In order to grab the huge opportunities in the US pharma market, India has to metamorphose in quite a few aspects during its journey through the US pharma market  maze and requires systematic navigation of many critical aspects of which ‘Data Integrity’ aspect   is the most critical. For the 5 W’s of Data Integrity and methods to combat, read on.

In order to boost the profitability in the face of slowing sales to 2014 since  many drugs are coming out of patents, pharma companies in USA have implemented a number of cost-cutting measures (in addition to strategic repositioning and diversification strategies). One of them is ‘outsourcing’ at a cheaper cost to lower their cost base.

Opportunity and the associated MAZE
When the global sourcing managers in America think of outsourcing drugs, especially the finished dosage forms at reduced costs, India definitely comes to their minds. Unfortunately, the appreciation Indian pharma gets  for its good modern plants, brilliant chemists, second largest pool of scientists, flexibility and fast reaction time etc, is often overshadowed by the thoughts of ‘low cost’ and ‘potential Data Integrity’ problems in their  minds.

Perceptions of Indian pharma
IMS, which has a local presence in India for over 10 years in a report on  the  Indian pharma says, “ The greatest concern is that the local market is also characterized by competition from biosimilars since there is no stringent approval process. Even though IPR regulations exist, enforcement is lacking and the influence of this on the market is expected to be gradual. Other concerns surrounding IPR relate to ambiguity in interpretation of Section 3(d) relating to ‘incremental innovations’, data exclusivity protection and the possibility of regulatory intervention in the establishment of launch prices for patented new drugs.”

According to a publication in Fierce Pharma , ‘New Jersey may still be America’s medicine chest, but India is fast becoming the world’s medicine plant. India’s home-grown pharma turns out more and more World’s Generic medicines’.

New York Times puts the  value of goods produced at $ 24 billion and a growth rate of 13 per cent .In a survey amongst 30 leading companies in the US and Europe, Livemint.com, most ranked India the highest for outsourced drug production. Some 83 per cent rate India’s technical capability at above average.

While all of this augurs well for the Indian Pharma, the ‘Achille’s heal could be the ‘Data Integrity’.

Many companies in the western hemisphere are of the same opinion.

For an Indian company to cater to American market, it is quite a challenge and having made all the efforts, for making an entry  and establishing itself in American market, Data Integrity aspects can be a hurdle to maintain the company’s presence in the US markets.

There are many other challenges starting from ; understanding the requirements, achieving customer service requirements, meeting deadlines, overcoming Indian formalities & technical problems and many more challenges including staying on top. “Data Integrity” practices is very difficult and is comparable to finding one’s way through a complicated MAZE.

According to Wikipedia, MAZE  is a tour puzzle in the form of a complex branching through which the solver must find a route for transit. For those who are conversant with Mahabharath, Abimanyu’s attempted passage through ‘Chakravyu’ is a good example of failure to traverse despite being the most competent person. The main reason was lack of proper knowledge of the complexities of the maze. Some Indian companies have already shown that they faired better than others and can navigate successfully, but many more are seriously effected. This MAZE is surmountable if there is adequate ‘insight into the complexities’ and ‘determination to conquer’.

As of now, the ‘data integrity’ could be a major hurdle to the Indian Pharma. The previous advantage edge of ‘low cost’ is also decreasing as the costs are going up and also that other countries are gearing up.

Though many Indian pharma companies have successfully entered the market (can be considered as half way through the MAZE) and at least 50 per cent  of the companies have been under the ‘Data Integrity’ scanner. The second half of the journey through this MAZE is the most difficult and  crucial part of the journey.

Once the ‘expectations are clear’ and the ‘understanding improves’, Indian pharma will surely be  capable of aligning itself to the required standards of ‘Data Integrity’

Many Indian pharma companies have met their Waterloo at ‘Data Integrity’. In many cases it was really small issues (negligence/ignorance) which could have been easily avoided, but they became construed as ‘data integrity’ issues even though there was no ‘intentional hidden agenda or material gain’. In many cases the Data Integrity issues did not have any impact on cost.

Having worked in the Indian pharmaceutical industry and presently engaged with the American Pharma, the importance given to ‘Data Integrity’ by the American companies is the most important thing I could learn from my US experience. Many of the Indian professionals working in USA and having a knowledge about working in India also agree to  this.

This ‘feeling’ does not make me ‘less patriotic’.But the HOPE that this write up will act as a wake up call to  help Indian companies in this ‘challenging crusade’ to come out of the ‘data Integrity MAZE is itself a  reflection of the  high sense of patriotism and the sense of commitment I have .

