TESTING LABORATORY RECEIVES STERILITY OBSERVATIONS

FDA FINDS LABORATORY CONDUCTING STERILITY AND ENDOTOXIN TESTING FOR COMPOUNDING CENTERS HAS SIGNIFICANT ISSUES WITH STERILITY ASSURANCE

The FDA recently audited Front Range Laboratories, Loveland, CO from August 5 through August 30, 2013.  Their five investigators issued a five Observation, twelve page document.  Enclosed is Observation 1 which primarily concerns sterility testing issues.

OBSERVATION 1

“There is no verification of any methods reported to be USP and/or validation of any internal methods for any drugs tested, this is evidenced by:

I)                 Sterility Accelerated Sterility Testing and 14-day Sterility Testing

1. a.     Your firm has not performed any verification of any methods reported to be USP and/or validation of any internal methods, this includes (b)(4) Accelerated Sterility Testing which has been in place since (b)(4).

                                                   i.     No validation studies have been conducted for the (b)(4) Accelerated Sterility Testing, including studies that demonstrate equivalency to USP<71>.  Sterility analysis indicated that approximately (b)(4)% of all sterility testing (according to analysts, approximately (b)(4) sterility samples are received/tested daily) is done using the (b)(4) Accelerated Sterility Testing method.  Your firm’s “Accelerated Sterility Testing” SOP (P-024) has no provisions for the microbial growth media to be challenged with Growth Promotion Testing.  The reliability of this sterility test has not been shown to be validated with the Bacteriostatic and Fungistasis test: these tests have not been conducted.  Additionally,

1. 1.    No validation studies have been conducted on the  (b)(4) flow cytometer used for (b)(4) Accelerated Sterility testing.
2. 2.    No verification of microbial growth, such as gram staining, is being performed on (b)(4) or (b)(4) tubes that are resulted as a “fail” by (b)(4).  As part of your process when a (b)(4) “fail” is resulted, a subculture is performed from the broth to a (b)(4) plate.  The (b)(4) plate is incubated for (b)(4) under aerobic conditions.  Identification is performed if any growth is observed on the (b)(4) plate.  Therefore, a verification of microbial growth, such as a gram stain, is needed in order to determine what the expected growth should be on the (b)(4) plates.
3. 3.    (b)(4) which is used to culture anaerobic microorganisms is being used as part of (b)(4) Accelerated Sterility Testing and is not incubated under anaerobic conditions per USP <71> to allow for the growth of anaerobic microorganisms.
4. 4.    You are not following procedure (MICRO-SOP-24).  According to your procedure, the (b)(4) Accelerated Sterility Testing is to be performed using (b)(4) broths.  When broths are analyzed using the (b)(4), there are inconsistencies with the number of broths analyzed.  In numerous instances only one broth tube(b)(4) or (b)(4) tubes) was analyzed instead of (b)(4). 

COMMENT:

            The Accelerated Sterility Testing, based upon the above Observation does not appear to have been demonstrated as equivalent to a standard 14-day USP<71> Sterility Tests.  Historically, when others have performed such tests, they have extended between 72 and 120 hours.  Since the Observation has been redacted (b)(4), it is difficult to ascertain the exact duration, but the time frame indicated would represent a good supposition. 

Any test using flow cytometry would require validation, not verification or qualification.   As part of the review of Section 4 above, it also appears that an insufficient number of tubes (Trypticase Soy Broth, TSB) may be used within the test, and, in addition, Fluid Thioglycollate Broth (FTM), is not being used as part of the test to obtain the growth of anaerobes.

ii          In the event that an (b)(4) sterility test result is found to be a “fail”, a (b)(4) of broth tubes and a subculture using (b)(4) plates is performed.  When no growth is observed on the subculture plates, a passing result is reported to the customer.  For example: sample (b)(4) (Bevacizumab 25mg/mL, expiry 11/5/2013), failed (b)(4) sterility test on 8/14/2013, and was subcultured on 8/16/2013.  No growth was found on subculture, and a passing sterility result was reported to the customer on 8/20/2013.  There are 33 examples using this same follow-up method for finished products which are still within expiry, between the time period of 5/1/2013 through 8/20/2013.  The above follow-up method has not been validated, including demonstration of equivalency to the methods described within USP<71> as required.  In addition, your firm does not investigate all (b)(4) sterility failures to determine whether results can be invalidated.

1. 1.    In one instance only, a (b)(4) of the broth tubes was performed:  Sample (b)(4) (testosterone cypionate 200 mg/mL, expiry 11/13/2013) failed (b)(4) sterility test on 5/14/2013 and no evidence of a subculture result was documented.  A passing sterility result was reported to the customer on 5/13/2013; before analysis was completed on 5/14/2013.

Your accelerated testing procedure (OP-024) is inadequate because fastidious growing microorganisms, anaerobes and molds may not be recovered since broths are only incubated for (b)(4).  Additionally, (b)(4) plates are being used for sub-culturing and have not been shown to support growth of a wide-range of microorganisms.  These plates are only being incubated aerobically for (b)(4).  Subsequently, since no verification of microbial growth (such as gram staining) is performed on broths, there is no way to determine if microorganisms should have been removed. 

