* * * INSIGHT * * *
A Friendly Discussion on “Why Do We Use RTD’s ... Process?”
By
Thomas A. Jennings, Ph.D.
Given the volume of responses that I received concerning the INSIGHT Vol. 6 No. 6 “Why Do We Use RTD’s to Monitor the Freeze Drying Process?” it seems that a raw nerve must had been reached. While some just shared their comments only with me, there were others who were kind enough to share with others and those comments can be read in Comment on Vol. 6 No. 6. I elected not to respond to any of these comments because of the time and space limitations on that web page. However, that is not to say that their comments went unnoticed or I did not feel I could respond to such comments - that is hardly the case. So I do thank those persons who shared their views on this topic and now it is only fair that I respond to at least one of them. But given it is summer and it is time for us to relax a bit and enjoy a change in scene, so it is with me and therefore I will let my friends at Surecure (Vol. 1 No. 8 and Vol. 2 No. 3) take on this task and at the same time share with you a slice of their own corporate life. Having said that, I can now sit back and listen with you as our friends Armondo and the Novice try to discuss, in a friendly manner, the comments and questions raised by Mr. Bogdam Oghina on “Why Do We Use RTD’s to Monitor the Freeze Drying Process?”
Monday Morning
It is the first Monday of the month and it is time for Armondo and his faithful assistant (the Novice) to have their regularly scheduled meeting first thing in the morning. Knowing how heavy the traffic was coming to work, the Novice was in no great hurry to reach Armondo’s office. Although Armondo takes great pride in a perfect “on time” record the Novice knows full well that it only lasts at best a week or two and Mondays tend to destroy the previously set record his friend may have in place. So he is somewhat surprised to hear Armondo shout “Come in!!!” after just a few taps on the door.
The Novice is further surprised not to find Armondo seated at his desk sorting through piles of papers in boxes he has named “Urgent”, “Do Later”, “Ignore” and “Forget” but at his window which over looks the parking lot for management personnel whose spaces are assigned by Miss Charm. Armondo would love to have a parking space in this lot but Miss Charm only assigns them on an “as needed basis.” Of course she is not considered management but does have a space because she “needs it”.
The Novice speaks first as he takes his usual seat opposite Armondo’s busy desk “Good Morning Sir” he says loud enough to make sure Armondo heard him.
“And a good morning to you my fine friend” replies a cheerful Armondo as he walks from the window to his desk. “And how are you on this fine morning my friend???” Before the Novice can utter a work Armondo continues with “now where the devil did I put those papers that I wanted to discuss with you?”
Having already known what Armondo wanted to talk about from his e-mail message, the Novice removed two stabled sets of papers from his folder and reached over to hand them to Armondo and said “Are these the papers you were looking for Sir?”
“Why yes.” replied Armondo “Why did you remove them from my desk - no wonder I could not find them.”
“Sir”, said the Novice “I would not dream of removing or disturbing the filing system on your desk - it is just that I had two extra copies with me.”
“Oh, thanks” says Armondo “I am sure I had them right on top of my desk. Maybe the cleaning people moved them over the weekend. If I have not told them once I have told them a thousand times not to disturb anything on my desk. Now where is my pen?”
“You have one in your shirt pocket ,Sir” helped the Novice.
“Your right it is there.” While removing the pen from his pocket Armondo gets up and walks to the window. Takes a quick look out the window and with a satisfied look on his face he returns to easy chair and starts to look at the papers given to him by the Novice. “Are you ready?” he finally asks.
“Yes Sir!!!” is the firm reply.
“Good - for I hate to waste time and so let us get down to today’s business.” The Novice can only grin as Armondo continues. “I thought the INSIGHT on the RTDs was OK but I really enjoyed that Comments the were published the following month. They were great and really put it to the “know-it-all” author - what’s his name?”
“Jennings” is the helping response
“Yes indeed they really put that Jennings on the spot that he couldn’t think of a reply.” Don’t you agree?” asks Armondo.
“Not really sure Sir but I am willing to hear what you have in mind” answers the Novice.
A now confident Armondo looks at the page and remarks “ Let us first take a look at the comments by Bogdam Oghina.”
‘“OK” is the reply.
I think that Bogdam Oghina has hit the nail right on the head by stating, in certainly a logical fashion, that there is no good answer to the question raised by the INSIGHT as to why we use RTDs. Certainly you must agree with Bogdam Oghina on that opening statement?” asks Armondo.
