Raising GMP standards for vaccines

India was the largest (second if the European Union is considered as one component) vaccine-exporting country in the pre-pandemic period (specifically 2017-19). Further, it is also home to the world’s largest vaccine manufacturer – namely, the Serum Institute of India, which accounts for the production of more than 1.5 billion doses. The country exports vaccines (for polio, diphtheria, tetanus, pertussis, BCG, hepatitis B, measles, mumps, rubella, etc.) to more than 170 countries, and 65 per cent of the children worldwide have received at least one vaccine manufactured by the Serum Institute. While the years 2020 and 2021 registered a reduction in the export of vaccines from India, it continues to be amongst the top five countries in the production of COVID-19 vaccines worldwide.

This being noted, India faced global regulatory blocks for its home-grown vaccine until April 2021-22. However, with the availability of additional trial data from April/May 2021 onwards, and published studies and research conducted by independent research centres (such as papers published by the Lancet, the Cambridge University Press and Dr Fauci’s institute), the discomfiting skepticism has eased. Further, basis the representations by the Government of India, Covaxin manufactured by Bharat Biotech may be approved by the World Health Organization (WHO) for emergency use by the end of this month.

Thus, India has huge vaccine manufacturing capabilities but ensuring strict adherence to Good Manufacturing Practices (GMP) will be crucial to build credibility in the safety and effectiveness of its vaccines for continued progress.

So, what will this entail? Let’s learn from the industry experts

Speaking about the existing standards of Good Manufacturing Practices (GMPs) for vaccines, Sidharrth Shankar, Partner, J Sagar Associates, says, “The Indian GMPs standards are covered primarily under Schedule M of the (Indian) Drugs & Cosmetics Act (D&C Act), which, inter alia, incorporates the spirit of WHO’s GMPs in terms of quality controls, stability studies, etc. The extant regulatory framework provides an extensive set of norms for quality assurance, self-inspection, and quality control system requirements, as also for clinical development of any vaccine, including the COVID-19 vaccines. In order to ensure quality drug formulation, manufacturers are required to comply with certain SOPs, detailed control systems, specifications, validation and process requirements about location and surroundings; building/premises; waste disposal protocols; conduct of personnel on the premises; health, clothing and sanitation; record-keeping protocols; etc.”

He added, “Some of the major exigencies in ensuring strict adherence of current GMPs (cGMP) during all stages of the product lifestyle are lack of proper training for the appointed employees that frequently leads to errors in maintenance of records and occurrence of contamination; inadequate protocols for quality assurance system and documentation management; and lack of awareness of the urgency for a comprehensive assessment of the manufacturing, processing and packaging of the facilities, final products and the systems in place.”

The Indian government has issued draft regulatory guidelines for the development of vaccines with a focus on the COVID-19 vaccine, especially quality controls, and the continued requirement of compliance with GMP norms specified under the law. In terms of the draft guidelines, end-to-end control testing (including testing for process additives and process intermediates) is required to be demonstrated by the manufacturers of COVID19 vaccines. Further, to ensure global compliance and strict quality assurance, and to bolster exports, the government is revisiting the current framework to bring it on par with the latest WHO-GMPs by incorporating extensive pharmaceutical quality systems, quality risk management, suppliers audit and approval requirements, he notifies.

According to Sanjiv Navangul, MD and CEO, Bharat Serums and Vaccines, GMP compliance take into account multiple factors right from a well-defined manufacturing process, a dedicated production facility, a finalised containment strategy as per biosafety levels, to having automated equipment with the least manual intervention from an employee safety perspective.

Keeping in mind the current scenario, he suggests, “All employees working in the manufacturing zone should be vaccinated with appropriate specific vaccines and periodic health checks.”

He also emphasises that every company has to ensure the use of clean-in-place and sterilise-in-place systems. Even the filtration of the exhaust is a process – filters need to be changed by employing bag-in bag-out housings and those have to be decontaminated and properly destroyed, once removed.

“Accidental spillages, especially of live organisms, must be dealt with quickly and safely. Validated decontamination measures should be available for each organism or group of related organisms. A campaign production strategy may be chosen based on a systematic risk management approach for each product, all this without compromising cross-contamination issues,” he adds.

