Lingering cGMP issues underline the importance of hiring right, rigorous training and continuous oversight to consistently comply with safety norms
By Viveka Roychowdhury
The globalisation of the pharmaceutical chain poses both opportunities and challenges. Making affordable, safe medicines more accessible benefits patients as well as the companies who makes these medicines. But the flip side is that the growing complexity of these supply chains adds to the risks at every level. And regulations and regulators are unfortunately left playing catch up.
Let’s consider the world’s largest pharma market. In the period 2011-2018, the number of US FDA registered drug facilities in the US has decreased by 10 per cent in the US but increased 63 per cent in India, followed by 51 per cent in China, according to a presentation by Dr Letitia Robinson, Country Director, India Office Office of International Programs, US FDA at the 4th Indian Pharmaceutical Forum 2019 (IPF 2019) held this February in Mumbai.
As the number of registered overseas facilities increased, there was a corresponding increase in inspections of these sites. According to a statement from FDA Commissioner Dr Scott Gottlieb dated last September 25, as of fiscal year 2017, about 5,063 pharma sites worldwide had routine surveillance inspections, of which 3,025 were overseas. For that year, the FDA conducted 1,453 drug surveillance inspections, including 762 overseas inspections.
Regulators are hard pressed to maximise their resources and strategically decide which manufacturing facilities are prioritised and scheduled for surveillance inspections. Dr Gottlieb’s statement gave a link to the Center for Drug Evaluation and Research’s (CDER) Risk-Based Site Selection Model which explains how a facility’s compliance history, recall trends, time since last inspection, inherent risk of the drug being manufactured, processing complexity and other factors are all weighed and considered. The risk-based site selection model is reportedly structured so that the inspection frequency for all facilities, regardless of where the facility is located, prioritises inspections of sites where the drug being produced and the manufacturing processes used pose the greatest potential risk for problems that could harm patients.
Gottlieb has since resigned from his post on March 5 but his statement of April 4, with Dr Janet Woodcock, Director, CDER, giving the agency’s list of known nitrosamine-free valsartan and ARB class medicines, is the most recent example of just how vulnerable the global pharma supply chain is.
Learnings from the valsartan case
On June 19 last year, Prinston Pharmaceuticals, a US manufacturer of valsartan products, notified the US FDA’s Center for Drug Evaluation and Research (CDER) that one of their suppliers, China based Zhejiang Huahai Pharmaceutical Co. (ZHP), had detected an impurity in the valsartan active pharmaceutical ingredient (API) supplied to Prinston. EU regulators were already investigating similar cases. The impurity, a chemical known as N-nitrosodimethylamine (NDMA) is a probable cancer-causing chemical found in trace amounts in water and some foods. However, the levels of NDMA in ZHP’s valsartan API – while still trace amounts – were deemed unacceptable.
Valsartan belongs to a class of drugs called angiotensin II receptor blockers (ARBs) that treat high blood pressure and heart failure. Considering the high incidence of these ailments across countries and that these medications are used on a daily basis over an extended period of time, the valsartan saga drew bad press not just for the API makers.
Patient groups accused regulatory agencies of sleeping at the wheel as experts now says that a process change made by ZHP in its valsartan manufacturing process way back in 2012 could be responsible for the introduction of the toxin NDMA. The process change was approved by auditors and multiple global regulatory agencies in subsequent inspections and none thought to specifically check for the presence of NDMA or a second carcinogenic impurity, N-nitrosodiethylamine (NDEA), found in recalled products made by ZHP and marketed in the US by India’s Torrent Pharma.
The US FDA collaborated with other global regulators like the European Medicines Agency, European Directorate for the Quality of Medicines, Regulatory Operations and Regions Branch and Therapeutic Products Directorate of Health Canada, and the Pharmaceuticals and Medical Devices Agency in Japan by sharing information to review medications containing valsartan API manufactured by ZHP and recalling batches. Since these alerts, experts and media reports estimate that more than 50 companies around the world, including the likes of Hetero Pharma and Aurobindo Pharma from India, have recalled valsartan and its combination products made from APIs sourced from ZHP.
But the recalls caused drug shortages and regulators had to step in once again to curb patient panic. On April 4, Gottlieb and Woodcock announced that they had so far identified 40 ARB medications where their assessment concluded they do not contain any known nitrosamine impurities, noting that this number would increase. The announcement also listed the possible reasons why such an impurity was formed during manufacturing, and cautioned API manufacturers on the possibility of contaminated raw materials, including and especially solvents and catalysts (particularly when these are reused). While the valsartan debacle seems to be finally under control, it is worthwhile to consider the learnings for pharma manufacturers across the world. Experts estimate that around 30 per cent of APIs sold in the EU come from India. India in turn is dependent on China for many key ingredients. Given the sizable export focus of pharma companies in India, the industry needs to double down on ensuring compliance to cGMPs.
