CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`201655Orig1s000
`
`
`MICROBIOLOGY REVIEW(S)
`
`
`
`
`
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF PHARMACEUTICAL SCIENCES
`NEW DRUG MICROBIOLOGY
`
`
`
`
`
`
`M E M O R A N D U M
`
`13 October 2010
`
`Craig Bertha, DARRTS
`
`
`
`
`
`
`
`
`
`
`
`
`
`Date:
`
`TO:
`
`FROM:
`
`Cc:
`
`SUBJECT: NDA 201655 Oxymorphone HCl
`
`
`From Second Review:
`
`The applicant maintains that no microbial limits testing is needed based on their data.
`Reviewer Comment: The response provided does not address the total microbiological load or in-process
`controls. Clearly microorganisms will not grow in the dry environment intended and some vegetative cells
`will die. The contract manufacturer has provided microbial limits for the coating solution
`that should apply to the complete tablet. A microbial limits test should be included in the release
`specifications .
`
`The following deficiency was provided in a discipline specific letter to the applicant dated 8 October 2010.
`
`ICH Q6a states “it is advisable to test the drug product unless its components are tested before
`manufacture and the manufacturing process is known, through validation studies, not to carry a
`significant risk of microbial contamination or proliferation.” Adequate information has been provided that
`the finished dosage form will not support growth but the introduction of contaminants during the
`manufacturing process has not been adequately addressed. The product specification should state that the
`product meets the requirements of USP <61>, <62>, and <1111> if tested. The batch release criteria should
`identify the specific manufacturing process tests and criteria used to assess the finished product as
`microbiologically suitable for release. These tests and criteria should include, for example:
`
`James L. McVey, Team Leader, New Drug Microbiology
`
`Stephen Langille, Ph.D., Senior Microbiologist, New Drug Microbiology Staff
`
` extended-release tablets. Third Review
`
`
`
` •
`
` Microbial limits data for critical raw materials,
`• Microbiological environmental monitoring data for critical processing steps, and
`•
`In-process control parameters
` that may affect product quality
`microbiology.
`
`
`Third Review: The applicant responded in a letter dated 12 October 2010, SDN 0011.
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Memoranda
`
`
`
`
`
`
`Endo agrees to amend the drug product specifications in include microbial limits testing. Section 3.2.P.5.1 has
`been updated to include the following. “Microbiological Examination, Total Aerobic Count
`
`
`
` and absence of Escherichia coli, per USP<61> and <62>. The
`Total Yeasts and Mold
`
`
`specification is footnoted to say that the testing is for release only.
`
`
`Acceptable
`
`END
`
`2
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JAMES L MCVEY
`10/14/2010
`Added Microbial Limits testing to product release specification.
`
`STEPHEN E LANGILLE
`10/14/2010
`
`Reference ID: 2849694
`
`

