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Administrator
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Registered: ‎02-22-2010
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USP 71 Sterility Testing and Extending BUD Webinar

[ Edited ]

Thanks for joining Eric Kastango and Scott Sutton in their webinar, "Understanding USP 71-Sterility Testing and Extending Beyond-Use Dating."

View the on-demand recording or download the slides.

 

Have a question for either Eric or Scott? Post it here and they will do their best to answer your question.

Occasional Visitor
Posts: 1
Registered: ‎07-10-2013
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Re: USP 71 Sterility Testing and Extending BUD Webinar

Dear Eric

During compounding of low risk items do you need to assign 797 medium risk dating if these items are prepared as a batch and are not patient specific?  Also is there any limit to the number in the batch that will move your dating to medium risk, such as only 2 or 3 units or will all batches be given medium dating?  For example if we prepare 3 bags of 20 units oxytocin in 1 liter of fluid for use during the day can we assign 48 hours room temp or do we need to assign 30 hours room temp medium risk dating?

Thank you

RBHS

Member
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Registered: ‎07-10-2013
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Re: USP 71 Sterility Testing and Extending BUD Webinar

If I may ask a question of the panelists from today's excellent webinar: 

 

Please comment on the correctness or not of the following:  

USP <797> does not require end product sterility testing for low risk and medium risk CSPs when remaining within the chapter's BUD limits...    

 

And further,  if the above is true, is the primary reason because of the complexity of a USP<71> compliant sterility test and the likely unreasonalbleness of meeting that on a regular basis in a typical pharmacy scenario?

Advisor
Posts: 16
Registered: ‎07-05-2013
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Re: USP 71 Sterility Testing and Extending BUD Webinar

Eric,

 

Can you elaborate on the necessity for sterility testing if terminal (heat/steam) sterilization is utilized?  We are having trouble finding a reference in the USP chapters.  Thanks,

 

Kelly

Occasional Contributor
Posts: 10
Registered: ‎06-21-2011
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Re: USP 71 Sterility Testing and Extending BUD Webinar

With regards to direct transfer testing...preparing prefilled syringes less than 1 ml fill amount in batches of less than 100.  Of the 10 syringes that would be used for testing--Would 5 syringes be injected into 1 vial of TSB and the other 5 syringes into 1 vail of FTM?  or would we use 5 vials of TSB and 5 Vials of FTM?

 

 

Occasional Visitor
Posts: 1
Registered: ‎07-10-2013
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Sterility testing requirements for batch process

Is sterility testing required for all batch processes?  More specifically, if we are batch processing IV's and assigning BUD as 48 hours room temp or 14 days under refrigeration, is sterility testing of the batch required by UPS 71?  Or does USP 71 sterility testing for batches only apply if we want to assign BUD beyond the guidelines set by 797?

Thanks,

Wendy Waldman, RPh

Occasional Visitor
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Registered: ‎07-10-2013
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Re: USP 71 Sterility Testing and Extending BUD Webinar

Thank you for your helpful presentation.  I have the following questions:

1)  For USP 797 compliant compounding, where a USP 71 sterility test is required:

    a) The sterility test should be performed for each and every batch? 

    b) A positive growth promotion test performed with each lot of ready prepared medium? 

    c) A method suitability test must be performed with each new product line? 

 

2)  Can you provide examples of a method not described in the USP which is verified by results to demonstrate that the alternative is at least as effective as the USP membrane filtration method?   What criteria should be evaluated to demonstrate equivalence?

 

3)  What is process simulation testing? An example?

 

Thank you,

Pharmqa

 

 

Administrator
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Registered: ‎02-22-2010
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Re: USP 71 Sterility Testing and Extending BUD Webinar

Here are questions and answers from Eric & Scott from our live presentation:

 

Q: ­Alteplase PI says only diluted solutions for 8 hrs due to lack of preservatives.  Can we use 797 low risk 48hr RT stability?­

Dr. Sutton: No comment.

Eric Kastango: No, since the manufacturer has explicit dating that supersedes the BUD in USP Chapter <797>.  

