Receiving Good Manufacturing Practice (GMP) certification and adhering to global regulatory norms would remain a distant dream if a company’s infrastructure is not up to the mark. Infrastructural up-gradation, as directed by these norms, is not a cake walk and many aspects need to be considered before making any structural changes in a manufacturing plant or lab facility.
Old is gold?
Global regulatory norms and GMP requirements are increasingly getting more stringent and so do the modifications required in the manufacturing plants. Pharma manufacturers have two options while complying to these norms, either modify the existing plant or set up an altogether new facility. In either of the cases, a considerable investment is involved. Setting up a new plant would escalate the cost but will also allow the manufacturer to introduce latest technological advances in the manufacturing plant.
“Constructing a new plant is a better option in order to have latest design, structural benefits and energy conservation possibilities,” opines Sanjay Singh, SVP Operations, Aurobindo Pharma.
There are many domestic and multinational pharma manufacturing plants operational in India for decades. Domestic companies willing to tap the world market tried to upgrade themselves as and when demanded by global regulatory bodies. As per industry experts, the main focus of overseas regulators is on hygienic conditions at the plant. However, the plant’s overall structure is also important because it houses all the sensitive operations undertaken by manufacturers. Whether to upgrade the existing facility or to construct a new plant is solely decided by the company management but, it is usually believed that setting up a plant would be a more feasible option.
|“The biggest hurdle in modifying existing plants is to stop/ suspend production for six to 12 weeks.”
Former Dy Drugs Controller (I) CDSCO and advisor to pharma companies in India
Kapil Bhargava, Former Dy Drugs Controller (I) CDSCO and advisor to pharma companies in India, says, “The biggest hurdle in modifying existing plants is to stop/ suspend production for six to 12 weeks. In case a fast moving product is made in such plants, the company will not take the risk of suspending production. Suppose a plant is 25-year-old, it must have undergone several modifications already. Further modification is rather difficult. In my opinion, a better and safer option would be to make a new plant that can sustain GMPs for 15 years or so. This may cost 30-40 per cent extra and I feel this would be worth spending.”
|“We have to change the mentality right from the top management and train each working professional on different aspects of cGMP, GLP, regulatory, data integrity etc.”
Founder & Director, Raaj Global Pharma RA Consultants
“Both options are feasible,” says Rajashri Ojha, Founder and Director, Raaj Global Pharma RA Consultants. Ojha is a regulatory Affairs (RA) and GMP expert and conducts audits, compliance workshops and trainings for pharma companies and CROs. She adds, “It purely depends on what kind of products are being planned. Capacity will also be an issue. Targeted markets like the US, Europe, the UK, Canada or ROW would also impact this decision. If the existing plant meets all the above requirements except the manufacturing capacity then you may expand the existing facility or you may think about constructing a new plant.”
Role of consultants and architects
Expansion or construction of a new plant involves many technical aspects. Architects, project managers etc need to be roped in to design and execute the construction of the plant. Consultants also play a crucial role in deciding the further course of action.
Singh says, “Many Indian and international consultants have expertise in the specific field of formulation or API manufacturing. Architects play a crucial role in designing the facility to have better man, material and scrap flows. Project managers keep track of review of the project at a defined frequency to identify any bottle necks / roadblocks and the ways to resolve them.”
Most company managements and boards of directors depend on their own production and engineering personnel to head such projects. Companies do engage consultants mainly for conceptual designs / drawings for all aspects depending on a company’s strengths and management approach. Bhargava explains, “At times there is a possibility where the new head of the company is purely from a finance or marketing field. In that case the management would like to appoint technical consultants mostly on a turnkey basis. Architects are generally not employed by companies and are hired from outside. They generally toe the line of management and do not offer what is concrete and correct. Project managers are basically executors and are also involved in machine selection and further stages of project execution e.g. completing their part of validations etc.”
|“It would be difficult to come out with a scheme for subsidy on facilities.”
Director, Oncology & Biotech facilitites, Technolutions Projects
“This is a bit of an issue. A pharma facility is much more than just an RCC structure,” opines PK Kulkarni, Director, Oncology and Biotech facilitites, Technolutions Projects. Kulkarni has designed many US FDA approved plants.
According to Kulkarni, many companies in the past first constructed the buildings based on a rough sketch or estimate by senior experienced managers and installed the operational hardware later on. Consequently, companies fist approached architects. Kulkarni informs, “However, with more emphasis on Quality by Design (QbD) and a much higher insistence of Quality Assurance (QA) by all regulators, the trend is now to design custom built flexible plants and laboratories. The manufacturing and research professionals, QA/RA experts and pharma engineers are playing a much bigger role than architects.”
Infrastructural shortcomings or defects have always given sufficient fodder to regulatory authorities to keep pharma companies companies on their toes, more so when such issues lead to contamination or quality compromise in manufacturing plants.
“Infrastructural shortcomings in buildings and premises are commented upon adversely only when these are not capable of avoiding contamination, cross-contamination and mix-up. Indian regulatory bodies take this more seriously as lay-out is to be further approved by them. They treat infrastructural defects as violation of condition of license, which may warrant penal action. According to me good neat and clean, well maintained and adequate size premises and support system will meet any GMP regulation. Operations are to be made safe for product as well as for patient. Such defects are not tolerated by any agency if critical products such as injections and other biological / critical care products are produced,” says Bhargava.