The perception of Data Integrity is quite different and the difference is as apparent as the stark naked f differences between America and India in everyday life; Some examples of differences;

• Traffic driving on the other side of the road when compared with Indian pattern,
• Writing dates in a different order with the order being month is written before the dates in USA,
• Littering is a crime in USA, not so seriously taken in India,
• Sounding the horn in USA is frowned upon, at the same time, Indian trucks still carry the slogan ‘Sound Horn OK’,
• Most of the   trees (perennials) change colours (green leaves change into beautiful fall colours of yellow, pink, red and scarlet ) in USA as against the ‘evergreens’ in India,

There are many more facts/practices like these  that are different. If we want to get into the developed country markets, we need to ‘change’. Probably the same applies to service any ‘Western hemisphere based companies’.

In the American Industry “Data Integrity” is taken up very seriously both in spirit and practice. It is really impressive to see the importance given to the ‘Integrity’ issue even in daily life. Most of the persons breathe ‘Data Integrity’ day in and day out.

This does not mean that there are no ‘Data Integrity‘ issues in American Industry. In fact the concept of  ‘Prior approval inspection’ (PAI) was born after the Data Integrity issues in many generic companies in USA were noticed in the 80’s and 90’s. The recent FDA citation on Cetero Labs, a CRO  from Texas is one such example. FDA in its letter dated July 26, 2011, cited that ‘The inspections and audits identified significant instances of misconduct and violations of federal regulations, including falsification of documents and manipulation of samples’.In summation, it is a relative index.

Lessons for US pharma
US companies were impacted during the 90’s with Data Integrity issues. The industry has passed through the ‘correction phase’ soon after and has now ‘matured‘ to achieve the present levels of ‘Data Integrity’.  There were a lot of adverse cases noticed during the 80’s when ‘generics’ started to be licensed (Hatch-Waxman Act). However, after this ‘learning’, there has been no looking back on this issue. Most of the companies ‘LIVE and BREATHE INTEGRITY’. It is the way of ‘life’ and practised  quite well. In fact many companies implement a ‘ZERO TOLERANCE POLICY’.  

Some cases of   Data Integrity issues resulting in 483’s :

• Laboratory records are deficient in that they do not include a complete record of all data obtained in testing.
• Written production and process control procedures are not followed in the execution of production and process control functions.
• Batch production and control records do not include the identification of the persons performing each significant step in the operation.
• The above reasons made it obligatory for the company to destroy their entire stock of finished goods ,materials under process and the raw materials which were opened for use.

For the purpose of learning, it is better for the Indian pharma to focus on the good aspects rather than start debating with examples showing the negative aspects of American pharma industry.

Similarly, it is not the time to be complacent with the feeling that there is a high level of ‘Data Integrity’ in some (handful) Indian pharma companies. It is important to note that recent inspection reports have cited even some of these top Indian companies for failure to establish ‘Data Integrity’.

Tackling the Data Integrity issue could augur well for Indian Pharma’s future and to retain its lead position as a ‘preferred source for outsourcing’ for pharmaceuticals.

It requires a ‘Himalayan effort’ to erase the generalised  accusation of Indian pharma. It is also true that FDA also looks upon US Pharma and other foreign  industry with similar scepticism.

Reviewing the warnings given out during 2010 indicates that, FDA authorities issued 483’s in 118  inspections (third highest reason ) under 21 CFR 211.100(b)  citing ‘written procedures and process control procedures are not followed / documented at the time of performance-This is an aspect of ‘Data Integrity’.

In fact, the FDA is strongly of the opinion that this problem exists in Indian and Chinese pharma industries and has special training given to reviewers and inspectors who are dealing with companies from India and China. Data Integrity is taken very seriously by the FDA.

FDA’s recommendations for Indian Pharma
According FDA Officials, Indian firms need  improvement in the following:

• Vendor qualification procedures
• Annual vendor performance evaluation and re-qualification
• Vendor disqualification criteria
• Develop ‘zero tolerance’ to  Acts leading to ‘Data Integrity issues’

While the first three  aspects are achievable, the aspect of ‘Data integrity’ requires a cultural shift and is  the most difficult part .

Understanding Data Integrity
One of the methods to successfully cross the MAZE is to first understand ‘Data Integrity’ and then improve level of ‘Data Integrity’.This part of the ‘white paper’ is dedicated to improving the understanding of the ‘Data Integrity’ by  the Indian Pharma.

Having worked in Indian pharma for about three decades and presently working in the American industry has given a good insight into this aspect. It is my and many other countrymen’s ambition to share our understanding and work to facilitate Indian Pharma imbibe these insights  into the company culture at the working level. This will  help in  successful navigation through the ‘MAZE’ to make  entry  into  the American market easier in the future.

