Why Quality of medicines in India can not be taken for granted

- Ganadhish Kamat

Introduction

India is considered as the Pharmacy of the world and supplies high quality medicines to countries world over. While Indian drug manufacturers are capable of supplying high quality medicines at low price, can all the medicines available in India be considered to be of same quality? First of all, how do you define the quality of medicines? 

Applying simple definition of Quality, "Fit for the purpose", a good quality medicine should produce desired effect after administration (Efficacy) without producing any undesired & harmful effect (Safety). Incase of products such as apparels, footwear, consumer products, food articles, electronics etc, consumers can judge the quality themselves based on sensory evaluation or evaluation of performance by actual use. If they are not happy with the quality, they have choice of not buying the product again or even sometimes returning it. This however is not possible for consumers of medicines (patients). Except in case of few medicines where there are visible symptoms, patient won't know whether the medicine is effective or not unless diagnostic tests are performed. In some cases they may get the effect but that may not be optimal. In case of emergency use medicines, there is no second chance and if the medicine doesn't have desired effect, the patient may loose the life or develop disability. It is even more difficult to detect undesired effects. For example carcinogenic or genotoxic impurities if present in the drug may show their effect long after the treatment is stopped. Presence of microbial contamination in injections may cause serious health hazard but such contamination comes to light when it is too late. Because of such high severity of impact of poor quality of medicines, it is imperative to establish adequate controls on the quality of medicines. 

Quality of medicines   

As mentioned earlier Efficacy and Safety are two facets of Quality of medicines. 

Efficacy of the medicines depend upon many aspects such as presence correct drug (active ingredient) in right amount as stated on the label, rate of dissolution or drug release after administration, rate of absorption of the drug in the blood stream to maintain right amount of plasma concentration etc. The rate of dissolution or release and the rate of absorption depends on the inactive ingredients (excipients) used in the formulation, their grades, particle sizes, quantities, sequence of addition, uniform distribution, various processing parameters etc. Sometime the drug may exhibit polymorphism (present in two or multiple crystal structures with varying orientations or conformations). In may cases only certain form may be active and other may be inactive or even toxic. For example L-propranolol is an effective beta blocker, while D-propranolol is not. Incase of anti tuberculosis drug Ethambutol, the (S,S)-(+)-enantiomer is effective, while the (R,R)-(-)-enantiomer can cause blindness. So the presence of right amount of drug in the tablet or capsule is not enough to demonstrate efficacy of the drug. The efficacy of the dosage form (tablet/capsule/syrup/injection/eye drop etc) requires -

1. Right drug in right form 
2. Correct amount as per the label
3. Right combination of excipients (correct quantities, grades, particle sizes etc)
4. Correct processing as per the validated process (correct order of addition, uniform distribution, process parameters as per the pre-established validated limits)
5. Right packaging
6. Proper Storage and Transportation conditions

Safety of the medicines depends upon following factors in addition to all mentioned above -

1. Absence or rare occurrence of serious adverse reactions and low incidence of other undesired actions from the drug itself
2. Absence of unwanted form of the drug or presence below safety level established by toxicity studies.
3. Control of any impurities  below limits established by tox studies, or levels specified in ICH guideline. 

While the drugs are designed so as to have maximum desired effect and minimum undesired effects, almost all the drugs have some or other adverse effects. Most of the times these undesired effects or adverse events are not serious such as drowsiness caused by some antihistaminic drugs or gastric irritation caused by NASAIDs and occur in small percentage of patients. Under rare circumstances however the drug may produce serious adverse reaction in very small percentage of patients such as anaphylactic shock caused by penicillins and cephalosporins which may even result in death. The desired effects as well as all the undesired ones noticed during clinical trials are taken into account while deciding about the approvability of a drug by regulatory agencies by means of risk/benefit analysis. 

