During the last few months the European Medicines Agency (EMA) has issued a series of revisions to Annexes and Guidances

Specifically, the following

Annex 15 – Validation and Qualification

Annex 16 – Certification by a Qualified Person and Batch  Release

Annex 17 – Real Time Release Testing

Guidance to Industry: Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission

To understand what they contain and what it means, I refer you to an article I wrote recently in

Pharmaceutical on line  and

Bioprocess on line

Posted in Clinical Manufacturing, Commercial Manufacturing, FDA Guidance, GMP, News, Process Validation, Quality by Design, Quality Management Systems, Risk Management| Tags: Services|Leave a comment

Guidances have been issued by the FDA and EMA for over three years now.  So are companies complying or are they finding it tough?  Read an article I wrote in Contract Pharma Article.  Happy reading

Posted in Commercial Manufacturing, FDA Guidance, GMP, Process Validation, Quality Management Systems, Risk Management| Leave a comment

Single use components have been used in operations for decades but their use is expanding rapidly.  The agencies are taking a closer look.  Just published an interesting article on the topic in BioPharmaceutical International . Enjoy the read

Posted in Clinical Manufacturing, Commercial Manufacturing, Contract Manufacturing, FDA Guidance, GMP, Quality Agreements, Quality Management Systems| Tags: Services|Leave a comment

Do you have deviations that just won’t go away?  Do they disappear for a couple of months only to reappear a few months later stronger than ever?  Have you ever wondered why?

I won’t try to say that there is one cause for this but one that I have found continuously is Human Error as a major cause of the problem.  The obvious CAPA for this observation is to retrain the operator and rewrite the SOP.  I have seen it often in companies.

When I go in to audit the QMS, this is one area I look for first.  I look at the CAPAs and tally up the retrain operator and the rewrite SOP ones and if I find it happens more than 10% of the time, I know where to focus.  Investigations are not thorough or in depth.

On a recent visit to a client, they had just exited from a grueling inspection by an agency with a total of 53 observations.  They had developed their responses which are really CAPAs in any other language.  There were a total of 135 CAPAs and 55% were “retrain operator” or “rewrite SOP”.  I asked the person in charge of getting the responses back and asked whether he thought it would correct the problem.  His reply was an honest “No, many of these problems we’ve seen before and tried that and it never works”.  So, I ask him why are you doing it again, remembering Einstein’s quote “insanity is doing the same thing again and expecting a different result”.  At least I think it’s Einstein.

I then asked, “Why did you do this when you know it will not work?”  The answer was a chilling “because the regulators will accept it and it will allow me to get back to making product!”  I wanted to say “Yes, in the same broken way as before”.

After talking with other people at the plant it became clear that their investigation skills and tools were deficient.  They could get to the human error point.  They recognized that somebody had made an error but they lacked the tools to investigate further as to why it occurred.  Was it a system that was defective, were the operators overloaded with work, were the work stations organized appropriately?

Very rarely is Human Error the root cause but rather Human Error is the symptom of things not functioning properly. It is often the result of a deficiency elsewhere.  No other industry accepts human error just our pharmaceutical one.

There are four main ways that that things fail and manifest as human errors. There has been plenty of research in this area but not in pharmaceuticals.