This ‘maze’ is very challenging partially due to different levels of understanding the meaning of ‘Data Integrity’. Once the actual meaning is fully understood, it is very clear how simple systems can achieve a good level of ‘Data Integrity’.

The first step into the MAZE is to properly understand the 3 W’s of ‘What is data Integrity?’What are the reasons for slackness and what in the Western Hemisphere makes it easier?

What is Data Integrity?
Data Integrity incident is the documentation of pattern or practice of wrongful conduct that raises significant questions about the reliability of data submitted and wrongful acts .

‘The Wrongful acts’ listed below also are ‘Data Integrity’ aspects.
Any act or conduct that subverts the integrity of the review process-for example;

• Submitting a fraudulent application
• Making an untrue statement of a material fact & false statement, mis- statement or an omission of a fact)
• Submitting unreliable data which raises  concerns of system-wide or firm-wide behaviour.
• An untrue statement of material fact is a false statement, a mis - statement or an omission of a fact that is important for review.
• Substitution of data, falsified records etc,.

FDA, normally assumes that all records are TRUE by giving the benefit of doubt to the applicant. The implication of this is that all data and information in records submitted to FDA and supporting documents in possession of applicant should be an accurate and true representation of the following :

The actual tests performed and the test results
Actual manufacturing and QC steps & procedures associated with the development and manufacture of the submission batches.

However if there are some cases where the Integrity is doubted, and it forms a pattern, there is no end to disbelieving the data they receive subsequently even if it is very integral.

Not documenting part of the observations or ignoring some data is also ‘Data integrity’. Similarly, signing and dating the document to reflect another date/time is ‘Data Integrity’.

System wide inconsistency is a wrongful act. When an untrue statement of material fact  is observed as a pattern prevalent through out is found, several serious steps of invoking the AIP (Approval Invoking Procedures)  and seizure of goods and facilities, recall of goods manufactured during the period which did not have reliable data have been initiated in the past.

This has cost companies millions of dollars and led to closure of  many companies  due to inability of  coping up with the damages. .

In a recent case of  the American based Cetero Labs, FDA has notified pharmaceutical companies that studies conducted by Cetero Labs during the past five  years may be carried out for revaluation.

It is critical that every pharmaceutical company trying to establish itself in developed markets should be willing to bring about a change in culture and give the highest  level of  priority to ‘Data integrity’. This is something that every professional manager/supervisor can bring about with the ‘blessings’ from the top management. It is important to understand that maintaining good level of Data Integrity need not mean increased costs in most cases. It should be a ‘way of life’.
 
Drivers of ‘Data Integrity’
It is important to understand why the perceptions in the western hemisphere are different. This will go a long way in improving our concepts and improving ‘Data Integrity’.

One of the  main reason for maintaining a high level of ‘Data Integrity’ because  the damages suffered by companies owing to lack of  ‘Data Integrity’ is transparent and everyone is aware of the consequences.

Most manufacturers in the developed nations have a strong ‘brand loyalty’. In case of generics, the brand loyalty affects  manufacturer’s reputation and hence  once a company has defaulted, it is very difficult to regain the market. The ‘saying’ that ‘there is only one life’ is very true. One incidence of Data Integrity could make the company loose the patronage for which it might have strived for many decades.

Normally the customers/regulators do not spend time in analysing the reason/justification for the failure in ‘Data Integrity’. Basically, it is not acceptable. It is a matter of different perceptions by different cultures to certain extent.

The possible reasons for the high level of ‘Data Integrity’ in developed countries could be one or a combination of more than one of the following:

1. Obsession with good documentation practices is probably ingrained in schools at a very young age.
2. It is also probable that the prevalence of an efficient patent protection system/practice has had a major role to play in making ‘Data Integrity’ a part of everyday life-as the innovations/improvements needed to be properly documented to fight the challenges.
3. Another major factor could be the type of information required in the submissions to FDA necessitates the proper training of all employees to respect good documentation practices and data Integrity.
4. Cultural differences and differences in management styles could have had a role to play in maintaining a good level of ‘Data Integrity’.
5. Employees/employers who do not report the ‘doubtful’ Data Integrity are liable for disciplinary action.
6. Seriousness in dealing with Data Integrity issues in terms of  penal actions of forcing ‘closures, recalls, cancellations, debarring the personnel involved, levying  fines has possibly been an effective deterrent. FDA also publishes a ‘list of ‘black listed personnel’ and debars companies from employing them.
7. All inspection reports are accessible by everyone-both regulators of other countries and also customers.

