J-Module 1.2 Preparation

(CMC): Model Document for

Manufacturing Process

Description

JPMA Biopharmaceutical Committee

Technology Working committee

Kei Nishimura

Contents

• J-Module 1.2

• Model document (Mock-up)

– Background / overview

– Example 1: Production culture

– Example 2: Affinity chromatography

• Summary

Current

• Guideline for Descriptions on Application Forms for

Marketing Approval of Drugs, etc. under the Revised

Pharmaceutical Affairs Law” (PFSB/ELD Notification No.

0210001, dated February 10, 2005)

• Study about impact of manufacturing process for bio-

products on the quality – Introduction of minor change

notification (Module 1.2 of bio-products) – (Toru

Kawanishi 2006)

• ICH Guidelines Q9, Q10, Q11 (2006, 2010, 2014)

• Lots of Bio-product approved

Structure of J-module 1.2

• Product Name

• Ingredient and Contents

• Manufacturing Process

• Dosage and Administration

• Indications

• Storage and Shelf life

• Specification and Testing Method

• Manufacturing Sites

・・・・・・・・・・・・・・・

Legally-binding

• Evaluation results

– Process evaluation

– Validation

– CQA evaluation

– Risk evaluation

– Control strategy

etc.

• Controls under GMP

– Raw material/labeling and packaging material

– Process

– Parameter

– Process control

– In-process control

etc.

Approval matters【Manufacturing process】

• Notice

• Review：

Inquiries

Information to support

manufacturing process section

• Module 3

• Module 2.3

Manufacturing process section

Information to be covered

• Preparation of gene expression constructs

• Preparation and control of MCBs

• Preparation and control of WCBs

• Manufacturing of drug substances

– Culture process and purification process

• Manufacturing of drug products

• Raw materials

• Manufacturing sites

• Manufacturing process flow chart

Change controls in manufacturing

process• Changes of manufacturing process should be

addressed by Partial Change Application (PCA) in principle.

• A Minor Change Notification (MCN) may be applicable. Ex. Acceptable range

• Manufacturing process column should clarify change procedure MCN/PCA.

≪ XX ≫：Target/Set Value. Should be changed by PCA

『 XX 』： Target/Set Value. MCN is applicable.

“○○○”：MCN is applicable

Mock-up (draft)

• JPMA Biopharmaceutical Committee

Technology Working committee prepares

specific description examples (Mock-up)

for the drug substance manufacturing

process section for general antibody

drugs.

Points to consider

• Guideline for Descriptions on Application Forms for

Marketing Approval of Drugs, etc. under the Revised

Pharmaceutical Affairs Law” (PFSB/ELD Notification No.

0210001, dated February 10, 2005)

• Study about impact of manufacturing process for bio-

products on the quality – Introduction of minor change

notification (Module 1.2 of bio-products) – (Toru

Kawanishi 2006)

• ICH Guidelines Q9, Q10, Q11 (2006, 2010, 2014)

• Company experience

Mock-up preparation process

• Based on J-module 1.2s and past application experiences

of the committee members, items (e.g. parameters) were

divided into two groups (included in J-module 1.2, and

not included). Then the individual items were reviewed

and reflected to the Mock-up.

# Process Critical

process

Param

eter

Assess

ment 1

Assess

ment 2

Mock

up

Examp

le

In-process

control

Reason

1-1) Seed

culture

No Scale Y/N Y N 0.0003

m3

Cell density …

Media Y Y Y

Amou

nt of

media

Y/N N N 100mL

Mock-up draft for bioproducts

• Each process has various process parameters and in-

process control tests. For this reason, an individual

approach should be taken to prepare J-Module 1.2 by

taking into account of assessment (e.g. process

evaluation, validation, CQA evaluation, risk evaluation

and control strategies ).

Antibody Drug (model)

• Antibody-producing cells: CHO/DG44

• Antibody class：IgG

• Non-sterile drug substance

Manufacturing process overview

• Production culture

scale: 15000 L

(volume)

• Media: Serum-free

medium

• Culture process yield:

approx. 3 g/L

• Purification process

yield: 50%

WCB

Seed culture

Expansion culture

Production culture

Harvest

Anion Exchange

Chromatography

Affinity

Chromatography

Caution Exchange

Chromatography

Low-pH virus

inactivation

Virus filtration

UF / DF

Drug

substance

Production culture: General picture

• Purpose: cell proliferation, production of desired

antibodies

• Culture vessel: SUS fermenter or single-use

bioreactor

• Add medium to production culture only once.

• Add a specified medium for nutrient supplement

at a specified day.

• Specified as a critical step.

Culture process: Production cultureThe expansion culture fluid is used to inoculate a culture vessel (with a capacity of 15000 L) containing ≪7000 L≫ of Medium 3 to a viable cell density of ≪1 ×105 cells/mL≫ and cultured at ≪37°C≫ and ≪pH○≫.

After ◊ days of culture, the culture is fed with ≪3000 L≫ of Medium 3 and further cultured at ≪37°C≫ and ≪pH○≫.

After ♦ days of culture, the culture is fed with glucose solution to a final concentration of ≪□ g/L≫ and production culture is continued for a total of ≪X days≫.

