Biologicals currently occupy a significant portion of the overall therapeutic industry. Large biotechnology companies like Genentech have led the way, but there are now thousands of companies working on cancer, Alzheimer’s, multiple sclerosis and many other indications. Likewise, monoclonal antibody therapies have been increasing in number since the first monoclonal therapy was approved in 1986 (Muromonab). Currently, dozens of monoclonal antibodies are on the market and many more will be approved in the coming years. It is of paramount importance that the production of biological products are tightly controlled so that the product tested in clinical trials is consistently produced when batch sizes increase during commercialization.
Many CMC activities take place during the development stage of a biopharmaceutical. Like a traditional pharmaceutical, a biological drug must be shown to be reasonably safe in the initial animal and laboratory testing. An investigational new drug application (IND) is submitted and if approved, clinical trials in humans can begin. If the clinical trials are successful, the manufacturer will submit a biologics license application (BLA) which is similar to a new drug application (NDA) that traditional pharmaceutical companies submit. If the FDA approves the BLA, they will grant a biologics license and the product can be marketed.
The FDA guidance for industry document titled, “For the submission of Chemistry, Manufacturing, and Controls Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody Product for In Vivo Use” describes the CMC requirements for obtaining a biologics license for a biological product. This section of the learning center summarizes this guidance document and covers both drug substance and drug product.
Drug substance is the unformulated active substance. Once formulated with excipients, the drug substance becomes the drug product. The following drug substance information required by the FDA for licensure will be summarized on this learning center page: Description and characterization of the product, manufacturer information, methods of manufacture, process controls, reference standards, specifications and analytical methods, container closure systems and drug substance stability. The drug product information in the guidance will also be summarized and consists of the following topics: Composition, specifications and methods for drug product ingredients, manufacturer information, methods of manufacture and packaging, specifications and test methods for drug product, container closure systems, microbiology, and drug product stability.
CMC Drug Substance Requirements
Description and Characterization
A description of the product should be provided to the FDA. This could include chemical structure, primary, and subunit structure, molecular weight, molecular formula, antibody class/subclass, ect.
Characterization of the drug substance is also necessary. All analytical testing performed on the manufacturer’s reference standard lot and qualifying lots to characterize the drug substance should be provided to the FDA. These test may include, amino acid sequence analysis, peptide mapping, SDS-PAGE analysis, isoelectric focusing, HPLC, mass spectroscopy, detection of product related proteins, detection of host proteins or DNA, endotoxin testing.
Biological activity, either in vitro or in vivo, should be performed. The description and validation of the bioassays used should be included with the application.
Manufacturer Information
Information about the facility that is performing the manufacturing of the drug substance should be provided to the FDA. This includes names of the manufacturer, address, FDA registration number, floor diagrams of the facility, a list of all other products being manufactured in the same areas as the drug product and contamination and cross contamination precautions used in the manufacturing process.
Methods of Manufacture
A list of all raw materials and reagents used in the manufacture of the drug substance should be included in the application. A description of tests and specifications of raw materials and reagents should also be provided. Flow charts of the manufacturing process flow should be included along with detailed descriptions of animal sources, cellular sources and batch records.
Process Controls
In-process controls, such as those used in fermentation, harvesting and downstream processing, should be provided. A description and documentation of the process validation studies should also be included in the application. These studies could include, validation studies for the cell growth and harvesting process, validation studies for the purification process, and sterilization validations.
Reference Standards
Primary reference standards should be well characterized with specifications for physicochemical properties and biological activity. SOPs should be in place for qualifying new reference standards. Working reference standards also need to be described and that description should include the preparation, characterization, specifications of the working reference standard.
Specification and Analytical Methods
The drug substance would need to be tested for release, shelf life and distribution. Release testing should consist of identity, purity, strength and potency. Validation of the analytical methods should be provided to the FDA. Certificates of analysis for at least three consecutive lots of the drug substance should be submitted.
Impurity profiles, with supporting analytical data, should be submitted with the application. Profiles of variants of the protein drug substance as well as non-product related impurities should also be included.
Container Closure Systems
The container closure system should be tested for compatibility with the drug substance. Results of compatibility, toxicity, and biological tests should be submitted. If the drug substance should be sterile then evidence of container and closure integrity for the duration of the expiry period should be provided to the FDA.
Drug Substance Stability
Stability of the drug substance should be tested and the study protocols and results supporting the stability of the drug substance should be submitted.
CMC Drug Product Requirements
Composition
A tabulated list of all drug product components should be submitted. The composition of all ancillary products that might be included in the final product should be included in the list.
Specifications and Methods for Drug Product Ingredients
Tests and specifications used to test all active ingredients, ancillary products, excipients (including process gases and water) should be tabulated and provided to the FDA.
Manufacturer
The information regarding the manufacturer of the drug product should be provided. This includes, company name, address, and a list of all other products made in the same rooms.
Methods of Manufacture and Packaging
A description of the manufacturing process of the formulated bulk drug and finished drug product should be provided. A flow chart should accompany the description. Processes such as sterilization, aseptic procedures, lyophilization and packaging should be included.
Specifications and Test Methods for Drug Product
A description of all test methods used to assure the identity, purity, strength, lot to lot consistency and potency of the finished drug product should be submitted along with the validation, specifications and the sampling procedures used to monitor each batch. The certificates of analysis and the results of at least three consecutive batches should be provided to the FDA.
Container Closure Systems
The container and closure system should be tested for compatibility with the final drug product. Toxicity and biological test results should be included in the application. For sterile products a container closure integrity study take place showing that the container and the closure maintain integrity for the duration of the products expiry period.
Microbiology
If the product is sterile, sterilization validations should be submitted to the FDA. The submission requirements for the drug product can be found in FDA’s Guidance for Industry, “For the Submission Documentation for Sterilization Process Validation in Application for Human and Veterinary Drug Products.”
Drug Product Stability
A description of the stability study and results should be provided to the FDA. This should include information on the stability of intermediate fluids and data on the drug product within the delivery device.
Large Molecule CMC Testing at Pacific BioLabs
Pacific BioLabs can help perform many of the CMC testing requirements needed to obtain a license for a biopharmaceutical. PBL maintains a robust stability program with chambers at the ICH conditions. Our analytical and bioanalytical lab can perform identity, purity, strength and potency testing for large molecules. The microbiology department can help perform the sterilization validations, endotoxin testing, sterility testing, container closure testing and other USP microbiology tests. Please contact PBL to see how we can help your company with its CMC requirements.