Prepare for Your Post-Pandemic GMP Inspection
GMP inspections are back. Regulatory authorities are returning to sites, and issues are being identified. Warning letters and findings can keep quality leaders awake at night. That is why it’s important to be prepared for a GMP inspection at your facility. Our expert team has written this article to highlight the areas that quality leaders need to consider as post-pandemic inspections continue.
In this article, we ask:
- What can you do to prepare your site for the future?
- What are the likely hot topics that will keep you up at night?
- What will you want to prioritize so that your staff, your subject matter experts and your departmental leaders are working on the right things at the right time for the right reasons?
The article also provides tips for tackling some of the difficult questions on vendor assurance, audits and regulatory inspections.
How Has the Pharma Industry Fared Since 2020?
Some companies have done well. They are thriving and busy, and their order books are full. However, that is not how it is for most of the companies we are dealing with. Many of the firms we are aware of and work with have been hit hard by the pandemic-related restrictions.
Supply Chain Interruptions
We continue to see many supply chain interruptions, weather-related disruptions, and shortages of raw materials, packaging materials and active ingredients. Trying to get the right bill of materials at the right place in the world at the right time continues to be a real difficulty, causing some significant drug shortages for the end users. Staff turnover, given the moniker of “The Great Resignation,” is also causing significant issues. Companies the world over are struggling to compete for talent. Added to that, temporary absences caused by positive COVID-19 tests and close contact rules have impacted the ability of companies to perform at optimum levels.
These “headwinds” faced by businesses are causing some people to make risk-based decisions based on the resources they have available to them. Often, these decisions are not based on what is the right thing to do for the quality assurance of the product. Therefore, tough decisions need to be made because of the staff availability issue. Furthermore, legacy facilities continue to be legacy facilities as CapEx investment has been reduced. Thankfully, we can also report we are starting to see a small uptick in that area recently.
How Did the Pandemic Impact Training and Education?
Straitened times resulted in staff development and training programs being “put on ice.” That meant subject matters experts did not develop their skills. Now, with restrictions in many parts of the world lifting, we are seeing a pent-up demand for new training and education programs.
How Did the Pandemic Impact Manufacturing Facilities?
Legacy facilities that were ready for an upgrade are two years older, and they still do not comply with GMP. Companies need to implement the new Eudralex, Volume 4, Annex 1, for sterile manufacturing. There are important items in the latest draft that firms must plan for and then invest in their facilities. That planning should have started one or two years ago. However, many companies have not been able to prepare because of pandemic-related disruptions.
We have also noticed that with schedule adherence, several issues across the pharmaceutical quality system (PQS) have not kept up with the target completion dates. Typically, deviation and investigation reports are being held over for too long, or they have not been engaged with in a timely manner or investigated adequately, and certainly have not been completed promptly in many cases. Every time we find a deviation, an OS or a change control that leads to a detailed root cause analysis, there is some degree of correction, corrective action or preventive action that is needed. We need to put in place a target completion date that must be respected. The seismic changes that are happening everywhere mean that many of the target completion dates have been defaulted against, leading to some known or even some unknown risks creeping into the production program.
Desperate times often bring about desperate measures. Firms are now considering actions they might not previously have done. They are now making some on-the-fly compromises in their pharmaceutical quality systems. To get things done, people and budgets are being moved around. These actions can have a knock-on effect. Subjective decisions can cause some divisions, stress, cultural issues and behavioral issues. Then the actions might not yield the results you were looking for. Fundamentally, this is all leading to both a reality and a perception that GMP deficiencies and product quality risks will become baked into your overall system.
The Typical Remediation Lifecycle
The first thing you’ve got to do with any risk is discover it. An undiscovered risk is a pothole in the road that you don’t see. The very first thing you need is a very good system for discovering risk.
The pharmaceutical quality system must be good at discovering issues. Finding an issue can often bring on a range of emotions: disbelief, denial, anger, finger-pointing and recriminations. The best companies try to short-circuit that as much as possible. Move out of that stage as quickly as possible, because it is a negative space, and you will waste valuable time.
Human nature means, however, that people often come through the blame stage and move into stasis. Common questions that people ask at this stage are:
- What do I do next?
