# Presentation: 806274

## Presentation to Public WorkshopSeptember 14, 2004Scientific Considerations Related to Developing Follow-On Protein Products

***Walter W. Hauck, Ph.D.******Statistical Consultant, USP***
***Professor, Thomas Jefferson University ***

## Topics

**USP and Biologic Products**
**USP Resolution 2 - 2000 Quinquennium**
**What USP Is Doing on Resolution 2**
**Process**
**Science**
**USP Standards Setting Activities**

## USP and Biologic Products

- Official monographs in USP:   		121
- Proposed monographs in PF:    		  28
- Monographs in development:   		  20
- r-DNA products approved by FDA: 	  90
- 	USP monographs: 				  11                              EP monographs:   				    9

## General Information Chapters For Biotechnology Products

*Water for Pharmaceutical Purposes *<1231>
*Microbiological Attributes of Nonsterile Pharmaceutical Products *<1111>
*Sterility and Sterility Assurance of Compendial Articles* <1211>
*Harmonized Biotechnology - Derived Articles - Tests* <1047>
- Amino Acid Analysis
- Capillary Electrophoresis
- Isoelectric Focusing
- Peptide Mapping
- Polyacrylamide Gel Electrophoresis          Protein Determination

## General Information Chapters For Biotechnology Products

*Cell and Gene Therapy Products* <1046>
*Validation of Biological /Biotechnological  Manufacturing Processes* (to come)
*Ancillary Products* (to come)                     Products  involved in the manufacture of biologicals/biotechnological products that are not part of the final product, e.g., antibiotics, antibodies, cell culture reagents, cytokines, growth factors, solvents
*Reference standards*Ingredients/products,* *procedures and ancillary products, reagents, other

## General Information Chapters For Biotechnology Products

- Biotechnology-derived products
*Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin* (ICH Q5A)
*Quality of Biotechnological Products - Analysis of Expression Construct in Cells Used for Production of r-DNA Derived Protein Products* (ICH Q5B)
*Quality of Biotechnological Products - Stability Testing of Biotechnological/ Biological products* (ICH Q5C)

## <111> Design and Analysis of Biological Assays

- Undergoing complete rewrite
- Writing committee includes representatives from academia, industry, FDA
- Will bring <111> from 1960’s to present in terms of statistical methods and types of assays

## Resolution 2—2000 USP Convention

*Explore the Feasibility and Advisability of Developing Guidance on Principles and Approaches to Assure Equivalence of Complex Active Ingredients (Including Botanicals and Dietary Supplements), Recognizing the Special Issues Associated With Agents of Biologic/Biotechnological Origin  Including Their Regulatory Control. Initiatives Should Be Undertaken in Collaboration With Appropriate Partners*

## USP Process for Resolution 2

- December 2002		Expert Panel Formed
- Ingredient/Product Experts
- Test Experts
- January 2003		First Meeting
- March 2003		Second Meeting
- April - October 2003	Further Meetings
- November 2003	USP Conference
- Outcomes
- Proceedings
- Publication of Expert Panel Deliberations

## ‘Difference’ and ‘Sameness’ Questions

- Standard statistical approaches for _safety and efficacy questions_ usually test the null hypothesis of no difference versus an alternative hypothesis of difference.
- Standard statistical approach for _equivalence questions_ usually test the null hypothesis of  inequivalence versus the alternative hypothesis of equivalence, which is defined by a specified equivalence criterion and limits.
- Need to identify tests that are the basis for assessing similarity and equivalence criteria for each; i.e., how similar is ‘sufficiently similar’

## Potential Tests to Address Equivalence

- Physicochemical
- Bioassays
- Non-clinical studies
- Pharmacology
- Toxicology
- Immunology
- Clinical studies
- Pharmacokinetics
- Pharmacodynamics
- Clinical safety and efficacy (immunogenicity)
- Surveillance

## Official USP Reference Standards

- Characterization
- Collaborative Testing for Content
- Label for Content:  Ingredients and Impurities (no longer 100%)
- For Complex Actives:  1) many laboratories; 2) perhaps different assays; 3) biologic potency.
- To assure stability in the biological drug substance over time for both the pioneer and the follow-on manufacturer