Professor Bejon Kumar Misra, Founder Director, Patient Safety and Access Initiative of India Foundation, informs that the guiding principle of GMP is that quality is built into a product, and not just tested into a finished product. Therefore, the assurance is that the product not only meets the final specifications but that it has been made by the same procedures under the same conditions each and every time it is made. There are many ways this is controlled – controlling the quality of the facility and its systems, controlling the quality of the starting materials, controlling the quality of production at all stages, controlling the quality of the testing of the product, controlling the identity of materials by adequate labelling and segregation, controlling the quality of materials and product by adequate storage, etc. All of these controls must follow prescribed, formal and approved procedures, written as protocols, SOPs, or Master Formulae, describing all the tasks carried out in an entire manufacturing and control process.

Regarding the current gaps in ensuring cGMP, he says, “We do not have any gaps, except we are unable to convince the global community about our competence and capabilities.” Adding to it, Vinay K Mayer, Director – Market Research and Consulting, Asia Research Partners, says that throughout the pharma manufacturing and supply world, compliance to cGMP is often problematic because of data management system design. The guidelines stipulate that data manipulation needs to be guarded against, but some current systems designed for providing access to data also enable it unintentionally by design. The key differentiating factor between intent and behaviour depends on how extensive and rigorous quality oversight is throughout an organisation’s internal processes – not through the false perception of end-of-arm devices or software.

Role of industry and policymakers

Mayer informs that for closing the gaps in cGMP, management must be open about quality and cGMP compliance risks and concerns, and the personnel must feel relaxed, safe, and able to openly communicate the risks and concerns so that they can be acknowledged, assessed, and addressed accordingly. A management response that “shoots the messenger” will widen the gap even more and leave the firm exposed to damaging non-compliance and regulatory citations. Moreover, understanding what is critical material within a specific procedure or area and working with a deeper knowledge of critical product attributes eventually leads to greater process control.

Professor Misra also suggests, “We must develop a robust communication strategy based on scientific pieces of evidence and engage with all the stakeholders globally to compete in an ethical manner and derail the well-designed propaganda against India-made pharma products. The Ministry of Commerce and Industry should engage with patient organisations globally and create the demand for Indian vaccines, which are already popular. I have been saying this to the Pharmaceutical Export Promotion Council of India for several years but certain vested interest working against India is not allowing our intervention to take place globally in the interest of our country and global community. We shall continue our efforts to attract the attention of our Prime Minister to ensure a pro-active role of the patients’ organisations to plug these gaps in terms of our image and ‘Made in India’ brand.”

On the contrary, speaking about the COVID-19 vaccines that are being manufactured in India and are facing hurdles in getting international approvals, S Srinivasan, Managing Trustee, Low-Cost Standard Therapeutics (LOCOST) and co-Convenor, All India Drug Action Network (AIDAN), states that it is because of the quality and transparency level of clinical trial data — these need to be in the public domain. “Lack of transparency creates avoidable buzz and suspicion. Over and above this, there has been no clear picture about the extent of ADRs caused because of the vaccine or reasons associated with it. At one level, this is also a problem worldwide because of the accelerated paradigm of emergency use authorisation and confounding pictures of the virus’ variants,” he says.

In Navangul’s opinion, the industry needs to comply with the rules and standards established for vaccine manufacturing and policymakers have to oversee and ensure conformity to those rules and standards.

“Vaccine development is a lengthy, multi-stage process where essential actions need to be taken up synergistically, and hence, industry players and policymakers need to work in tandem and jointly accomplish the goal of accelerating vaccine development. Policymakers should work closely with the industry to evaluate GMP requirements with regard to Quality Risk Assessment,” he mentions.

Shankar points out that to improve its global market presence, Indian vaccines need expeditious approvals in larger markets. This goal is possible if, the industry, with assistance from policymakers, collaborates with regulatory agencies of other countries for the exchange of best practices, focussing on the specific issues faced by Indian companies.