- What should happen next?
- What do I need?
- Who can help me?
The sooner companies can move on to acceptance to assess and evaluate the risks and begin to plan out what is needed, the better. You can then get into fixing issues, executing actions and verifying that those actions have been completed satisfactorily. That is the ideal place to be.
You can go straight from anger to execution if you wish, but I would counsel against that. It may be the short-term, reactive thing to do, but we see time and again that when firms fail to go through acceptance, evaluation and planning and go straight from disbelief to execution, they find they’ve been busy fools. They’ve done a lot of actions that have no effect. It doesn’t improve the quality of the product. They feel good because they’ve ticked off many things that have been done, but it didn’t do what you wanted it to do.
When you do this, you’ve wasted time. You’re going to have to rework the project and redo or reiterate some of the documents because they just weren’t thought through properly. At this stage, I would urge you to think very hard about:
- How you do the risk assessment and evaluation
- How you do the planning
- How you derive your actions before you get into the execution stage
What Is Happening With Regulatory Agencies?
In short, there is a large backlog of inspections. As we have written about recently, FDA inspections are back. Other regulatory authorities are also traveling to sites. In a regulatory inspection, the inspector wants to see the evidence that people have followed their policies and procedures. They want to see that the fabric of the facility is what it should be.
We at NSF International anticipate that there will be a significant ramping up of regulatory inspections in different parts of the world in the coming months. Also, we believe there is going to be a need for increased regulatory reinforcement over the next year to 18 months, which means more budgeted spend or unbudgeted spend, more GMP remediation programs, and more change to get back to where you need to be: in line with the internationally recognized cGMP expectations.
The Hot Topics — The FDA’s Quality System Inspection Technique
It is convenient to group the likely hot topics alongside the six parts of the quality system as defined by the FDA’s Quality System Inspection Technique approach. That is under the reference of 73.56.002. This six-system approach is a process for performing regulatory inspections. Let us ask: What are they interested in? What will be the hot topics you need to be aware of and prepare for? Firstly, with materials control, they are going to be very interested in looking at any short-dated or expired materials. During all these supply chain issues, have you had to justify using either expired or short-dated materials in your production process?
Have you short-circuited any of your incoming QC checks or had to enhance them because of the use of an unapproved or approved-under-conditional-options supplier? Many times, with supply-related issues, there has been a need for far more storage capacity for work in progress. That approach necessitates a shoring up of stops around the factory. However, ask yourself, have they been stored appropriately in the right temperature conditions to avoid mix-ups and help ensure that they are correctly labeled and status controlled? Many of these issues related to materials control are centered on how you have approved your suppliers, how you perform ongoing vendor quality assurance and how you make sure your materials are suitable for the intended production process.
When we look at manufacturing control, particularly for those firms that have taken on new products or increased the outputs in their facilities, we have seen some evidence of overstretching those assets. Now you must assess how those assets are controlled and managed.
- How do they help ensure that the facilities themselves are appropriate for the new products?
- Production staff over the last two years invariably have been phenomenally busy. How have they contributed to the responsibilities and the expertise required around process deviations?
- How do we know that the right decisions have been made by the right people, some of whom have been incredibly busy?
You must make sure you are using your subject matter experts, however busy they are, in the right areas. The stresses of recent years have placed people in all walks of life under immense strain. That strain can enable errors to creep in.
The Root Causes of Errors and Deviations
Before an inspection, you must look at all the root causes of error and deviation, and specifically look at systems that are not working as they should be or are creating human error within the production process. Our experts are seeing overstretching of those assets and several situations where the batch sizes have become much smaller, which means there are many more line clearances. An increase in line clearances results in a need for additional stripdown, increased cleaning and more setups. Sometimes line clearance efforts can be defaulted or disrespected, and we see line clearance failures. If the site has had any evidence of line clearance failures, either in cleaning verification failures or line clearance failures, they will certainly be a hot topic in your next inspection.
People have also had to make value judgments about performing in-process checks. At times, these checks have been reduced because of a lack of availability of qualified staff.
