Quality Standards for Medicines, Supplements, and Food Ingredients throughout the World

USP Standards for Ancillary Materials

Fouad Atouf, Ph.D. Scientist, Biologics and Biotechnology

8th Annual Somatic Cell Therapy SymposiumSeptember 22-24 2008

USP Mission

. . . To improve the health of people around the world through public standards and related programs that help ensure the quality and safety of medicines and foods.

Roger L. Williams, M.D.EVP-CEO

An 1820 USP Monograph

United States Pharmacopeia (USP)

• Independent Standard Setting Organization• Established in 1820 by Medical Community• Recipes for Pharmacist• Permanent Legal Recognition in late 1800’s

– via State Laws• Permanent National Recognition in 1906

– via Pure Food and Drugs Act• Food, Drug and Cosmetic Act in 1938

– Created FDA & Mandated Enforcement of USP

Official Recognition

• The U.S. Federal Food, Drug, and Cosmetics Act designates the USP–NF as the official compendia for drugs marketed in the United States. A drug product in the U.S. market must conform to the standards in USP–NF to avoid possible charges of adulteration and misbranding.

Documentary vs. Physical Standards

Documentary Standards Physical

Reference Standards

Documentary Standards: Monographs vs. General Chapters

• Monographs– Products-specific– Requirements for the product to meet

• General Chapters with number <1000– Enforceable by FDA or other regulatory authority– Test methods chapters– Methods referenced in product monographs

• General Chapters with number >1000– Interpretive and intended to be informational – Used as a guidance

Documentary StandardsDevelopment.

Initiated by Industry, Regulators, USP Staff and

Expert Committees

Approval by-- Council of Experts-- Board of Trustees

Monograph Becomes official andPublished in USP-NF

Review by USP Staff liaison

Publication in PF

Public Comments

90 days

Reprinting in PF

USP Expert Committee Review

Approval

Review by Expert Committee

Standards Setting Approach:A Collaborative Process

• USP Develop Standards for– Drugs– Biologics

• Blood and Blood products• Cell, Gene, and Tissue Therapies• Proteins and Polysaccharides• Vaccines

– Excipients– Dietary supplements– Food and Food ingredients

Biologics and Biotechnology at USP

USP CGT EC Members and USP staff

Members• William E. Tente, M.S., Chair• Darin J. Weber, Ph.D., Vice-Chair

• Scott R. Burger, M.D. • Nancy H. Collins, Ph.D. • Maria A. Croyle, Ph.D. • Gary C. du Moulin, Ph.D. • Joseph F. Gallelli, Ph.D. • Beth M. Hutchins, Ph.D. • Deepak Jain, Ph.D. • Ann A. Jakubowski, M.D., Ph.D. • Nicole C. Provost, Ph.D. • Elizabeth J. Read, M.D. • Anthony A.G. Ridgway, Ph.D.

USP Staff• Fouad Atouf, Ph.D. • Tina Morris, Ph.D.

Biologics and Biotechnology (B&B) Standards at USP

B&B ProductsCell, Gene and Tissue Therapies

Equipment

ProcessMaterials Selection

Devices

Operator/Technologist

Environment/Clean Rooms

Ancillary Materials

Raw Materials

Procurement/Source Material

Ancillary Materials (AMs)

• Biological and Biochemical substances that are used to manufacture cell therapy, gene therapy or tissue-engineered products or therapeutics derived from cell culture (i.e. vaccines, proteins) but are not intended to be in final product.

• Include raw materials, processing and purification aids or agents used during manufacture.

• Ancillary Material requirements are intended to help standardizethese items.– Protein A – Fetal Bovine Serum– Trypsin– DNA Nuclease– Transferrin– Interleukin-4

Ancillary Materials Standards: Development Strategy

<1043> Ancillary Materials for Cell-, Gene-, and Tissue-Engineered

Products

Ancillary Material Requirements- Specific

Products

Ancillary Material Reference Standards

Official Chapter

Under Development

<1043> Ancillary Materials - Official Chapter

• Quality of ancillary material can affect stability, safety, potency and purity of medicinal products

• Validation of manufacturing processes to ensure removal of ancillary materials from final products

• Residual testing is important as residual ancillary material may trigger immune reaction

• Development of qualification programs for AMs used in cell manufacturing

• Risk-based classification of AMs

• Identification• Selection• Suitability of use• Characterization• Vendor qualification• QA/QC data

<1043> Ancillary Materials –Qualification Programs

Qualification Programs (Cont’d)

• Identification– Source material– Concentration of use – Tests for identification– Manufacturing steps

• Selection– Early phase of development– Microbiological – BSE/TSE risk assessment

Qualification Programs (Cont’d)

• Suitability of use– Evaluate the risk associated with transmission of

diseases, when using human or animal-derived AMs– Material traceability – Risk can be reduced by using a quantitative or semi-

quantitative risk-assessment tool (e.g. FMEA)

• Characterization– Level of testing is based on the risk assessment profile– Specifications to be established for each AM used in

manufacturing, to ensure quality of the product– Acceptance criteria should be based on pre-clinical

studies and early clinical studies

• Vendor qualification– Vendor should be qualified early during development– Audit of vendors should include their GMP and testing

program for AM– Vendors should be familiar with principles of validation

• QA/QC data– Qualification program need to comply with cGMPs and

should be monitored by QA/QC unit– QA/QC data to include: Inspection and release of AM prior to

use in manufacturing, vendor auditing, certificate of analysis, stability testing

Qualification Programs (Cont’d)

Risk-based Classification of Ancillary Materials (AMs)

• USP chapter <1043> lists four(4) risk-based categories, with examples for each category

• The tables are provided only as a guide• Other criteria for risk assessment are the amount and

stage of use during manufacturing as part of a risk assessment strategy (not addressed in the tables of chapter <1043>)

Risk-based Classification of Ancillary Materials (AMs)

Four categories of ancillary materials:

Tier 1 – Low-Risk, Highly Qualified Materials with Intended Use as Therapeutic Drug or Biologic, Medical Device, or Implantable Material

Tier 2 – Low-Risk, Well Characterized Materials with Intended Use as AMs, Produced in Compliance with GMPs

Tier 3 – Moderate-Risk Materials Not Intended for Use as AMs (frequently produced for in vitro diagnostic use or reagent grade materials)

Tier 4 – High-Risk Materials, Materials not Produced in Compliance with cGMPs and materials not intended to be used in cell manufacturing

Ancillary Materials –Current Chapters

• Requirements for specific ancillary material products will be included in chapters– <130> Protein A Quality Attributes (official)– <1024> Bovine Serum (PF)– <90> Fetal Bovine Serum- Quality Attributes (Draft)– <92> Cytokines & Growth Factors, in cell manufacturing (Draft)

• These Chapters can specify reference standards that to demonstrate compliance to compendial tests

• Reference standards may also be qualified for use as markers and calibration standards for residual testing

• The qualification programs described in <1043>, and the risk-based categories are provided as a guide

• Qualification programs need to be developed on case by case basis for a specific material to be used in a specific application

• Specifications and acceptance criteria should be established foreach AM used in manufacturing, to ensure quality of the product

• Reference materials associated with chapters and monographs can be used to demonstrate compliance with the requirements

• The USP Cell, Gene, and Tissue Therapies Expert Committee is considering a revision of chapter <1043>

• Your feedback is appreciated (send comments to fa@usp.org)

Conclusions

Quality Standards for Medicines, Supplements, and Food Ingredients throughout the World