Regulatory lag
As the valsartan case demonstrates, besides documenting changes in the process, the source materials etc, it is equally important to also be alert to out-of-the box possibilities. For instance, given that the process change at ZHP was made way back in 2012, how was the impurity detected so many years later? Was it detected but not reported? For this, we need to have a culture of compliance to cGMPs ingrained in all employees at every level.
India continues to bag a fair share of cGMP-related regulatory raps. As of September 30, 2018, the US FDA issued 15 cGMP warning letters within the US itself, 18 in China and 10 in India. But inspection outcomes for pharma companies in India have improved and are more in line with global norms. Data from McKinsey presented at IPF 2019 shows that in terms of inspection outcomes, while India’s share of global US FDA inspections in 2018 was 14 per cent (174 inspections), the share of No Action Indicated (NAIs) at 76 and Voluntary Action Indicated (VAI) at 91, have increased while that of Official Action Indicated (OAI) (7) has decreased. In the previous year, 145 US FDA inspections in India resulted in 22 OAIs, 80 VAIs and 43 NAIs. But India’s GMP compliance for EMA sites continues to be a concern. In 2018, India’s share of GMP non compliance issued by EMA was 43 per cent (seven of the total 16 sites).
The third eye
These inspection outcomes have ensured that cGMP remains on a top priority for pharma companies and training initiatives has increased. Many companies, following the remedial actions prescribed by the US FDA inspection reports, have also turned to third-party consultants to get an independent impartial view of their systems and processes as well as train their teams. How effective are such GMP consultants, given that they remain ‘outsiders’ and insiders might have a better chance of identifying cGMP gaps? More so, since they will move on once the period of their consultancy is completed? How can a company internalised the advice and make more permanent changes?
Ajaz S Hussain, President, The National Institute for Pharmaceutical Technology & Education (NIPTE), served as Deputy Director Office of Pharmaceutical Science at the US FDA and is also credited with leading some of the agency’s major initiatives to develop regulatory policies during his decade long term. Post senior level assignments with pharma companies like Sandoz, Philip Morris International and Wockhardt, he founded his consulting practice Insight Advice & Solutions in July 2013, He thus has a unique perspective of both the regulatory well as corporate side of the fence.
Taking an overall systems perspective, he says, “Insight, advice, and solutions to help pharma companies identify, correct and prevent deficiencies in their practices are embodied in the phrase: Care is research, knowledge is power, and wisdom is in practice. This phrase describes a useful perspective, which when understood provides clients an optimal solution to leverage the experience of a ‘GMP consultant’ to the benefit of all – the profit seekers, the patients, the professionals, and public-health authorities.” Explaining his approach, he makes the point that pharma operations are considered to be complicated and not complex. That is, in a complicated system causes and their effects, although multi-factorial, are knowable by those who have adequate education, training, and experience (see US regulations at 21 CFR 211.25). In pharma operations, starting conditions (development, regulatory applications, raw materials, validation of processes and people) and operating procedures are defined to ensure that following established routines or standard operating procedures (SOP) will yield predicted results. When actual results deviate from expected results – we ask why?
According to Hussain, there are two types of errors: errors of commission, i.e., due to an action taken, or errors of omission, i.e., when action has not been taken. Knowing the type of error defines the path to a practical solution. Helping clients understand these fundamentals is essential for them to self-author – both the starting conditions and SOPs.
He stresses that the third-party consultants must be competent to address both systematic and systems issues to help clients self-author solutions they can practice (after the consultants depart). Consultants must help clients appreciate the value of careful research, channel the power in their knowledge wisely to personify it in all their practices.
Pharma companies have been hiring external GMP consultants for the past few years but though there is some improvement in inspection outcomes, certain warning letters seem to have a long shadow stretching for years. To this, Hussain emphasises, “Only the client is responsible for manufacturing, not the GMP consultant. Unfortunately, this simple fact is often confusing to many and GMP remediation efforts can linger on for years and costs hundreds of million dollars.” Giving the larger picture, he points out, “It should not surprise us when a prominent US Senator, who is also a candidate for the President in 2020, has called for the US Government to manufacture generic drugs. This proposal may not be oxymoronic as it appears in the first instance.”
