th IABS, PMDA and JST joint Symposium Scientific … · Categorization of Materials Used in...

1Pharmaceuticals and Medical Devices Agency 1Pharmaceuticals and Medical Devices Agency

Scientific Points to Consider:

Starting Cells, Other Raw Materials,

Manufacturing-Related Substances and

Non-cellular Components Constituting

the Complex Final Products

Feb.18th, 2015

IABS, PMDA and JST joint Symposium

Daisuke MAEDA, PhDOffice of Cellular and Tissue-based Products

Pharmaceuticals and Medical Devices Agency (PMDA), Japan

Disclaimer:

The views and opinions expressed here are those of the

presenter and do not necessarily represent those of PMDA.

2Pharmaceuticals and Medical Devices Agency

1. Overviews of materials for manufacturing

2. Starting materials

3. Other raw materials and manufacturing-

related substances

4. Non-cellular components constituting the

complex final products

Contents





related substances



Contents


Manufacturing Process of CTPs

Collection of Cell Source

Starting cells

Culture (amplification)

Cell Bank/ Cell Stock

Culture (differentiation)

Filling

Final Product

(Cryopreservation)

Raw Materials

Raw Materials

Raw Materials

Excipients

Manufacturing-Related Substances




Case of Autologous Cultured Epidermis ＪＡＣＥ(MAA: 29th Oct. 2007 )

･･･Excipients

Patient’s skin ･･･Source Tissues

Protease/ collagenase

Culture media

FBS

Feeder cells

Recombinant insulin

Human EGF

Cholera toxin

Antibiotics

Trypsin

Dulbecco's PBS

Collection of Cell Source

Starting cells

Culture (amplification)

Filling

Final Product

Culture flask

Carrier,

Cover sheet・・・Manufacturing-

Related SubstancesStorage buffer

Excerpt from Review Report on JACE,

http://www.pmda.go.jp/english/service/p

df/medical_devices/jace_oct2007_e.pdf

・・・Manufacturing-

Related Substances

Cell Stock

Raw

Materials


Categorization of Materials Used in Manufacturing

Starting materials

Human and

animal-derived

Excipients/ Non-cellular components

of final products

FBS, Human Serum,

HSA, Feeder Cells,

Trypsin, Heparin

Tissues, Cells

Storage buffer, Scaffolds, Sponge,

Support membranes, Fibers

Collagen matrix

Raw Materials Manufacturing-Related

substancesNon animal-derived

Culture dishes/ flasks,

Columns, Filters,

Vessels, Tubing, Bags

Culture media

Recombinants

(animal-free)

Antibiotics

D-PBS


No Japanese equivalent for “Ancillary Material” as a legal term.

Ancillary materials (AMs)

include a wide variety of raw materials and materials used in

process,

are used to ensure the safety, effectiveness, and consistency of

the final product,

come into contact with the cells or tissues during

manufacturing,

are not intended to be part of the final product formulation.

Materials or components that are intended to be in the final

product dosage form are not AMs.

→ USP General Information <1043> Ancillary Materials

What’s “Ancillary Materials” ?



Starting materials

Human and

animal-derived


of final products

FBS, Human Serum,

HSA, Feeder Cells,

Trypsin, Heparin

Tissues, Cells



Collagen matrix




Columns, Filters,


Culture media

Recombinants

(Animal-free)

Antibiotics

D-PBS

Ancillary materials


Design

Quality

Product

Quality

Quality

Management

Procedure

Equipment

Process

Material

Quality Risk Management /

Knowledge Control

Product Quality is affected by various factors. Better understanding the variables in the process, leads to

good quality control.

Assurance of Product Quality


Output

Control

on material attributes

• Starting cells

• Raw materials

• Excipients

• Primary packaging

materials

etc.

Quality of Materials for Manufacturing

in the Control Strategy

ICH-Q10

Input

Manufacturing process

Procedural controls

• Sequence of

processing stepsIn

put

Outp

ut

In-process control

Parametric control

In-process control

In-process testing

Control

on end-product

• Release testing





related substances



Contents


1. Source and Selection of Human Cells/

Donors

2. Donor Eligibility

・Test for the infectious diseases

・Information about clinical history

3. Collection, Storage, and Transport of

Cells and Tissues

Points to Consider for Starting Materials


Characteristics in biological structure/function of the

starting cells/tissue should be provided by

appropriately selected parameters such as

・morphological characteristics

・growth characteristics

・biochemical and immunological parameters

・HLA typing

・other relevant genotypic or phenotypic markers.

