Temperature effect on classified areas

GOOD MANUFACTURING PRACTICE (cGMP)
#1

Hi Colleagues,

Our firm initiated RISK BASE APPROACH and FMEA in our facility. while analyzing the temperature effect on the Environmentally controlled areas , there was huge discussion happened and a common question has been raised, just i want to summarize that below.

  1. Suppose we are operating a fermentor at 30C and Temperature limit for the Classified area is 19-25C. During the activity area temperature found out of limit.i.e 28C.
    What will be impact on the batch running in the fermentor?
    Why industries typically follow the 19-25 C range for operational areas.

Please share your thoughts.

Thanks in advance…

R.Dasaratha Rami Reddy

#2

Dear rdasaratharamireddy,
I think we need to look at two different aspects, to answer this question.
Your HVAC is of adequate capacity if something happens which you mentioned below. Cooling temeprature for your fermenter which you are running the batch.

  1. If your fermenter operating temperature is 30oC, and HVAC temperature is 19-25oC. If the temeprature comes down as 28 oC then your cooling fluid and control system associated with it has to take care of this.
    Offcourse, the temperature of the HVAC does matter but in the fermenter scenario i think it is the control system and temperature of the cooling fluid which is circulating through the jacket.

  2. Temperature control is required to provide stable conditions for materials, instruments, and personnel comfort. Human comfort requirements typically in the range of 72F-78F. We need to consider every aspect. As per Schedule M “GOOD MANUFACTURING PRACTICES AND REQUIREMENTS OF PREMISES,
    PLANT AND EQUIPMENT FOR PHARMACEUTICAL PRODUCTS” in section 3.10 which states that ------ Unless there are product specific requirements, temperature and humidity in the aseptic areas shall not exceed 27 degree centigrade and relative humidity 55%, respectively.

I hope it helped you.

Regards,
Prashant Chawla

#3

[quote=rdasaratharamireddy]Hi Colleagues,

Our firm initiated RISK BASE APPROACH and FMEA in our facility. while analyzing the temperature effect on the Environmentally controlled areas , there was huge discussion happened and a common question has been raised, just i want to summarize that below.

  1. Suppose we are operating a fermentor at 30C and Temperature limit for the Classified area is 19-25C. During the activity area temperature found out of limit.i.e 28C.
    What will be impact on the batch running in the fermentor?
    Why industries typically follow the 19-25 C range for operational areas.

Please share your thoughts.

Thanks in advance…

R.Dasaratha Rami Reddy[/quote]

Dear R.Dasartha Rami Reddy,
the reason for keeping temperature & humidity in classified area is for microbial control. In this temperature microorganisms does not form spores. they form vegetative cells and can be destroyed by disinfection procedure.

As far as your temperature in classified area is concerned, it looks like that you have not done PQ of area properly. Performance Qualification is done when all the machinary are in place and in working conditions. Accordingly HVAC engineer can set the temperature as required.
If you need any help do write to me.

Dr.Pardeep Nagalkar
Head, Quality Control,
Haffkine Bio-Pharma Corp.Ltd.
A.D.Marg, Parel,Mumbai 400012
(M) 09820389069
e-mail: nagalkarp@yahoo.co.in

#4

Dear Mr.Reddy,
Every one thinks about this problem and we faced it too during 2003 during process scale-up of our recombinant strains in EU.
We have designed a small chamber or a glass enclosure which is almost covering the entire surface area of fermentor and it is thermostatically controlled.
Later after these studies we have purchased improvised Fermentors which could handle temperatures independently inside the Broth rather depending on external conditions.
We did observe that the cell mass was not up to the yield or specified weight when there was a temeperature fluctuation and there was a wide difference between the shake flask cell mass and fermentation mass.This had a bigg larger impact on our purification yields and much of the product could not been recovered even after proper refolding mechanism.

Since bacterial cultures especially recombinant cultures react to temperature fluctuations immediately, we designed that praticular enclosure which served our scaling purpose.