The impurities in the medicines can be of various types and can come from different routes. Broadly they can be classified as below -

1.  Process impurities - Impurities generated during the manufacturing of the drug such as -
1. Unreacted starting materials
2. Metallic impurities coming from the equipment, starting materials and catalysts used in the process
3. By-products
4. Drug excipient adducts
5. Residual solvents
2. External contamination / cross contamination - Such impurities may include -
1. Particulate & other contamination from equipment, environment, personnel, processing aids, raw materials etc
2. Cross-contamination with traces of other drug made using same area/equipment due to inadequate cleaning of area and equipment or faulty design of area and air handling system.
3. Microbial contamination from environment, personnel etc due to poor facility or process design, inadequate gowning, inadequate cleaning etc. 
3. Degradation products - All drugs are prone for degradation on storage or handling due to exposure to heat, moisture, light, oxidative agents, acidic or alkaline environment. Such degradation results in fall in purity (potency) of the drug and increase in impurity levels. Such impurities are called degradation products. 

All such impurities can lead to undesired effects on the patients. For example, Para Amino Phenol, an impurity which can be present in commonly used drug Paracetamol, can cause genetic defects. It can also cause methemoglobinemia, which can lead to headaches, fatigue, dizziness, and blue skin and lips. High level of this impurity can cause breathing trouble, collapse, and even death. Presence of Heavy metals lead, mercury and arsenic can have many toxic effects on humans such as brain damage, memory loss, abnormal heartbeat, neuropsychiatric disorders, kidney damage, liver damage, anemia, miscarriage, reproductive organ damage, and female fertility defects, increased risk of developing cancer, skin lesions, gastrointestinal dysfunction, abdominal colic pain, bloody diarrhea, cardiovascular toxicity. Presence of traces of solvents such as benzene, methylene chloride etc can cause various types of cancers, liver and kidney damage.  

 

For common impurities such as metallic impurities and solvents, globally accepted safe levels have been established through efforts of International Conference on Harmonization (ICH) with participation of global experts and based on toxicity studies carried out on animals. Safety levels of possible impurities and degradation products specific to the drug and the process are established by performing toxicity studies in animals by the manufacturer during drug development. 

When a new drug is developed, the efficacy and safety of the same is established first during pre-clinical studies carried out in-vitro studies and in animal studies. Same is confirmed during the clinical trials. 

For the generic drugs, the efficacy and safety is established by demonstrating Pharmaceutical equivalence to innovator drug. This involves demonstrating that -

1. The drug present in the generic drug product is identical (same chemical structure, same form) to that in the innovator medicine.
2. The drug product does not contain impurities higher than those found in innovator medicines or levels prescribed in ICH standards throughout its shelf life (demonstrated by conducting stability study under controlled conditions). If any new impurity is identified due to difference in the process, its safety levels are established by performing toxicity studies in animals.
3. In case of orally administered drugs the product is bioequivalent (plasma concentration achieved with respect to C-Max and T-Max is similar) to the innovator drug.
4. In case of products such as injections, eye/ear drops etc equivalence is demonstrated by comparing the formulations with the innovator. 

Obviously such methods of demonstrating efficacy and safety cannot be used for routine quality control of drugs. For routine testing of commercial batches, scientifically sound specifications and test method are developed and validated. If the product meets the pre-established specifications, when tested using such validated methods it can be considered to be safe and effective. 

A typical specification for drug substance (Active pharmaceutical ingredient) includes tests & limits following characteristics (Quality attributes) -

• Description
• Identification 
• Solubility
• Optical rotation
• Polymorph
• Water content
• Assay (purity/potency) 
• Organic Impurities
• Chiral impurities
• Residual solvents
• Metallic impurities
• Particle size distribution
• Microbial limit tests
• Endotoxin (If intended for use in injections)

A typical specification for solid oral dosage form (Tablet/capsule) includes tests & limits following characteristics (Quality attributes) -

• Description
• Identification
• Dissolution rate
• Water content
• Assay
• Impurities (Degradation products)
• Residual solvents (If solvents are used in the process)
• Microbial limit tests

Incase of injectables there are tests such as sterility and endotoxin in addition to tests mentioned above.