Again, this issue will be a hot topic. How can you justify a reduction of in-process checks? Of course, when you’re working those packaging lines harder than they have been worked before, what’s the mean time between failure as that comes down and the number of changeovers? Has that created more breakdowns? When there have been breakdowns and repairs, have those burning periods created more risk? These are all very important questions to ask yourself.
You need to be clear, when questioned by a regulatory authority, about how labeling and packaging equipment have worked. Inspectors will want to know performance figures for:
- Packaging defects
How Does This Impact Legacy Facilities?
Of course, we must look at the condition and compliance of legacy facilities.
Can we justify continued use of legacy facilities, particularly those not in line with either current technology or available tech, or maybe not in line with cGMP requirements?
How do we do our patient safety and product quality risk assessments to confirm that we can still use this equipment in the production process?
We must remember that not all old equipment is bad equipment.
Well-calibrated, well-maintained and well-performing old equipment can work perfectly. However, you must ensure that everything is functioning as it should be and risks have not crept in during these last two years of COVID-19 restrictions, particularly if you have experienced degrees of change issues or, indeed, new product introduction.
For example, let’s presume that you have a piece of equipment that has had a broken key component, and you have not been able to source an identical replacement for that component. An instance like this will have meant that you have had to modify the component or put an alternative product part in place. How do you know for sure that the lack of availability of the approved part and the replacement with an unapproved part have not led to increased production risk or product quality risk? Also, how do we verify that there are no adulteration risks during product changeovers in terms of quality control?
Despite the stresses of operating in unprecedented times, the QA team still needs to ensure that they have provided sufficient oversight of QC. QC needs to have been able to engage with terminated analysis. If something goes wrong and an analysis is terminated, QC must be able to provide a justification for what has happened.
You must keep all the data so that you can be clear that you have a QC lab that is generating proper end-to-end data traceability. NSF experts have seen examples where out-of-specification studies and deviation investigations have come under pressure. Each time our experts have seen this, they have asked the same questions that a regulatory authority inspector would ask:
- What type of investigation has been done?
- What root causes have been identified?
- What CAPA has been put in place to deal with the issue(s)?
How Do You Fix the Issues?
The first thing that personnel at companies must do when an issue is identified is to own the problem.
It is important to be realistic about what can be done in the time available with the resources available. NSF can be incredibly helpful in adding bandwidth to your team, either operationally or in corporate QA/ QC. We can help ensure that our support is value-adding, not just for the immediate term when it comes to fixing issues, but also to prevent issues reoccurring.
Get the Right Additional Support
At a difficult time like this, it is easy to get distracted with gossip, hearsay, institutional knowledge, quick perceptions and reactive perceptions. However, data is king. Firsthand evidence and data to show what’s going on are crucial.
Because you don’t have time to work on things that are not important, you don’t have time to work on things that are not going to give you what you want in the future. You have time only to fix the issues objectively and based on evidence. So really concentrate on that. The next tip is around timing, in a way.
We always advocate that companies be in a perpetual state of cGMP readiness. However, this is not always the case. So if you have received notice of an inspection, how do you get as much done as possible in a finite amount of time? What should you focus on?
We recommend that you look at the following:
- Adulteration: You must be able to prove during your inspection that there is no chemical, microbial, viral or any other type of contamination in your product. You must verify the purity of the product to prove its safety and efficacy.
- Prove that your facility is operating to GMP standards. Otherwise, you are misbranding the product. If you say that your product is USP EPP standard, you must prove it.
- Data integrity: You must prove that the data that has been shown is a true and accurate representation of reality.
Fundamentally, some firms will just rush into doing tasks because they want to be busy. It takes an effective leadership team to prepare in a very methodical way to help ensure that things are being completed correctly.
Rachel Carmichael, an NSF expert and ex-MHRA inspector, always recommends that companies never try to defend the indefensible if something isn’t right. Therefore, processes need to be clearly defined. Ensure that processes adhere to cGMP and that staff are following them in full. Finally, make sure processes and procedures bring about the desired outcomes. Otherwise, they are worthless.
Finally, companies should not have to go through this on their own. NSF International employs a team of former FDA, MHRA and other regulatory body inspectors, and we work with clients all over the world, ensuring that their processes are inspection ready.