“What type of temperature transducers do we use on our freeze dryers?” the Novice answers with a question.
“Why I believe we use thermocouples - but that is not the point of Bogdam Oghina’s logical statement.” answers Armondo.
“And why do we have thermocouples on our dryers?” comes another question.
After a slight pause, Armondo replies “Well our dryers are made by the “Perfect Freeze Dryer Company” and I we know they stand behind their equipment.”
“Did anyone in our company specify that “Perfect” install thermocouples as temperature transducers?”
“No!” answers Armondo, “all freeze dryers manufactured by “Perfect” are equipped with thermocouples. So what is your point and we could have just as easily specified RTDs.”
“Not exactly” replies the Novice, and Armondo frowns every time he hears that expression, “you see thermocouples and RTDs are not interchangeable. To change from one to another would require extensive software changes especially in the process control and data collection systems.”
With his head now resting on his hand as he leans on the top of his desk, Armondo asks “So what is your point? Please get to it for we have a lot more to do.”
“Sorry Sir” apologizes the Novice, “but there is an answer to the question raised by the INSIGHT and that is that RTDs are used because they were installed by the manufacturer and the user assumes the manufacturer has been in business for so many years that they must know what they are doing. In a sense they do but then most freeze dryer manufacturers tend not to manufacture anything with their dryers so how would they know if there were any serious problems associated with the use of RTDs?”
Nodding in agreement, Armondo thoughtfully adds “ I see your point, people will tend to use the RTD because they really don’t have a choice in the matter. So they just have to learn to live with them. It is not like a radio where you can change the station if you don’t like the music.”
Having finished what he feels is a summarizing statement, Armondo stands up, stretches and strolls over for a quick glance out the window and then returning to his desk he picks up his paper and after reading briefly, asks” Surely you can disagree with the next statement by Bogdam Oghina”
The Novice leaned back in his chair and responds “Except for some periods when the product is being loaded, the end of the freezing process and maybe the secondary drying process, there will be a temperature gradient present in the product. However, it is precisely this temperature gradient that makes the RTD inaccurate for use a temperature sensor.”
“Why is that?” asks Armondo.
The Novice continues, “The accuracy of the RTD depends on a uniform temperature across the sensor and, as a result of this temperature gradient which is constantly changing, one does not really know the temperature at any one given point in the product. So one obtains a temperature reading that is really not representative at any one point in the product.”
“So the RTD provides a temperature reading but one really doesn’t know exactly what it means.” replies Armondo who then continues with “But won’t that be also true of the thermocouple?”
“No!” sharply replies the Novice “The thermocouple is a point sensing device and its output does not reflect a temperature gradient like that of the RTD.”
‘Yes that is true.” answers Armondo and continues with “But at what point do you measure? As Bogdam Oghina points out do you measure top, bottom, center, side? I must say he has certainly made a good point here.”
The Novice nods his head in agreement, “Yes he does brings out a most important point. The logical place to position a point sensing device would be in the middle of the product about 1 - 2 mm from the bottom of the vial. By placing it there you will not only obtain a good measure of the degree of supercooling during freezing but this is at the location where the last ice will be present in the product. When the drying front drops below the thermocouple junction (See INSIGHT Vol. 6 No. 7) there will be an increase in the temperature of the cake and that rise in temperature will signify the completion of the primary drying. The size of the RTD prevents us from knowing when that last bit of ice was sublimated.”
Leaning back in his chair and starting at the ceiling, Armondo likewise nods his head in agreement and replies “I see your point and I agree with you. I must say that Bogdam Oghina is way off when he then speaks of product temperatures. I am sure you will agree with me on that?“ Armondo asks in a sort of half hearted voice not being sure exactly how the Novice would respond.
Much to Armondo’s disappointment the Novice slowly shakes his head “No” and then responds, “I am sorry Sir but I must disagree with you and tell you Bogdam Oghina is right on this point. There will not be a product temperature but product temperatures”
Disappointment now slowly turns to frustration with the young inexperienced colleague for it seem he can never say anything right. “But every one including yourself have talked about the product temperature and now you are telling me it is product temperatures? Now tell me once and for all is it a product temperature or product temperatures.?
Softly the Novice answers his somewhat frustrated and confused supervisor with merely the words “Its product temperatures.”
Armondo is now really besides himself and asks “How is that possible?”
