Pharmalink Consulting - Worldwide Regulatory Affairs

Biologics

Pharmalink organizes training for our staff on a regular basis. A recent training program was a workshop series on biologics
The training course was a 3 day workshop and was divided into three Modules:
Module 1- Biotechnology Products in the Pharmaceutical Industry Market
Module 2 – Manufacturing and testing of biologics
Module 3 – Biosimilars, follow on biologics

As this is such a vast topic we have provided a short basic review of the subject from a US perspective, including what are biologics, an overview of the regulations and development issues that apply to biologics, followed by a few lines on biosimilars.

A US perspective – Overview

Biological products, like other drugs, are used for the treatment, prevention or cure of disease in humans. In contrast to chemically synthesized small molecular weight drugs, which have a well-defined structure and can be thoroughly characterized, biological products are generally derived from living material -human, animal, or microorganism, are complex in structure, and thus are usually not fully characterized.
These medications are usually one of three types:
º Substances that are (nearly) identical to the body’s own key signaling proteins, eg the blood-production stimulating protein erythropoetin, or growth-stimulating hormone.
º Monoclonal antibodies. These are similar to the antibodies found in the human immune system, but they are “custom-designed” (using hybridoma technology or other methods) and can therefore be made specifically to counteract or block any given substance in the body, or to target any specific cell type.

º Receptor constructs (fusion proteins), usually based on a naturally-occurring receptor linked to the immunoglobulin frame. In this case, the receptor provides the construct with detailed specificity, whereas the immunoglobulin-structure imparts stability and other useful features in terms of pharmacology.
Section 351 of the Public Health Service (PHS) Act defines a biological product as a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings.” FDA regulations and policies have established that biological products include blood-derived products, vaccines, in vivo diagnostic allergenic products, immunoglobulin products, products containing cells or microorganisms, and most protein products. Biological products subject to the PHS Act also meet the definition of drugs under the Federal Food, Drug and Cosmetic Act (FDC Act). Hormones such as insulin, glucagon, and human growth hormone are regulated as drugs under the FDC Act, not biological products under the PHS Act.

Development and regulations

Following initial laboratory and animal testing that show that investigational use in humans is reasonably safe, biological products can be studied in clinical trials in humans under an investigational new drug application (IND) in accordance with the regulations at 21 CFR 312. If the data generated by the studies demonstrate that the product is safe and effective for its intended use, the data are submitted as part of a marketing application. A biologics license application (BLA) is required for biological products subject to licensure under the PHS Act. Like a NDA (New Drug Application) filing for drugs, a 356h form is completed for a BLA submission.

Issuance of a biologics license is a determination that the product, the manufacturing process, and the manufacturing facilities meet applicable requirements to ensure the continued safety, purity and potency of the product.
Among other things, safety and purity assessments must consider the storage and testing of cell substrates that are often used to manufacture biologics. A potency assay is required due to the complexity and heterogeneity of biologics.
Because, in many cases, there is limited ability to identify the identity of the clinically active component(s) of a complex biological product, such products are often defined by their manufacturing processes. Changes in the manufacturing process, equipment or facilities could result in changes in the biological product itself and sometimes require additional clinical studies to demonstrate the product’s safety, identity, purity and potency. Traditional drug products usually consist of pure chemical substances that are easily analyzed after manufacture. Since there is a significant difference in how biological products are made, the production is monitored by the agency from the early stages to make sure the final product turns out as expected.

The regulations regarding BLAs for therapeutic biological products include 21 CFR 600, 601 and 610.
Biologics are subject to provisions of both the FD&C Act and the PHS Act. Because of the complexity of manufacturing and characterizing a biologic, the PHS Act emphasizes the importance of appropriate manufacturing control for products. The PHS Act provides for a system of controls over all aspects of the manufacturing process. In some cases, manufacturing changes could result in changes to the biological molecule that might not be detected by standard chemical and molecular biology characterization techniques yet could profoundly alter the safety or efficacy profile.

Biosimilars

Biologics generally exhibit high molecular complexity, and may be quite sensitive to manufacturing process changes, unlike the more common small molecule drugs. The follow-on manufacturer does not have access to the originator’s molecular clone and original cell bank, nor to the exact fermention and purification process. In addition, nearly undetectable differences in impurities and/or breakdown products are known to have serious health implications. This has created a concern that generic versions of biologics might perform differently than the original branded version of the drug. Hence, unlike most drugs, generic versions of biologics are not authorized in the US or the European Union through the simplified procedures allowed for small molecule generics. Notable exceptions include several of the earliest biopharmaceuticals made via recombinant DNA technology, including biosynthetic ‘human’ insulin and human growth hormone, which are grandfathered under the U.S. Federal Food, Drug & Cosmetic Act. By comparison, vaccines and most other biotech drugs are governed under the Public Health Services Act, which would need to be amended by U.S. Congress and signed into law by the President to allow for generics.
In the EU a specially-adapted approval procedure has been authorized for certain protein drugs, termed “similar biological medicinal products”. This procedure is based on a thorough demonstration of “comparability” of the “similar” product to an existing approved product.

Pharmalink Consultants Available

UK based Biologics Consultant – available to assist you from September 2009. A biotechnology graduate with 8 years experience in Regulatory Affairs and extensive working knowledge of Biosimilar and Biotech products. Having worked on several time and business critical projects, she has assisted in ensuring projects completed on time and below budget. Skills include:- working knowledge of EU procedures ( Centralised, Decentralised, National and MRP) ; PILs and SmPCs; fluent in English, French, Spanish, Catalan, Russian and Arabic.

US based Biologics Consultant – now available to assist you with your BLA and sBLA regulatory needs. Over 7 years experience with biologics. Extensive knowledge of both US and international regulations. In addition has a solid working knowledge of clinical affairs, manufacturing and CMC for products in several therapeutic areas. Worked with products in both the pre-approval and post-approval stage. Based on the East coast and available to work in the US and international locations. Fully bilingual in English and Spanish.

We have recently seen an increase in requests for consulting roles in Asia. We currently have colleagues based in Dubai, Kuala Lumpur and Japan, all working on a large compliance project. In addition several of our projects have required our consultants to work remotely and provide specific regional advice on regulatory requirements for Asian and Latin American countries. If you need assistance with regulatory project work in these regions, please contact:
Asheesh Bhimsaria at our AsiaPac office – +91 22 4030 9595
Kevin O’Toole at our UK office – +44 (0)1628 860300
Stephen Loughrey at our US (New Jersey) office – +1 973 218 2725