Is government funding an option?
The Indian government has high expectations from the pharma industry. Supply of cheap medicines is one such demand and there is no doubt that its help in reducing operational cost would definitely help in lowering drug prices. Should the Indian government (centre and state) arrange for subsidy/incentive schemes for pharma companies to set up their plants or is it already in place?
“There are no such incentives. It would be difficult to come out with a scheme for subsidy on facilities. It may be possible on products since a plant can produce many products,” says Kulkarni.
Ojha says, “Currently I am not sure whether we have government incentives or subsidy schemes for setting up of plants in India. However, it would be a good idea if such schemes will be made available in future. In India we have enough talent and many pharmacists who are jobless can start their own small scale manufacturing units. A holistic approach should be considered while building a plant. Sufficient market survey and regulatory intelligence should be gathered and people should be trained to take up the challenge and risk in life.”
In comparison with their global peers, Indian manufacturers have generally opted for less complex moelcules . This is mainly because an increase in complexity leads to an increase in the investment. However, there is one view that since Indian players mostly focus on the the generics side of the business, the cost is contained to a greater extent. Thus Indian pharma companies would seem to be capable of self-financing their capex requirements and government incentives may not be required.
“I think Indian companies do not need subsidies,” opines Bhargava. He explains, “I feel our current pharma industry is capable of generating their own resources for upgrading / re-modelling their infrastructure, if there is strong will and the commitment from management. The companies must have commitment to make good and safe products and demonstrate such an attitude.”
Bhargava adds, “We produce mostly generic formulations, our operations are rather simple and it is not as complex to design manufacturing plants. Whereas in Europe and other developed countries, the formulations are specialised and plants are made to suit such operations. Automation is also designed in that manner. The machines and other support systems are computer controlled or atleast computer assisted. They are geared more towards good automated manufacturing practices (GAMP). We make more versatile plants so that the number of simple or even complex products can be produced there. Our Small Scale Industries (SSI) or such companies have not even today understood the importance of contamination and cross-contamination and have not paid much attention to workers’ comfort and safety, whereas this is an important aspect in western countries. Automation and computer assistance in manufacturing is slowly creeping in and may take 10-12 years.”
Uncalled for warnings
India has the highest number of US FDA approved plants outside the US. But of late, India’s share of inspection observations (483s) and import alerts is larger than other countries. Is it because the infrastructure is outdated and becomes obsolete very fast? Are pharma managements unable to/cannot keep up with the change in technology?
“There is an increasing concern about the large number of observations and warning letters issued by the US FDA to Indian pharma manufacturers. A closer look at these observations shows that most Indian pharma manufacturers are struggling with maintaining data integrity and updated records. The US FDA does not discourage the largest producer of generic pharma products. At the same time, they wish to have quality products and will enforce their quality standards,” says Singh.
Bhargava says, “India having the largest number of US FDA approved plants is mostly due to the fact that we supply APIs to several countries. I feel formulation plants will constitute 25-30 per cent of total number. 483s issued to our sites are not due to suboptimal infrastructure; they are more on aspects that we do not follow like good practices. We take things for granted, our data is not considered reliable and we are not able to demonstrate that we are honest in our operations and activities.”
Bhargava adds, “We try to be in readiness more for inspections and not at all times. If you go to the warning letter site of the US FDA you will hardly find comments on infrastructure. The US FDA therefore expects more of automation so that mistakes can be traced back. Our managements probably are not confident of implementing a zero defect approach and not too willing to install for computer controlled systems. They are more comfortable with high speed, less automation and minimal computer assistance.”
Kulkarni echoes Bhargava’s views, opining that the insistence on data integrity is actually a shame for India. He says, “There is no problem at these plants as far as hardware is concerned. It is the problem of software, mainly attitude, aptitude and transparency in everything we do.”
Ojha further analyses the reason behind warning letters. She says, “The reason being that lack of knowledge, improper on-job training, non-compliance and attitude and behavioral problems. We have to change the mentality right from the top management and train each working professional on different aspects of cGMP, GLP, regulatory, data integrity, electronic data/records handling and maintenance system as per 21CFR part 11. Also, we need to train them on soft skills, people management, motivational skills etc. The quality system should be in place along with a risk, mitigation plan. The training should be continuous as technology is evolving and many rules and regulations change frequently. People should be trained on country-specific cGMP and regulatory requirements.”
Not just about infrastructure
Infrastructure would hold little value if skilled manpower is not there to operate it. India has many pharma educational institutes, however, finding the right talent, at the right place, at the right time is still a challenge for recruiters. The industry’s needs and courses offered at the institutes hardly keep any pace with each other.
Singh feels that the Indian pharma industry is gearing up on this aspect and many training programmes and workshops are being conducted to make the pharma fraternity aware of the latest trends in the field of pharmaceutical sciences.
According to Kulkarni, Indian companies have not yet placed the same premium on training as on production equipment as far as funds are concerned.
There are many industrial zones and Special Economic Zones (SEZs) in the country. Though recent warning letters to Indian pharma companies are mainly due to quality related issues, manufacturing facilities and its premises that provide space for various operations should also be properly taken care of. As discussed, experts from different fields are involved in making plants functional. It should be the prerogative of these experts to develop the infrastructure for the Indian pharma companies that will stand upto the expectations of not just Indian but also global regulators.