Vaccine worries

THE Cover Story by Frontline (April 11, 2008) and other media reports on the suspension of vaccine production by the Central Research Institute (CRI), Kasauli, in Himachal Pradesh; the Pasteur Institute of India (PII), Coonoor, in Tamil Nadu; and the BCG Vaccine Laboratory (BCGVL) in Chennai, following the Drug Controller General of India (DCGI)’s order on the grounds of non-compliance of good manufacturing practice (GMP) in January 2008, became the basis for the filing of a public interest litigation (PIL) petition in the Supreme Court in February 2009 (S.P. Shukla and others vs. Union of India) and the observations of the 34th Parliamentary Standing Committee on the Ministry of Health and Family Welfare on the revival of the three public sector undertakings (PSUs). As a result, in June 2009, President Pratibha Patil announced the reopening of the PSUs. The Ministry too drew up plans to make the units GMP-compliant and reopen them by June 2010.

The Javid Chowdhury Committee, set up by the United Progressive Alliance government, in September 2009 recommended that the suspension of the PSUs be revoked in order to produce vaccines for domestic use, pending government investments in modernisation, and GMP compliance for exports. In the meantime, the closure resulted in vaccine shortages and deaths in many States. This was documented in the media and in several parliamentary standing committee reports.

Subsequently, the government ordered the vaccine units to resume production and sanctioned funds for modernisation and GMP compliance. The first to complete its GMP civil works was the CRI; work is on at the PII. The revival of the BCGVL remains uncertain. Meanwhile, the government continues to procure most of its vaccine needs from private suppliers. It continues to justify the suspension of the licences of the PSUs, and the need for a vaccine park in Chengalpattu, undesirable combination vaccines, and the private sector. The petitioners are dubbed the “anti-vaccine lobby”.

In 2009, doctors, scientists, policy analysts, public health experts, activists, lawyers and NGOs came together to produce a draft framework for an Evidence-Based National Vaccine Policy, which was published in the Indian Journal of Medical Research (2010). In a knee-jerk response, a national vaccine policy was drafted by N.K. Ganguly, the former Director General of the Indian Council of Medical Research (ICMR). The National Technical Advisory Group on Immunisation (NTAGI) approved it without much discussion or modification, totally ignoring the points made by the civil society’s draft. The government also adopted it hurriedly without adequate consultation with the public or in Parliament. The National Vaccine Policy (2011) thus legitimises the ongoing practices that benefit the private sector.

The PIL (Shukla vs. Union of India) has challenged the National Vaccine Policy (2011) on the following grounds:

• The policy does not provide an uncompromising scientific basis on which a vaccine can be introduced in the Indian Universal Immunisation Programme (UIP) and does not commit itself only to need-based and evidence-based vaccination;

• In its eagerness to push vaccines, the policy totally ignores the very idea of selective immunisation and implies that all immunisation is universal; and,

• It focusses more on supply-side factors such as public private partnerships (PPP), innovative (speculative) financing, global funds through agencies such as GAVI, PATH and BMG Foundation, and advance market commitments which directly impinge on our sovereignty in evidence-based subsequent decision-making in the immunisation programme.

The upshot of all this is that the suspended and reopened vaccine PSUs have not been producing/supplying universal vaccines to their full capacity owing to lack of purchase orders from the government. They have also not been made current GMP-compliant so far, despite the Javid Committee recommendation that it should be completed within three years “to become fully functional and self-sufficient in production”. Furthermore, bureaucratic and procedural delays, and the engagement of unnecessary foreign consultants, have bogged down the GMP-compliance approval for production processes by the DCGI even for the CRI, whose GMP-compliant infrastructure was in place in 2013 itself. In the other two units, even GMP-compliant structures are not in place and it appears that these would be completed only in the timeframe 2016-17.

ON January 15, the production licences of three vaccine-manufacturing public enterprises under the Ministry of Health and Family Welfare (MoH&FW) were cancelled, and they were ordered to suspend production forthwith by the then Drug Controller General of India (DCGI), M. Venkateswarlu, for reasons of non-compliance with good manufacturing practice (GMP) norms under the Indian Drugs and Cosmetics (D&C) Act of 1945.

The units are the 103-year-old Central Research Institute (CRI), Kasauli, in Himachal Pradesh; the 100-year-old Pasteur Institute of India (PII), Coonoor, in Tamil Nadu; and the 60-year-old BCG Vaccine Laboratory (BCGVL) in Chennai. They were also told not to supply from the stocks they held and to stop procurement of raw materials.

