· 20 min read
NSF Vice President Sanjay Shetgar looks at five issues driving growth in the Indian pharmaceutical sector in 2023. He considers how proactive quality management, training and education, agile regulatory management, and other elements will drive the success of the third largest pharmaceutical industry in the world.
The figures above show the excellent position the sector is in. Nevertheless, there are threats to the success of the industry. This webinar looks at two specific areas that threaten the industry’s success and that companies need to be mindful of as we head into 2023.
The two specific areas that are of most concern and that we will address in this webinar are:
Multiple global factors impact companies’ ability to get raw materials and ship finished products to their destinations. COVID-19-related delays have been prevalent in recent years. However, in the summer of 2022, climate-related issues have also impacted supply chains. There have been many reports in newspapers and other media on how rivers, particularly those used as important shipping routes for world trade, have shrunk, causing shipping companies to take lighter loads to help ensure their passage along the way.
We know that supply chain issues will impact our companies at some stage, just as we know that quality issues will arise. What are you doing to prepare for such problems? Some people might sit back and hope for the best. Others will have changed their supply chain and quality structure (possibly because of a reduced workforce, an issue we covered previously). These changes are reactive.
On the other hand, many companies have approached these difficulties proactively. They have acted first to secure their supply chain and to help ensure that their quality system is fully compliant.
Most companies, however, sit somewhere in the middle, making some changes to get ahead of issues and being forced to make others after problems have been identified. Regardless of where your company is on the preparedness scale, the cost of getting quality right is vitally important.
Our experience has shown that proactive companies have lower quality costs.
Let us look at an ideal scenario: Imagine that your company has had no product failures and no quality events. That is an amazing feat — a proactive company reducing the cost of quality by its actions. This can be achieved through robust risk-based development, manufacturing processes, effective GMP processes, well-trained and educated staff, and effective audits.
The reality, though, is never so simple. Several variables can negatively impact the quality system: technology transfer, scale-up issues, facilities and equipment (particularly aging facilities), and the issues surrounding the supply chain.
Mistakes are bound to occur, and we expect the quality system to pick them up or identify them in an audit. We sometimes fail to realize that we are only human and that any organization can fall victim to mistakes.
Everybody knows that the U.S. FDA can come and visit a facility and conduct a comprehensive audit. But you might not know that the FDA was subject to an audit by the Office of the Inspector General and that the report was released in June 2022.
What does this show? It shows that every organization needs to keep a watchful eye on its systems and processes. No organization, not even the FDA, is immune.
Most pharmaceutical companies attending this webinar will have several audits at their facilities each year: regulatory, internal, company and due diligence audits. Outcomes will be listed in the reports throughout the above-listed audits. Each audit report presents an opportunity to see what has been found and to spot new issues arising.
Some companies have the same issues arising time and again, and they need to ask themselves, “Why do these issues keep cropping up?” and “What went wrong?”
We always advise companies to avoid a blame game if they genuinely try to address the identified issues and bring about sustainable changes. One easy method to adopt to avoid recriminations and to learn from an audit report is to treat an audit as a free consultancy report that provides guidance and reveals gaps that must be addressed.
COVID-19 restrictions are lifting, and there is a strong sense in the market that the FDA will ramp up the number of audits it carries out in India in 2023. The organization has a backlog to clear, and, as referenced at the beginning of the webinar, India has the highest number of FDA-compliant plants outside of the United States. Therefore, it stands to reason that India will be a focus of activity for the agency as travel restrictions are lifted.
Look at FDA audit trends with Indian companies over the last three years.
Firstly, COVID-19-related travel restrictions impacted the number of inspections that could be carried out. 2020 saw 101 inspections carried out. Ninety-five of those inspections went well, with only six showing significant issues. As we move through 2021 and 2022, we see that the number of inspections reduced significantly as COVID-19 restrictions took hold. 2021 saw only four significant issues, with none in 2022 to date.2
There are five main categories of findings from the past three years of inspections:
The Quality Maturity Model (QMM) will bring a more mature approach. Companies must integrate the QMM requirements strategically to stay ahead of their competitors and remain compliant.