 

Q: ­What are examples of elements of a validated process that exceeds membrane filtration? ­

Dr. Sutton: I assume the question refers to likelihood of sterility as an outcome.  In this regard, terminal sterilization by moist heat under pressure (autoclaving) is the best option.  Note that this sterilization cycle, as all methods of sterilization, must be qualified and that failure to qualify the sterilization method has become a frequent FDA 483 citation of compounding pharmacies (see http://microbiologynetwork.com/content/APR_2013-April_GMP-Compounding-Pharmacies.pdf)

Eric Kastango: No additional commentary


Q: ­Compounding companies producing large quantities of admixtures are unable operationally to test for sterility, then incubate for 14 days before shipping out to multiple different hospitals.  Is this acceptable considering the NECC situation?­

Dr. Sutton: No.  Change the operation.  Release of product must be preceded by a complete batch release document.  All release tests must be complete.

 

Eric Kastango: Absolutely agree with Dr. Sutton. 

 

 

Q: ­Question for Dr. Sutton: As it relates to anti-infectives and potentially extending the BUD, my understanding was we are testing for a process that maintains sterility and that it would be acceptable to use 'substitute' products that mimic the process to compound the antibiotic. ­

Dr. Sutton: No.  You are testing that batch of product.  The process should have been previously validated.  The process validation serves as the patient’s primary assurance of the sterility of the CSP, the sterility test is a final check only.   You cannot document compliance of a batch with a release test by testing a “substitute”.

 

Eric Kastango: You need to verify your compounding procedure and staff can demonstrate proper aseptic technique when compounding by various methods (e.g., pooling, use of volumetric pumps) but sterility testing is required by USP Chapter <797> if the default BUDs are exceeded.

 

 

Q: ­Would testing of a "batch" include doses made for a specific patient, compounded warrant to a prescription, such as 21 doses of cefazolin 2gm or 7 bags of PN?  Is it typical that a b­­atch would be made by a manufacturer?­

Dr. Sutton: <797> uses the word “batch” repeatedly.  It is my understanding that a “batch” is the preparations of a CSP with the same formulation made at the same time.   This could be one unit or 100,000 units.

 

Eric Kastango: Agreed.  Manufacturers typically makes tens of thousands of units in a batch.  USP Chapter <797> doesn’t define this term currently but will with the next revision. 

 

 

Q: ­Is it necessary to perform a method suitability test on each batch, or just once if the exact method is repeated? How often should it be repeated?­

Dr. Sutton: The method suitability is a control experiment on the formulation to demonstrate that the sterility test incorporates a suitable method of neturalization and recovery of micreoorganisms.  If the method (in all particulars) and the formulation of the CSP (in al particulars) do not change, there should be no need to repeat the test.

 

Eric Kastango: No additional commentary

 

 

Q: ­Can you talk about rapid scan technology?­

Dr. Sutton: Yes, but that is a completely different topic and well beyond the scope of this webinar.  I would refer you to USP chapter <1227> for qualification expectations of these methods.

 

Eric Kastango: there has been a lot of information published and available online.  It is my understanding that rapid micro methods need to demonstrate equivalence to USP Chapter <71>.

 

 

Q: ­If you are doing large volume filtration and then preparing less then 25 units for dosing is sterility testing a requirement. This is assuming USP <797> is in full compliance at the pharmacy performing the large volume filtration...­

Dr. Sutton: As I read <797>, my personal opinion is that it depends.   First of all, you must have a validated method, have sterile containers, have a valid media fill (process simulation) study for that process, have appropriately trained and gowned technicians in an appropriate environment, etc, etc.    Then the next question is the status of the CSP (low, medium or high risk) to set the BUD that does not require a sterility test – these durations and the conditions of storage conditions vary widely.   My reading of <797> would be that if you exceed the restricted BUD for any CSP categories, then a USP <71> sterility test is mandatory.  If you do not exceed the BUD then it becomes a risk decision (my decision would be to conduct the test for every batch of sterile CSP as a safety check).  As an aside, I think this question comes from the section “FINISHED PREPARATION RELEASE CHECKS AND TESTS” which discusses high-risk CSP.   I would also refer the practitioner to the section in USP <797> entitled “CSP MICROBIAL CONTAMINATION RISK LEVELS” which clearly states the relevant requirements for sterility testing for each CSP category.