For years these three institutes have met the bulk of the requirement of primary vaccines for the national immunisation programme. Launched in 1978, the national programme, called the Expanded Programme of Immunisation (EPI), aims to protect children against six “vaccine-preventable diseases”, namely diphtheria, pertussis, tetanus, poliomyelitis, typhoid and childhood tuberculosis.

In 1985, targeting universal coverage of children, this programme was renamed the Universal Immunisation Programme (UIP). Under the UIP, typhoid was discontinued and measles was included. Thus, the UIP vaccines include the Bacillus Calmette-Guerin (BCG) vaccine to prevent childhood TB, the triple diphtheria-pertussis-tetanus (DPT) vaccine, the oral polio vaccine (OPV) and the measles vaccine.

Besides these vaccines and others belonging to the DTP group, such as diphtheria-tetanus (DT) toxoid and tetanus toxoid (TT) vaccines, these units produce non-UIP vaccines such as the anti-rabies vaccine (ARV) for animals and humans, the typhoid vaccine and, most importantly, the yellow fever vaccine. They also produce sera, including the anti-snake-bite serum. The Kasauli institute is, in fact, the only unit in the South-East Asian region to produce the yellow fever vaccine.

Over the years, with 26 million births being added every year, the national immunisation programme has grown and so has the demand for vaccines. With these units unable to meet the demand, private players entered the field and made up the shortfall in the government procurement from the public sector units.

For instance, OPV is supplied entirely by private sector companies, which import the vaccine in bulk and package it for domestic consumption. This situation came about after Bharat Immunologicals and Biologicals Corporation Ltd. (BIBCOL), a public sector unit under the Department of Biotechnology (DBT), stopped production some years ago for inexplicable reasons.

For the other vaccines, however, these three units still constitute the backbone of the national immunisation programme. The BCG vaccine, for instance, is supplied solely by the BCGVL, though the Pune-based Serum Institute of India (SII) has reportedly begun to produce it of late. Clearly, the suspension of production will impact the national programme badly, particularly with regard to BCG, and that too immediately, given the directive to the units that they should not supply vaccines even from stocks held. Supply of cheap ARV and yellow fever vaccine will also be affected adversely.

A centralised “vaccine park”, which will have state-of-the-art infrastructure for production and research for both UIP and non-UIP vaccines, including the new generation vaccines, is proposed to be set up in Chengalpattu near Chennai in lieu of these three units. Hindustan Latex Ltd. (HLL), a public sector undertaking of the Ministry, has been identified to set up this complex.

Specifically, the suspension order of the DCGI pointed out non-compliance by the three units with the conditions (a) (i) and (p) of Rule 78 of the D&C Act, 1945. The former has to do with “maintaining adequate staff and adequate premises and plant” and the latter concerns following “good manufacturing practices (GMP) as laid down in part 1 and 1-A of Schedule M under the D&C Rules”.

The events leading to the suspension are roughly the same with regard to all the three institutions. The decisions followed two rounds of inspections to the facilities, once in August 2007 and the second in January 2008, by a GMP assessment committee constituted by the Ministry. In December 2007 they were all served show-cause notices as to why their licences should not be suspended.

In their replies to the DCGI, the institutes stated their problems in meeting the requirements of full compliance with GMP norms. These were essentially a reiteration of issues they had brought to the Ministry’s notice earlier. These basically stem from the limitations of functioning as government institutions with limited funds, governed by government rules and regulations that lack the flexibility required to run industrial units in the area of biologicals.

For instance, the PII Director, N. Elangeswaran, wrote to the Ministry in August 2007 pointing out some of the constraints the institute had to operate under and seeking greater autonomy in its functioning. The constraints included the lack of qualified officers and staff because of the need to follow government norms in matters of recruitment, finance, staff structure and so on, and the dependence on the Ministry for budgetary support every year in the form of grant-in-aid. In response to the show-cause notice, the PII stated on January 4 that it would not be able to rectify all the deficiencies, especially those relating to structure and manpower, but would try its best to rectify the deficiencies within the limitations.

The question that naturally arises is why did the CLAA wake up suddenly? After all, these units have been operating for decades and the D&C Rules have also been in existence for years. “It was following the recent assessments by the National Regulatory Authority [NRA] under the supervision of World Health Organisation [WHO] observers,” said B.K. Prasad, Joint Secretary in the MoH&FW.