Drug approval process & Regulatory controls on quality in advanced countries (and most of the developing countries)

When a manufacturer submits an application for seeking marketing authorization of a new drug or generic drug in all advanced countries and most of the developing countries, they have to submit all the experimental data generated during drug development to demonstrate the safety and efficacy of the drug and adequacy of their controls to assure the quality. This data includes (but not restricted to) -

• Complete characterization of the drug substance, 
• Impurity profiles,
• Scientifically sound specifications for the drug substance and drug product,
• Validated test methods which have been demonstrated to be stability indicating, 
• Specifications and source of the excipients used,
• Detailed formulation (composition) and manufacturing procedures including critical control parameters for the drug substance and the drug product,
• Data of forced degradation studies,
• Multi-media dissolution profiles ,
• Summary of drug development (Critical Quality attributes, Critical material attributes, Critical Process parameters, Control strategy etc),
• Exhibit (test) batch records including results of all test conducted on the same,
• Stability data for the drug substance and drug product generated as per the climatic zone and at accelerated conditions,
• Data & controls to demonstrate sterility assurance incase of sterile products,
• Data of Clinical trials / Bio-equivalence studies,
• Packaging configuration and packaging material specifications

All above data is thoroughly evaluated by the experts in regulatory agency to assess its adequacy before decision is taken to approve the drug application or granting marketing authorization. If any deficiencies are identified in the submitted application, same are notified to the manufacturer and till the satisfactory corrections are done (by way generation of additional data, modification of controls, tightening of specifications etc) the application is not approved. 

In addition to the review of application, the regulatory agencies conduct pre-approval inspection of the drug substance and drug product manufacturing sites to verify the authenticity of the data submitted in the application, compliance to Good Manufacturing practices, readiness of the site for commercial manufacturing of the product. If any critical or several major deficiencies are identified during the inspection, it may result in withholding approval till the identified deficiencies are satisfactorily addressed by the manufacturer.  Sometimes such inspections are waived if the site was inspected in recent past and outcomes were satisfactory.

Drug approval process & Regulatory controls on quality in India

Unlike most of the countries, Indian regulatory system follows dual approach. As per the Indian drug laws, there are two drug regulatory organizations, one at the center called Central Drug Standards Control Organization (CDSCO) and other at the states, Food and Drug Administration (FDA). These Central and State agencies fall under respective health ministries and hence are largely independent of each other. Their responsibilities also differ quite a bit. Under the Drug and Cosmetics Act, the CDSCO is responsible for approval of New Drugs, Clinical Trials in the country, laying down the standards for Drugs, control over the quality of imported Drugs, coordination of the activities of State Drug Control Organizations and providing expert advice with a view to bring about uniformity in the enforcement of the Drugs and Cosmetics Act. CDSCO is also responsible for approval of licenses of specified categories of Drugs such as blood and blood products, I. V. Fluids, Vaccine and Sera. On the other hand the state FDA is responsible for regulation of manufacture, sale and distribution of Drugs in their state. In addition state FDA has dual role of controlling the quality of food. Thus while CDSCO is responsible for new drug approval, state FDA is responsible for granting license for manufacture of drugs which are more than 4 year old in the country. This 4 year clause is quite irrational and unscientific. 

For the new drug approval, CDSCO is required to follow the process described in NDCT rules, which is largely aligned with the process followed by advanced countries. The quality of the review however is questionable looking at the some of the approvals granted for new drugs in recent past, type of deficiencies identified in the review process. There is also no rigorous pre-approval inspection to verify the authenticity of the data submitted in the application. This is evident from the fact that while foreign regulatory agencies such as USFDA identifies significant violations in Indian firms including, data falsification, back dating, destruction of GMP documents, compromises in sterility assurance etc, inspections conducted by Indian regulators rarely identify them. There is also lack of transparency as the results of clinical trials and rationale for approval etc are not available for public scrutiny. 

The process followed by the State FDAs is worse. First of all there are no written rules which they are required to follow for grant of license. This results in wide variability in the process followed in different states. To illustrate this I have given below a table to compare the documents a manufacturer is required to submit for obtaining manufacturing license in different states.