 

Eric Kastango: The 25 units applies to high-risk level CSPs.  Technicially you could do a batch of 100 cefazolin or any other low or medium-risk level CSPs and as long as the default BUD is not exceeded, no testing is required.  Using batch size to game the system to avoid sterility testing for high-risk level compounding is not appropriate.  I understand the technicalities but other strategies should be considered.

 

 

Q: ­Does the method suitability test need to be performed for each sterility test, or once initially?­

Dr. Sutton: See answer above.

Eric Kastango: No additional commentary

 

 

Q: ­If I prepare a one liter batch of a concentrated high risk product and then use that batch to draw up and dilute individual doses (one at a time) over a period of time, please address the sterility tests required.­

Dr. Sutton: See answer above to the question of large volume filtration. 

 

Eric Kastango: Your one liter batch of concentrated high-risk level stock solution needs to be treated as a single-dose container and used within 6 hours.  You cannot keep using this bag until it is empty.  Another question that needs to be answered is what do you consider the dose made from the bulk source container.  USP has determined that once a high-risk level CSP, always a high-risk.  I don’t agree with that position and believe that if you do your sterility testing and potency that you can treat the bulk solution similar to a FDA approved commercially available drug solution.   However, the chapter says that low and medium-risk level CSPs are made from FDA approved commercially products.  Making your own stock bag does not meet that requirement.

 

If you are making a one liter bag and using approximately 100mL/day, I would aliquot the solution into 100mL bags/vials, test these units according to USP 71 and potency test and use treat them as single-dose vial, using it within 6 hours. 

 

 

Q: ­Do the state board of pharmacies utilize USP <71> in their audits of facilities or is it only FDA?

Dr. Sutton: It varies.  See http://microbiologynetwork.com/content/APR_2013-April_GMP-Compounding-Pharmacies.pdf for more information.

 

Eric Kastango: Individual state boards of pharmacy have been examining sterility test practices more closely.  I know the Virginia Board of Pharmacy has been very aggressive in making sure that any sterility testing is done strictly in accordance with USP Chapter <71>.  

 

 

Q: ­While large batch volumes benefit from the filtration method, would small batch volumes (one preparation under 500mL for multi-dose use) be adequately addressed with the direct inoculation method?­

Dr. Sutton: Either method, performed as described in USP <71>, is acceptable.    Membrane filtration is the preferred method.  USP <71> states “The technique of membrane filtration is used whenever the nature of the product permits…” in the section TEST FOR STERILITY OF THE PRODUCT TO BE EXAMINED.

 

Eric Kastango: it is important that direct inoculation is not the preferred method since almost everything we compound can be filtered for the purposes of this test.  The major limitation/consideration of direct inoculation is the ratio of test volume to volume of each growth media used.  The volume of test volume cannot exceed 10% of the total volume of the growth media used. 

 

 

Q: Media should be incubated in two different temperatures, for 20 - 25 C is it fine to keep it at room temperature not in an incubator?­

Dr. Sutton: If this is done, you must be able to document the constancy of the room temperature within this range just as you must document that the equipment used during the test was functioning properly.

 

Eric Kastango: Absolutely agree with Dr. Sutton.  If you do this testing routinely, you should be investing in the proper equipment.

 

 

Q: ­This is very complex.   What recommendations would you make to hospital pharmacies that are doing batch compounding to acquire the knowledge and expertise to understand and do this appropriately?­

Dr. Sutton: There are several things that can be done.  1). Read USP <71>   2).  Continue to find opportunities for continuing education such as this webinar 3).  Bring a subject matter expert in house or on retainer to assist with specific technical questions (this last recommendation is clearly self-serving, but accurate even so).

 

Eric Kastango: There are several training programs that are commercially available.  Millipore/Associates of Cape Cod sponsors a Best QC training program (you can google it).  Consider joining Dr. Sutton’s PMF listserv and joining PDA (Parenteral Drug Associate) to get inculcated with the current state of art in QA/QC procedures.