“It is not only possible but really does occur and the reason for it is that there is a frequency distribution of heat transfer coefficients for the vials [1] and when you throw in temperature variations across the shelf and from shelf to shelf - one simply must realize that there are going to be a frequency distribution of product temperatures.” states the Novice rather firmly.
“So what do mean when you talk about product temperature and what about the usual relations that hold say during primary drying - do we now throw them out?” demands Armondo.
The Novice can sense he is frustrating his friend but at the same time wishes to help him to understand that there is a statistical aspect to lyophilization that is generally overlooked for the sake of simplification. So he continues now more slow. “When I talk of product temperature I am referring to the mean product temperature but I keep in mind at all times that there will be vials that will dry faster and some that will dry slower as a result of a difference in the product temperatures. As far as the usual relationships are concerned they are still very much in place and that there will be a relationship, particularly during primary drying, between the shelf temperature, the chamber pressure and the product temperature. That relationship is based on the phase diagram of water ( see INSIGHT Vol. 5 No. 2) and thus will not be altered by how we measure the product temperatures.
It comes as both a surprise and even a relief for the Novice when there is a knock on the door and a now very frustrated Armondo shouts out “COME IN!!! OR DO YOU WANT ME TO GET UP AND OPEN THE DOOR FOR YOU!!!”
The Novice sinks into his chair and covers his eyes as a somewhat bewildered looking Miss Charm steps into the room. But seeing the look of shock, fear and change in color on Armondo’s face, the bewilderment now quickly turns to anger as she slams the door behind her. “Is that now how you respond to people knocking on your door? she demands in a booming voice.
The room is air conditioned and comfortable but there are now beads of sweat starting to form on Armodo’s brow as he gropes for a response. The Novice wishes he were somewhere else at this moment but tries not to look at Armondo and it seems like a year before Armondo blurs out. “ I thought you where the cleaning person who comes in to empty my waste cans”
“Just because they are going to empty your waste cans, is that still anyway to talk to someone?” Miss Charm demands. She then adds “Don’t the cleaning personnel come in the offices only after working hours just so they don’t disturb anyone while they are working?”
A now very humble Armondo finally has regained his composure and standing up faces the angry Miss Charm and says “ You are 100 % right I should not have spoken to you or anyone else in that tone of voice but you see I was .... no you are right - 100% right and I do apologize. Please have a seat and rest assure it won’t happen again - no never will it happen again - please have a seat Miss charm.”
Now standing next to Armondo’s desk she replies “ Thank you but I will stand for what I have to say won’t take that much of your precious time.”
“Take all the time you want.” replies Armondo “I wasn’t that busy. I was just talking with him” as he motions towards the Novice who is staring down at the floor.
It is then the Novice has enough courage to look up and see that Miss Charm is carrying a large white poster board in her hand which, after pushing some of the file boxes to the other side of the desk she places the poster board on the top of the desk. Upon doing so she starts with “As you must know by now I have been appointed by our very top management of our Company to be Director of Social Activities.”
“Yes, Yes, I heard that and congratulations on your promotion and I am sure they picked the right person for the job.” responds Armondo.
Looking directly at Armondo, Miss charm corrects him with “ It was not a “promotion” - it was an “appointment” to a very key Corporate position that has been unfilled since the Company was first founded some 15 years ago and it is not a “job” but a “position” in the company.
‘You are right absolutely right again” replies Armondo “ Can you tell me what I am looking at here?” eager to talk about something different.
“As any intelligent person can see from the legend on the drawing that it is the layout for the Annual Surcure Beach Party.”
“Did we have one before?” asks a meek Armondo.
“No” is the reply “But we will be having one each year from now on. So pay attention to what I am going to show you.”
“I am all yours - I mean you have my full attention” say Armondo with a bit of a grin.
Miss Charm ignores the remark and continues. “As you can see there is a line of white colored beach umbrellas facing the ocean. Those are for our top management and the members of the BoD and their families. Behind them is a row of blue umbrellas and they are for our directors. Please note your umbrella is on the end right next to the jetty and is number 13.
“Number 13, I won’t forget it - number 13” mumbles Armondo.
Now enjoying herself with Armondo, Miss Charms continues. “Do try to remember and perish the thought if I have to move you. Now the rest of the employees like him - pointing to the Novice - are located in back of the blue umbrellas. They must bring their own umbrellas so please instruct your group that none of their umbrellas can be colored white or blue nor have any wording on them that would be visible from the air.