1. Culture – the culture allowing or encouraging people to not follow procedures. Initially it may be innocent. “I know the procedure is wrong, but we cannot change it”. “I know it says that, but this short cut will get you there quicker and we have a goal to get on the shift” – implying doing it by the rules won’t let you get there on time. This often occurs in cultures that are volume driven. “Get the product out the door at all costs”. One company even had a goal of “Speed over perfection”. That was a difficult one to puzzle out.
2. Systems – the systems in place just don’t work. The poor operator just can’t get it to work based on the equipment, layout, QMS in place. This can be a change control process that is no longer serving the plant, a deviation process that everybody avoids, a CAPA process that is viewed as a encumbrance. The systems are viewed as punishment. Gone has the goal that the systems are tools to help you stay on top of your processes. The goal of everybody is to move the paper to the next person as quickly as possible. These systems are often put in place at the Corporate level or by management without asking the practitioners how it should be done. The same occurs in lay out of equipment and processes. They are not designed with the user in mind but often by a corporate engineer in central headquarters. Often operators have to take readings, remember them and go to the other end of the room or even next door to log the data into the permanent record.  This also breeds scrap paper use for data transcription.
3. Procedures – this is where the procedures, batch records are wrong. It is often because they were not written by users but rather other bodies.                                                                                                            In one case I came across batch records being filled out and there appeared to be lots of   extraneous comments.     I asked about them and queried why.  “The batch records are wrong” was the response.  “Why don’t you change them?” I questioned.  “We can’t. We are not allowed to “ was the answer.  “Why can’t you?”, I asked. “Because Process Science owns them. They write them for us”  “If they write them, do they have the same equipment as you operating at a similar scale”.  “No”.     No wonder they are wrong. Nobody consulted the actual people operating the equipment.
4. People – which brings us to the people. They make mistakes for many reasons. The reasons are many and varied. It could be that the training was inadequate. Yes they know what to do but not why. They do not understand the criticality of the key steps. They don’t know why it must be done this way. They are rushed and in the rush they revert to the old way.

As you read through the examples above, you will see a lot of similarity and overlap and that is because, it is rarely only one of the above that fails.  It actually starts at the management level with culture.  They set the tone that creates the systems, procedures and people to fail.

So how can you detect that you have a culture problem?  A systems problem?  Poor procedures? Or people prone to human errors?

You know you have problem or potentially one if you can say yes to any of the following:

Culture Problems include

• Silos with poor communication between
• Box checking mentality
• Firefighting all day and everyday
• Deadlines that are never met
• Deviations are considered bad and people are punished
• A blame culture that never learns from mistakes
• People unwilling to raise the alarm for fear of punishment
• Heavy reliance on final check – QA will catch it
• Metrics that drive the wrong behaviour

System problems are evident by these

• Congestion on the plant floor
• Poor work flows
• Physical conditions not adequate – lighting, temperature, humidity
• Unreliable equipment that breaks down
• Poor ergonomics of operators
• Electronic systems that are no longer tools serving the worker
• People avoiding using e-systems
• Don’t know the cost of non-conformance
• User not involved in design

Procedure problems are exemplified by

• Long complex SOPs – they read like War and Peace
• Too many double or even triple checks
• SOPs written to satisfy auditors or regulators not for operators
• CAPAs never working
• All investigations / CAPAs must be complete in 30 days
• Everything given equal importance

Which brings us to People

• No time for breaks
• Workers operating on permanent overtime
• Multitasking that does not work
• Reliance on memory because documents and records aren’t where the work is
• Training explains the how but not the why. No understanding of the consequences of the procedure
• Too many distractions
• Training in a class room versus where the job is done

Of course this is not a comprehensive list but you get the picture!!

To get rid of all these types of problem requires both management and workers to take responsibility.  We must move to a culture exemplified by

1. Create a positive attitude to human error. People make mistakes because the systems supporting them fail them. The error is pointing out an opportunity for improvement.
2. Create a blame free culture. We must have a freedom to speak out where we see an issue and focus on the event and not who did it. Ask the question “what went wrong?” rather than “what did you do wrong?”
3. Drive out complexity. Complexity is the enemy, it makes SOPs unworkable and an unworkable SOP translates to error. Reward simple procedures.
4. Use user centered design. Get the workers involved in writing SOP, Batch Records, designing equipment and process layout. You will create ownership and it will be right.
5. Introduce safeguards into processes, equipment. The operator knows what can go wrong, what they do under stress. Ask for their advice.
6. Have a rapid reporting system. A system that responds in hours, not days, week or never.
7. Seek out and remove risk. The workforce is your best friend to identify what or could go wrong. They see it every day.
8. Create education and not training programs. Education explains how and what but also why it is done this way. It includes what can go wrong if steps are done wrong. Tells you what the critical steps are and why the new is better than the old.
9. Management must assign roles and responsibilities and hold people accountable. Ownership and pride in the job well done ensues.