Developing and leading a quality culture is integral to the Quality Maturity Model. There are three parts to this:
Companies must help ensure that these three elements work well to have an effective quality culture at their manufacturing facility. The FDA must be able to recognize it, as must your customers and suppliers.
Let’s look at the proactive quality management system.
Four elements constitute proactive quality management:
Firstly, quality must be part of any five- or seven-year manufacturing strategic plan. Like other departments, the quality department must play a role in such planning. Companies acting with a proactive mindset will give quality a seat at the table in planning, and they will also look at the plans for the year ahead to check that the objectives laid out are attainable.
Strategic plans cannot be implemented without conducting a quality risk management exercise to code the risk associated with the systems, procedures and product development processes. Senior management at the company must get behind the quality elements of the strategic plan. Doing so sends a message to the entire organization that a quality culture is an integral part of the company. Furthermore, it makes good business sense. Proactive quality systems cost less to run than reactive systems that need to spend time and money remediating issues and cleaning up.
Let’s look at the elements in a detailed manner. A proactive approach always has annual risk-based quality planning embedded within the organization. This way of working demonstrates to everybody that quality behaviors are at the core of what the company does.
It is also important to be mindful of risk/mitigation measures and to revisit these where necessary, as part of the development process or as part of the manufacturing strategy. Certain risks will need to be taken. However, it is best to check that the mitigation measures around these risks are robust and to assess if the threats have changed, therefore necessitating a change in the mitigation measures.
Returning to the QMM, companies that are proactive in their approach and embrace the Quality Maturity Model will see benefits in their quality operation. They will see reduced numbers of audits, faster approvals or priority approvals.
Quality metrics and continuous improvements must be developed based on the findings of gap assessments. They must be measurable. Remember that it is possible that the metrics will not be the same for every company. It will depend on the area you have chosen to assign metrics. The simple mantra of “what gets measured gets done” is very apt. Knowing where your metrics are now will give you an understanding of where you need to get to.
It’s quite possible that the metric may not necessarily always be the same for all organizations, depending on which area you are trying to look at. It’s important to make a measurement over there, make an improvement and then move on to the next, depending on how you use your resources. So that’s where data trending and analysis come in.
When considering areas you want to improve, it’s important to look at patterns developing out of this data. Then use simple tools like the PDCA cycle, document your assessments and move toward the continuous improvement cycle.
While continuous improvement is one of the asks from the regulators, it’s also important for us, from an industry perspective, to know that emerging technologies effectively detect issues.
Finally, nothing stands still. Regulations are constantly changing, and you need to help ensure that the relevant teams are aware of any statutory or non-statutory developments that might impact the company. This level of awareness needs to be preemptive so that the company is prepared for any regulatory changes when they come into play. The QMM is an excellent example to use in this case. It is coming, and you need to be prepared.
The senior management review is the most cited from the review perspective. Senior management reviews send a message that the organization is serious about quality. They can document what needs to be done, what actions can be taken and the required resources to remedy any outstanding issues. The review also needs to highlight upcoming problems, as referenced earlier, and regulatory changes that might impact the product or the company.
Here is an example: The guidance on nitrosamines is something we have known about for quite a while. However, some companies are still being cited for nitrosamine-related issues. This demonstrates that they have not kept up to date with regulatory or legislative issues that impact their products.
Companies that want to grow in 2023 need to have robust GMP processes. They need to have processes to deal with any failures or human errors that impact the manufacturing process. Quality by design (QbD) principles must be applied, and the critical attributes of quality, material and process are known for all products. For the failure modes, you must understand what is to be done and that there are mitigation measures available so that product doesn’t move toward a failure mode. Avoiding failures is important from both analytical testing and product points of view.
Companies also need to consider the risk of contaminants and whether the risk is internal or external. Knowing this in advance as part of a quality-by-design review will enable personnel to categorize the risk so that priorities can be determined and the most important issues receive the most attention.
Defining a control strategy is essential. This will enable companies to set specifications and understand processes’ variability, and help them choose the right methods for testing product transfers or knowledge transfers. A defined and documented strategy reduces the risks of human errors during manufacturing.
