

suckling mice

Nucleic acid amplification techniques (PCR) for adventitious viruses

relevant to the passage history of the seed

Control of Adventitious Agents for Virus Seeds

44

Quality Control* (1/2)

45

Sample Provisional Test Items Provisional

Acceptance Criteria

Cell

cultures

Control cell culture No CPE observed

Test for haemadsorbing viruses Not detected

Tests for cytopathic, adventitious agents in control

cell fluidsNot detected

Identity test Vero

Monoval

ent bulk

Identity Dengue virus

Tests for bacteria, fungi, mycoplasmas and

mycobacteriaNot detected

Tests for adventitious agents Not detected

Virus titration for infectivity For information only

Tests for host cell proteins For information only

Tests for residual cellular DNA <10 ng/dose (WHO)

Tests for consistency of virus characteristics For information only

*Guidelines on the quality, safety, and efficacy of dengue tetravalent vaccines (live, attenuated), Annex 2 of

WHO Technical Report Series No.979, 2013

Sample Provisional Test Items Provisional

Acceptance Criteria

Tetraval

ent bulk

Residual animal serum protein <50 ng/dose (WHO)

Sterility Pass

Final

product

Appearance For information only

pH For information only

Identity Detect four serotypes of

dengue virus

Sterility Pass

Potency For information only

Thermal stability For information only

General safety No abnormal toxicity

Residual moisture <1%

Quality Control* (2/2)

46

*Guidelines on the quality, safety, and efficacy of dengue tetravalent vaccines (live, attenuated), Annex 2 of

WHO Technical Report Series No.979, 2013

Items Target Product Profile

Target Indication Prevention of symptomatic dengue fever

Target Population Individuals 24 months of age and older

Administration Subcutaneous injection

Dosing Schedule One administration

Formulation Lyophilized, preservative free, multi dose vial

Stability 3 years, 2~8C

Efficacy Prevention of symptomatic dengue fever

SafetySeverity and frequency of local and systemic

reactogenicity comparable to licensed live virus vaccines

KD-382 Target Product Profile

47

Thank you for

your attention

Documents

Session I: Manufacturing for Investigational Products ...thaitect.org/noppadol/thaitect_16th/04-08-2016/04082016-04-Kengo-… · Generally, the CMC department of a pharmaceutical