Probably such enclosure would cost you 50 to 60 thousand rupees in india (Approx 1300$ US)

Regards

#5

I talk about common controlled room. when the temperature was out of limit in several time during processing should it be judged as out of specification - or we could calculate the mean kinetic temperature (MKT) to determine whether it was still in the specified temperature range or not? thanks in advance.

#6

Hi Syx,
When we qualify the controlled rooms we also qualify the rooms for having certain temperature all the time. We will have a fixed limit (internal limits you may call) and this is noted daily in the log sheets.
The reason for fixing such temerature range is that it might effect the product or it will cause discomfort to operators and staff (in case of humans it increases prespiration).In both casses it will spoil the quality of product.

When we observe the temperature shooting up or falling down the specified internal limits we will call OUT OF SPECIFICATION.

Mean kinetic temperature terminology cannot be used for such rooms & by calculating such thing you cannot stop the above risks.

#7

so, where or when could MKT be applied?

#8

Mean Kinetic Temperature (MKT)

Measurement and recording of temperatures is vital to the storage of perishable goods, but there is more than one way to record an average.

The ICH defines the mean kinetic temperature as being “a single derived temperature that, if maintained over a defined period of time, affords the same thermal challenge to a drug substance or drug product as would be experienced over a range of both higher and lower temperatures for an equivalent defined period”.
MKT expresses the cumulative thermal stress experienced by a product at varying temperatures, during storage and distribution. It differs from other means (such as a simple numerical average or arithmetic mean) in that higher temperatures are given greater weight in computing the average, thus, recognizing the accelerated rate of thermal degradation of materials at higher temperatures.

MKT is a calculated fixed temperature that simulates the effects of temperature variations over a period of time. It expresses the cumulative thermal stress experienced by a product at varying temperatures during storage and distribution. Good warehousing and distribution practice requires that warehouse temperatures are controlled and monitored and that appropriate action is taken if temperatures exceed the storage conditions stated on product labels.
• Strict conditions should be applied to the use of MKT
• It is applicable only to the storage of products under controlled
room temperature conditions, such as those labelled ‘do not store above 25°C’
• MKT should not be used to compensate for poor temperature control of storage facilities

Regards

#9

Mr Prasad, thanks a lot for your explaination above. however, WHO TRS No. 908, 2003 Annex 9: Guide to good storage practices for pharmaceuticals mentions that drug products that must be stored under defined conditions require appropriate storage instructions. Unless otherwise specifically stated (e.g. continuous maintenance of cold storage) deviation may be tolerated only during short-term interruptions, for example, during local transportation.
It is not mentioned how short the interruptions, but my opinion, we should consider the MKT here. please correct me if I wrong. thanks.

#10

Syx,
I know about WHO TRS annex no:908.
When this document was written in 2002-2003 there was not that much scientific evidence about MKT. Now you will hear soon their updated guideline.
Comming back to your question I must say you are very correct.
Bigg warehouse and Distribution houses will have walk-in cold rooms. In such rooms this is widely used.
Regards

#11

I found this statement in USP General Notices: 10. PRESERVATION, PACKAGING, STORAGE, AND LABELING:
“Controlled room temperature” indicates a temperature maintained thermostatically that encompasses the usual and customary working environment of 20 to 25 (68 to 77F); that results in a mean kinetic temperature calculated to be not more than 25; and that allows for excursions between 15 and 30 (59 and 86F) that are experienced in pharmacies, hospitals, and warehouses. Provided the mean kinetic temperature remains in the allowed range, transient spikes up to 40 are permitted as long as they do not exceed 24 hours. Spikes above 40 may be permitted if the manufacturer so instructs. Articles may be labeled for storage at “controlled room temperature” or at “up to 25”, or other wording based on the same mean kinetic temperature. The mean kinetic temperature is a calculated value that may be used as an isothermal storage temperature that simulates the nonisothermal effects of storage temperature variations.