Reasons for selection of the cell/tissue should be

provided.

1. Source and Selection of Human Cells/ Donors


2. Donor Eligibility Criteria

When collecting human cell / tissue material,

depending on the purpose of their use, relevant

bacterial, fungal and viral infections have been

denied through interviews, screening tests.

The test parameters and methods used should be

justified in light of the latest knowledge of infectious

diseases, etc..

The donor’s clinical history of having received

blood transfusion or transplantation must be taken

into consideration when determining donor

eligibility.


2. Donor Eligibility Criteria (continued)

According to the test parameters and

methods, the re-testing and other infection

controls at the right time should been made,

taking into consideration the window period.

However, it does not necessarily require a

donor screening when the donor is the

same person as the recipient (autologous).


Autologous Human Cells/Tissues

Infectious status of donor, including

infections of HBV, HCV, HIV, and

HTLV.

Risk of viral replication or re-activation

in manufacturing processes

Robust process control to minimize

unevenness of “custom-made”

products

Limited amounts of samples for

quality evaluation of products

Allogenic Human Cells/Tissues

History, source, derivation

Donor screening/testing and donor eligibility

(compatibility with donor qualification criteria,

including ethical and medical aspects;

freedom from the presence of HBV, HCV,

HIV, HTLV and parvovirus B19 by screening

and testing; exclusion of potential infection of

CMV, EBV and WNV by testing; clinical

history; experience of blood transfusion or

implanting; genetic variants etc.)

Records of donor

Derivation of cell strain

Cell banking

Viral assays at the final product level

Immunological relevance

Autologous C/T vs Allogeneic C/T


2. Donor Eligibility Criteria (continued)

Donor Recordkeeping

The records of donors should be maintained and stored so as to verify information required to secure safety of the cell and tissue as materials.

For each experimental sample of the donor and the patient, the content of information and its storage measure may depend on the intended use.


3. Collection, Storage, and Transportation

of Cells and Tissues

(1) Eligibility of medical professionals and institutions

collecting the samples

(2) Suitability of the sampling site and method

(3) Interviews or tests to ensure donor safety

(4) Informed consent for donors

(5) Protection of donor privacy

(6) Storage methods and measures to prevent

erroneous sampling (mix-up)

(7) Transportation methods

(8) Preparation of records for (1)-(7) and record-keeping

procedures





related substances



Contents



Starting materials

Human and

animal-derived


of final products

FBS, Human Serum,

HSA, Feeder Cells,

Trypsin, Heparin

Tissues, Cells



Collagen matrix




Columns, Filters,


Culture media

Recombinants

(animal-free)

Antibiotics

D-PBS

Ancillary materials


The quality of AMs is very important to ensure the stability,

safety, potency and consistency of CTPs as following;

The precise mechanism by which an AM exerts its effect may

not be known.

The impact of variations of the AM on the quality and safety

of the final product may not be understood.

AMs of human or animal origin may present an infectious

disease transmission risk.

Some AMs may elicit an immune reaction to the human.

Some AMs have toxic properties.

The risks attributed to the quality of AMs on the quality and

safety of CTPs are often increased due to the limited ability

to conduct extensive in-process and release tests.

Impact of AMs on Quality and Safety of CTPs


Whenever possible, it is preferable to use AMs that

are approved as drugs because they are well

characterized, have an established toxicological

profile, and are manufactured according to controlled

and documented procedures.

Conversely, the AM “for research use only” may not

satisfy the level of qualification necessary for use in

the production of a therapeutic product.

In either case, CTPs should be developed with

comprehensive and scientifically sound qualification

plans to ensure the traceability, consistency,

suitability, purity, and safety of the AM.