Summing up, Hussain reasons, “The GMP regulations in the US and around the world are a bit dated for the complexity and uncertainty of the 21st century. For example, the US 21 CFR 211.25 requires adequate “education training or experience” for pharma professionals and third-party consultants. What is adequate “education,” “training” and “experience”? Perhaps, now – with the chaos and the widespread product recalls, the community will begin a process to recognise that to be true to our first principle “first, do no harm” we must appreciate: Care is research, knowledge is power, and wisdom is in practice.”
Going digital is not a quick fix
Analysing the warning letters and 483s over the past few years, McKinsey data shows that while data reliability and good documentation practices were the leading cause of observations in 2015, making up 41 per cent of observations, this number was down to 17 per cent in 2018. While data reliability, and investigation and root cause assessment related errors reduced, the leading source of non-compliance is now the gaps in manufacturing systems and lab controls.
Most pharma companies have gone or are planning to go digital in all GMP documentation in a bid to increase compliance. But Shirish G Belapure, an industry veteran and consultant to pharma companies, cautions that there is great risk of data breach, manipulation or theft if adequate controls are not being built while designing the system or not secured after wards.
According to him, “In today’s pharma world, GMPs are often confused with compliance and quality. All these are three different terminologies. Both compliance and cGMPs are aimed at achieving quality. Compliance is merely ensuring that whatever you have communicated to regulatory agencies is being followed regularly. Many times it is observed that GMPs are overlooked just to be compliant. It is essential that the ‘c’ in cGMP needs to be ensured by filing necessary updates to regulatory bodies using various regulatory mechanisms like changes-being-effected (CBE) or Prior Approval Supplement (PAS) in case of FDA or type variation in case of EMEA.”
Going back to the basics, he points out that the whole concept of GMP is based on the ALCOA (Attributable, Legible, Contemporous, Original, Accurate ) principle and thus data is very critical. This fact is being demonstrated in recent inspections of the FDA or MHRA. With a view to meet these requirements, most pharma companies are planning to become digital in all GMP documentation. This is a welcome step; however it is not a panacea for getting all the issues resolved.
As Belapure cautions, “Most of the systems are quick-fix and not designed to avoid security breaches. There is a great risk of data breach or manipulation or theft if adequate controls are not being built while designing the system or not secured after wards. It is absolutely necessary as almost all Quality Management Systems (QMS) which are an essential part of GMP like LIMS, document management system, track-wise all are based on digital platforms and are vulnerable to this risk.”
Therefore he advises that it is essential to use tools like risk assessment/mitigation with the help of IT experts to avoid these problems. To prove his point, he harks back two years, when all operations of Merck came to a standstill due to a ransomware virus. He sees the Merck case as just a warning; the future could see the hacking of systems to create issues for competitors, data theft etc. to create chaos. This underlines his message that there is need to have greater awareness to consider this risk and take appropriate actions to avoid risk of GMP being compromised.
GMP culture is about the right nature or nurture?
External auditors and consultants play a big role in helping pharma companies get their strategies and infrastructure right but ultimately, systems and processes are only as good as the minds and hands that control them. As Rajashri Survase-Ojha, Founder and Managing Director, RAAJ GPRAC puts its, “GMP is all about people and how they should behave while manufacturing medicines. Why is it all about people? Because only people can practice. The emphasis is on the word ‘practice’, because practice becomes a habit, becomes an attitude, becomes the culture.”
How does one ensure that every employee, follows basic tenets like ‘Do what you document and document what you do?’ Analysing the common causes of non compliance in pharma companies in India, Amit Rajan, Managing Director, Prosfora Technologies says, “We need to design our manufacturing units, install machines, develop technologies, write procedure and follow operations so that we do not put undue pressure on the compliance set up of the unit. Not following the Standard Operating Procedures (SOP), forcing an output more than expected, improper cleaning of equipment in a multi product facility, non concurrent documentation etc. are the hazards which put the maximum stress on compliance framework of any unit.”
He points out that all big pharma set ups in India have sometime or the other compromised on these critical compliance matters, thereby inviting criticism from various regulators. “A combination of these non-compliance leads to what we now know as the dreaded term ‘data integrity.’ This term is a resultant of poor implementation of procedures, compromised honesty in operations (generally at the leadership level), trying to brush surprises under the carpet and destroying poorly documented data. Failure to meet this preamble in successive regulatory inspections have brought some of the big Indian pharma companies to the state of decimation.”
