GMP Capabilities - Facilities, Quality, & Regulatory

We maintain a completely animal-free environment; no animal-containing materials are permitted inside the facility or in contact with the laboratory equipment. The facilities are constructed to ensure there is no exposure of the product to contamination by animal-containing components, and there is clear segregation of all labware such as plasticware, tubing, gloves, pipette tips, and instruments. Our animal-free proteins share the same biological activities as those produced for our standard research grade, easing the process of transition between protein formats.

• Animal-free Certificates of Origin from raw material suppliers.
• All raw materials are traceable through batch records
• Fermentation and purification processes follow approved SOPs
• Validated equipment cleaning procedures
• Dedicated animal-free fermenters
• Bacteria are grown in animal-free media
• Dedicated product-specific, animal-free columns
• Column cleaning validated for animal-free manufacturing
• Proteins filtered using certified animal-free filters
• Animal-free labware
• Animal-free containers and dedicated cold storage room
• Classified vialing clean room and dedicated animal-free lyophilizer
• Animal-free vials, stoppers, and crimp caps 

We have recently invested even more in the future of cell and gene therapy, because we are committed to supporting the increasing demand for GMP-grade ancillary proteins.

Our new facility with approximately 61,000 square feet is dedicated to supporting large-scale production of GMP-grade materials including E. coli-derived recombinant proteins. Multiple fermenters and purification suites allow us to manufacture the large quantities of GMP proteins required in cell and gene therapy manufacturing processes.

Learn More About Our New GMP Manufacturing Facility.

Our headquarters facility, home to R&D Systems, hosts a comprehensive team of expert scientists and proudly manufactures R&D Systems™ GMP recombinant proteins, GMP antibodies, GMP cell culture products, and custom GMP projects.

Certifications

• R&D Systems ISO 13485 Certificate
• R&D Systems ISO 9001 Certificate
• R&D Systems ISO 14001 Certificate
• R&D Systems MDSAP Certificate
• R&D Systems is a registered Medical Device Establishment under the U.S. Food, Drug, and Cosmetic Act, registration number 2182501, and is routinely inspected by the FDA.

Regulatory Guidelines Followed and Applicable Standards Followed 

• Quality System Regulations for Medical Devices
• Code of Federal Regulations (21 CFR 820)
• USP Chapter <1043>, Ancillary Materials for Cell, Gene, and Tissue-Engineered Products
• Applicable sections of the World Health Organization Good Manufacturing Practices for Biological Products: TRS, No 822, 1992 Annex 1
• Ph. Eur. General Chapter 5.2.12, Raw Materials of Biological Origin for the Production of Cell-based and Gene Therapy Medicinal Products
• The In Vitro Diagnostic Directive 98/79/EC
• The Canadian Medical Device Regulation

Standard Testing for GMP Proteins Includes

• Mass spectrometry
• HPLC
• SDS-PAGE
• N-terminal sequencing for first 10 amino acids
• Mycoplasma
• Endotoxin
• Purity
• Host cell protein and DNA
• Bioburden/sterility in accordance with USP 71
• Validated activity
• Formal stability testing program over product shelf-life

Additional On-site Capabilities for Enhanced QC Testing

• High resolution mass spectrometry: Intact mass, post-translational modifications, protein identification
• Gel permeation chromatography/size exclusion chromatography (GPC/SEC): Aggregation assessment
• Reverse phase HPLC: Purity assessment can reveal truncations, mixed disulfide patterns, and more
• Light scattering analysis (SLS, DLS): Aggregation, oligomer analysis, and molecular weight determination when used in tandem with analytical sizing aggregation, oligomer analysis, and molecular weight determination
• Advanced HPLC testing: Homogeneity
• Surface plasmon resonance: Binding kinetics
• Differential scanning fluorimetry (DSF): Protein stability and protein-ligand interactions
• Cell bank and viral testing 

Our Bristol facility manufactures GMP-grade small molecules and guarantees batch-to-batch consistency, consistency of supply, traceability from starting materials to final product, and animal-free production. We also provide R&S Systems Quality and Regulatory Support.

Regulatory Guidelines Followed

• Relevant sections of ICH Q7 guidelines (Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients)
• USP Chapter <1043> Ancillary Materials for Cell, Gene, and Tissue-Engineered Products

Tocris Bioscience – ISO Certification.

