Vaccination is the most effective public health intervention of all time. This is especially true in developing countries, where many families cannot find or afford health care when they get sick. The prevention offered by vaccines can be lifesaving.
The vision for the field of vaccine manufacturing comprises protecting and improving the public health globally and facilitating the development, approval and access to safe and effective products and promising new technologies.
With the aid of vaccines, small pox is now eradicated globally, polio is nearly so, and, in countries where children regularly get their shots, there is not too much worry about diphtheria, measles, pertussis and rubella. But there are still many diseases for which vaccines are not available and market forces alone are not always strong enough to drive the development of vaccines.
For immunization safety , vaccine quality and safety should be ensured. This must occur from the development stages through clinical trials, vaccine production, quality control and distribution, up to the point of use, where adequate practices for immunization must be in place. Vaccine regulation includes several procedures to ensure vaccine quality and safety, which comprises characterization of starting materials by supplier audits, cell banking, seed lot systems, compliance with the principles of good manufacturing practices, independent release of vaccines on a lot-by-lot basis by fully functional national regulatory authorities, demonstration of production consistency and enhanced pre and post-market surveillance for possible adverse events, following the use of these vaccines. These procedures help assure vaccine quality, efficacy and safety.
All the safety-related things of current Good Manufacturing Practices (cGMP) should be implemented before Phase 1, which includes adequate documentation (traceability), sterility assurance, safety assessments, and control over the manufacturing process. Complete compliance with GMP is rarely ever met at the pre-clinical phase of product development. As stated in 21 CFR 312.23(a)(7) "Although in each phase of the investigation sufficient information is required to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information necessary to make that assurance will vary with the phase of the investigation, proposed duration, dosage form and amount of information otherwise available."
The product characterization data and lot release data demonstrating the safety, purity, and potency of the vaccine candidate are critical components to support vaccine safety. Pre-clinical safety assessments may also include immunogenicity studies,pyrogenicity studies as well as challenge/protection studies.
A number of requirements have to be met before the manufactured vaccine product(s) can be used in pre-clinical safety testing. Performing pre-clinical safety testing on material that is not sufficiently well characterized may result in invalid studies. It is preferable to perform the pre-clinical studies on the same lot of vaccine that one intends to use in the initial clinical trial(s), although it is acceptable to perform the studies on pilot lots made by the exact same manufacturing process provided product characterization data are available demonstrating comparability of the pilot and clinical lots.
The clinical doses are frequently based on a dose(s) shown to be immunogenic in "proof of concept" or immunogenicity studies conducted in animal models. After the manufacture of the final bulk material under GMP, vaccines are generally filled for pre-clinical safety studies based on the dose(s) described in the protocols. At least, the highest dose to be used in the proposed clinical trial should be studied in the animal model. Although aliquots of bulk vaccine material can be diluted or formulated into doses within a day or two before animal immunization, these doses must be verified to be what they were supposed to be either at the pre-clinical safety testing site or by the vaccine manufacturer.
This testing should include a potency determination. In cases when it is necessary for the pre-clinical safety testing facility to formulate the doses to be given in the pre-clinical study(ies), dose verification, dose stability under the conditions of use, and uniformity testing must be performed to verify the delivered immunization dose(s).
A slot of the bulk may be kept aside for performing stability studies and for filling clinical trial material. Formulating and filling of final containers for the clinical trials usually is not performed until after results from the pre-clinical testing indicates no significant toxicity was observed at or above the proposed clinical dose. Clinical doses proposed in the final clinical protocol should be based on the outcomes of pre-clinical safety and immunogenicity studies.
The Indian scenario
Producing a safe and effective vaccine requires more than 10 - 15 years of research and costs are estimated between $500 million and $1 billion. This means that the vaccine industry is unlikely to invest in a product that will not both pay for itself and turn a profit, characteristics which almost require a significant demand in wealthy, developed countries. As a result, many potentially vaccine-preventable diseases, such as those primarily impacting the developing world, are left without large-scale research interest from the multinational vaccine manufacturers.
The current Indian market for vaccines is around US$260 million. India is among the major buyers and makers of vaccines, locally as well as globally, and has traditionally aimed at self-reliance in vaccine technologies and production.
In India, many institutes involved in vaccine production like Shantha Biotech, Serum Institute, Panacea Biotec, Wockhardt, and many others, have production facilities that are best in terms of equipment and human resources, which is essential to ensure high quality vaccines. The manufacturing facilities conform to WHO current Good Manufacturing Practice (cGMP) requirements. Serum Institute also produces hundreds of millions of doses of the Measles, Mumps and Rubella group of vaccines annually. This company meets 100 per cent requirements for Measles vaccine of the Government of India and also the global requirements. Here, the unique large bioreactors for DTP group of vaccines have a huge batch size to produce millions of doses. Serum Institute is the first and only laboratory in the world where the Cobe Spectra is used for plasmapheresis of immunized equines.
Safety of vaccines
There is no such thing as a “perfect” vaccine. Even the most effective vaccine may produce some undesirable effects which are mostly mild and clear up quickly. Now-a- days, people have become increasingly concerned about the risks associated with vaccines. Furthermore, technological advances and continuously increased knowledge about vaccines have led to investigations focused on the safety of existing vaccines which have sometimes caused concern.
Allegations regarding vaccine-related adverse events that are not rapidly and effectively dealt with can undermine confidence in a vaccine and ultimately have dramatic consequences for immunization coverage and disease incidence. Not all events thought to be related to the administration of a vaccine are due to the vaccines itself, but many are simply coincidental events, whereas others are due to human or medical error. This is especially the case in developing countries. Alternatively vaccine-associated adverse events may affect healthy individuals and should be promptly identified to allow additional research and appropriate action to take place. In order to respond promptly, efficiently and with scientific rigour to vaccine safety issues, WHO has established a Global Advisory Committee on Vaccine Safety.
Regulation of vaccines
It is known that WHO guidelines for clinical evaluation of vaccines are available to assist in evaluation of clinical trials as a part of the regulatory overview. The guidelines outline the data that should be obtained during the different stages of vaccine development to support a marketing approval. Additionally, that apply to all existing vaccines, several specific issues should be considered as prerequisites for initiation of clinical trials of plant-derived vaccines. The problem to date is the production of a single dose delivery that is made under current GMP (cGMP) type manufacturing control. Employing food protein manufacturing techniques, the antigens could be extracted and concentrated using lose cost high throughput methods.
In early 2008, four of India's biggest vaccine manufacturers - Pasteur Institute of India, Haffkine Bio-Pharmaceutical Corporation, BCG Vaccines and Central Research Institute - have had their licenses suspended by the Government of India after failing to meet GMP requirements.
In May 2008, Merck's bulk drug substances used to manufacture many of its vaccines were found adulterated and the FDA is requesting a meeting with senior management to expedite the firm's corrective actions.
The principle of the existing GMPs for drugs/biologics should be applied universally to all. However, considering the unique aspects of manufacturing vaccines in transgenic plants, additional requirements and modification of the existing regulations should be implemented. GMP should apply from the beginning, i.e., plant banking system to the final product.
All said and done, now it is to say that all action proving, in accordance with the principles of GMP that any procedure, process, equipment, material, activity or system actually leads to the expected result.
-The author is Team Lead, Drug Safety, TCS, Mumbai