Encapsulating the task before every pharma leader Rajan says, “Cultural changes and continued compliance to it, is a huge pain to take and a great challenge requiring commitments at all levels of the organisation.” Moving forward, he emphasises that the need is to nurture an environment at the work place which keeps reminding all the staff, right from operators to the chairman that ‘honesty is “still” the best policy!’
To the proposition on whether a quality culture is dependent on nature or nurture, Vishalakshi Naik, Founder, Quality Solutions cautions, “It is only possible to nurture something that already exists. There are certain principles, ethics and core values which are primarily essential in the person if he needs to be part of a culture of GMP compliance. A few of them are most important like attitude, quality, humanity, sharing, transparency, truth, and empathy.” So her mantra to build a culture of GMP compliance in the organisation would be selecting the right person for the right job with good character and good attitude, core values and nurturing these values in a conducive environment.
When things go wrong, it is human tendency to start a blame game. Survase-Ojha from RAAJ GPRAC makes the important point that, “In many companies, it is observed that quality compliance is the responsibility of the quality assurance (QA) department only. If there is any failure, they are directly responsible. This perception needs to be changed as quality compliance is the responsibility of all persons in the organisation, from the sweeper to the top management.”
Another perception that she highlights is the false impression that by meeting regulatory specifications/ guidelines, product failure (due to quality, efficacy and safety) is the responsibility of the regulator. This perception needs to be changed.” Thus, this cultural change will have to be spearheaded by GMP champions from within organisations rather than relying solely or even largely on external resources like external GMP auditors, consultants or trainers.
Grooming human capital of the future
To conclude on a more positive note, efforts could now focus on training employees as early as possible, probably to avoid the consequences of reputational loss for the organisation as well the individual’s need to un-learn/re-learn core concepts. Giving more details, Rahul Guha, Partner and Director and India Lead, Healthcare Practice, BCG says, “A core group of HR leaders working in collaboration with Operations & Quality leaders from the industry, along with facilitation with BCG conceptualised the development of an Entry Level Training (ELT) academy. The team worked for almost two years to build the curriculum, align the Life Sciences Sector Skill Development Council (LSSSDC) curriculum and set up the academy in partnership with Yashaswi Group. The overall concept has been developed and rolled out with a pilot centre in Goa which will train 300 students in this year and following the training, they will join the respective companies.” The first batch consisted of 990 students from Cipla, DRL and Lupin.
Explaining the rationale behind the course, he says, “In order to meet the industry’s dynamic as well as growing needs, it is imperative that the workforce is adequately trained. Pharma companies need to equip their workforce with the requisite knowledge and skills, in an efficient and cost-effective manner. Integral to this initiative is identifying possible areas of intervention and structuring training and upskilling programmes that can ably meet the human capital demands of the industry.”
Introduced in November 2018, the ELT programme is aimed at training 10+2/ITI students and BSc/B Pharma students. The six-month ‘finishing school’ programme includes three months of classroom and practical training and another three months of on-the-job training (OJT). The first three months are further divided into 1.5 months of instructor led training and 1.5 months of simulation. It finally culminates in a final examination and selection. Guha says the testing results and attendance so far has been fairly encouraging with 85 per cent attendance and 95 per cent pass test scores achieved.
At completion, successful candidates receive an LSSSDC certification and employment in the sponsor company. Candidates can also choose to opt for continuous education post the six-month programme. By training and upskilling themselves, individuals could boost their career path and can expect an eventual increase in salary as well. The industry benefits as well, by having a trained pool of resources joining the company.
The industry has been heavily involved in this programme and has made significant commitments. Support garnered so far includes donations in the form of 100+ equipment, 415+ hours of curriculum as well as a commitment of Rs 2.5 crore to partner in the first year and 250+ on job training and jobs.
This is a clear win-win situation but it’s early days yet. As Guha outs it, “Any new initiative that is designed to have a larger impact on the industry, is initially fraught with challenges. For the ELT programme, challenges include initial issues with respect to infrastructure and accommodation, procuring live test equipment, managing diversity, securing engagement and success and getting OJT well settled. However, these are simply initial teething issues which can be addressed through judicious planning and industry collaboration. The pilot batch has been a great experience and the aim is to incorporate the learnings from the same to refine the program further. Going forward, the focus will be on stabilising the batch strength to 90 per quarter, making the programme available to member companies beyond the core committee and defining the timeline for expansion.”
One hopes that the initiative which is facilitated by the IPA, will soon have non-member companies as participants in order to build a wide and deep enough talent stream of GMP trained pharma manufacturing professionals in India.