What are the differences between GMPs for solid-dosage products compared to biologics?

Ancillary materials (AMs), also known as ancillary products, ancillary reagents, and process reagents, are raw ingredients that are not intended to be included in the finished product yet are essential in its manufacture. Unlike most small-molecule medications and many biologics, cell- and tissue-based therapies are often manufactured in specialized facilities that contain equipment and methods for culturing, testing, and packaging live cells. Biologics are manufactured in a living system such as a microbe, plant, or animal cell. The requirements for the collection, testing, and quality control of Ancillary materials are defined by a quality assurance system that is based on the existence of a national structure that is independent of manufacturers and adheres to GMP principles and guidelines. Because the synthesis of biologically active substances and biological medicinal products for human use requires some specific considerations arising from the nature of the products and manufacturing processes, it is important to take some special precautions. For cell product manufacturers, the nature of an AM’s production process is critical. Some AMs may be authorized medicinal products in their own right. Heparin and insulin, for example, are GMP-grade ingredients that are often utilized in cell product manufacture. 

GMP is a system that assures that pharmaceutical products are manufactured and tested consistently in accordance with specific quality standards. Ancillary materials manufacturers can provide GMP quality by following all applicable GMP standards advised for pharmaceutical products. These GMP guidelines include manufacturing, testing, and quality assurance. If Ancillary materials are manufactured in accordance with all relevant GMP guidelines, documented verification of purity, potency, consistency, and stability may be supplied. As a result, GMP is one of the most important quality assurance systems for ensuring the safety and high quality of Ancillary materials.  

GMP criteria must be followed in solid dosage form facilities. “Only staff authorized by supervisory personnel must enter those portions of the building and facilities designated as limited-access areas,” according to the US GMPs. GMPs need validated cleaning processes with documented cleaning methods performed by trained personnel. Validated analytical test procedures that demonstrate the lowest level of detection and quantitation are required for a solid cleaning validation strategy. Global GMPs demand physical separation of items to prevent cross-contamination. HVAC offers ventilation for people and must be designed to avoid cross-contamination of products by airborne particle transfer. CGMP requires that when fine particle dust is formed, particular steps be taken to minimize cross-contamination and to make cleaning easier. 

What challenges should biologics manufacturers be aware of when producing biologics under GMPs?

Since many AMs are complex biological materials, evaluating their qualities can be challenging. The intricacy of biologics, as well as the application of emerging technology, offer challenges for cGMP compliance. In general, complying with the FDA’s GMP requirements is not difficult, but there are several intricacies that might provide a barrier. For instance, it is simple to do gap analysis and confirm that processes are in accordance with the many regulations, guidelines, and technical publications that comprise contemporary CGMPs. But exist the quantity of complicated formulation work required in biological products is quite challenging. 

Biologics are difficult to work with since they are derived from living materials, which are naturally variable. As a result, the most difficult challenge from a GMP standpoint in ensuring consistent product quality, which is dependent on both incoming raw materials and manufacturing procedures. When additional complexity is included, such as a non-traditional dose form, [consistency] becomes increasingly challenging. 

What are some best practices for manufacturing biologics under GMPs? 

Quality standards are evolving in response to current GMP rules. The original GMP regulations began with a focus on the product and quality control. The focus then shifted to procedure and quality assurance. With the new model of quality systems, pharmaceuticals and biologics firms are now facing a massive paradigm change. This GMP paradigm shift will change the fundamental assumption of the manufacturing process, radically shifting the regulatory and scientific emphasis by transferring the regulatory anchor from fixed processes to fixed (constant) outputs. 

Following the revision of GMP regulations and the implementation of new technological advances, the FDA anticipates that manufacturers will continuously maintain high-quality products and improve production efficiency. The FDA believes that this will help lower costs and minimize shortages of important medications caused by failures that may result in product recalls. It’s indeed important to note that the FDA believes that the CGMP rules necessitate a higher level of calibration and maintenance than other nonpharmaceutical quality-system models. 

Current GMP regulations will have a far greater impact on manufacturing and development. 

What can you tell us about the EU’s revision to Annex 1? What changes should manufacturers be aware of, specifically for biologics?

The EU’s revision to Annex 1 provides basic recommendations for the production of all sterile products utilizing Quality Risk Management (QRM) concepts to guarantee that microbiological, particle, and pyrogen contamination is avoided in the final product. Much is dependent on the personnel’s ability, training, and attitudes. Quality assurance is very critical in this form of manufacturing, which must strictly adhere to well-established and validated methods of preparation and procedure. Any terminal procedure or finished product test should not rely only on sterility or other quality factors. 

This revision is designed to improve clarity, integrate Quality Risk Management concepts to enable the incorporation of new technology and innovative processes, and change the structure to a more logical flow. The following are significant changes: 

• Introduction of new sections; 
• Introduction of QRM Principles; 
• Restructured to give more logical flow; 
• Added detail to a number of the previous sections to provide further clarity. 

Has the revised Annex 1 addressed some of industry’s concerns?

The most recent revised document, the proposed draft of which was published in February 2020 and has undergone a second consultation period. 

The specific changes in the newly revised guidance document that will significantly impact the industry will be technical and organizational. 

This revised document is an excellent illustration of what a coordinated effort can achieve, providing a connection with the ongoing mutual recognition process between the United States and the European Union. Industry experts anticipate changes with the proposed Annex 1, particularly in the areas of quality risk management, contamination control strategies, and environmental and process monitoring. 

Are there any upcoming changes to FDA or ICH guidelines for sterile/aseptic manufacturing that manufacturers of biologics should be aware of?

The general guidance on components and raw materials (including AMs) is available from a number of sources, including the FDA, and the ICH Requirements for Registration of Pharmaceuticals for Human Use. Their guidance materials, however, give little data on how manufacturers might establish and implement AM qualification programs. AMs can be equivalent to components and product-contacting containers, as detailed in the cGMP rules for completed pharmaceuticals outlined in the US Code of Federal Regulations (CFR) Parts 210 and 211. AMs are also classified as “supplies and reagents” under 21 CFR Part 1271.As a result, cell and tissue-based products are regulated by the FDA as either 361 (“minimally modified”) or 351 (“more than minimally manipulated”) products. These products need compliance with both good tissue procedures (CGTPs) and good manufacturing practices (CGMPs); sponsors must file both an IND and a BLA. Furthermore, prospective evaluation of AM quality occurs throughout the IND review, pre-BLA inspection, and GMP inspection. Because of special FDA requirements for AMs of human and animal origin, the evaluation of AM quality for 351 products is more extensive. In addition to the ICH Q7 and Q10 quality standards, a 2006 FDA advice specifies quality system models for analyzing any materials that come into touch with a medicinal product, including AMs. The purpose of such assessments is to ensure that suppliers produce materials that fulfill standards and that pharmaceutical and biological products makers have mechanisms in place to control outsourced operations and the quality of acquired components. This covers the selection of suppliers as well as the monitoring of incoming materials. Most regulatory agencies agree on the importance of establishing robust pharmaceutical systems for developing, evaluating, documenting, and monitoring procedures and activities. 

Jeffrey Lacouchie is a Regulatory Affairs Specialist at Polyplus®. After graduating from the Faculty of Pharmacy of Strasbourg with a double degree, Doctorate in Pharmacy and Master’s degree in Regulatory Affairs, he worked as a Regulatory Affairs Product Manager in a Pharmaceutical & Cosmetics company. He joined Polyplus-transfection® in June 2021.

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