Animal Serum - an unregulated commodity and …...•Animal serum is a Class I Medical Device 21 CFR...

2017 Presentation for USAHABiologics and Biotechnology Committee

October 17, 2017

Percy W. Hawkes, DVMRegulatory Affairs ConsultantBiowesthttps://www.biowest.net/

Animal Serum - an unregulated commodity and industry?

Data from mammalian cell culture impacts almost all parts of the life science industry

Large industries in life science are driven by data generated in cell culture experiments

Academia

Pharma/biotech

Ethics

In vitro diagnostic

Manufacturing

• Basis for new publications

• Text books

• Data mining for both basic and applied research

Publications

Data repositories

Small molecule-based

Peptide/protein based

Production optimization

Process innovation

• Target/drug discovery

• Drug development

• Clinical application/label information

• Cell line usage for production of biologics (antibodies and therapeutic peptides/proteins)

• Process development for upscaling and production

• Research use

• IOUs

• ASRs

• LDTs

• Companion diagnostic

• IVDMIAs

Who uses FBS?

• Vaccine manufacturers 45%

• Research 50%

• Diagnostic laboratories 5%

Questions arise concerning FBS

End users most affected by issues with FBS

•Small purchases •Research institutions•Universities•Diagnostic labs

Two categories of potential problems with FBS products

• Composition

• Origin

Types of problems that can occur

• Additional ingredients

• Other species

• Age of animal (e.g. FBS vs NBCS)

• Origin declared is not correct

• Irradiation doses different

• Dates incorrect

• COA tests results incorrect

• Samples not representative

• Imports circumventing customs clearance

• Problems with export / import documents

Processing of FBS – Flow Chart

Raw FBS Selection Thawing Pooling and Pre-filtration

Sterile Filtration

Packaging

Sampling for QC

Storage Final Labeling Freezing Labeling

Gamma Irradiation Delivery Distributor End User

Regulatory reform essential

Large price differences between raw FBS of different origins exists

US$75/liter

(non-USDA approved origins)

vs.

US$300 - 900/liter or more

(USDA-approved origins)

• Creates financial incentive to misrepresent origin

• Low risk of getting caught

• Virtually no risk of serious sanctions

Why great price differences of FBS from different origins

• Need to import serum

• Two widely divergent worldwide importation standards• USDA

• EC

• Price differences means industry has incentive to promote expensive origins

FBS exporting countries

Adventitious Viruses of concern Viruses of Importation Concern

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FINLAND + + + + + 2010 1994 2007 5 1959 - - - - + 1 6NORWAY + + + + + 2005 1992 2012 5 1952 - 2010 - - + 1 6SWEDEN + + + + + 2011 1995 1886 5 1966 - 2009 - - + 1 6

DENMARK + + + + + + 2005 1982 6 1983 - 2009 - - + 1 7NEW ZEALAND + + + + + + + - 7 - - - - - - 0 7

CHILE + + + + + + + + 8 1987 - - - - - 0 8URUGUAY + + + + + + + + 8 2001 - - - - - 0 8CANADA + + + + + + + + 8 1952 1949 + - - - 1 9

COLOMBIA + + + + + + + + 8 2009 + 2007 - - - 1 9HOLLAND + + + + + + + 2012 8 2001 - 2009 - - + 1 9

FRANCE + + + + + + + 2015 7 2001 - + - - + 2 9

PARAGUAY + + + + + + + + 8 2012 - + - - - 1 9

MEXICO + + + + + + + + 8 1954 + Unkwn - - - 2 10

AUSTRALIA + + + + + + + 1867 7 1871 - + + + - 3 10BRAZIL + + + + + + + + 8 2006 + + - - - 2 10

UNITED STATES + + + + + + + + 8 1929 + + - - - 2 10

Magnitude of problems?

No way to tell, but in our opinion:

• Prior to 2006 – ??????????????????

• Today - ????

• Absent regulatory reform, current problems difficult to quantify.

Effects of FBS problems on customers

Type of Institution impacted

• Research

• IVD Diagnostics

• Cell banks and others

• Vaccine development and production

• Pharmaceutical products

Possible Implications

• Research results – validity

• Diagnostic test results

• FDA product registrations

• Quality and side effects of pharmaceutical products –recalls

• Vaccine production – viral risks may be different

• Reproducibility

The “reproducibility crisis” is a real phenomenon

USDA APHIS

Center for Veterinary Biologics (CVB)

National Import Export Services (NIES)

FDA

CDRH (Center for Devices and Radiological Health)

CBER (Center for Biologics Evaluation and Research)

Agencies responsible for regulating animal serum

USDA APHIS Center for Veterinary Biologics (CVB)

• Virus-Serum-Toxin Act 21 USC 151-159 et. seq.

