CMC ANALYTICAL REQUIREMENTS AND CHALLENGES IN...

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:


“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


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)


CHEMICALS VS BIOLOGICALS

= DIFFERENT ANIMALS!

Statin MW 405

DRUG

IgG MW 150,000

BIOLOGIC


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?


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)


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


http://www.jimmunol.org/content/173/11/6831/F1.large.jpg

http://www.uct.ac.za/depts/mmi/stannard/emimages.html

Albrecht Dürer, “Rhinoceros” (1514)


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.”


What unique analytical similarity study is required for biosimilar products, and what are the technical challenges?


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


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


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


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?


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


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!


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


BUT!

RBP

SBP

???

What is Your True Process Variability?


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?


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?


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


PLUS the analytical similarity studies…in much less time!

Non-clinical Clinical Commercial Region

A


B


C

Quality (CMC) Quality (CMC) Quality (CMC) All

Regions

RBP RBP RBP* All

Regions

?


(*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


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 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 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


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


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 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 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


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!”


Executive Rhinos…

Who will succeed (has succeeded) in developing and commercializing

biosimilar products?


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


* 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

CMC ANALYTICAL REQUIREMENTS AND CHALLENGES IN...

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