th iabs, pmda and jst joint symposium scientific … · categorization of materials used in...
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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
3Pharmaceuticals 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
4Pharmaceuticals and Medical Devices Agency
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
Manufacturing-Related Substances
Manufacturing-Related Substances
5Pharmaceuticals and Medical Devices Agency
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
6Pharmaceuticals and Medical Devices Agency
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
7Pharmaceuticals and Medical Devices Agency
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” ?
8Pharmaceuticals and Medical Devices Agency
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
Ancillary materials
9Pharmaceuticals and Medical Devices Agency
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
10Pharmaceuticals and Medical Devices Agency
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
11Pharmaceuticals 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
12Pharmaceuticals and Medical Devices Agency
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
13Pharmaceuticals and Medical Devices Agency
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
14Pharmaceuticals and Medical Devices Agency
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.
15Pharmaceuticals and Medical Devices Agency
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).
16Pharmaceuticals and Medical Devices Agency
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
17Pharmaceuticals and Medical Devices Agency
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.
18Pharmaceuticals and Medical Devices Agency
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
19Pharmaceuticals 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
20Pharmaceuticals and Medical Devices Agency
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
Ancillary materials
21Pharmaceuticals and Medical Devices Agency
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
22Pharmaceuticals and Medical Devices Agency
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
23Pharmaceuticals and Medical Devices Agency
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
24Pharmaceuticals and Medical Devices Agency
USP’s risk-based approach (continued)
F. Atouf et al, BioProcess International 11(8) 12-21, 2013
25Pharmaceuticals and Medical Devices Agency
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)
26Pharmaceuticals and Medical Devices Agency
Types of bovine serum
Origin(country, strain)
Vendor
Grade
Lot size available
Selection of Bovine Serum (as an example)
27Pharmaceuticals and Medical Devices Agency
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
28Pharmaceuticals and Medical Devices Agency
• Culture media (composition)
• Recombinant growth factors, cytokines (animal-
free)
• Monoclonal antibodies for cell sorting/purification
• Antibiotics
Other Raw Materials
29Pharmaceuticals and Medical Devices Agency
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.
30Pharmaceuticals and Medical Devices Agency
• Culture dishes
• Columns
• Filters
• Bags
Manufacturing- Related Substances
• Leacheables / Extractables
• Foreign matter
31Pharmaceuticals 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
32Pharmaceuticals and Medical Devices Agency
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
Ancillary materials
33Pharmaceuticals and Medical Devices Agency
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
34Pharmaceuticals and Medical Devices Agency
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
35Pharmaceuticals and Medical Devices Agency
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)
36Pharmaceuticals and Medical Devices Agency
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)
37Pharmaceuticals and Medical Devices Agency
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
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Strategic Consultation