• Regulates Veterinary Biologics (9 CFR 101.2 and 101.3)

• Licensee is responsible for compliance of ingredients • sterility or testing of ingredients of animal origin ( 9 CFR 113.53)

USDA APHIS CVB

Ingredients of Veterinary Biologics

• § 113.50 Ingredients of biological products.

• All ingredients used in a licensed biological product shall meet accepted standards of purity and quality; . . . . . . .

• § 113.25 Culture media for detection of bacteria and fungi.

• (a) Ingredients for which standards are prescribed in the United States Pharmacopeia, or elsewhere in this part, shall conform to such standards. . . . .

USDA APHIS CVB

Labeling requirements for Biological Product

• § 112.1 (b) No person shall apply or affix to or include with, or cause to be applied or affixed to or included with, any carton or final container of a biological product, any label, stamp, mark or statement that is false or misleading in any particular, is not in compliance with the regulations, or is not approved by APHIS.

USDA APHIS CVB

Reporting ingredient-related issues for Veterinary Biologics

An adverse event:• Immuno-biological product - Illness or reaction• Disease diagnostic product - anything that hinders a correct diagnosis

Report first to Manufacturer, then to CVB

• On-line: Adverse Event Electronic Report Worksheets• By telephone: (800) 752-6255 (CVB)

•General phone number for CVB is 515-337-6100 (Ames, Iowa) Ask for Inspection and Compliance

USDA APHIS – National Import Export Services (NIES)

1998 Import Notice for Animal Serum (modified version)

Import permit required

Approved origins of FBS: North and Central America, Chile and Oceania

USDA Quarantine and Sheep inoculation safety test• Bluetongue virus

• Akabane virus

USDA APHIS – NIESEfforts to update animal serum import requirements

1994 - Proposed Rule published then withdrawn

(gamma irradiation 2.5 Mrads as importation option)

1998 Import Notice for Animal Serum (original version)

(included gamma irradiation 3.0 Mrads as option)

2004 – 2006 proposed rule prepared then never published

(was to include gamma irradiation)

2014 – 2017: risk assessment completed but . . . How to implement?

Confusion of USDA acronyms in labeling of FBS

• USDA Tested

• USDA Approved

• USDA Certified

• USDA FBS

• USDA Standard

• USDA

• USDA Premium

• USDA Grade

• USDA Origin

USDA APHIS - Investigative and Enforcement Services (IES)

Reporting issues with serum products• Contact APHIS' Investigative and

Enforcement Services (IES)

• APHIS HeadquartersUSDA, APHIS, IES4700 River Road, Unit 85Riverdale, MD 20737-1234(301) 851-2948FAX: (301) 734-4328

• Western RegionUSDA, APHIS, IES2150 Centre Ave.Building B-3W10Ft. Collins, CO 80526-8117(970) 494-7485FAX: (970) 494-7487

• Eastern RegionUSDA, APHIS, IES920 Main Campus DriveSuite 200Raleigh, NC 27606(919) 855-7080FAX: (919) 855-7090

FDA

• CDRH (Center for Devices and Radiological Health)

• CBER (Center for Biologics Evaluation and Research)

FDA authority to regulate animal serum

• Virus-Serum-Toxin Act 21 USC 151-159 et. seq.

• Food, Drug and Cosmetic Act -FD&C Act 21 USC Chapter 9

• Regulates Human Biologics (Section 351 of the Public Health Service (PHS) Act

• In vitro Diagnostic Products21 CFR 809.3 (a)

• Animal serum is a Class I Medical Device 21 CFR 864.2800

• Recognizes official compendium (USP) standards which includes labeling FD&C Act Section 501 (b) and (g) and PHS Act (42 USC 262)

• Sterility or testing of ingredients of animal origin ( 9 CFR 113.53)

Class I Medical Devices

• Exempt from the premarket notification procedures

• Simple in design• Have little to no potential risk

Examples of other Class I Medical Devices: • Tongue depressors• Elastic bandages• Hand held dental instruments• Examination gloves

General Controls include:• Adulteration FD&C Section 501• Misbranding FD&C Section 502• Registration and listing• Recall procedures• Good Manufacturing Practices FD&C

Section 520(f)

Number of FDA Establishment Registrations & Device Listings

(for product code KIS-animal serum)

17 companies registered and products listed

• 10 from USA

• 7 from 5 other countries

• Most companies are not registered nor their products listed as Medical Devices

Medical devices – Exempt from labeling regulations21 CFR 801

• § 801.116 - Medical devices having commonly known directions.

§ 801.119 - In vitro diagnostic products.

§ 801.122 - Medical devices for processing, repacking, or manufacturing.

§ 801.125 - Medical devices for use in teaching, law enforcement, research, and analysis.

• Label must bears the a statement such as:

"Caution: For manufacturing, processing, or repacking”

Investigational Device Exemptions21 CFR 812

Exempts a device from

• Misbranding

• Registration

• Listing

• Records and reports

• Good manufacturing practice

• A device intended solely for veterinary use.