In summation, the reasons for having differences in perception of ‘Data Integrity’ in developed countries could be broadly grouped as follows:
A.    General attitude: Safety First. Under this the requirements of safety of the  consumer is paramount and only documented traceability can assure ‘safety’.
B.    Schooling and upbringing and training on good documentation practices are ingrained at the very young age. This is the reason most tend to make corrections and annotate and date them in line with good ‘documentation practices’. Corrections to data without ‘annotation,signature and date are considered to be serious Data Integrity issues.
C. Environment: The environment in which  the people in the developed countries  grow up is a very ‘patent oriented’ or a ‘data oriented’ society. This calls for good training on documentation practices in all companies and every activity has to be tied to a person, time and place.
Most of the companies are relying on some products which give  high profits to compensate losses due to ‘recalls or rejections’ in cases of data integrity issues, hence do not hesitate to take necessary actions.
D.    Work culture: This can be explained in many contexts: Most of the companies are big corporations and hence the cost of not complying with the ‘Data Integrity‘ aspect  is very high and also being very professional, the designated Quality executive’s decisions of rejections in cases of doubtful data are respected and the  disposition decisions upheld.
E.    Management practices: The level of standardization is very high. The aspect of ‘standardization’ may lead to ‘rigidity’ and ‘reduce flexibility’(distinct disadvantage)-But this has lead to higher standards of data standardization which reduces the chances of creating mistakes.

The timelines for projects are framed after a detailed evaluation of time requirements and resource availability. Absence of ‘rush’ jobs also increases the chances of accurate and systematic documentation.
F.    Zero tolerance: In many of the companies, at every level there is ‘zero tolerance to Data Integrity’ issues  and none of the other aspects like good experience, skill level ,cost of training etc., will be considered while terminating a person for ‘Data Integrity issue’. This is exhibited by taking prompt dismissal actions whenever Data Integrity issues are noticed.
G.    Regulatory frame work: The depth of strict implementation by FDA whenever  a ‘pattern’ of Data Integrity issue is noticed has been one of the major drivers to decrease cases of ‘Data Integrity’. FDA penalizes the company and pays 10 per cent  to the ‘whistle blowers’ even if he is an employee of the company. In a recent case one of the whistle blower of a leading pharma company was paid as much as $ 90 million. During 2010, FDA has been able to recover $ four billion from the industry, hospitals, doctors and other healthcare companies. This amount is almost equivalent to the annual sale of medicines in India.

The table lists out some of the penal actions levied during the past decade
At this point, it is necessary to clarify that it is also true that, Indian pharma companies definitely give importance to ‘Data Integrity’ but   the levels of understanding ‘Data Integrity’ is distinctly different. What some of us may consider as a simple mistake or an oversight is considered a serious Data Integrity issue in the Western hemisphere.

I am aware that we (Indians) can go defensive and claim that Indian companies are not different from other companies in the developed world. This could go until the ‘cows come home’ as the saying goes, However, it is in our interest that   we need to look at things more closely and take into consideration what the general perceptions of our customers are  and work on the gaps.

In India, how often do we see recalls of millions worth of drugs being withdrawn based on doubtful   ‘Data Integrity’ on the premise that the ‘patient’s safety could be endangered though the chances are less than one per cent ?

How often do we see termination of employees who fills up a blank space in a GMP document after the date/time ?

How often do we reject a batch which did not have the required on-line testing results or observations entered in the batch record for some of the many time periods?

How often does a person get punished for having not reported any of noticed data integrity issues?

Yet, in countries like

USA and Western hemisphere, such actions are quite common.
There could be many justifications/reasons/root causes for the blips in ‘data integrity’ in Indian industry. Some of these could be:

• Cultural diversity
• Statutory laws being impractical for business (Labour law where in an employee is considered to be permanent if he/she works for more than 240 days )
• Management style-
• predominantly directive style,
• Problems due to working language not being a native language and there being many local languages (325 languages having 24 different scripts)
• Inadequate attention and seriousness  to training, etc.
• The root causes for the Indian companies being faulted for ‘Data Integrity’ could be mainly and largely  from, ‘ Not understanding the requirements’.

It s also the lack of supervisor’s  tolerance to indiscipline and non-compliance at the working level in the manufacturing and testing activities and the inaction of top management for proliferation of such incorrect practices which can be construed as a Data Integrity issue.

It is also true that American industry was affected by ‘Data Integrity’ and ‘other issues’in the past.

It is a fact that Data Integrity issue was prevalent in American Pharma, but the industry has learned its lessons and has evolved to exhibit higher levels of Data Integrity. Having learned this critical lesson, the expectations from foreign pharma is high.

It is time for us to learn and build higher levels of ‘Data integrity’.

It is my fond dream that India should no more be in this shadow of ‘Data Integrity’.