Documents required	AP	TS	MH	Gujrat	MP	HP	J&K	Sikkim
Cover Letter	Y	Y	N	Y	N	Y	Y	Y
Form 24/27	Y	Y	N	Y	Y	Y	Y	Y
Challan/Fees	Y	Y	Y	Y	Y	Y	Y	Y
Copy of approval status from DCG(I)/IP 2010/M&M permission	Y	Y	Y	Y	Y	Y	Y	Y
Copy of valid manufacturing license	Y	Y	N	N	N	Y	Y	Y
Copy of valid GMP certificate	Y	Y	N	N	N	*	N	N
Composition (unit dose)	Y	Y	Y	N	N	*	N	N
Brief manufacturing process and flow chart	Y	Y	N	Y	Y	*	N	N
Specifications and method of analysis of raw materials	Y	Y	N	N	N	*	N	N
Specifications and method of analysis of Finished product	Y	Y	Y	Y	Y	*	N	N
List of equipment (Both QC and Manufacturing)	Y	Y	N	N	N	*	N	N
Draft specimen label	Y	Y	Y	Y	N	*	Y	Y
List of technical staff	Y	Y	N	N	N	*	N	N
Consent letters of technical staff and copies of their approvals (1 QC and 1 manufacturing chemist)	Y	Y	N	N	N	*	N	N
Stability Data with valid T license copy	Y	Y	Y	N	Y	*	Y	N
Copy of authorization letter	Y	Y	N	Y	N	Y	N	N
Production block Details	Y	N	N	N	N	N	N	N

* To be provided only if requested.

Apart from the lack of uniformity in the requirements for documents to be submitted to seek product permission, the list of documents indicate that there is very little technical evaluation done at the time of granting the manufacturing license. For instance, most important documents which are required to be reviewed to assure quality, efficacy & safety of the product, namely the product development report, analytical method validation reports, justification of specification, BA/BE study report etc are not part of requirement in any of the states. Although 9^th amendment to D&C rules dated 3^rd April 2017, made it mandatory to submit BE results for BCS class II & IV drugs, same has not been implemented in most states. For the products which are not official in Pharmacopoeia, the manufacturer can get away by setting their own specifications which may not be in line with ICH requirements. It is not mandatory to include important tests such as dissolution rate for solid oral dosage forms and test for related substances, metallic impurities and residual solvents. Since it is allowed to have shelf life limit of not less than 90% of label claim for the drug content, the product may show degradation as high as 10% and still meet the specification. The degradation products formed may produce severe adverse effects if not controlled under established safety limits. In absence of BA/BE study showing that the drug product is bioequivalent to Innovator product or Reference Listed Drug there is no guarantee that the product will produce same effect as seen in the clinical trials. If the drug product or the drug substance is official in Indian Pharmacopoeia or other recognized Pharmacopoeia, the drug law mandates compliance to the official monographs. This however is not adequate to assure quality. The Pharmacopeial monographs are minimum standards a drug is required to comply with. They however don't take into account the manufacturing processes of different manufacturers which can generate different impurities as mentioned earlier. So to assure quality it is important establish suitability of Pharmacopeial monograph by carefully evaluating the manufacturing process. It may be noted that the drugs manufactured in one state can be freely sold in entire country so the FDA in a state has no control over the quality of medicines being sold in their states. 

Control of changes 

After receiving the approval for any drug, the manufacturers often do many changes to their process, equipment, source of raw and packaging materials for improving efficiency, cost and quality.  Driving such improvements is quite normal in all the industries. However, since such changes can have significant impact on the safety and quality of the drugs, there needs to be adequate regulatory oversight on the same. Regulatory agencies of advanced countries such as USFDA, EMEA, UKMHRA, TGA, have well laid down systems for categorizing and evaluating such changes based on their nature and severity of the impact on quality. These systems clearly define categories of changes, data required to be generated to support changes of different categories and nature. Some changes require prior approval from the agency before implementation of the change, while some are allowed to be implemented with notification to agency at the time of implementation or as part of annual update. No such system of controlling changes exists in India. So once a manufacturer obtains license to manufacture drug. It is free to make any changes to its process, source or specifications without permission from or information to the state or central regulatory agency. This can have serious impact on the safety and efficacy of the drugs as such changes may introduce new impurities, solvents etc and may impact the stability of the drugs. The revised Schedule M has introduced a clause which requires manufacturer to take approval for any changes from licensing authority. However system for handling such changes has not been established. The licensing authorities have not made provision for additional resources to evaluate change proposals in time. Also since the current state licensing procedure does not require to obtain all the necessary details about the process, material, controls etc as described earlier at the time of granting license, there is no way they will be in position to evaluate the impact of changes to those. 

