Biological Standardization has been pivotal to the success of traditional biological products, such as vaccines, antitoxins, and immune globulins. Its principles have supported the development and manufacturing of safe and effective modern biological products, including hormones, therapeutic proteins, and monoclonal antibody products. They continue to play a vital role in advancing new cutting-edge biological products like tissue, cellular, and gene-therapy products.

My introduction to biological standardization and vaccines started in 1977 with my first job at the Division of Biological Standardization and Quality Control (DBSQC) at the Central Research Institute, Kasauli (CRI). DBSQC was founded at the CRI in 1955 by the dynamic Director of the CRI then, Dr. J.B. Srivastava. DBSQC was the National Control Laboratory for lot release testing of biological substances.

As with other vaccine manufacturing units throughout the world that were established during 1890 to 1910 to manufacture diphtheria antitoxin and rabies vaccine, the CRI was founded on the 3rd of May 1905 with a mandate of research in the field of medical and public health, manufacture of vaccines and antisera, specifically Semple’s rabies vaccine, and to act as a national referral center for public health problems. The institute was famous in Northern India as a place to get treatment for rabies after dog bites and for venom poisoning after snake bites during the middle of the 20th century. National Salmonella and Escherichia Centre (NSEC), the National Reference Centre for serotyping of Salmonella and Escherichia coli, was established at CRI in 1958 in collaboration with the World Health Organization with assistance from the Central Public Health Laboratory, Collindale (U.K) and Institut Pasteur, Paris.

A significant contribution of CRI to biological standardization was the development of Brown’s Opacity Set at the CRI during 1913 - 1919, which was manufactured in my Laboratory by a very talented technician, Mr. Gian Ram. As the field of microbiology was progressing during 19th century, there was a need to determine the number of cells in bacterial suspensions for standardization purposes, for manufacture and testing vaccines, potency tests for live bacterial vaccines and other products, for suitability testing of sterility method, to prepare challenge cultures for potency tests, for preparation of antigens for the serological tests, specifically Widal test, etc. In my experience of more than 40 years, using various methods to determine the number of cells in bacterial suspensions, Brown’s Opacity Set developed at the CRI was the most innovative and the best for this purpose.

My foundation with biological standardization was strengthened due to the discussions and interactions with the highly talented and dedicated scientists from Pasteur Institute of India, Coonoor (PII), specifically Dr. Gutla V. J. A. Harshavardhan (I am still in touch with Dr. Harsha), who were getting training at the CRI in the manufacture of diphtheria, tetanus, and pertussis vaccine in 1977/78. On top of it, Dr. Harminder Singh, in charge of the DBSQC, assigned topics related to the manufacture and testing of vaccines to all the DBSQC and PII scientists for presentation and discussion. My topic was the “Philosophy of Biological Standardization,” and I read an excellent book on the topic, suggested by Dr. Singh (Biological Standardization by J.H. Burn, 1937), which I still refer to.

Throughout most of the 20th century, CRI was the leading vaccine manufacturer in India, providing most of the vaccines for national immunization programs. However, the biotechnology revolution in the 1980s changed the landscape of manufacturing vaccines, antisera, and immune globulins (traditional biological substances) from public/Government manufacturing units to the private sector. The driving force was the implementation of current Good Manufacturing Practices (cGMP) in manufacturing traditional biological substances, particularly the controlled environment (clean rooms) and quality systems. CRI, PII, and many old vaccine manufacturing facilities could not keep up with the developments in manufacturing these traditional biological substances under cGMP regulations. Survival of CRI was threatened in the 1990s after WHO mandated cGMP requirements for all vaccine manufacturers, and the manufacture of most products was suspended at CRI. A major reason for the decline of CRI, which started in the late 1990s, was the bureaucratic nature of governing the Institute from New Delhi by bureaucrats appointing the Director with a degree in medicine and microbiology with no experience in vaccines, manufacturing operations, and pharmaceutical microbiology. The Institute could not keep up with the developments in manufacturing operations, particularly implementing cGMP regulations. After struggling for over 25 years, the CRI seems to have modernized manufacturing facilities to comply with cGMP regulations. However, the appointment of physicians as senior management with no experience in vaccines or biological substances is still ongoing, and the future of CRI seems doubtful in a rapidly advancing and competitive industry. The original intent of appointing senior management with medical degrees, including the Director of vaccine manufacturing units around the world, was clinical evaluation of new vaccines under the guidance of a physician. Over the last 75 years, the CRI did not develop any new vaccine requiring clinical development. The manufacture of generic vaccines, such as diphtheria, tetanus, and pertussis (DTP) vaccine, and the Japanese encephalitis vaccine, was implemented at the CRI over these years, mainly by technology transfer from other international Institutions, without much clinical development.

As I was getting passionate about biological standardization, a significant development happened at the CRI in having an International Workshop on testing of polio and measles vaccines in 1978/79, where I got the opportunity to meet Dr. Frank T. Perkins and listen to his presentation. Dr. Perkins and Professor R. H. Regamey were the founding editors of the Journal of Biological Standardization (JBS), started by the International Association of Biological Standardization (IABS) in 1973 to encourage the advancement of the standardization of biological substances. Dr. Perkins was the President of the IABS at that time and Chief of the Biological Standardization unit at the WHO. The IABS changed the name of the JBS to Biologicals in 1989. The JBS until 1989 and Biologicals from 1990 completed 50 years of advancing biological product development, manufacturing, quality, and regulatory aspects. My association with the JBS started early in my career in 1981 when I submitted my first article to the JBS, which was reviewed by Dr. Frank Sheffield, who joined Dr. Perkins as a co-editor. JBS was a prestigious journal at that time and was suggested by my colleague and friend, Mr. Dinesh Sood. The article was published from the DBSQC, CRI, in 1982. During the next seven years, I published 14 more articles in JBS, comprising 15 articles in JBS. As far as I know, I have published the highest number of articles in the JBS because JBS was replaced with Biologicals in 1990. I continued publishing in the Biologicals, and I am honored to be appointed as Section Editor, Vaccines, for Biologicals in 2022. The impact of publication in the JBS was so high that when I visited various vaccine institutes in Japan in 1984, everybody I met told me they knew me from my articles in JBS, which had 3 articles that year. Due to my articles in the JBS, I was invited to co-chair a couple of workshops at the Eighth International Conference on Tetanus in Leningrad (now St. Petersburg) in 1987. I was amazed at the respect I received due to these publications. When I met Dr. A. Galazka and introduced myself, I still remember that he mentioned, “Who does not know Dr. Gupta after a series of articles in JBS.”

I joined IABS in 1981 and continued learning about biological standardizations from the proceedings of meetings organized by IABS and the technical report series on the ECBS. Later, I was a member of the IABS committee on human vaccines from the late 1990s until the early 2000s. I made several presentations at the meetings organized by the IABS, including keynote presentations and co-chairing sessions.

Full artcile is available at the links below.

https://www.researchgate.net/.../387271377_The_Vital_Role...

https://www.linkedin.com/.../rajesh.../recent-activity/all/