Qualification


USP’s risk-based approach

Tier Risk Properties of materials

1 Low highly qualified materials with intended use as

therapeutic drugs or biologics, medical devices, or

implantable materials (e.g. heparin for injection)

2 Low well-characterized materials with intended use as AMs,

produced in compliance with GMPs

3 Moderate materials not intended for use as AMs (frequently

produced for in vitro diagnostic use or reagent-grade

materials)

4 High High-risk materials(e.g., FBS, animal-derived(including

human) extracts, animal or human cells used as feeder

layers, chemical entities with known toxicities)

USP General Information

<1043> Ancillary Materials for Cell, Gene, and Tissue-Engineered Products


USP’s risk-based approach (continued)

F. Atouf et al, BioProcess International 11(8) 12-21, 2013


The source is to be clarified.

Efforts are to be made to reduce the risk of infection

for adventitious agents;

minimize their amounts used

explore alternative substances or sources (i.e., plant

or chemically synthesized).

ensure donor’s and donor animal’s health

The manufacturing process is to be evaluated on the

potentials to eliminate/inactivate adventitious agents

Records in manufacturing are to be kept to ensure

their traceability.

Human and Animal-Origin Raw Materials

(except Starting Materials)


Types of bovine serum

Origin(country, strain)

Vendor

Grade

Lot size available

Selection of Bovine Serum (as an example)


EMA

GL on the use of bovine serum in the manufacture of human

biological medicinal products(30 May 2013, EMA/CHMP/

BWP/457920/2012 rev.1)

US Pharmacopoeia

<1043> Ancillary Materials

<1024> Bovine Serum

<90> FBS Quality Attributes and Functionality Tests

Guidelines for Bovine Serum


• Culture media (composition)

• Recombinant growth factors, cytokines (animal-

free)

• Monoclonal antibodies for cell sorting/purification

• Antibiotics

Other Raw Materials


Selection of Raw Materials

Select the materials on a risk-based

approach based on own/existing knowledge

for the product, referring to literatures and

GLs, and then,

Provide the rationale for their selection and

the quality control to your competent

authorities, and consult with them.


• Culture dishes

• Columns

• Filters

• Bags

Manufacturing- Related Substances

• Leacheables / Extractables

• Foreign matter





related substances



Contents



Starting materials

Human and

animal-derived


of final products

FBS, Human Serum,

HSA, Feeder Cells,

Trypsin, Heparin

Tissues, Cells



Collagen matrix




Columns, Filters,


Culture media

Recombinants

(animal-free)

Antibiotics

D-PBS

Ancillary materials


1. In case of bio-absorbable materials, perform the

necessary tests for the safety of the degradation

products.

2. Evaluate the consequences of interactions between

non-cellular components and cells:

(a) any deleterious effects on the function, growth

activity, or stability of the cells

(b) any potential mutation, transformation, and/or

dedifferentiation of the cells

(c) no loss of the expected properties of the non-cellular

components

Points to Consider on Non-cellular Components


Quality of the materials is one of the critical

factors and should be determined on case-

by-case basis approach depending on the

characteristics of the product and its control

strategy as a whole.

Take-home Messages


As for starting materials;

Donor eligibility criteria are key elements;

infectious agents.

Reasons for selection of the cell/tissue should be

provided with its desired/ targeted cell profile.

The characteristics of their structure and

biological function should be shown.

Appropriate handling and processing is required.

Take-home Messages (continued)


As for other materials;

Adequacy of using other raw materials and

manufacturing-related substances should be

shown, and it is necessary to perform

appropriate quality control with defined

acceptance criteria.

Non-cellular components constituting the final

products should be justified in term of the

quality and the safety of CTPs. Appropriate/

sufficient information should be collected and

provided.

Take-home Messages (continued)


PMDA Pharmaceutical Affairs Consultation

on R&D Strategy

Clinical Use

Innovative

Products

Basic Research

Pharmaceuticals

and Medical

Devices

candidates

Non-

Clinical

Study

Quality

Study

Clinical

Trial

Consultation on quality or

toxicity study of biologics, or

cellular therapy products

Consultation on

endpoints or sample size

of early clinical trial

Strategic Consultation


Thank you

for your kind attention!

Date post:	01-Sep-2018
Category:	Documents
Upload:	hakien
View:	213 times
Download:	0 times

th IABS, PMDA and JST joint Symposium Scientific … · Categorization of Materials Used in...

Documents