According to Prasad, the WHO/NRA assessment on the basis of the qualifying criteria for cGMP (current GMP) was carried out three times in the recent past: in 2001, 2004 and 2007. “The government units could meet most of the criteria, but in 2004 the GMP norms were made more stringent, because of which they failed to qualify. In 2007, they were made even more stringent and our units could satisfy only two of the six basic criteria,” said Prasad.

The criteria, according to him, basically concern structural, process and documentation deficiencies. “While the process deficiencies were by and large rectified, structural and documentation deficiencies remained. Our systems are very poor in documentation,” he added. “But the new facility, the proposed vaccine park, will be fully GMP compliant and will be ready in two years’ time.”

Union Minister for Health Anbumani Ramadoss said: “In 2001, the WHO made very harsh remarks on the quality of vaccines produced by these units and even wanted the NRA restructured because of its failure to maintain standards…. In 2004, they came again and made essentially the same remarks. In 2007, when things were not to their satisfaction, they warned of derecognising the Indian NRA itself. We deliberated on the issue and finally we had to relent in August as the WHO Director-General set December as the deadline to set our house in order. Initially I was adamant, but they put a lot of pressure…. How can you give poor quality vaccines to Indian children? they asked.”

The WHO is only an advisory body and does not have executive powers. Lack of WHO cGMP certification for these three units or pre-qualification of their products would only affect exports from these units. So one could argue that there was no need to come under the WHO pressure and shut them down even before the vaccine park was established.

Responding to this, Ramadoss said: “Derecognising Indian NRA as a country means even private units that are cGMP certified will not be able to export. Today India exports vaccines worth nearly Rs.1,000 crore to international agencies, such as UNICEF, all of which will be cancelled.”

“There was never any problem with the product; only the manufacturing environment and regulations are in question,” said T. Jacob John, the eminent virologist from Christian Medical College (CMC), Vellore, Tamil Nadu. He added: “We did not do it right. It seems to be a desperate move. International regulations are quite stringent if we want to compete internationally. How do we respond to this? The issue is complex. You have to be like the Chinese who use their autonomy very strongly and say it is our indigenous product and we will use it. International certification can come later. We do not exercise our autonomy.”

But did they have to be shut down immediately? Said Jacob John: “Their closure was perhaps inevitable. But if you ask why before a GMP facility is set up, and at the cost of the national programme, I have no idea what the internal compulsions are. It should have been done in parallel. I also do not understand the philosophy of closing down public sector units and starting a new public sector unit for the same purpose. A government-budgeted enterprise is not commensurate with the vibrant management required for international GMP standards. What is the guarantee that HLL will be able to deliver?”

“There has never been any problem with the quality of our vaccines,” said Jacob M. Puliyel, a paediatrician at St. Stephen’s Hospital, New Delhi. “Something like Rs.30 crore would have been sufficient to upgrade the CRI, and probably a similar amount for the Pasteur Institute. Ramadoss, however, feels that these units are too old to be brought to international standards even with more funds. “We have put in money,” he said, “but things have not really improved.”

Yes, there may be limitations to making the structural changes that the WHO cGMP norms demand, but from the production data of these units over the past few years, one can see that production in all the units has shown a distinct upward trend with investments towards process improvements and new equipment.

The production capacities, too, have gone up. For instance, at the PII the annual DPT capacity has gone up from 40 million doses to 70 million doses, that of TT from 30 million doses to 180 million doses, and that of DT from 15 million doses to 70 million doses. Similarly, at BCGVL, the capacity has gone up from 35 million doses to 80 million doses.

Of course, Ramadoss was quick to clarify that he was not closing down the units. “We are only restructuring them,” he said. Justifying the move to have a vaccine park at Chengalpattu and have HLL set it up, he said: “There is no space at Kasauli or Coonoor even to build new facilities. Besides converting them into testing facilities, the plants will be used for bottling and serum production.”

As for HLL, he said: “It is a highly professional and modern organisation. I am confident that it will be able to execute this without any problem.”

He gave the assurance that the closure would not result in shortage of any of the essential vaccines in the interim period of two years and more before the vaccine park comes up. “The private sector WHO-certified GMP companies have committed on paper that they will meet the demand with better quality vaccines at the same price.”

As regards BCG, he said the SII had started production of the BCG vaccine and should be able to supply the same for the UIP. “”