Storage and distribution 

A drug is required to meet the specifications till the end of the shelf life. The shelf life is required to be established by conducting stability study at the temperature and humidity prescribed for the climatic zone applicable for the country where it is distributed. Incase of India the long term stability condition prescribed is 30degC and 75% RH. Most drugs are prone to degradation on storage and the stability of the drug depends at what conditions they are stored or exposed to. While short exposures to marginally higher temperature than recommended don't have impact on quality, prolonged exposures and exposure to very high temperatures can certainly result in degradation impacting the safety and efficacy. Currently there is no adequate control on the storage & transportations of medicines in India. Recently CDSCO has issued a draft guideline for comments from stakeholders. Till the guideline becomes effective and enforced across the country we have to rely on manufacturer's internal policies for proper storage and transportation. 

Recalls

In spite having appropriate controls, occasionally things go wrong resulting in risk to the quality of drugs distributed in the market. Such failures may get detected during regular stability testing (Indian drug laws do not mandate this), inspection of control samples, market complaints, investigations of deviations etc. In advanced countries, manufacturer is required to report any such issue promptly (typically within 3 days) to regulatory agency. They are also required to conduct thorough investigation to identify the root cause of failure and impact on other distributed batches. If there is risk that any distributed batches are likely to have doubtful quality, all such batches need to be voluntarily recalled in co-ordination with the regulatory agency. All such recalls are notified on the websites of the regulatory agencies. Almost every month there are news articles about some or other Indian manufacturer recalling drugs from US market. Whereas, there are rarely any news about recall of drugs from Indian markets. While Drugs and cosmetics rules mention about the recalls, there is no effective system in place in India. Even when some drugs are found to be failing in testing in government labs, the manufacturer is directed to recall only the failing drugs. While some failures could be due to batch specific issues, most are due to design problem, due to issues in the starting materials or some systemic failures and hence could impact many more batches than those detected in random sampling & testing. Every month CDSCO publishes list of around 50-60 failing drug samples but information about what action was taken on those batches and other impacted batches is not available in public domain. CDSCO website has a Tab for recalls but very few recalls are listed there mostly related to medical devices. In 2020-21 death of 12 children was reported from a hospital in Jammu due to liver toxicity. These were linked to presence of diethylene glycol (DEG) in the cough syrups they had consumed. Similarly deaths of more than 100 children were reported from Uzbekistan and Gambia in 2022-23 which were linked to diethylene glycol contaminated cough syrups made in India. Such incidences should have resulted in thorough investigation by Indian regulatory agency to identify exact root cause and extent of the problem. Most likely cause of such deaths is adulteration of propylene glycol used as an excipient in the cough syrups. Since the contamination came from the raw material it would have impacted whole batch of the cough syrup or multiple batches. Since one batch contains 10,000 to 50,000 bottles, there is possibility of impact on large number of children. Regulatory agency should have issued a nationwide alert clearly specifying the impacted product names and the batch numbers and promptly directed recall of all such batches from the market. No such actions were however taken. Only action which government took after Uzbekistan/Gambia case was to issue an order to test all the cough syrup batches meant for exports in government lab before shipment, leaving Indian citizens to the mercy of God.

Good Manufacturing practices  & Regulatory inspections

While scientific evaluation of development data and control measures by regulators at the time of granting approval is essential for ensuring that quality is built into design, adherence to Good manufacturing practices (GMPs) is essential to make sure that the manufacturing and related activities are carried out as per the design and in adherence to scientifically established systems and procedures so as to ensure consistent good quality of medicines. Adherence to good manufacturing activities also helps in preventing contamination of drugs from external contaminants, cross-contamination from other drugs manufactured in the facility, mix-ups etc. For example, if the manufacturer of cough syrups mentioned earlier had complied to GMPs, contamination with DEG would not have occurred thereby saving lives of so many innocent children. 

