Special Feature

Special Feature

Good and better

The continual compliance of cGMP is a subject which deals straight with the human life by helping to maintain consistent quality of the drugs produced. Sonal Shukla tries to find out the importance of continual compliance and the roadblocks in the process

No one in the pharma industry can deny the significance of Current Good Manufacturing Practices (cGMP) in drug manufacturing units. Being viewed as a preventive measure, non-adherence to cGMP norms can lead to cross contamination and affect the quality of the drug. According to Dr Nandkumar Chodankar, M D of Sekhsaria Chemicals, cGMP goes beyond mere sample testing. “Sample testing is not a solution because the sample which is tested is no more available for consumption. One cannot test each unit of medicine like for example unit tablet or unit capsule before swallowing it, as there is no way to test and then to consume it.” The only way to ensure quality is by following cGMP.

There is yet another interesting angle to the increasing importance of cGMP in India. That would be the big export pie the industry is eyeing. Increased competition in this arena is making pharma companies opt for regulatory approvals and improving production standards, which are tickets to global trade. The competition is such that just with local Schedule M compliance, it is difficult to survive in the competitive environment. “The need for continual compliance is largely to wither the competition,” believes Mehul Shah, MD of Encube Ethicals. Unless one complies with cGMP on a continual basis and exports to regulated markets, long-term survival for a drug manufacturing company in India is difficult, he opines.

The approvals are given by regulatory bodies like USFDA or UK MHRA for two to three years. “If the manufacturer is not following continual compliance the renewal gets affected as regulatory bodies will not renew the facility,” says Shah. After getting the compliance accreditation from regulatory bodies, the status checks done depends on the type of deficiencies or observations.

Accreditation by regulatory bodies is perceived as a way of investigating whether the manufacturer follows cGMP or not. These regulators are expected to inspect the quality assurance systems/cGMP norms followed by the manufacturer based on the applicable guidelines. This can be helpful if these audits are taken seriously both by the regulators and the manufacturer. During these audits, the inspector carefully checks the quality of the people, quality systems followed during product development at all the stages of manufacturing and testing. Such inspections lead to approval of the facility or identification of deficiencies (resulting in observations called 483’s), or warning letters (serious or critical errors or frauds), re-inspections, injections to shut the facility.

Big or small

Is cGMP the only for companies who want to take the global share from the regulated markets? cGMP is something that requires consi-derable investments. “If one is prepared to invest for four to five years, only then he can get the benefits. Thus, for a small company, it could be difficult,” asserts Shah. But does it mean that small companies do not comply with the norms? As per industry experts, there are cases where a manufacturer does not give importance to cGMP norms or adhere to the norms only substantially.

However, cGMP practices go beyond small or big companies. As medicines manufactured by small pharma or big pharma cannot have different standards, they cannot have different cGMP requirements. “There should be improvement in the level of implementation of uniform cGMP norms. One must understand that if one wants a quality product, it is going to cost little more. A simple example—if one has a heart disease, and substandard medicine is consumed, it is not going to benefit, and can result in a disaster,” says Chodankar.

Uniform application of all the rules and regulations is required irrespective of the size of the company. The basic requirements of cGMP must be followed by one and all. There are a few non-flexible requirements, which are to be justified by the manufacturer before implementation. cGMP involves cost. However, what is not understood is the magnanimity of the loss that could result if cGMP is not followed. “The downside is too heavy and can wipe of everything and result in loss of human life and permanent disability,” says Chodankar.

Why not?

Irrespective of necessity, there could be many factors responsible for non-adherence of cGMP norms. Most of the industries, which started a few years back, manufactured pharmaceuticals without implementing cGMP, because it was not mandatory. Testing was the only means of accepting the quality (quality control). In fact, many a times, if the first sample of the product failed to meet the quality, second sample was tested and this continued till the next sample passed the required quality test. “This was due to lack of understanding. However, this has become a habit. Things continue the same way without realising that this can result in a disaster and it would be too late to take corrective action. Most of these industries do not realise the consequences of an error,” opines Chodankar.

Other factors include lack of understanding of cGMP norms and the logic behind them, changes or continuous improvement in the norms and regulations.

Yet another issue is the high attrition rate amongst trained personnel. cGMP requires documentation of each and every activity and thus requires trained human resources. Training adds to the cost of the product, which makes companies side-track cGMP norms. Also, pressure from the customer for quick deliveries can affect adherence. Manufacturing activity requires validation of all critical systems and processes and thus, requires time and resources. In order to introduce the product to the market quickly, these norms are put aside. Quality has to be built in the product and this requires time for designing product (R&D), specifications, and knowledge of the critical process parameters, impurity profile, toxicity data and many more things.

Implementing cGMP

Implementing cGMP is a step-by-step process. The manufacturer has to study the cGMP guidelines, check appropriate means to implement these guidelines and quality assurance systems, have a cGMP policy in place and continuously train the staff involved in all activities of manufacturing. cGMP system takes off from the product development stage. Finally, all the analytical methods like cleaning, change control systems, computer systems, preventive maintenance systems, self-audits need to be validated and continuously evaluated to maintain the state of compliance.

Qualification must be carried out at every stage like design qualification, installation qualification, operational and performance qualification. cGMP implementation depends on the nature of the product, mix of products that are manufactured in the same facility, design of the product, design of the equipment, the documentation and the data that is generated, the discipline that is followed, training that is given to the personnel and attitude of the people. “It is a process of continuous improvement. You can start from Schedule M or ICH guidelines or Orange guideline of MHRA, or WHO GMP guideline, and it does not matter. There is no ideal cGMP as it can be improved continuously,” says Chodankar.

There cannot be different standards in the norms of cGMP. However, every manufacturer can define the criticality of the cGMP, which is to be followed. Chodankar sights an example of a company, which has been manufacturing aspirin as the only product for a number of years. The staff is experienced and is trained for the critical functions. If the process has not undergone any major change and if there are no product failures, product recalls or quality complaints, it could be considered that minimum cGMP norms are met. However, if it is found that even after batches starts failing, investigation and root cause analysis is not done, and corrective measures are not taken, then cGMP is not followed. In addition, in cases where a company manufactures two kinds of medicines in the same premises, cGMP norms are a must due to cross contamination issues.

Training right

Training is the most important part of cGMP compliance. ‘One must understand that one can spend millions of dollars on plant and machinery. However, if the people, who are supposed to use this machinery are not trained, they can push a wrong button and the result can be a disaster,’ asserts Chodankar. A few of the associations like IPA, IDMA, DIA conduct regular conferences, workshops, training courses in India. There are a number of experts, who visit India on regular basis to give in-house training.

Mehul Shah of Encube Ethicals strongly feels that government has to take part in conducting training prog-rammes. Though USFDA consultants conduct such training programmes, they are way too expensive for small companies. The number of seats at post graduation in master pharmacy and PhD level should also be increased. Furthermore, internal self-audits are to be taken seriously and done at regular intervals. Management should take proactive steps to ensure cGMP. “If the idea is to serve the society with a win-win concept, one can achieve the goals. One of the most important parts is to inculcate CGMP norms in the minds of the staff. Quality assurance systems, and organisation’s policies, must flow from the top. The top management must be clear about the objectives, mission, and vision,” asserts Chodankar.