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1Pharmaceuticals and Medical Devices Agency
PMDA Perspective on Specifications for Biotechnological Products
Yasuhiro Kishioka, Ph.D. Principal Reviewer
Office of Cellular and Tissue‐based Products Pharmaceuticals and Medical Devices Agency (PMDA)
The views and opinions expressed in this presentation are those of the presenter and should not necessarily represent the views and opinions of the PMDA.
WCBP 2016, January 26‐28, 2016, The Mayflower Hotel, Washington, DC, USA
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…this plenary session will explore through case studies the industry’s desire to move to a scientifically‐sound, patient‐centered and risk‐based approach to developing and defending specifications, with the goal of ensuring and maintaining the integrity of global supply.
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Outline
Introduction Frequently discussed points in the
application in Japan Future perspectives
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ICH Q6B Key principles described in ICH Q6B are still fundamental to set specification. Specifications are one part of a total control strategy designed to ensure
product quality and consistency.
Specifications are chosen to confirm the quality of the drug substance and drug product rather than to establish full characterization and should focus on those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product.
Acceptance criteria should be established and justified based on data obtained from lots used in preclinical and/or clinical studies, data from lots used for demonstration of manufacturing consistency and data from stability studies, and relevant development data.
...Etc.
Adopted in 1999 by ICH SC(published in Japan in 2001)
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Biotech. Products approved in Japan
No. of a
pproved biotechn
ological produ
cts
0
80
120
140
‐2000 ‐2015
Enzymes, 15
Coagulation factors, Albumin, 11
Hormones, 27
Vaccines, 5
Cytokines, 25
mAbs, Fusion proteins, 38
20
40
60
100
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Identity test System suitability for liquid chromatography Potency assay Regional testing
Frequently Discussed Points
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Q6B: The identity test(s) should be highly specific for the drug substance and should be based on unique aspects of its molecular structure and/or other specific properties.
What is PMDA’s recommendation on setting identity tests for biotech. products?
PMDA strongly recommends applicants should first consider a peptide map for the identity test for the drug substance of biotech. products, as it’s highly product‐specific in its own ability and suitable for confirming the stability of the primary structure of proteins in detail.
BioPharm International APRIL 2003: Using Peptide Maps as Identity and Purity Tests for Lot Release Testing of Recombinant Therapeutic Proteins“...a peptide map may not be needed as a lot release test as another or a combination of other analytical tests can suffice to appropriately establish product identity or purity.”
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What considerations should applicants make concerning the system suitability for liquid chromatography?
Japanese Pharmacopoeia (JP): (General Tests 2.01)“System suitability ... is used to ensure that the performance of the chromatographic systems used is as suitable for the analysis of the drug as was at the time when the verification of the test method was performed. System suitability testing should be carried out at every series of drug analysis. The test procedures and acceptance criteria of system suitability testing must be prescribed in the test method of drugs.In system suitability testing of the chromatographic systems, the evaluation of “System performance” and “System repeatability” is usually required. For quantitative purity tests, the evaluation of “Test for required detectability” may also be required.”
http://images.alfresco.advanstar.com/alfresco_images/pharma/2015/03/09/8c28a611-40f4-45d2-81e1-f1fb5582b749/fig6web.jpg
PMDA recommends applicants should follow the key principles described in JP. If applicants think of alternative ways, we encourage early communication and discussion.
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Examples of system suitability (1)Epoetin Alfa (Genetical Recombination) (JP16th Editon Suppl. I)
Purity (1) OligomersPerform the test with a volume of Epoetin Alfa (Genetical Recombination), equivalent to 50 mg of protein, as directed under Liquid Chromatography <2.01> according to the following conditions. Determine each peak area by the automatic integration method, and calculate their amounts by the area percentage method: the total amount of the peaks other than epoetin alfa is not more than 2%.
JP 16th Edition (in English)https://www.pmda.go.jp/english/rs‐sb‐std/standards‐development/jp/0005.html
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Examples of system suitability (2) Test for required detectability
To 1 volume of Epoetin Alfa (Genetical Recombination) (EA) add 49 volumes of the mobile phase, and use this solution as the solution for system suitability test. Confirm that the peak area of EA obtained with a volume, equivalent to 1 mg of protein, of the solution for system suitability test is equivalent to 1.5 to 2.5% of that obtained with the same volume of EA.
System performanceDissolve 40 mg of bovine serum albumin for gel filtration molecular mass marker and 20 mg of chymotrypsinogen for gel filtration molecular mass marker in 100 mL of the mobile phase. When the procedure is run with 50 mL of this solution under the above operating conditions, bovine serum albumin and chymotrypsinogen are eluted in this order with the resolution between these peaks being not less than 4.
System repeatabilityWhen the test is repeated 6 times with a volume of EA, equivalent to 50 mg of protein, under the above operating conditions, the relative standard deviation of the area of the principal peak of EA is not more than 2.0%.
The allowable limit is normally defined as the relative standard deviation (RSD) of the response of the test ingredient in replicate injections.
the range of expected response to the injection of a certain volume of target impurity solution at the concentration of its specification limit
the resolution and the order of elution(when appropriate) number of theoretical plates and symmetry factor
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What should applicants consider when setting potency assays for mAbs (and Fc‐fusion proteins)?
Potency assays should reflect the clinical mechanism of action in indications for use.
PMDA generally requests bioassays (e.g. cell‐based assays) be used as potency assay as they ensure the biological activity of the product regardless of unexpected changes.
If applicants (should) propose binding assays as potency assays, many factors should be considered, including: Relationships between the results of bioassays and the results of
binding assay/ other physicochemical assays (lot release, stability) Involvement of effector functions Extensive characterization and
manufacturing experience http://www.genengnews.com/Media/images/Article/Thermo_LC167311Edgeplate6024314183.jpg
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Do the final release tests of biotech./biological products have to be performed in Japan?
In principle, all final release tests of biotech./biological products must be performed in Japan.
If the results of release tests are certified in MOU countries (Germany, Sweden, Switzerland, Australia), only appearance and identity test are required to be performed in Japan.
PMDA recommends applicants should plan a technology transfer of test methods (specifically, potency assays) from the early stage of development.
http://www.benchfly.com/blog/wp‐content/uploads/2009/08/Tech‐transfer.jpg
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Future perspectives
Product Lifecycle Management
Standard program(Traditional approach)
Know
ledge
Product LifecycleApprovalApproval
Standard program(QbD approach)
?
Residual Risk
Control Strategy
Post‐Approval
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Thank you for your attention!
kishioka‐[email protected] and Medical Devices AgencyOffice of Cellular and Tissue‐based Products
Yasuhiro Kishioka, PhD.
Acknowledgements• Colleagues in the Office of Cellular and Tissue‐based Products