In-process control test:

Bioburden: < ○○ CFU/mL

Adventitious virus: no evidence of viral contamination

Mycoplasma: negative

Media pH Components

Medium 3 ■ Glucose ≪A g/L≫, Fatty acids ≪B

g/L≫, Synthetic IGF-1 ≪C g/L≫, ---

Glucose solution

(supplement medium)

- Glucose ≪ε g/L≫

Production culture: Information to be described

(proposal)

Culture

fluid

Culture vessel

MediaMedium components

(PCA)

Viable cell viability (description

omitted)

Capacity (PCA)

Medium addition volume

(PCA) Target viable cell density

(PCA)

Culture conditions

Dissolved CO2 level, Dissolved

oxygen concentration (DOC),

Osmotic pressure, Agitation

speed, Vessel internal pressure,

Aeration rate (description

omitted)

Initiation of the

culture

Temperature/pH (PCA)

Final cell viability is ensured

when a specific culture

condition is established.

These parameters should be

described if they pose a high

risk based on risk assessment.

Final cell viability is ensured

when a specific culture

condition is established.

* PCA: Partial Change Application

Production culture: Information to be described

(proposal)

Initiation of culture

Monitoring

Residual nutrient component level,

and metabolite level (descriptions

omitted)

Medium addition

Timing of medium

addition (PCA)

Medium

Amount of medium addition (PCA)

The process was validated;

changes are not expected

unless abnormalities occur.

Culture conditions

MonitoringResidual nutrient component

level, and metabolite level

(descriptions omitted)

Dissolved CO2 level, Dissolved

oxygen concentration (DOC),

Osmotic pressure, agitation speed,

Vessel internal pressure, Aeration

rate (description omitted)

Addition of

supplement medium

Timing of culture

addition (PCA)

Composition of medium (PCA)

Target final concentration (PCA)

Temperature/pH (PCA)

Supplement

medium

Production culture: Information to be described

(proposal)

Addition of supplement

medium

Culture conditions

Monitoring Residual nutrient component

level, and metabolite level

(description omitted)

Dissolved CO2 level, Dissolved oxygen

concentration (DOC), Osmotic

pressure, agitation speed, Vessel

internal pressure, Aeration rate

(description omitted)

Temperature/pH

(PCA)

Production

culture fluid

Total culture days

(PCA)

Maximum number of population doublings, Viable cell

density (final) , Cell viability (final), Cell productivity, Cell

production volume, Purity (description omitted)

Based on validation data.

Endotoxin (description omitted)Endotoxin test is clarified in the drug

substance specifications and test methods.

Bioburden, Adventitious virus, Mycoplasma (PCA)

Affinity chromatography process:

General picture

• Purpose: Purity improvement, Remove raw materials/process-related impurities/HCP

• Protein A column is used.

• Precolumn is not used.

• The entire amount of fluid obtained from the previous process is loaded.

• No critical intermediates to be isolated and held.

Purification process: Affinity

chromatography1) Affinity chromatography

The harvested culture fluid is loaded onto an affinity column packed with 『X

L』 of resin (PRODUCT NAME or equivalent) to allow adsorption of desired

antibody. The column is washed with Buffer A, followed by elution with Buffer B at a flow rate of 『○○ cm/h』. With the absorbance monitored at 280 nm, the

fraction containing desired antibody is pooled (start of pooling at OD280

『○○』; end of pooling 『××』) to obtain the eluate pool.

Buffer Components pH

Buffer A Tris 『×× mol/L』, --- -

Buffer B Sodium acetate ≪×× mol/L≫, --- 『6.5』

Affinity chromatography: Information

to be described (proposal)

Column Column material/resin, and size (PCA)

Equilibration

Composition of buffers

(description omitted)

The maximum number of column reuse will not

be described, on the premise that its change is

subject to control under GMP.

Number of column reuse (description omitted

In principle, appropriate conditions may be set according

to the column characteristics and controlled under GMP.

Equilibration buffer

Amount of buffer fluids to be run or

loaded (description omitted).

Affinity chromatography: Information

to be described (proposal)Harvested

culture fluid

Column

Washing

Elution

Evaluation results showed that the

acceptable range for flow rates is wide,

and it is not allowed to run the upper

limit of the column pressure.

Flow rate (omitted)

In principle, appropriate conditions

may be set according to the

column characteristics and

controlled under GMP.

Load volume

(description omitted)

As the entire amount of process

fluid is loaded.

Washing bufferComposition of buffers

(PCA/MCN)

Amount of buffer to be run (description omitted).

PCA: Partial Change Application

MCN: Minor Change Notification

Description items relating to the affinity

chromatography

Elution Elution buffer Composition of buffers

(PCA/MCN)

The flow rate and the range of pooling (MCN)

pH, conductivity (descriptions omitted)

It was assumed that study results identified the

flow rate and the range of pooling as process

parameters of this stepFraction

Column

Storage Regeneration buffer Composition of buffers

(descriptions omitted)

In principle, appropriate conditions may be set according

to the column characteristics and controlled under GMP.

Summary

• The current status on the J-Module 1.2 application (legal binding part) is

mainly to be prepared by the company experience and policy, in

addition to the previous reference proposed in 2006.

• Recently due to the detailed description in J-M1.2 previously, it

increases the prior to approval matters and then increase the supply risk.

• In order to reduce the change control items with the essential items in J-

M1.2, JPMA is under preparing the Mock-up draft with describing more

necessary legal binding information for the approval.

• At present, JPMA approach is focused on the draft preparation for the

manufacturing process of drug substance, reflecting the risk evaluation

information from the process evaluation/process validation results until

now.

• JPMA will start the discussions on the Mock-up preparation with PMDA

near future.