Kapil Bhargava, Former, Dy Drugs Controller (I) CDSCO, elaborates on India’s journey in pharma sector post independence till today
In earlier years (1940s and 1950s) manufactured formulations were tincture spirits, pills and ointments. The pharmacy practice was centred to compounding the powders (prepared either from medicinal powders or by pulverising the pills) and dispensed in folds of butter paper. Students were even taught in pharmacy classes as to how to make a ‘neat paper packet’ for patients.
Manufacturing was centred in the eastern part of India, mainly Kolkata and few other towns of Uttar Pradesh (both having a strong presence of industry climate). This was probably because pharmacy education started in Banaras Hindu University (1950s). In Kolkata, Dey’s Medical Store used to be main retail pharmacy along with a few smaller ones. After retail dispensing and practising pharmacy, companies thought of manufacturing and producing some liquid oral preparations. Around the same time, few of the companies from western world (mostly the UK and the US) got attracted to India and set up their plants in India. Squibb chose western part (Baroda) while others like Martin & Harris and Organon set up plants in Kolkata and number of others were concentrated in Mumbai. This was in early to late 50s in the 19th century. Manufacturing in other cities also sprang up and a number of tiny manufacturing sites (again promoted by retailers and whole-sellers) produced mostly liquids and syrups to sell in the local markets and manufacturing license were also granted to these units.
The regulations
Conditions for granting license were mentioned in Drug Rules and were also mentioned in a separate schedule of the rules. A few details were mentioned in a separate schedule, a Schedule M of Drugs & Cosmetics Rules, which was then sub-titled as ‘requirements for manufacturing premises.’ Except few conditions such as minimum area needed and list of some machinery, it did mention about other details of pharma manufacturing.
Smaller factories manufacturing formulations were mostly located in residential areas . In SSI, the procedures were mostly manual or partly mechanical and a general cleanliness and hygiene was expected to be maintained.
Gradually few international medicinal products were manufactured here. Tablets and other formulations were manufactured mainly in western part of India. Penicillin was then a recent antibiotic and sulphonamides were anti-bacterial. Though penicillin was considered a sensitive medicinal product, the words ‘contamination’ and ‘cross-contamination’ were not common. Schedule M then, did not mention any of these conditions which need to be adopted by manufacturing sites. Multi-national companies operating in India followed their principle’s manufacturing document for safer products which mainly were manufacturing procedures (Manufacturing practices and operating procedures were not popular terms).
The progression
As years passed, product range also expanded. Antibiotics, hormones, anti-cancer and other very sensitive category products viz. corticosteroids, were being manufactured in form of oral preparation (tablets capsules and liquids) and parenteral preparations both. Bigger companies introduced manufacturing practices and operating procedures which later were called as good manufacturing practice (GMP) and standard operating procedures (US FDA further added the word ‘current’ as for them good was not enough).
GMP regulations thus have come a long way since its introduction in 1960 by Canadian Authorities which started as QUAD programme. In India, GMP acceptance spurred by serious events of contaminated IV Fluid in UP (BJ Pharma Kanpur) and Gujarat (Sanitex Baroda) in early 70s (1971 – 1975) resulting into deaths of a number of patients. Regulators here realised the dangers to patient community due to quality failures in manufacturing. They realised that poor quality medicines are not only a health hazard, but a waste of money for both governments and individual consumers. A poor-quality medicine may contain toxic substances that have been unintentionally added. A medicine that contained little or none of the claimed ingredient will not have the intended therapeutic effect. They realised GMPs as regulatory codification of generally known quality principles.
Since mid-70s, WHO has been supporting medicines supply to various countries (mainly prophylactic vaccines and other diseases like malaria and tuberculosis) and was procuring medicines from manufacturing locations spread over several countries. It introduced scheme of certification of pharmaceutical product (COPP) moving in international commerce. For this scheme, ensuring GMPs was essential.
World Health Assembly in 1975 (WHA 28.65) published GMP text that was titled “good manufacturing practice and quality of drugs.” This text was implemented for ensuring GMPs for purpose of grant of COPP. Since India did not have a GMP text of its own, the Indian companies participating in COPP scheme and the regulators, followed ‘good manufacturing practice and quality of drugs’ document for ensuring GMPs.
The GMP regulation
In mid 80s, work began to draft GMPs for India and revise the then Schedule M. The initiative taken and guidance provided by the then Drugs Controller India, Dr PK Gupta. Schedule M was revised in 1988 and was sub-titled as Good Manufacturing Practice instead of ‘requirements for manufacturing.’ It addressed a number of vital quality issues which were earlier taken for granted. These, besides other factory act requirement, were manufacturing operations and controls precaution against contamination, mix-up and quality control system. Cross contamination issue was addressed emphatically and adequate segregation of contamination causing ingredients appeared for the first time as a part of GMP.
Since early 90s, Indian companies were exporting their products to 100 plus countries. New manufacturing locations emerged and companies were constructing bigger and better factories, providing better manufacturing environment. Indian companies were also venturing into API manufacturing to reduce their import dependency. There was an improvement in manufacturing equipment quality. With the advancement of NCEs, newer and potent molecules were being formulated for patients and GMPs were being enhanced by the manufacturers. Quality concept graduated from ‘quality control’ to ‘quality assurance.’ GMP text was under revision once again for ensuring more rigorous controls. For other regions of SouthEast Asia, WHO took initiative and published ‘Specifications for Pharmaceutical Preparations’ in 1992. It addressed vital activities such as quality assurance, validation, water systems, air-systems, self-inspection and many others. It also spelt out GMPs for APIs. Once again Dr PK Gupta was mainstay for compiling this on behalf of WHO.
Since India’s drug control administration and government machinery supported GMP implementation and was bringing this to forefront of regulatory supervision, it started revising Schedule M. In doing this, stake-holders including manufacturers form SME were invited to participate in drafting Schedule M. The final version was published in December 2001. Since changes were quite a few, good briefing through workshops and seminars was given to manufacturers and regulators by CDSCO. The revised Schedule M was made applicable since January 2004 and is under implementation today.
Current scenario
India’s capacity to supply generic medicines to even advanced countries during the past ten years or so have increased manifolds. Newer quality concepts emerged and Indian manufacturers have positioned themselves in advance science-based products adopting recent technologies. Quality concepts have improved and there is an effort to further revise Schedule M. The first draft has been published for public comments. Though patchy in contents at places, it is appearing to be graduating from ‘quality assurance’ to ‘quality management system’ incorporating the designed to minimise the risks involved in any pharma production that cannot be eliminated through testing the final product. It has emphasised that good quality must be built in during the manufacturing process and cannot be tested into the product afterwards.
In the past 70 years, since independence pharma manufacturing has seen huge changes and have given good products to ailing community. Manufactures and entrepreneurs today have understood that GMPs prevents errors that cannot be eliminated through quality control of the finished product. Without GMP it is impossible to be sure that every unit of a medicine is of the same quality as the units of medicine tested in the laboratory. Quality management is not merely quality control, it mostly concerns quality assurance and QA gives confidence for GMPs. All concerned have realised that making and distributing poor quality medicines leads to loss of credibility for everyone, both public and private health care and the manufacturer.
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