COMMENT: 

            A common theme is noted above where there exist 33 failures within a 3.5 month period.  This many initial failures with satisfactory follow-up subculturing suggests that the laboratory has not performed significant investigations and should have initiated these before the release of product.  The use of a Gram stain to assist in the determination of growth in the initial tubes becomes especially valuable when no growth is observed on subcultured plates.

            2) iii) 1) b.)  Your firm is without any verification of any methods reported to be USP and/or validation of any internal methods, this includes 14-day USP <71> Sterility Testing.

                        i.  No Growth Promotion test and Bacteriostatic and Fungistasis     Tests have been conducted in accordance with USP<71> for any drug             tested at any time.  Sterility analysts indicated that (b)(4) % of all   sterility testing is done using the traditional 14-day sterility testing.  Your firm’s “Sterility testing via (b)(4) Method“ SOP (MICRO-SOP-009) provides no provisions for Growth Promotion test and the Bacteriostatic and              Fungistasis test.

COMMENT:

            USP<71> Sterility Tests require the qualification/verification using both  Growth Promotion and Method Suitability testing.  Not having this        methodology within the test invalidates the test method itself.

                        1.  No verification of microbial growth, such as gram staining, is             performed on positive (turbid) results (b)(4) in order to verify growth and to determine if microorganisms are present.  General media plates are      used for sub-culturing positive (turbid) results and they are being             incubated aerobically,  If growth is (b)(4) observed on the (b)(4) plates,             identifications(s) are performed.

                        2.  No definite read dates for the sterility tests are recorded on             laboratory worksheets indicating when the final read of each individual             sample takes place.  According to a sterility analyst, there is a final date             that represents when all samples on one worksheet were finalized.  This             includes any culturing due to positive results.  In some instances, 14 day  Sterility Testing worksheets indicate that the incubation period was less             than the required 14-day period required by USP <71>.  It cannot be             verified that samples were run for the specified 14-day period if a final             read date is not recorded for every sample.

COMMENT:

            Documentation is essential to assure that the result can be verified.  Many             laboratories will perform examination of Sterility Tests at five, nine and     fourteen days and record the results observed at each examination.

            ii.  Anaerobic microorganisms may not be recovered using (b)(4) plates  that are incubated aerobically.  The 14-day sterility sample analyses are set up in the clean room using (b)(4) .  The (b)(4) that was used for a 14-     day sterility testing is incubated for 14 days.  Any positive (turbid) growth  is subcultured to a (b)(4) plate.  The (b)(4) plates are not incubated under anaerobic conditions according to sterility analysts.

COMMENT:

            Incubating subcultured tubes on plates that are incubated under aerobic  conditions will permit only the growth of facultative anaerobes.        Attempting to grow bacteria such as P. acnes is futile when cultured             aerobically.  In fact, P. acnes growing within FTM will often not appear  within the broth until the 13th or 14th day.   

GENERAL COMMENT:

            Since the audit of this laboratory, a number of Compounding Facilities have initiated recalls of selected lots of material that are within their Expiration Dates because of sterility concerns.  These Compounding Facilities included: 1) JCB Laboratories, 2)  Wellness Pharmacy and 3) Avella Specialty Pharmacy.  The laboratory in question has also defended its position based upon several areas to include the comment that they follow USP<797>.  A review of USP<797> indicates that sterility tests or their equivalent are required for aseptically filled products and that they must follow USP<71> protocols.  The FDA throws into question whether Front Range Laboratories was following the USP testing method.

COMMENT:

Front Range Laboratories recently posted the following on their Web site following the FDA issuance of the Form FDA 483.  Please review this and then make your own determination as to the actions of the FDA, recalling Companies and Front Range Laboratories.

“Recently, the U.S. Food and Drug Administration (“FDA”) inspected Front Range Laboratories. This inspection was not prompted by any inaccurate laboratory test results, safety concerns, serious adverse event reports or quality issues related to products tested by our lab for our compounding pharmacy clients.

Front Range Laboratories provides testing services and support to compounding pharmacies. We are not in the business of drug manufacturing and do not knowingly conduct business or provide testing services to entities that manufacture finished drug products. We are not aware that any of our clients are registered with FDA as drug manufacturers, nor have we knowingly tested manufactured drug products. Yet, FDA inspected our testing procedures and operations against FDA’s Current Good Manufacturing Practice (“cGMP”) regulations which, by definition, do not legally apply to compounding pharmacies unless they are acting as drug manufacturers. cGMP also do not apply to facilities such as Front Range Laboratories, whose business is the testing of drug products compounded by pharmacies.

For over 10 years of operation, Front Range Laboratories has relied on state law (i.e., boards of pharmacy) and United States Pharmacopeia (“USP”) guidance when performing all of our product testing. Specifically, the methods we use to assess sterility and other quality attributes are established by USP. Patient health and safety is an ongoing and primary concern within our industry, and Front Range Laboratories has always been extremely diligent in adhering to applicable guidelines including those put forth by the organizations that govern the compounding pharmacy community. Our exceptional and unblemished safety record over the past decade demonstrates our commitment to patient health and safety.

Notwithstanding our compliance with state law and compounding industry expectations, we are cooperating with FDA. We have voluntarily committed to certain changes in our operations that will address use of cGMP in our testing operations. In addition, in the next few days, we will be sending a letter to our clients detailing the findings of the inspection and our plans for serving our compounding pharmacy clients moving forward.”