cmc analytical requirements and challenges in...
TRANSCRIPT
Nadine M. Ritter, Ph.D.
President and Analytical Advisor [email protected]
www.GlobalBiotechExperts.com
CMC ANALYTICAL REQUIREMENTS AND CHALLENGES
IN THE DEVELOPMENT OF BIOSIMILAR PRODUCTS:
THE “RHINO” PARADIGM
Why do biotechnology products have different CMC regulations versus traditional chemical products for
comparability, specifications, and shelf life determination?
© 2015 N. Ritter, Ph.D.
Biological/Biotechnological vs. Chemical Pharmaceutical Products
Raw Materials Production Processes Handling Conditions Physiochemical Characteristics Formulations Methods of Analysis Reference Standards
Stability Profile C/C Interactions
Specifications
Storage Conditions Expiration Dating
Significantly Different:
© 2015 N. Ritter, Ph.D.
“GENERIC” CHEMICALS
“SIMILAR” BIOLOGICALS
Due to the complexity of biological/biotechnology-derived products, the generic approach is scientifically not appropriate for these products. The “similar biological medicinal products” approach, based on a comparability exercise, will then have to be followed. CHMP/437/04 Guideline on Similar Biological Medicinal Products Oct 2005
© 2015 N. Ritter, Ph.D.
Parenteral Delivery: FIRST Concern is SAFETY
Biotechnology Products and Biosimilars Injection or Infusion of Therapeutics
(Inhalation of some Vaccines)
Must be sterile – contaminants will be directly introduced to body
Cannot put in autoclave (denatures protein) – must use aseptic processes (low bioburden) and sterile filters (sterile, low endotoxins)
Protein impurities (eg HCPs) can trigger immunogenicity reactions
Degradants (eg aggregates) can trigger immunogenicity reactions
Leachables can trigger immunogenicity reactions
Must clear or inactivate adventious agents from cell culture (infectious)
© 2015 N. Ritter, Ph.D.
CHEMICALS VS BIOLOGICALS
= DIFFERENT ANIMALS!
Statin MW 405
DRUG
IgG MW 150,000
BIOLOGIC
© 2015 N. Ritter, Ph.D.
What CMC characterization, comparability, release specification and stability data packages are required for a biotechnology-based product
throughout product development and at time of commercial approval?
© 2015 N. Ritter, Ph.D.
Typical CMC (Chemistry, Manufacturing, and Controls) Data Packages for Pharmaceutics
1. Product physiochemical profile (compositional and structural analysis)
2. Reference material characterization (establish product gold standard)
3. Test method qualification (linearity, precision, accuracy, specificity)
4. Test method validation (robustness, stability-indicating capability)
5. Lot release testing (manufacturing consistency and product quality)
6. Formulation screening (excipient selection, formulation stability)
7. Degradation evaluation (forced degradation to assess product, methods)
8. Stability testing (accelerated and ongoing real-time/real condition)
9. Extractable/Leachable studies (DP C/C; possibly DS and process)
10. Comparability assessment (pre and post approval process/product changes)
11. Similarity– Biosimilar products (comparisons to reference biotech drug)
© 2015 N. Ritter, Ph.D.
Primary
http://psychology.wikia.com/wiki/Amino_acids
Secondary
Cozzone, A. J. Proteins: fundamental chemical
properties. in Enc.of Life Sciences (Nature Publ
Group, London, 2001)
Tertiary
Protein Tertiary Structure Prediction;
D Xu, Y Xu; in Current Protocols in
Protein Science (May, 2001)
P. Rudd, et. al; J. Immunology, 2004, 173: 6831-6840
Quaternary Linda Stannard, Dept of Medical Microbiology, U of Cape Town
Complex Structure
Protein Biomolecular Analysis
© 2015 N. Ritter, Ph.D.
Albrecht Dürer, “Rhinoceros” (1514)
© 2015 N. Ritter, Ph.D.
Blinded Single-Feature Elephant Analysis
“All of you are right. The reason every one of you is concluding something different is because each of you touched only ONE UNIQUE PART of the elephant.
Actually the whole elephant comprises ALL OF THE FEATURES that were detected, plus many that you DIDN’T touch.”
© 2015 N. Ritter, Ph.D.
What unique analytical similarity study is required for biosimilar products, and what are the technical challenges?
© 2015 N. Ritter, Ph.D.
Biotech Products Comparability Guiding Principles: Nature of the Process Change
The more upstream of the manufacturing process the change is made, the greater the potential for impact of the change, and the greater the body of data required to demonstrate comparability For each step in manufacturing that is changed, all claims made for that step (eg removal of a specific impurity) must be confirmed Biosimilar products present the ultimate process change: An entirely new expression system, with limited ability for direct analytical comparability to the original process
© 2015 N. Ritter, Ph.D.
Similarity of Your Product to Their Product
Consistency of Your Process and Product
For Biosimilar Products, TWO Types of Analytical Comparison Studies are Required
Batch 1 Batch 2 Batch 3 Batch 4 Batch 5
Your Product Their Product
© 2015 N. Ritter, Ph.D.