He says, “The revision of Schedule M of the D&C Act in line with the global guidelines is a welcome step. However, for high-income countries to readily accept Indian vaccines, manufacturers and policymakers are required to address the shortfalls like insufficient manpower and lack of well-trained and qualified employees -the fundamental cause of GMPs non-compliances. The pharma companies and government need to work together to formulate a systematic programme for regular staff training and monitoring infrastructure. The extensive training has to be imparted not only to the high-level management cadre, but also to the junior-level personnel engaged in production, who need the skills for confidence in taking charge of quality controls; constant examination and observation, including surprise audits by the health inspectors, that would help in ensuring quality assurances and effective control systems, and thereby conform to GMP standards at all times; ensuring the highest-quality drug formulation which requires that the pharmaceutical products are GMP-compliant, as per the WHO standards. To ensure the best practice, policymakers, in consultation with all other stakeholders, could set certain pre-qualification assessments before launching the final product. All such measures that sustain GMP compliance have a direct impact on the validation of the safety and efficacy of the vaccines.”

The current perception

Navangul highlights that the Indian pharma companies currently meet more than 50 per cent of the global demand for different vaccines needed for global immunisation problems. The country had initiated the ‘Political Declaration on Equitable Global Access to COVID19 Vaccines’ that garnered support from over 180 UN member states.

“India has supplied more COVID-19 vaccines globally than any other country. Companies like SII are manufacturing, developing and commercialising the vaccine in India. Despite the fact that many countries globally are procuring COVID-19 vaccines manufactured and approved in India, the perception that there are gaps in regulatory robustness still exists. Indigenous vaccine approvals need to be backed with efficacy data to wipe out these perceptions,” he asserts.

Shankar, talking about vaccine hesitancy, gives his take on why India’s homegrown vaccine had to face scepticism within India and globally.

“Vaccine hesitancy in India was fuelled by concerns over vaccine safety and scepticism about the efficacy of the Covaxin vaccine, which had been hurriedly approved before the completion of the phase-III clinical trials. As public trust in the efficiency of the handling of the pandemic was already at an all-time low, reports of CDSCO allegedly acting in a manner outside its regulatory purview, and the subsequent opacity in the conduct of the drugmakers, further aggravated public morale, undermining the value of the indigenous vaccines on the international stage,” he opines.

However, in a statement released last month, Bharat Biotech had put to rest any concerns on the quality of Covaxin, claiming that every batch of the vaccine is subjected to over 200 quality control tests at the company’s facilities, followed by submission samples to Central Drugs Laboratory (CDL), only based on approval/release by CDL, are batches released commercially.

It had also been said that since early June, manufacturing of Covaxin has commenced at its sites at Malur, Karnataka and Ankleshwar, Gujarat, prior to which engineering batches were also executed to study equipment functionality. Products manufactured from these facilities were to be available for supplies during September. This is based on the company’s 120-day timeline for manufacturing, testing, release, regulatory approvals and distribution.

“Vaccine manufacturing, testing and release at Bharat Biotech follow validated, stringent GMP processes which were established over 20 years, with several billion doses of vaccines supplied within India and globally,” informed the company.

Prof Misra provides a counterview and assures that India is perceived as one of the best manufacturers of vaccines globally. He explains that during the COVID-19 vaccines manufactured in India, the country faced several regulatory challenges in the international markets because of the negative propaganda promoted by vested commercial entities to undermine the vaccines as those were competitive and affordable.

“It is most unfortunate that globally India is always projected in a negative manner to mislead the patients globally from accessing our products based on reasons best known to them. There is always a bogey created about our quality and efficacy,” he laments.

Mayer says that the Indian vaccine market is still in its infancy, compared to that of other developed countries including the US, Europe, AusAustralia and Canada. The IMARC Group estimates that the Indian vaccine market will reach $1.08 billion by 2021-22 at a CAGR of 17.8 per cent.

“Pharma companies from the US and EU are looking at India as a potential market for generic drugs, especially vaccines. Efforts are being made by the Indian government to make vaccines affordable and accessible for the masses. However, not all Indian vaccines are perceived the same way in the international markets. On COVID-19 vaccines, there is a pressing need for international coordination. As UNICEF provides procurement services and WHO provides technical assistance, a global effort is needed to deal with coronavirus that crosses over national interests and mobilises resources in the times of economic recession,” he states.

Path to progress

The fact remains that a majority of Indian companies involved in the production of vaccines face troubles entering advanced economies. Vaccine producers for medical markets such as the US and EU have found it hard to penetrate these markets due to certain factors including unfavourable regulations, lack of patient compliance and high expenditures. It’s important to work on improving India’s infrastructure for equipment and inspections to meet standards and avoid regulatory barriers to consolidate India Vaccine Inc’s position in the world markets.

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