“What is wrong with the wording on the umbrella?’ asks Armondo.
“There will be an aerial photograph taken at 1:00 p.m. and we want everyone under their umbrellas at that time. Also tell your employees that they cannot place their umbrellas outside of these lines defined by the white and blue umbrellas. Note that there are two tents in the back for changing.”
“Why just two tents? asks Armondo
“One for ladies and the other for men and boys” is the reply. “And just one more thing, when you or your employees want to go into the water tell them they must walk around the white Umbrellas and not through them. Is that clear!!!”
“Perfectly clear, it is perfectly clear to me ” is the reply “And I might just add that this Beach Party has been well thought out and will be a huge success.”
“Of course” answers Miss Charm as she picks up the poster board and walks toward the door but adds before leaving “Why else would they appoint me Director Of Social Activities.”
As the door closes a much relived Armondo stands for a moment or two in front of his desk and once again walks to take a quick look out the window. Then with a smirk on his face he returns to his chair and asks the Novice “ Where were we?”
The Novice was puzzled by Armondo’s interest in looking out the window, but the “smirk” look on his face now had him bewildered as to just what was going on. However, trying to put such thoughts out of his mind he replies, “ Sir we were just about to start with question 5 that was asked by Bogdam Oghina”.
Armondo reads question 5 and asks “We don’t have any problem positioning the thermocouple sensor in a product container do we?”
“No Sir - we have no problem whatsoever and it is a routine procedure for our operators.” is the reply
“Forgive me for I am still trying to recover from Miss Charms visit” states Armondo. “But if we are not having any problem and I am sure there are many others out there also not having any problem the what is the point of his question? I must be missing something.”
Learning forward in his chair the Novice, coming to the defense of Bogdam Oghina’s question, responds “Bogdam Oghina is making a very valid point here. You see the only reason we are not having any problem with measuring the product temperature is that we are using thin thermocouples and we are manually loading the system. I certainly agree with Bogdam Oghina that positioning an RTD in a container is a completely different problem and would consume more of the operator’s time and it still may not be precisely positioned as in the case of thermocouples. No doubt the positioning of the RTDs in an automatic loading system will only compound the problem even further.”
Armondo nods his head in agreement and then with a perplexed look on his face replies “ Then tell me why any one would use RTDs if they pose such problems?”
This last question brings a laugh from the Novice “But Sir we already answered that question in the very beginning of our conversation. Companies use RTDs because they are the temperature sensor system supplied with the freeze dryer. It just happens that “Perfect” dryers elected to use thermocouples that we have thermocouple sensors.”
Armondo nods in agreement and continues “ Your right there and I would have to say Yes to Bogdam Oghina next question. No doubt the mass of the RTD and even its volume, when used to sense the temperature of products having small fill volumes, could greatly alter the fill height of the product and interfere with the freezing and drying of the product. The temperature sensor should be a none intrusive measurement!!!”
The Novice smiles and answers “You are 100% right there and I think your point about the measurement being none intrusive is very well taken!!”
Perhaps it is that Armondo does not often find the Novice to be so agreeable and even eager to embrace his statement he just wants further assurance and asks “You really like that term “none intrusive” didn’t you?”
“Yes I do!!!” is the enthusiastic repose from the Novice.
“Well, that is a good lesson for you to learn. So keep that in mind anytime there are measurements made with regards to the product they should be performed in a “none intrusive” means. I don’t want to have tell you again about this.” firmly lectures Armondo.
A now serious Novice replies “You won’t have to tell me again - I got your message loud and clear.”
“Now that I have answered the more difficult question, I will let you try your hand with Bogdam Oghina’s next question I believe that it is number 7.” command a very confident Armondo.
Looking at question 7 the Novice answers “I will try my best Sir” but before he can continue he is interrupted.
“That’s all I ever ask of anyone working for me is to try their best - sorry for the interruption. You can continue now” says Armondo as he leans back in his chair and gazes at the ceiling.
“Thank you Sir” continues the Novice “In response to Bogdam Oghina’s question number 7, I would say to him given that he recognizes that freeze drying is a statistic process is indeed a fact, the question as to if it (statistic process) is accepted by those using the freeze drying process is a mute question. Since a fact is something that is real and can be demonstrated there is no need for an approval process in order for it to exist. When dealing with a process in a statistical manner, the tolerances will be defined by the nature of the frequency distribution. For a very narrow well defined distribution the process can be performed within very close tolerances; however, give a very broad and even skewed distribution the tolerances may have to be quite large.”
