Learning Objectives
Welcome to the pharmacy inspection podcast powered by lyceumce.com where we discuss topics related to both sterile and non-sterile compounding pharmacy in an effort to promote compliance and increase quality please welcome your hosts brian prince and seth d pasquale good morning everyone this is sethi pasquale board certified sterile compounding pharmacist happy
Friday to you and since it’s friday that means there’s another special edition of the pharmacy inspection podcast every friday we look at a 483 to try to help us understand and learn more about compliance within sterile compounding so let’s jump right in the learning objectives for today’s 43 are discuss the importance of low levels of endotoxin in parenteral
Preparations discuss the limits of endotoxin for various routes of administration and discuss the ways to control the levels of endotoxins in final preparations so in this week’s 43 we’re going to be talking about bacterial endotoxin and the testing related to endotoxins let’s first take a look at the observation then we’ll discuss what endotoxins are and why
It’s important to keep them out of your preparation so here in observation number one it says your firm release drug product in which the strength differs from or its purity or quality falls below that which it purports or is represented to possess specifically your firm does not have assurance that your intrafecal drug products contain safe levels of bacterial
Endotoxin the non-sterile active pharmaceutical ingredients baclofen bupivacaine clonidine hydromorphone and morphine sulfate used in the production of those intrathecal drugs do not contain results for bet testing or bacterial endotoxin testing on their certificates of analysis or coas due to this and combined with the fact that you do not perform testing
On your intrathecal drug products the result is a lack of assurance that your intrathecal products produced with those apis are free from bet or bacterial endotoxins so first thing that we should be talking talking about uh specific to this 43 is that we’re dealing with preparations that are intrathecals or that will be injected directly into the spinal fluid
One thing to know about intrathecal injections in particular is that they have a lower limit of endotoxins than other injections when performing final testing for preparation one of those tests is bacterial endotoxin this test is performed according to usp chapter 85 bacterial endotoxins test for parentals that are not intended for intrathecal administration
The limit is five eu’s or endotoxin units per kilogram for intrathecal injections the limit is 0.2 endotoxin units per kilogram the per kilogram is the weight of the patient so there’s going to be a little bit of a calculation here with each product that you’re sending off for for testing the fact that there’s a much lower limit of endotoxin specifically for
Intrathecal injections should give you an indication as to the importance of having very low levels of endotoxin in the final preparation this particular pharmacy is probably compounding intrathecals in either very low batch sizes less than five or one at a time as they’re ordered by a physician by not batch compounding the intrathecals there’s not enough
For of the final preparation to send off for testing my guess is that these are being made one at a time per order and are delivered to be administered within 24 hours so what are bacterial endotoxins and where do they come from most common endotoxins are byproducts of the gram-negative bacterial cell lysis they are lipopolysaccharides that make up part
Of the cell wall gram-negative bacteria are common are commonly found in water sources so if at any point you’re either using water in the preparation itself or using materials that have been washed i.e glassware there is a very high risk of having bacterial endotoxins in the preparation if there aren’t any controls in place to limit the level of bacterial
Endotoxins if glassware is being washed and reused for processing the preparation the glassware should go through a deep hydrogenation cycle meaning they would be held at a temperature of 250 degrees celsius for a minimum of 30 minutes the time may vary depending on the glassware and oven that’s being used for the deep hydrogenation process deep hydrogenation
Cycles of glassware should be validated to show that the process of departure nation is producing a three log reduction in bacterial endotoxins even if the process for limiting endotoxins and glassware is in place you still need to consider any of the raw materials you’re using i.e the active pharmaceutical ingredient or api water is used quite frequently in
The manufacturing for pharmaceutical ingredients and the certificates of analysis for your api should include the limit of endotoxin and the results of testing four endotoxins it’s pointed out in this 483 that the certificates of analysis do not include results of endotoxin limits for the apis so why are endotoxin limits so critical when a sufficient amount
Of endotoxins are injected this could result in a fever or can be as severe as death particularly if injected into the spinal fluid where there’s no immune system since this pharmacy doesn’t have coas that show the endotoxin limits and results uh that are not being tested for endotoxin in their final preparation they really have no way of showing that their
Intrathecal injections are meeting the required limits for endotoxins there are several ways that this pharmacy could increase the level of insurance that their process is limiting the endotoxin and the final preparation according to usp chapter 1228 bacterial endotoxins according to usp chapter 1228 depyrogenation there are three ways of controlling endotoxin
And parenteral products number one indirect control which is and this is a direct quote right from 1228 which is com comprised of a series of preventative measures that control bioburden the potential endotoxin contribution by formulation components examples given raw materials apis excipients water primary packaging components equipment and the manufacturing
Environment including personnel the second is process control in which endotoxin is monitored at monitored at critical control points during processing to ensure that there is no increase in endotoxin these process control elements are subject to validation or qualification and then third direct control or the direct destruction or removal of endotoxin from
Product streams equipment and primary packaging materials as with controls on processing direct measures of endotoxin destruction or removal must be validated so first you need to evaluate the process for compounding the preparation at any point is water being used in the process i.e glassware and other materials for compounding if so are you using the proper
Process to control the endotoxins are there ways to possibly eliminate the need for glassware materials that may have endotoxins in other words could you use single-use deposited and sterilized materials equipment lastly is there a way to compound the intrathecals in batches so that a percentage of the batch is sent off for testing to increase the level of
Assurance that endotoxins are at low enough limits for the injectable being compounded so that’s that’s what i have for for this week for the 43 fridays um this is often a subject that’s confused between endotoxins and endospores which are two totally different things um endotoxins again like i pointed out are the result of uh the cell being broken down a
Gram negative cell being broken down and their cell wall components being released into the into the water um so i i hope you find this very uh helpful and and gives you a little bit more of an idea of of how important endotoxins and controlling endotoxins in your final preparation is so that’s all i have for this week i hope you have a great weekend and as
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Transcribed from video
FDA 483 #9 – Bacterial Endotoxin Testing By Seth DePasquale
