HISTORY OF BCG VACCINE LABORATORY

The BCG Vaccine Laboratory, Chennai is a sub-ordinate office of the Directorate General of Health Services (DGHS) under the Ministry of Health and Family Welfare of the Government of India. It was established on 1st May, 1948. The activities of this Laboratory are as follows �.:

1. Manufacture of Freeze Dried BCG Vaccine for the control of Childhood Tuberculosis and Tuberculous Meningitis in children and supply to Expanded Programme of Immunization (EPI) of the Government of India and to other needy medical faculties/ Hospitals:

2. Manufacture and supply of Freeze Dried BCG Therapeutic (40mg) for cancer Chemotherapy especially Carcinoma of Urinary Bladder all over the country.

BCG VACCINE

Production of BCG Vaccine :

BCG Vaccine is a live freeze-dried vaccine made from an attenuated strain of Mycobacterium bovis. It is used for the prevention of tuberculosis. During the year 1948 this Laboratory was producing and supplying liquid BCG Vaccine from DANISH-1331 BCG Seed Strain. The BCG Seed Strain was initially obtained from Statens Serum Institut (SSI) Copenhagen, Denmark through World Health Organization (WHO) for production of liquid BCG Vaccine. This strain is one among the best strains available in the world. Subsequently BCGVL started preparing its own BCG Seed called Madras Working Seed Lot (MWSL)

Change of technology from liquid form to Freeze Dried form of BCG Vaccine:

The BCGVL started manufacturing Freeze Dried BCG Vaccine with a shelf life of more than 2 years in the form of 50 doses ampoules along with liquid BCG Vaccine. In view of unique advantages of Freeze Dried BCG Vaccine over the liquid BCG Vaccine, the BCGVL, switched over completely from liquid BCG Vaccine to Freeze Dried BCG Vaccine during 1973. Due to the increased wastage during immunization using 50 dose BCG Vaccine per ampoule, BCGVL changed its preparation of vaccine from 50 doses per ampoule to 20 doses per ampoule from the year 1982.

Change of technology from ampoules to vials:

The manufacture of BCG Vaccine in ampoules has to undergo the process of sealing of ampoules. It was observed that during the process of sealing of ampoules, major wastage of ampoules occur. It was also observed that production of BCG Vaccine in vials instead of ampoules would lead to saving in electricity, man-power and also other consumables. Hence, BCGVL switched over to production of BCG Vaccine in vials from 2001 onwards for which it installed machineries & equipments to the tune of 1.5 crores.

The installed capacity of this laboratory for production of BCG Vaccine till 1998 was 400 lakh (40 million) doses. But the need for BCG Vaccine for Expanded Programme of Immunization of Ministry of Health & Family Welfare was 550-600 lakh (55 to 60 million) doses. As a result, the Ministry of Health and Family Welfare has to import BCG Vaccine of 200 lakh dose/year from other countries through UNICEF incurring the Government exchequer.

To increase the production of BCG Vaccine in order to meet the Country�s Demand for Expanded Programme of Immunization and to reduce the cost of production, this Laboratory opted to change its technology of production. It installed new Freeze Driers with vial stoppering facility at the cost of Rs. 1.5 crores, through Hospital Services Consultancy Corporation, Noida. By purchase of these major equipments, this laboratory was able to switch over to manufacture of BCG Vaccine in vials from ampoules, by which loss during sealing of the ampoules has been reduced and in turn the production quantity has increased. It attained self-sufficiency from the year 2000 onwards and import of vaccine through UNICEF was also stopped.

Year	BCG Vaccine (in lakh doses)
1997-98	411.78
1998-99	242.27
1999-2000	527.35
2000-01	774.35
2001-02	543.68
2002-03	658.52
2003-04	923.17
2004-05	853.61
2005-06	580.46
2006-07	831.47
2007-08	599.01
2008-09	��
2009-10	��
2010-11	��
2011-12	14.17

From the year 2005 onwards, BCG Vaccine is being manufactured as 10 dose per vial.

Dosage and Administration

For children upto one month 0.05 ml. and above one month and upto one year 0.1 ml. and others of reconstituted vaccine is given intradermally. Reconstitute only with the diluent supplied by the manufacturer. Special syringes allows administration of exact dose. A sterile syringe and a sterile needle should be used for each injection. The skin should not be cleaned with antiseptic. Jet injection do not generally provide a reliable dose of BCG and should not be used. Special care is needed in opening the vials and reconstituting the vaccine so that the vaccine is not blown out of the vial. Because of sensitivity to daylight, the vaccine must be kept in the dark. When withdrawals are made from the vial, the vaccine must be exposed to the light for a minimum period of time, and never for longer than four hours. If not used immediately after reconstitution, the vaccine should be kept on ice and at the end of a session (maximum 4 hours) must be discarded. Skin testing with tuberculin is not generally carried out before giving BCG, but when performed those who are found to be positive reactors need not be immunized.

Immunization:

BCG should be given routinely to all infants at risk of early exposure to the disease. For a maximum protection, this vaccine should be given as soon after birth as possible. It can be given at a same time as DPT, DT, TT, measles, polio vaccines (OPV & IPV), Hepatitis-B and Yellow Fever vaccine.