Adherence to GMPs is verified by regulatory agencies by conducting periodic inspections of the manufacturing sites. Regulatory agencies of advanced countries like USA, UK, EU, TGA etc mostly conduct such inspections once in two years. The exact frequency & duration of inspection is decided based on risk assessment and past inspection history. The duration of inspections vary from 5-15 days with 1-3 inspectors depending upon the complexity of the site.

Indian law requires inspections of manufacturing sites to be conducted by state FDA once in a year. Such inspections are carried out by 1-2 inspectors over 1-2 days. Obviously these inspections are quite inadequate to detect serious GMP deficiencies. Couple of years back CDSCO started risk based inspections of manufacturing sites. As per last report, CDSCO conducted inspection of around 400 manufacturing sites. Approximately 1/3rd of these sites were found to be operating with serious violations of GMPs warranting their shutdown. This clearly shows inadequacy of the inspections by state FDA. India has around 10,000 manufacturing sites most of these are run by MSMEs. Some of these are manufacturing drugs for large scale companies under contract manufacturing agreement. If we extrapolate findings of CDSCO inspections to all sites, we can expect more than 3000 sites to be operating in violation to GMP norms. At the pace of 400 inspections per year, it will take forever for CDSCO to inspect all the facilities. India has around 600 manufacturing sites approved by USFDA. Most of these are operated by large scale companies and are expected to have better compliance as compared to other sites. USFDA inspections have many times identified serious GMP violations including falsification of data, destruction of GMP documents, risk of cross-contamination, inadequate controls on sterility assurance, inadequate investigations etc. resulting in actions such issue of warning letter or import alert. I don't remember seeing any similar actions taken by Indian regulators (central or state) on these sites. Unlike USFDA where inspection reports are available to public through Freedom of information (FOI), Indian regulators do not share inspection reports. So it is difficult to assess the depth of inspections, kind of deficiencies identified and kind of risks they pose to public health. 

Conclusion

In the article, I discussed about what the quality of medicines really mean and how our regulatory controls (the drug laws and their enforcement) are inadequate to guarantee it in the drugs distributed in Indian market. Some may argue that if the situation is so bad, how come patients are recovering and why large number of deaths or serious issues are not getting reported. While the regulatory system is inadequate, it doesn't mean all drugs will be of bad quality. Only a small percentage are likely to be of bad quality to produce noticeable adverse health outcome. Secondly my experience show that there is very low reporting of Adverse Drug Events (ADEs) in India. In a year, large companies where I worked, used to receive less than 10 ADEs from Indian market in entire year. Whereas from US market we used to receive more than 100 every month, of course most of them where known side effects of the drug. This show that neither the patients nor the healthcare givers report ADEs observed in the patients. Another issue in India is very low rate of Medical  of Cause of death (MCCD). Figure below taken from Government of India's report on MCCD for year 2020, show that most states have MCCD below 25%, few between 25-50% and only 3 above 80%. So when a cough syrup batch of 10,000 bottles is contaminated with DEG, it is not possible that only 12 children were affected but it more likely that all those affected were not identified and traced to the contaminated batch. 

While many pharmaceutical firms in India have high ethical and quality standards and establish scientifically sound controls to assure quality of medicines, some of the manufacturers do bare minimum to merely comply with the laws of the land while some even take shortcuts in adhering to already lax laws. Indian citizens can not be left to the mercy of the manufacturers to provide high quality drugs. India's drug regulatory system needs to be made robust by way of making the drug laws in line with global standards and their strict implementation to ensure that every drug sold in the country meets same high standard of safety and quality. 

Our Drugs and Cosmetics act was enacted in 1940 and Drug rules in 1945. There have been incremental changes in the rules over period of time but now the time has come to overhaul the system. Suggestions for the same can be found in my other blog on Modernization of Drug Laws in India.