Demonstrate no clinically meaningful differences in safety, purity and potency between products
Biosimilar Product Similarity Requirements
Comparison studies designed in tiered strategy: 1. Analytical data 2. Animal testing 3. One or more clinical studies, unless the
regulatory body deems this not necessary
© 2015 N. Ritter, Ph.D.
Reference
Product
Biosimilar
Product
How is Analytical SIMILARITY affected by Process CONSISTENCY?
YOUR
PROCESS
VARIABILITY
From
Lots A, B, C
THEIR
PROCESS
VARIABILITY
From
Lots X, Y, Z?
© 2015 N. Ritter, Ph.D.
How many lots of each can you get at the same time for the analytical studies?
Comparability of the API (ICHQ6B: Product-Related Substances)
Highly abundant biomolecular species can be characterized with multiple physiochemical and functional analytical methods
© 2015 N. Ritter, Ph.D.
Reference Biotech Product (RBP) Similar Biotech Product (SBP)
What if you see differences in API Product-Related Substances?
It is not the method, it is the PROCESS… So check your clones before committing to one!
© 2015 N. Ritter, Ph.D.
Reference Biotech Product (RBP) Similar Biotech Product (SBP)
Must also characterize all “Minor” Species
Some of these seemingly ‘minor’ species may be at or below LOD of our analytical methods
These species may not be below LOD of the human body We have a very sensitive immune system with a long memory
© 2015 N. Ritter, Ph.D.
BUT!
RBP
SBP
???
What is Your True Process Variability?
© 2015 N. Ritter, Ph.D.
Fewer lots are usually made during biosimilar product
development than originator product development
You only have access to Rx forms of the reference biotech product, which are formulated and filled DP lots of various ages, with unknown ages and unknown numbers of the DS batches used in the production of each DP batch.
Biosimilar Comparability: Your DS to Their DP?
© 2015 N. Ritter, Ph.D.
SBP
DS
RBP
DS
RBP
DP
RBP
DP
RBP
DP
RBP
DS
RBP
DP
RBP
DS
RBP
DS
How does all of this put significant pressure on the CMC work required for biosimilar products vs originator
biotech products?
© 2015 N. Ritter, Ph.D.
You have to do EVERYTHING that the originator did….
Non-clinical
Quality (CMC)
Clinical
Quality (CMC)
Commercial
Quality (CMC)
Requirements for Originators
MODULE 3: QUALITY 3.2.S. DRUG SUBSTANCE S.1 General Information S.2 Manufacture S.3 Characterization S.4 Control of Drug Substance S.5 Reference Standards or Materials S.6 Container Closure System S.7 Stability 3.2.P. DRUG PRODUCT P.1 Description and Composition P.2 Pharmaceutical Development P.3 Manufacture P.4 Control of Excipients P.5 Control of Drug Product P.6 Reference Standard or Materials P.7 Container Closure System P.8. Stability 3.2.A Appendices A.1. Facilities and Equipment A.2. Adventitious Agent Safety Evaluation A.3 Novel Excipients 3.2.R. Regional Information
© 2015 N. Ritter, Ph.D.
PLUS the analytical similarity studies…in much less time!
Non-clinical Clinical Commercial Region
A
Non-clinical Clinical Commercial Region
B
Non-clinical Clinical Commercial Region
C
Quality (CMC) Quality (CMC) Quality (CMC) All
Regions
RBP RBP RBP* All
Regions
?
© 2015 N. Ritter, Ph.D.
(*Interchangeable status of commercial SBP might require continuing comparative link to RBP)
So you literally can’t afford to make CMC mistakes – you have do the
right things at the right times to meet the expected timelines
PLUS Biosimilars must FRONT LOAD THE ANALYTICS
© 2015 N. Ritter, Ph.D.
So you have to start highly complex analytical structural and functional
characterization studies MUCH EARLIER than originators
Quality (CMC) Quality (CMC) RBP Quality (CMC)
Quality (CMC)
RBP
Quality (CMC)
SBP
RBP
Quality (CMC)
Phase 1 Clinical Commercial Pre-Clinical
QUALIFY METHODS (RE)QUALIFY METHODS (RE)QUALIFY METHODS (RE)QUALIFY METHODS
QUALIFY METHODS*
INITIAL PRODUCT CHARACTERIZATION
1ST REFERENCE STD CHARACTERIZATION
NEW REFERENCE LOT CERTIFICATION
COMM CHANGE COMPARABILITY
CLIN-COMM COMPARABILITY
CLIN-CLIN COMPARABILITY
PRELIMINARY FORMULATION TOX LOTS
STABILITY – DP CLIN LOTS STABILITY – DP CLIN LOTS STABILITY – DP CLIN LOTS STABILITY - DP 1 ANNUAL LOT
LOT RELEASE – DS CLIN LOTS
LOT RELEASE - DS CLIN LOTS
LOT RELEASE – DS CLIN LOTS
LOT RELEASE - DS COMM LOTS
STABILITY -DS TOX LOTS STABILITY – DS CLIN LOTS STABILITY – DS CLIN LOTS STABILITY – DS CLIN LOTS STABILITY – DS 1 ANNUAL LOT
NEW REFERENCE LOT CERTIFICATION
NEW REFERENCE LOT QUALIFICATION
VALIDATE METHODS (RE) QUALIFY METHODS RE-VALIDATE METHODS
FORMULATION SCREENING STUDY
STABILITY- DP TOX LOTS
FORMULATION SELECTION STUDY
*VALIDATE QC SAFETY METHODS
TOX - CLIN COMPARABILITY
SELECT QC RELEASE DS and DP METHODS*
EXT & LEACH STUDY
FORM or C/C CHANGE RE-DO E&L
SELECT CHAR-COMP DS and DP METHODS
© 2015 N. Ritter, Ph.D.