The move to digitization or automation in manufacturing requires considerable planning, particularly for companies currently working in aging facilities. It is important to have a clear policy and a road map, especially for paperless or hybrid options.
A common issue we encounter as we work with companies worldwide is that moving from paper-based to paperless/hybrid systems confuses with no clear policies available. A set of SOPs in one format (paper) might contradict SOPs in another form (digital). As we have stated, this is a common issue, and it repeatedly arises in inspections. It is a simple one to fix and even simpler to prevent.
We always say that companies need to have simplified processes on the digitizing automation front. However, one of the points to note when moving into a digitized or automated process is to not simply try to mimic the paper process. Look at it separately. Identifying repetitive processes and automating them based on criticality is a good way to frame this.
Our second factor looks at the application of quality risk management. QRM is not a one-time exercise; it needs to be revisited periodically and where risk management actions need to be documented. The risks must be documented as lower, medium or high risks.
Always remember that proactive approaches are simple. The reactive approach often disturbs the simple nature of the SOPs, systems or processes. Companies need to develop mitigation plans as complexity increases, which might mean moving toward digitization or automation. It is also useful at this point to remember that the risk register is a live document that needs to be kept updated at all times.
Here are some of the systems and procedures that will make a difference:
Pay attention to these systems as written systems. Once it is available, it’s important that what is written is followed exactly.
The product-filing strategy is a critical element to consider with any product at the outset. Markets and extensions need to be thought about at this stage.
The dossier-filing strategy is connected to the product-filing strategy. Therefore, it is important to be aware of potential queries that may come from the reviewers and to ensure that there is a strategy in place for how the queries will be answered promptly.
At this stage, it would be beneficial to consider any changes that might occur in the months and times ahead. These might include changes in manufacturing equipment or raw material suppliers. Factoring these potentialities into an application will reduce the costs of filing applications again and incurring additional expenses.
Here is a scenario: If you think that in a year, your sales will be such that you will need to change the manufacturing equipment, it makes sense to start preparing for that as soon as possible. Make preemptive moves rather than waiting for observations to arrive and acting upon receipt of them. Ensure that the changes in the manufacturing setup are addressed promptly. There should not be a situation in which changes have been implemented and delayed the filing.
Ongoing compliance and audits are essential, along with staying abreast of changes in regulations. Again, proactive auditing can make a difference to the business. Conducting gap assessments at periodic intervals, prioritizing changes and identifying risk areas are ways to help ensure that these changes are identified and documented. This should be supported with a CAPA program. The proactive audit must be risk-based, and issues identified must be worked on as soon as possible.
Do not forget that your supplier assurance program is also an essential element that needs to be audited. Such audits do not apply just to raw materials or packaging that might come into contact with the product, but also to services obtained from external suppliers, such as consultancy firms.
Finally, approach each periodic audit with a fresh set of eyes. The danger with repeatedly carrying out the audit similarly is that things become familiar and issues might get overlooked. In situations like this and others, assumptions can impact the integrity of the audit and the legitimacy of the results. Look at the facts and the evidence.
The FDA Form 483 provides insight into how regulators look at the requirements. The interpretation of the FDA 483 might differ from company to company. It is important to take a view and not to take it at face value.
The words education and training are often used interchangeably. However, we need to be aware that we educate for knowledge and train for skills. This must be understood. Whenever we do training or education sessions, we must address “how factors” and “why factors.” Both education and training are the keys to unlocking the benefits of the quality management system.
Companies that wish to progress along the Quality Maturity Model recognize the importance of training and educating their staff.
I suggest revisiting your education and training processes, identifying the gaps, and documenting and eliminating the associated errors. Identify what kind of training works for your team, understand the needs of the team members and then try to keep it as simple as possible. Coaching also has a part to play here and should not be overlooked.
1 The Food and Drug Administration’s Foreign For-Cause Drug Inspection Program Can Be Improved to Protect the Nation’s Drug Supply. https://oig.hhs.gov/oas/reports/region1/11901500.asp
2 FDA Inspection Classification Database. www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-classification-database