“Will the tolerances have any impact on the validation process?” asks Armondo as he continues to gaze at the ceiling with a look of someone in very deep thought.
“It sure will.” replies the Novice “As the necessary tolerances increase so are the efforts required to validate the process.”
“I agree and since you are doing so well why don’t I let you try your hand at Bogdam Oghina’s next question” as Armondo now closes his eyes to help with his thought process.
“Thank you Sir for your confidence in me. I will try my best to address question 8.” replies the Novice and after reading the question he continues by looking at the question. “Well if one is going use shelf fluid temperature instead of the self surface temperature (see INSIGHT Vol. 1 No. 7) you may only have perhaps, depending on the manufacturer, just one temperature reading. So you can hardly apply statistics to a single measurement and the same would be true for the chamber pressure. I would have to agree with Bogdam Oghina that it makes no sense to apply statistics to the other dryer operating parameters like condenser temperature (see INSIGHT Vol. 1 no. 1), foreline pressure or other external environmental conditions that would be completely ludicrous. BUT, and this is a big “but” a statistical knowledge of the product temperature is another question given its dependency on the previously mentioned parameters for if one of those parameters were to change significantly it could seriously impact the drying process and its impact can only be determined by knowing the product temperatures (See INSIGHT Vol. 1 No. 2). Don’t you agree Sir?” asks the Novice as he looks up only to find that not only are Armondo’s eyes closed as he faces the ceiling but now his mouth is wide open. Not quite sure what to do the Novice makes some noise by moving his chair on the tile floor.
Armondo suddenly comes to life and looks at the Novice with a particular look on his face.
“Do you agree with my response to question 8?” again asks the Novice.
“Certainly, I do or I would have interrupted you..” replies Armondo as he tries to regain his composure. Looking at the question 9, he says “You have done very well with those easy questions let me try and tackle the next question. I would tend to agree with Bogdam Oghina that placement of the closures prior to the lyophilization process is an important consideration and one that should not be overlooked. Certainly impeding the gas flow from the vials will impact the lyophilization process. Don’t you also agree?”
“I certainly do.” replies the Novice
Stretching his arms and walking to the window Armondo asks” Why don’t you respond to Bogdam Oghina’s last statement.
“Thank you Sir. In my opinion the problems that we have just pointed out with regards to the use of the RTDs as temperature sensors will also exist when they are used to develop the lyophilization. Further I would say that defining the lyophilization process from an accurate measurement the product temperatures not simply “nice” but a “necessity” if one is going to use the data to transfer the process from a development dryer to a production dryer and manufacture using cGMPs. Do you have anything you would like to add to this? asks the Novice.
With a very satisfied look on his face and now fully awake Armondo takes his seat. “No I have nothing to add to what you have just said. I am certainly glad we went over these questions for no doubt the answers will help you to improve your performance in the department. I am sure you won’t forget to remember to keep in mind what I told you about the measurements being “none intrusive”.
“It is firmly etched in my brain.” answers the Novice.
“Say it near lunch time already - how the time flies by - just wait a moment and I will go to lunch with you but first I must make a quick phone call.” Armondo presses the keys on his phone and waits and finally speaks. “Miss Charm - Armondo here. (pause) Armondo the Director of the Validation Department ( another longer pause) yes, that Armondo Miss Charm and no I have not forgotten I have umbrella 13 next to the jetty. Yes, Yes, I can’t wait but that is not why I called.” (another pause) Now a smile lights up Armondo’s face “The reason I called Miss Charm was to tell you that you left the headlights of your car on this morning when you came to work. (pause) Yes, it is your car, the blue one with yellow banana painted on its side. Yes I know that is you car. No, No there is no need for you rush - take your time. The headlights are out now. (another pause) I can tell you are upset Miss Charm but do try to enjoy the rest of your day - Bye, Bye!!!”
The Novice is speechless and can only think to himself “ And so the war continues.”
Reference
1. T. A. Jennings, Lyophilization - Introduction and Basic Principles, Interpharm Press,Buffalo Grove, IL 1999.
Acknowledgment
On behalf of personnel at Surcure, I would like to extend my sincere thanks to Bogdam Oghina’s thoughtful question which he shared with us and made this INSIGHT possible.
Vol. 6 No. 9 September 2003