Phase 2 Clinical Phase 3 Clinical
QUALIFY METHODS* VALIDATE METHODS FORCED DEG STUDY RE-VALIDATE METHODS SELECT QC STABILITY
DS and DP METHODS*
LOT RELEASE – DS TOX LOTS
LOT RELEASE – DPCLIN LOTS
LOT RELEASE - DPCLIN LOTS
LOT RELEASE – DPS CLIN LOTS
LOT RELEASE - DP COMM LOTS
LOT RELEASE – DPTOX LOTS
Initial Clinical Commercial Pre-Clinical
QUALIFY METHODS (RE)QUALIFY METHODS (RE)QUALIFY METHODS (RE)QUALIFY METHODS
QUALIFY METHODS*
INITIAL PRODUCT CHARACTERIZATION
1ST REFERENCE STD CHARACTERIZATION
NEW REFERENCE LOT CERTIFICATION
COMM CHANGE COMPARABILITY
CLIN-COMM COMPARABILITY
CLIN-CLIN COMPARABILITY
PRELIMINARY FORMULATION TOX LOTS
STABILITY – DP CLIN LOTS STABILITY – DP CLIN LOTS STABILITY – DP CLIN LOTS STABILITY - DP 1 ANNUAL LOT
LOT RELEASE – DS CLIN LOTS
LOT RELEASE - DS CLIN LOTS
LOT RELEASE – DS CLIN LOTS
LOT RELEASE - DS COMM LOTS
STABILITY -DS TOX LOTS STABILITY – DS CLIN LOTS STABILITY – DS CLIN LOTS STABILITY – DS CLIN LOTS STABILITY – DS 1 ANNUAL LOT
NEW REFERENCE LOT CERTIFICATION
NEW REFERENCE LOT QUALIFICATION
VALIDATE METHODS (RE) QUALIFY METHODS RE-VALIDATE METHODS
FORMULATION SCREENING STUDY
STABILITY- DP TOX LOTS
FORMULATION SELECTION STUDY
*VALIDATE QC SAFETY METHODS
TOX - CLIN COMPARABILITY
SELECT QC RELEASE DS and DP METHODS*
EXT & LEACH STUDY
FORM or C/C CHANGE RE-DO E&L
SELECT CHAR-COMP DS and DP METHODS
© 2015 N. Ritter, Ph.D.
Additional Clinical
QUALIFY METHODS* VALIDATE METHODS FORCED DEG STUDY RE-VALIDATE METHODS SELECT QC STABILITY
DS and DP METHODS*
LOT RELEASE – DS TOX LOTS
LOT RELEASE – DPCLIN LOTS
LOT RELEASE - DPCLIN LOTS
LOT RELEASE – DPS CLIN LOTS
LOT RELEASE - DP COMM LOTS
LOT RELEASE – DPTOX LOTS
ANALYTICAL SIMILARITY ORIGINATOR RBP
???
ANALYTICAL SIMILARITY ORIGINATOR RBP
INTERCHANGEABLE SIMILARITY?
Biosimilar CMC Activities
are now the Critical Path!
“We can have a biosimilar product on the market in half the time with half the resources!”
© 2015 N. Ritter, Ph.D.
Executive Rhinos…
Who will succeed (has succeeded) in developing and commercializing
biosimilar products?
© 2015 N. Ritter, Ph.D.
Those biosimilar groups who will succeed will:
• Know* all of the inter-related, international requirements for biotechnology CMC, including
Module 3 “Quality” of the ICH Common Technical Documents
© 2015 N. Ritter, Ph.D.
* Or find someone who does ** Or find someone who can *** Or find someone who knows
• Know* how and when to do each of the critical CMC process and analytical studies needed for all
biotechnology-based products, plus the unique ones needed for biosimilar products
• Implement** current as well as proven technologies for process and analytical
sciences for maximum utility and reliability
• Know* where platform technologies are appropriate, and where customized approaches are
necessary in biotechnology processes or test methods
• Design** project strategies to seamlessly integrate all data collected in each CMC study,
and leverage each for future studies (but don’t get locked into the past…)
• Learn *** from the mistakes of others and adopt the ‘best practices’ seen in the global biotech
industry
• Participate in professional meetings and conferences, read guidance documents and
industry white papers, to remain up-to-date on emerging expectations and challenges for all
biotech products
Success Isn’t LUCK – It’s INFORMED PLANNING