 

Q: ­Does the method suitability test need to be performed for every batch of a particular solution, or once it has been performed, can the first results be applicable for subsequent batches of the same solution (understanding that sterility testing would be do­

Dr. Sutton: See answer above.

Eric Kastango: I agree.

 

 

Q: ­is sterility testing only for high risk? if yes does that mean preparing a batch of 25 units medium risk or low risk no need to perform sterility testing?­

Dr. Sutton: See answer above.

Eric Kastango: This was answered earlier but no, sterility testing is not required. Only if exceed the default BUDs is sterility testing required.

 

 

Q: ­Do MedImmue closed system spikes extend BUD of single use vials?­

Dr. Sutton: I can’t comment on specific vendor’s products.

Eric Kastango: I agree.  I have yet to see any studies to demonstrate that any CSTD can maintain the sterility of a SDV.  Attaching a CSTD is an aseptic procedure so how do you know it was done properly each and every time?  How do you properly disinfect the vial prior to attaching the CSTD? 

 

 

Q: ­If you are adherent to 71 testing and your results after 14 days so no growth, what extended time frame can you give your CSP?­

Dr. Sutton: This is a new topic generally referred to as “Stability Dating” or “Expiry Dating”.   FDA is clearly on record as expecting formal studies to be performed showing that the CSP is stable for a defined period of time under defined conditions.   The record of recent 483 observations against compounding pharmacies demonstrates this expectation (see http://microbiologynetwork.com/content/APR_2013-April_GMP-Compounding-Pharmacies.pdf for more information).   A good Email discussion group on stability topics is described at http://microbiologynetwork.com/psdglist.asp with the registration.

 

Eric Kastango: One element of CSP sterility that is not in USP Chapter <797> is the concept of container closure integrity testing.  Meaning, how do you know that the packaging, cap on the syringe etc. can maintain it closure properties to prevent the ingress of microorganisms during the desired storage period?  Not sure how long we need to date our CSPs past 30-45 days.  We are preparing them under less than ideal conditions even when complying with USP 797. 


 

Q: ­Is there any discussion within USP or the FDA on application of USP 71 to medium risk sterile to sterile compounding versus high risk non-sterile to sterile compounding.  It appears the risk is much greater in high risk compounding.­

Dr. Sutton: I cannot comment for either organization.

Eric Kastango: I have no additional commentary.  We have seen several events of contaminated Avastin, which were prepared under medium/high-risk level conditions.  When you take a stopper out of a vial, it is technically a high-risk level activity. 

 

 

Q: ­You had mentioned that single dose vials would get a 48 hour exp dating at room temperature.  What about if the product is refrigerated, what expiration dating should the product receive?­

Dr. Sutton: No comment.

Eric Kastango: I don’t understand the question re: SDV.  Are you referring to low-risk level CSPs?

 

 

Q: ­Can we anticipate any update on testing for closed system transfer devices? I am curious on your take of the new FDA ONB code and prevention of microbial ingress. ­

Dr. Sutton: No comment.

Eric Kastango: Update from whom?  I have yet to see any studies to demonstrate that any CSTD can maintain the sterility of a SDV.  Attaching a CSTD is an aseptic procedure so how do you know it was done properly each and every time?  How do you properly disinfect the vial prior to attaching the CSTD? 

 

 

Q: ­Anazao came under scrutiny of the FDA on this topic.  How do you handle situations where the state board (specifically Florida) haven't adopted the USP 797 regulations since we are obtaining their products?­

Dr. Sutton: I have several suggestions in this regard, but in reading these please remember that I am not competent to give legal opinion.  These are only my personal opinions.  In this situation, I would recommend:  1).  Hire an attorney competent in this area of the law   2).  Don’t accept product that is not of acceptable quality according to your state’s regulations   3)  Be prepared for change. 

 

Eric Kastango: Florida does require comply with USP 797 from my last read so you should contact the company directly to address your questions/concerns or the state board of pharmacy.

