GMP Manufacturing Capabilities

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 

1. How do you ensure the raw materials you use in your manufacturing are appropriate to make products that can be used for ex vivo manufacturing?

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.

2. What advice would you give to cell therapy developers when sourcing their raw materials?

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. 

3. How do you ensure a smooth transition from research use only (RUO) to Good Manufacturing Practice (GMP)? 

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.

4. Cell and gene therapy manufacturers need to bridge batches (lot-to-lot consistency, GMP testing against master lot). How can you ensure lot-to-lot consistency and reduce variability?

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.