QC Testing Available

• Purity
• Product Identification
• Water Content
• Residue on Ignition
• Residual Solvents
• Solubility
• Bioburden
• Endotoxin

In Newark, our Professional Assay Services offer tissue sectioning, ISH staining, high resolution full slide scanning, scoring, and image analysis to support clinical and preclinical studies. Our dedicated team of highly trained specialists, scientists, and board-certified pathologists performs RNAscope™ ISH, BaseScope™ ISH, and miRNAscope™ ISH assays in singleplex, duplex, and multiplex formats. We operate under Good Clinical Laboratory Practice (GCLP) guidelines which encompass all aspects of individual laboratory operations including sample processing, generation of data, safety and security, employee training, documentation, and sample retention and recovery.

Certification

• ISO 13485:2016

Regulatory Guidelines Followed 

• GCLP compliance according to 21 CFR 820

QC Testing for Our Raw Materials

• Incoming inspection
• Visual inspection
• pH
• Conductivity
• Osmolality
• Enzymatic/end-point activity plate measurements
• ISH functional types of testing

Our Cliniqa facility provides dynamic, flexible, and regulatory compliant contract services with in-house experts that support manufacturing organizations in the IVD market.

Certifications

• ISO 13485:2016
• MDSAP; approval includes US, Canada, Brazil, Japan, Australia

Registrations and Licenses

• Health Canada Establishment License: 2970
• USDA Technical Blood Facility, Intermediate Product Facility CA-TEC-0046 and CA-TEC-0053
• U.S. DEA Manufacturer and Exporter Registration
• California State Medical Device Manufacturing License: 50393

Service Capabilities

• Assay development
• Technology transfer
• Packaging development
• Regulatory support
• Technical support
• Stability programs

Manufacturing Capabilities

• Liquid formulation/filling
• Powder formulation
• Powder blending and filling
• Reagent tablets
• Lyophilization
• Off-line/in-line labeling
• Kit assembly/packaging
• Final product testing

In Devens, we provide technical and logistical resources for technology transfer and full product development across controls, buffers, calibrators, and standards for the IVD market.

Certifications

• ISO 13485:2016
• ISO/CAN 13485:2003
• ISO 9001:2008

Regulatory Guidelines Followed

• 21 CFR Part 820
• 78/79 EC for IVD

Analytical Testing Services

• HPLC, chemistry, Immunoassays
• Spectrophotometry
• Conductivity, viscosity, pH, turbidity
• Microbiology
• Preservative efficacy

Analysis and Reporting

• Protocol generation
• Method validation
• Documentation and reporting

Stability Testing Services

• Real-time, transport, open container and accelerated
• Validated storage capable of -60 °C to +60 °C
• Environmental control settings of 10-80 %RH
• Consistent with European standard EN 13640:2002

Manufacturing

• Formulation batch sizes from 15 mL to 1000 L
• Ampoule filling from 1 mL to 5 mL
• Pasteurization, autoclaving, irradiation
• Bottle and vial filling in a multitude of configurations
• Single use packaging in a variety of configurations
• Vision systems and weight checks
• Validation services
• Detailed documentation
• Custom design

We design, build, and validate ProteinSimple™ analytical instruments for use in clinical manufacturing environments. These instruments operate with 21 CFR Part 11-compliant software that ensures reliability, documentation, and data security.

Our Instruments Provide:

• Secure access with comprehensive audit/log files
• User permission controls
• Automated batch protocols
• Method-based analysis protocols
• Automated date and time stamps
• Unique electronic signatures for each user
• Protected data repository
• Comprehensive reporting
• Electronic audit trail generation

Our 21 CFR Part 11-compliant Instrument Platforms Include: 

• Simple Western™ systems for automated, capillary-based immunoassays that combine the power of CE-SDS or cIEF with the sensitivity of immunodetection, enabling size- and charge-based screening of complex sample types.
• iCE Maurice™ systems for capillary electrophoresis that automates protein profiling by size or charge, employing pre-assembled cartridges and featuring onboard sample mixing.
• Micro-Flow Imaging™ for analysis of protein aggregation for stability measurements following stress testing. Up to 90 samples/ run, and up to 150 µL/minute at 900,000 particles/mL.
• Simple Plex™ for automated ELISAs to detect fragments and oligomers of cytokines and growth factors with low assay CVs. Single or multianalyte cartridge format options available.