 

 

Q: ­Is there currently any guidance on the recommended incubation times for rapid micro testing? Still 14 days or can it be decreased?­

Dr. Sutton: See answer above.

Eric Kastnago: I have no additional commentary.

 

 

Q: ­For High Risk shouldn't a pyrogen test be done prior to use and a sterility test be done even if there are 24 doses or less from the batch? ­

Dr. Sutton: It depends on the CSP’s use.   As I read <797> there are many ways to define a high-risk CSP, not all necessarily require pyrogen testing.   These are really two different questions.  The Sterility Test topic is asking if there are organisms in the CSP that shold not be there.   The “pyrogen test” (by this I assume you mean doing something like a bacterial endotoxin test rather than a rabbit pyrogen test) is appropriate for particular routes of administration where pyrogenic material will cause harm to the recipient.

 

Eric Kastango: I believe that a CSP if prepared from nonsterile components should be terminally sterilized if at all possible.  This method is so much more reliable than filtration.

 

Q: ­I'm still not real clear on definition of "batch" as it applies to individual patient specific Home infusion prescriptions.  Could you please clarify this definition?­

Dr. Sutton: See answer above.

Eric Kastango: I understand your question (sort of) but what other question are you trying to answer by defining what a batch is?

 

 

Q: ­Where can I find literature on extending BUD over 14 days?

Dr. Sutton: The following are suggestions provided only for consideration.  It must be noted, however, that FDA has been citing compounding pharmacies for failure to justify extending BUD.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072873.pdf
http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm128204.pdf


Eric Kastango: USP Chapter <797> refers to USP Chapter <795> for additional BUD. It is critical to understand the differences between chemical stability and microbial sterility.  References like Trissel’s Handbook of Injectable Drugs can help you with stability data.

 

Q: ­Is it possible for a CSP MDV (medium risk) containing preservatives be given a one year BUD?­

Dr. Sutton: If there is supporting data from a well-designed stability study to support the practice.

Eric Kastango: Why do you need to date a compounded MDV CSP with 1 year dating?  This is outside of scope of pharmacy in my opinion.

Occasional Advisor
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Registered: ‎02-21-2013
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Re: USP 71 Sterility Testing and Extending BUD Webinar

Hi Erik,

 

One of the questions you addressed at the end was B.U.D. for drawing up individual syringes from MDV and you classified this as a "Low-Risk" process. Fentanyl is on shortage and I'm looking at what can help. Trissel's gives good stability data for Room Temp and refrigerated. Is it acceptable from a <797> standpoint to give the syringe 48hrs @ RT and 14 Days @ Refrigerated based on being Low-Risk and stability data from Trissel's?

 

Thanks,

Richard

Administrator
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Registered: ‎02-22-2010
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Re: Sterility testing requirements for batch process


wendygw wrote:

Is sterility testing required for all batch processes?  More specifically, if we are batch processing IV's and assigning BUD as 48 hours room temp or 14 days under refrigeration, is sterility testing of the batch required by UPS 71?  Or does USP 71 sterility testing for batches only apply if we want to assign BUD beyond the guidelines set by 797?

Thanks,

Wendy Waldman, RPh


Dr. Sutton's answer:

 

I cannot speak for USP, but as a consultant reading chapter <797> (chapter <71> of course does not require testing, it is the test method) it seems that you are describing BUD conditions for low-risk CSP.  While I personally find these recommendations in USP <797> lax, it is important to realize that the “low risk CSP” is prepared under the most stringent and controlled conditions in <797> and is not capable of supporting microbial growth.  

 

Purely as a matter of interpretation of the guidance, there is not enough information in your question to provide an answer.   That the medication is an IV is irrelevant.  The relevant concern, in my interpretation of USP <797>, is whether or not the medication is a “low-risk” CSP.  What were the conditions of its preparation, was the process validated, are the technicians adequately trained and garbed, does the CSP meet all the criteria of a “low-risk” CSP as defined in the chapter?   As many of these requirements deal with the compounding process and environment, the actual form of the CSP is not a consideration, nor is it even mentioned in the section “CSP Microbial Contamination Risk Levels”.