Side effects:

A local reaction is normal after BCG vaccination a small tender red swelling appears at the site of the injection which gradually changes to a small vesicle and then an ulcer in 2-4 weeks. The reaction usually resides within two to five months and in practically all children leaves a superficial scar 2-10 mm in diameter. Rarely, nodule may persist and ulcerate. Occasionally enlargement of axillary lymph nodes may appear in 2-4 months following immunization. Inadvertent subcutaneous injection produced abscess formation and may lead to ugly retracted scars

Contra indications:

The vaccine is contra indicated in those with cell-mediated immune deficiency. Keloid and Lupoid reactions may occur at the site of injection and such children should not be revaccinated.

Human Immuno-deficiency virus injected infants:

HIV infected, non symptomatic infants should be immunized with BCG Vaccine according to standard schedules. Infants with clinical (symptomatic) AIDS should not receive BCG Vaccine (but should receive other EPI vaccines).

Storage:

Freeze Dried BCG Vaccine should be stored between 2� to 8�C. Protect the vaccine from direct sunlight. Diluent should not be frozen, but it should be kept in cool temperature.

NRA INSPECTION DETAILS :

The DCG(I) has suspended manufacturing licence of BCG Vaccine vide his O.M. No. X.11026/1/06-D dated 15.1.2008 on the ground that BCGVL failed to comply with the conditions of licence in respect of:

1. Condition (a) (i) of Rule 78 in not maintaining staff and adequate premises and plant as provided in Drugs and Cosmetics Rules.

2. (B) Condition (p) is not complied as the good manufacturing practices as laid down in part 1 and Part 1 A of Schedule M of Drugs and Cosmetics Rules are not followed/adapted in the manufacture and quality control of the drugs manufactured under licence number 09 dated 1.1.97.

Hence, there was no production of BCG Vaccine and supply of vaccine from 2008-09 to 2011-12. Subsequently, the suspension of manufacturing licence was revoked vide Ministry�s Order No.X.11035/2/2010-DFQC dated 26.2.2010. The order also indicated that the unit shall be made current Good manufacturing Practices (cGMP) compliance within three years.

PRODUCTION ACTIVITIES:

The details of production activities at BCGVL during the last three years is furnished below

YEAR	DETAILS
2009-10	a) Manufacturing activities started at BCGVL in the existing premises, after standardization, cleaning, validation of procedures and equipments.
2010-11	a) The production of BCG vaccine started in the month of July, 2010 in the existing premises. b) Meanwhile, the BCG seed was reported as NIACIN positive. c) Till then, 35.70 lakh doses of 27 lots vaccine manufactured, passed IPQC test and the samples were sent to CDL, Kasauli for lot release certificate. d) The production was stopped in March, 2011, due to NIACIN positivity. e) Supply Order for 274 lakh doses of BCG Vaccine was issued by Vaccine Procurement Cell, MH&FW, New Delhi for the year 2010-11 vide Order dated 26.4.2010. f) Since production activities started only in June, 2010, after revocation of manufacturing licence, the demand of 274 lakh doses of BCG Vaccine could not to be supplied in 2010-11
2011-12	a) After the clearance from DCG(I) & DG, ICMR, New Delhi, vide Order No.X-11026/195/10-BD dated 18.8.2011 and letter No. DG/ICMR/ Institutes/2011 dt. 17.8.2011 respectively, about the issue of niacin positivity, the BCG production restarted in September, 2011. b) The vaccine produced from July, 2010 to March, 2011 (i.e. 35.70 lakh doses) which was submitted to CDL, Kasauli for lot release, was not passed due to inconsistency. c) About 60 batches were produced, out of which 10 lots have passed all IPQC testing and ready to be sent to CDL for lot release certificate, which amounts to 14.17 lakh doses. Remaining lots are under testing at BCGVL. Consistency batches have been sent to CDL, Kasauli. d) BCGVL installed On line vial washing and filling machine in the production area. Due to this, production activities was stopped from the months February, 2012 to April, 2012. The production was resumed from the month of May, 2012.

NEW FACILITY:

Further, the details about the present status on the progress of work for upgradation of BCGVL premises for achieving cGMP are furnished below :

1) As per Ministry�s Order No.28-4/2010-IFD dated 26.4.2010, M/s HLL Lifecare Ltd., has been appointed as Project Management Consultant for taking up the new project work for achieving cGMP at BCG Vaccine Laboratory, Chennai.

2) Memorandum of Agreement has been entered into between BCGVL & HLL on 29.3.2012 for revival project work at BCGVL.

3) Ministry has accorded approval for upgradation of BCG Vaccine Laboratory for Rs.64.73 crores vide Order no.Z.16025/1/2010-VI dated 27.12.2011.

4) Administrative Approval and Expenditure Sanction was accorded by the Ministry for Rs.18.35 crores in 2011-12 towards utilization of funds for HLL project work,vide Ministry�s Order dated 4.1.2012 & 29.3.2012 and the said amount has been transferred to HLL Account.

5) The Contract of Consultancy services between BCGVL & HLL was signed on 29.3.2012 (Memorandum of Agreement).

6) Requisite application for building planning approval was sent to CMDA along with drawings.

7) CMDA issued approval for new building construction work on 20.7.12 and requisite scrutiny fees and other development charges were paid to CMDA to the tune of Rs.21.22 lakhs on 26.7.12 and an amount of Rs.12.72 lakhs was paid to Chennai Corporation on 5.9.2012 towards building licence fee and regularization charges.

8) Work has been initiated in the construction site at BCGVL premises by the Contractors engaged by M/s HLL Lifecare Ltd.