• Labeled "CAUTION--Investigational device. Limited by Federal (or United States) law to investigational use."

FDA- CBER

Office of Compliance and Biologics Quality (OCBQ)

Office of Compliance and Biologics Quality

Center for Biologics Evaluation and Research

Food and Drug Administration

1093 New Hampshire Avenue

WO Building 71

Silver Spring, MD 20993

Labeling CBERAPLB@fda.hhs.gov

Biological Product Deviation Reporting (CBER)

(240) 402-9160bp_deviations@fda.hhs.govhctp_deviations@fda.hhs.gov

Consumer Affairs Branch (CBER)(800) 835-4709(240) 402-8010ocod@fda.hhs.gov

US Pharmacopeia Cell & Gene Therapies Standards

Chapters

• <1043> Ancillary Materials

• <1046> Cell and Tissue Based Products

• <1047> Gene Therapy Products

• <1027> Flow Cytometry

• <1024> Bovine Serum

• <90> FBS Quality Attributes and Functionality Tests

• <92> Cytokines and Growth Factors Quality Attributes

• Other Biologics and biotechnology related chapters

Monographs

• Monographs for Tissue-based products

• Monographs for Cell therapy products

Reference Standards

• Physical RS associated with AMs Chapters

• Photomicrographs associated with tissue products histology tests

• FBS

USP <1024> Bovine Serum

Labeling

• Finished product labels must contain the following information: product description, lot number, storage conditions, name and address of manufacturer, and a statement indicating the intended use. Materials intended for research purposes are exempt from labeling regulations (21 CFR 801). Typically, serum manufacturers supply a lot-specific Certificate of Analysis (COA) that is classified as part of the product’s labeling. See COA requirements in the following section.

Certification/Documentation

Certificate of Analysis

• The COA should provide information about a specific lot of serum, including tests performed and test results (according to the serum manufacturer’s specifications for release), as well as critical labeling identifiers such as lot number, catalog number, description of type of bovine serum, country of origin, and either or both dates of manufacture and expiration. This document is distinct from the certificate of health issued by the competent authority of the country of origin.

Certificate of Origin and Certification of Animal State of Health

• The Certificate of Origin establishes the country in which the bovine blood was collected and veterinary certification of the health of the animals pre- and post-collection (9 CFR 327.4).

USP <90> FBS Quality Attributes

Initial Ranges for FBS quality attributes based on data from suppliers, while trying to harmonize with the European Pharmacopeia

Published chapter <90>, quality attributes adjusted based on USP multi-lab study (USP Lab, 2 Contract Labs, 4 Industry Labs)

• Osmolality: 280-360 mOsm/Kg

• Total Protein: 30-45 mg/mL

• pH: 7.00 – 8.00

• Endotoxins: <10 Units/mL

• Hemoglobin levels <30 mg/dL

• Identification: Radial ImmunoDiffusion (RID): species ID, IgG levels

• Functionality Assays

• Growth Curve

• Clonal Assay

Alarming news for scientists How have problems affected research?

Example: suspected mislabeling of FBS origin European testing of imported FBS

• 2011 – Atypical Pestivirus contamination detected in Europe from 13 imported batches of FBS claimed to be from 4 different USDA approved origins, including the USA.

Source: Xia H, Vijayaraghavan B, Belak S, Liu L: 2011, Detection and identification of the atypical bovine pestiviruses in commercial foetal bovine serum batches. PLoS One 6:228553

Table 1. The batches of foetal bovine serum tested by real-time RT-PCR.

Xia H, Vijayaraghavan B, Belák S, Liu L (2011) Detection and Identification of the Atypical Bovine Pestiviruses in Commercial Foetal Bovine Serum Batches. PLOS ONE 6(12): e28553. https://doi.org/10.1371/journal.pone.0028553http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028553

Figure 1. Neighbor-Joining analysis of a 249-bp fragment of model. the 5′UTR sequences under Kimura 3-parameter

Xia H, Vijayaraghavan B, Belák S, Liu L (2011) Detection and Identification of the Atypical Bovine Pestiviruses in Commercial Foetal Bovine Serum Batches. PLOS ONE 6(12): e28553. https://doi.org/10.1371/journal.pone.0028553http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028553

New tools to help detect discrepancies

Age of animals

• IgG levels

• GGT levels (Gamma Glutamyl transferase)

Geographical Origin

• Trace Element and Stable Isotope testing (Oritain)

• Metabolite profiles-Metabolomics (MSX-metaSysX)

Conclusions

• FBS for many uses is exempt from standards

(research, in vitro diagnostics, teaching purposes)

• Problems with FBS can only be investigated by USDA and FDA, if it involves a human or a veterinary biological product.

Recommendation that USDA obtain authority to establish:

• Labeling standards for Fetal Bovine Serum products

• Penalties, recall responsibilities and fines