Raw materials are sourced from qualified suppliers with supplier qualification and monitoring systems in place. We also perform risk assessments for critical raw materials used in GMP processes every three years. This includes visual inspection of raw materials with documentation tracking of the Certificate of Analysis (CoA), Certificate of Origin (CoO), TSE/BSE statements, and animal-free statements, if applicable. Identity confirmation is performed for some critical raw materials before accepting. For animal-derived materials, we always source from countries considered to be a negligible or controlled BSE risk.

We advise cell therapy developers to always source raw materials from USP-grade or GMP-grade if possible. Our GMP-grade products are manufactured and tested according to applicable standards in Unites States Pharmacopeia (USP) Section <1043> Ancillary Materials for Cell, Gene, and Tissue-Engineered Products, and European Pharmacopeia (Ph. Eur.) General Chapter 5.2.12 Raw Materials of Biological Origin for the Production of Cell-based and Gene Therapy Medicinal Products. A supplier should have a certified quality management system (QMS), such as ISO 9001:2015 or ISO13485: 2016. This means the supplier has been independently audited and has policies and processes in place designed to meet the needs of their customers. Suppliers of these raw materials should be further qualified and monitored by questionnaire, performance of on time delivery, SCARs, and other auditing activities. The Certificate of Analysis, Certificate of Origin and other related documents should be received from each supplier and kept as development and manufacturing records.

Developers should have early discussions about quality and supply agreements with suppliers to avoid surprises as you progress into production. A manufacturer should have the ability to scale up and meet your future needs in order to avoid late-stage changes that might require costly revalidation.

Secondary suppliers should be identified early as well. Raw materials may look identical on a Certificate of Analysis but could behave differently in your biological system. It should never be assumed that you can easily switch between suppliers for a given raw material. Validation studies are required to show equivalency between raw materials from different suppliers. 

If the same vendor is used, ideally, the physical characteristics of RUO-grade raw materials would be the same as GMP-grade. They would differ only in robust documentation, such as Quality Assurance personnel performing final review and approval of batch documentation, and formal validation conducted for GMP products. There should also be extensive safety testing of raw materials that might come into contact with patients. It is fair to ask a vendor whether the manufacturing processes are the same for RUO and GMP raw materials.

If clinical applications are the goal, it is suggested that the switch to GMP be made early. Even during preclinical stages if possible. It is far easier to do equivalency testing early in product development than during later stages when changes can be costly and time-consuming.

Choosing a vendor with experience can also be advantageous. This can mean having a good understanding of quality management systems, protein biochemistry, and analytical testing methods. In addition, experience in regulatory matters is key. An experienced vendor can help when navigating changing regulatory landscapes. Availability of Drug Master Files (DMF) that contain detailed information about the raw material can assist regulatory authorities and ease investigational new drug (IND) applications. If possible, audits of vendor facilities should be conducted, and virtual audits should be made available for those that can’t be done in person. The relationship between vendor and customer needs to be a partnership, and experience counts. A minimum of three consecutive lots are manufactured, tested, and released in accordance with approved standard operating procedures to meet pre-determined acceptance criteria. (The Quality Control department is responsible for final review and approval of RUO products). For products that were developed with RUO raw materials, there may have been modifications in the manufacturing process and/or final product testing which are applicable to the GMP product.  In this case, it is advisable that the GMP product is used for any ex vivo clinical studies.

Cytokines and growth factors are made in biological systems and can be susceptible to variability. They should only be released to market after successful manufacturing of many consecutive batches that have passed stringent specifications. This builds a solid foundation for future manufacturing consistency and reliability.

Manufacturing processes must be controlled with rigorously documented SOPs and highly trained staff. This information should be made available during audit. It is fair to request data from several lots in order to assess a vendor’s ability to make proteins reproducibly. Ideally, materials from multiple lots should be obtained so they can be tested for consistency in your system. At Bio-Techne, we maintain master control lots. Each new bulk lot is compared against the master lot prior to release to market. This reduces variability and ensures consistent product performance.