The road is a long one fraught with challenges but as my father used to wisely tell me “Knowing you have a problem is 50% of the way to solving it”.  How true!!!!

Posted in Commercial Manufacturing, GMP, inspections, News, Quality Management Systems, regulatory citations, Warning Letter| Tags: Services, SOPs|2 Comments

You’ve heard of it. You’ve probably experienced it. You may even have survived it. Yes, I am talking about “Project Operations Excellence”. Don’t get me wrong. The principles behind it are very good, even admirable. The premise is that we are operating presently as a result of processes that have evolved over time. A Band-Aid here, a Band-Aid there. The result is a set of processes that are inefficient not targeted to the customer and to be honest often counterproductive, sometimes counterintuitive. It does not sound good, does it?

Wouldn’t it be wonderful if we could deconstruct our processes and start again? That is what these companies sell you. The promised land of operations that are logical, lean (which brings me to another element of this concept, but I’m not getting drawn into that now – hint it suffers some of the same issues), lacking in superfluity, less is more, you get my drift.

So you sign on the dotted line and then in come the saviors. Most often it’s not the A team that did the sales pitch, the Dog and Pony show but if you are lucky it’s the C or D team. A couple of people who’ve seen the inside of an operations for a couple of hours together with a band of neophytes, fresh out of MBA school. They know the jargon, are excellent at powerpoints (I think that is one of the majors), the theory is at their command. Practical experience gained from case studies, that never go wrong.

Don’t I sound cynical and negative? No actually, I am not cynical or negative. I did not expect anything else. I’ve been through this exercise 5 or 6 times at different companies using some of the industry best companies and I’ve seen it at some of the companies I consult with. The problem is that we are our worst enemies. We do not challenge these saviors with data or facts or our experience. Just because they conclude something, does not mean it’s the best idea. It is an idea that should be considered. But often in these short 30 minute interviews to gather their data, they do not gather all the right information, they do not ask the right questions. Often it seems like they have gone in to these companies with the answer and are gathering data to support the results.

An example that came up recently, when talking with a client, related to an operational set up of a piece of equipment. On first glance, it appeared that after the equipment was set up, and then it was checked twice before using. The saviors immediately pointed out duplication and eliminated the second assessment. Nobody asked the question of why there were two checks. The junior person being interrogated did not have the answer. Voila, the step was removed. It was only afterwards, that a more senior person with experience of when the second check was put in place, that the explanation was clear. This piece of equipment had a tendency to drift in setting and the second check just before use was to monitor whether it had or not.

Perhaps the first check could have been removed? But that was never asked. An A team member with good process experience might have caught that one.

Modern day root cause analysis contends that silver bullets do not exist.  Rather it is a series of events (each incapable of causing the problem themselves) align and it is this alignment that causes the event.  So often we end up with corrective actions which are several to improve each element.

Is this example given an isolated incident? I contend no, because I have been into many companies reeling from these assessments. In fact one company that is in regulatory trouble now can trace their decrease in performance in operations, to an Operations Excellence episode. The results of the study were taken as gospel and implemented blindly. Clearly, all were at fault. An incomplete analysis, and accepting everything as correct etc.

So I caution everybody to think through how you manage an Operations Excellence project.

1. Don’t assume that their answers are right – they are suggestions.
2. They only get a snap shot of what is going on
3. If you don’t ask all and the right questions, the answers may not be right.
4. You are the ones who know what you do and why.

Remember that these people coming in to assess do their work and leave. They do not have to operate with what they leave. They are like a flock of seagulls, they fly in, squawking, leave you a present (hint, it is not paper) and fly off. What you should be looking for with an Operation Excellence is a team to evaluate, propose solutions and help you implement. And make sure you get the A team.

Posted in Commercial Manufacturing, Contract Manufacturing, GMP, Quality Management Systems, Risk Management, Warning Letter| Tags: Services|2 Comments