In the first instalment of our multi-part series, the key differences between biologic drugs and traditional small molecule drugs such as active pharmaceutical ingredient source, molecular size, structural complexity and immunogenicity were introduced. In this second instalment, we explore the history and evolution of biologic drugs and their impact in how biologics are regulated today.
Origin of Biologic Drug Regulations
Evidence of the use of medicinal compounds are found in ancient written records as early as 2800 BC. These compounds were comprised of herbs and plant extracts used to treat painful toothaches, gastric distress including parasites, and the treatment of wounds to prevent infection and aid in healing (Sharma et al., 2021). As the story goes, an English physician, Dr. Edward Jenner, attempted to move from treatment to the prevention of illness. In the late 18th century, Jenner inoculated a healthy 8-year-old child with exudate matter collected from the sore of a milkmaid infected with cowpox. After a localized reaction and feeling unwell, the child made a full recovery. Two months later, the same child was inoculated with matter from a human smallpox sore and remained in perfect health. Jenner’s inoculation work is often credited as the foundation of immunology which ultimately led to the complete eradication of smallpox in the 1970s.
During the 19th century, the presence of living organisms invisible to the naked eye and their role in fermentation and disease were beginning to be understood. As a result of this understanding and the work of scientists including Louis Pasteur, Anna Wessels Williams and Emile Roux, vaccines to prevent illness were first introduced for farm livestock with positive results. This led to the introduction of vaccines for life threatening human diseases such as rabies, diphtheria, tetanus and typhoid fever between1885 and 1900.
Unfortunately, it didn’t take long for tragedy to strike with the broader use of vaccines. In 1901, several children died after being inoculated with diphtheria antitoxin and smallpox vaccine contaminated with tetanus in two separate incidents. As a result of these tragedies, the first regulation of biologic drugs was enacted with the passage of the 1902 Biologics Control Act by the U.S. Congress. The Biologics Control Act required that manufacturers of biologic drugs must be licensed, inspected, and supervised by a qualified scientist and introduced requirements for product labelling. This keystone Act remained in effect until it was later incorporated into the 1944 Public Services Health (PSH) Act.
Even with the PSH Act, the importance of the oversight and control of the manufacturing processes to consistently yield safe biologic drugs was again tragically demonstrated in 1955 when improper viral inactivation allowed live poliovirus to be present in over 100,000 doses of vaccine. As a result of this tragedy, government testing and review of biologic drug batches prior to release was introduced and continues today which is a requirement unique to biologic drugs.
Origin of Drug Regulations
During this same period in the early 20th century, the Pure Food and Drug Act (PFDA) was passed in 1906 which introduced consumer protection laws against adulterated and misbranded food and drugs in interstate commerce. While PFDA focused on interstate commerce, it also introduced concepts for small molecule drugs to meet defined active ingredient standards such as the United States Pharmacopeia, the requirement to identify and list ingredients that are deemed addictive and/or dangerous on product labelling, and established inspections and penalties for non-compliance.
The PFDA was later replaced with the 1938 Food, Drug and Cosmetics Act (FD&C Act) as a response to a tragedy similar to the tragedies that served as the impetus for the 1902 Biologics Control Act. A new sulfanilamide oral elixir preparation was developed to treat streptococcal infections. After successful lab testing of the elixir for flavor, appearance and fragrance, the new drug was shipped for distribution to the market. Disastrously, the elixir manufacturer was unaware that the diethylene glycols used to dissolve the drug to a convenient liquid form for oral dosing was poisonous to humans and other mammals resulting in the deaths of at least 100 patients. As a response to the elixir tragedy, a key principle of the new FD&C Act included the mandate that all new drugs be proven safe as part of a pre-market approval prior to commercialization. Additional principles included in the original Act were the prohibition of false therapeutic claims, authorization of manufacturer inspections and added the use of injunctions as an enforcement tool. The FD&C Act and its later amendments continues to serve as the foundation for all drug regulation in the U.S today.
Additional Requirements for Biologic Drugs
While both small molecule and biologic drugs are regulated by the FD&C Act, the additional requirements of the 1902 Biologics Control Act and later PSH Act continue to also be applicable for biologic drugs. These additional regulations are recognition of the additional complexities and controls required for the consistent testing and manufacturing of biologic drugs vs small molecule drugs. Examples of the differing regulations for biologics include:
- Biologic drugs require submission of batch samples and release of each batch to FDA’s Center for Biologics Evaluation and Research (CBER) prior to distribution as part of FDA’s real-time system to monitor product quality unless a waiver is granted (21 CFR §610.2).
- Biologic drugs require additional product information in product distribution reports and more frequent reporting to FDA than small molecule drugs unless another frequency is approved by FDA (21 CFR §600.81 and §600.90).
- Biologic drugs require the submission of Biologics Product Deviation Reports (BPDRs) to FDA within 45 days after discovery of a deviation after distribution while small molecule drugs require the submission of a Field Alert within 3 days. The difference in the required reporting time is recognition of the potential complexity of biologics and the need for a thorough investigation while small molecule drug deviations are most often related to defects in packaging or labelling (21 CFR §600.14).
- A pre-license inspection by FDA is generally required for facilities used for the manufacture of biologic drugs while inspection of facilities used for small molecule drugs are performed following a risk-based assessment by the FDA (21 CFR §601.20).
A thorough understanding of the nuanced differences in the FDA’s regulation of biologic drug products is necessary during all phases of clinical product development including licensure and the eventual transition to post-approval life-cycle management. The Syner-G BioPharma Group offers a team of experienced regulatory affairs and technical professionals that can provide the expert consultation and support needed to successfully navigate those differences throughout all phases of development and commercialization.
Syner-G Biopharma Group
Syner-G Biopharma Group is a leading solution provider specializing in Regulatory Strategy and Chemistry, Manufacturing, and Controls (CMC) services for the life sciences industry. Here is how we can assist you:
- Technical Development: Syner-G can support or lead your product development efforts. Whether you need assistance with biologics, small molecules, or combination products, our expertise covers a wide range of therapeutic areas and global regulatory requirements.
- Regulatory Strategy and Execution: Syner-G offers regulatory services to guide your regulatory strategy and execution including submission via the FDA gateway. Quality and GxP Compliance: Syner-G emphasizes quality and compliance. Their comprehensive approach ensures that your CMC activities meet the highest standards, from manufacturing to post-marketing.