`

`Memoranda
`
`Date:
`
`05 October 2010
`
`T0:
`
`Craig Bertha, DARRTS
`
`FROM:
`
`James L. McVey, Team Leader, New Drug Microbiology
`
`Cc:
`
`Stephen Langille, Ph.D., Senior Microbiologist, New Drug Microbiology Stafl‘
`
`SUBJECT: NDA 201655 Oxymorphone HCl— extended-release tablets. Second
`Review
`
`Previous Review dated 18 Augst 2010:
`
`The applicant does not propose any microbial limits testing for the drug product. The reason for
`not doing so is reproduced belo .
`"Oxymorphone hydrochloride _extended—release tablets are a non-sterile oral
`product.”
`
`
`
`The tablets are manufactured usin Research studies demonstrate that the final drug product does not promote microbial growth. Not
`
`less than 2, 7, 0.7 and 3, 7, 0.7 log reduction from the initial count of the bacteria Staphylococcus
`aureus, Pseudomonas aeruginosa, and Bacillus subtilis, respectively, was observed after 14 and
`28 days of incubation. For the mold Aspergillus niger, no increase from the initial count was
`found after 14 and 28 days.
`
`“Therefore, it is deemed appropriate not performing microbial test for the release and stability
`monitoring of the drug product."
`
`Also from the application:
`“Oxymorphone hydrochloride, a semi-s
`
`10 mg, 15 mg, 20 mg, 30 mg, and 40 mg“extended—release tablet strengths for oral
`
`thetic o ioid analgesic, is supplied in 5 mg, 7.5 mg,
`
`administration. The tablets contain the following inactive ingredients: hypromellose, polyethylene oxide,
`polyethylene glycol, a-tocopherol, citric acid, polyvinyl alcohol, titanium dioxide, macrogol and talc. In
`addition, the 5 mg, 7.5 mg, and 30 mg tablets contain iron oxide red. The 7.5 mg tablets contain iron oxide
`black, and iron oxide yellow. The 10 mg tablets contain FD&C yellow No. 6. The 20 mg tablets contain
`FD&C blue No. l, FD&C yellow No. 6, and D&C yellow No. 10. The 40 mg tablets contain FD&C yellow
`No. 6, and D&C yellow
`No. 10.”
`
`fluemfamocess wande—
`
`

`

`Reviewer comments:
`
` No
`
`bioburden information is provided for the excipients used. Although the data summary provided demonstrates
`that the compendial organisms do not grow in the product, there is no evidence of the extent of
`microbiological contamination before or after manufacturing. The growth capabilities of the indigenous
`microorganisms may be more significant than the compendial testing demonstrates.
`
`Recommended Comment to Applicant.
`
`Include a test for microbial limits (USP<61>, <62>) in the release specifications for this product. USP
`<llll> provides recommendations for acceptable limits. The information provided does not address
`the microbiological load or in-process control. It is recommended that the appropriate ingredients also
`
`be tested for bioburden as part of the microbiological control of this manufacturing process.
`
`Over time it is possible that the product may take on water and support growth. This issue should be
`
`addressed in the stability plan. Annual testing is recommended.
`
`Second Review:
`
`The applicant maintains that no microbial limits testing is needed based on their data. The above
`comment was provided to the applicant in a letter dated 2 September 2010 as question 4. A response was
`provided from the applicant dated 14 September 2010. The applicant states that the tablets and all the
`compendial excipients used in its manufacture meet current USP requirements and no USP requirements
`include at test for microbial limits. Decision tree #8 in ICH Q6a was consulted and the applicant determined
`that the tablets
`dosa e form and that the have data that demonstrates
`
`
`
`microbial
`
`
`
`An additional study was conducted at
`a— for the
`coatin sus nsions. The total aerobic count was less than
`
`
`
`and the total yeasts and mold was less than
`No indicator organisms were found in the
`coating suspensions. The same conclusion was drawn as before. No testing for microbial limits is needed.
`
`
`
`Reviewer Comment: The response provided does not address the total microbiological load or in-process
`controls.
`
`

`

`Memoranda
`
`Clearly microorganisms will not grow in the dry environment intended and some vegetative cells will
`die. The contract manufacturer has provided microbial limits for the coating solution
`
` that should apply to the complete tablet. A microbial limits test should be included in the release
`specifications .
`
`ICH Q6a includes the following comment:
`Section 1.2 “Specifications are one part of a total control strategy for the drug substance
`and drug product designed to ensure product quality and consistency. Other parts of this
`strategy include thorough product characterization during development, upon which
`specifications are based, and adherence to good manufacturing practices (GMP's), e.g.,
`suitable facilities, a validated manufacturing process, validated test procedures, raw
`materials testing, in-process testing, stability testing.”
`And
`Section 1.3 “The quality of drug substances and drug products is determined by their
`design, development, in-process controls, GMP controls, process validation, and by
`specifications applied to them throughout development and manufacture. This guidance
`addresses specifications, i.e., those tests, procedures, and acceptance criteria that
`play a major role in assuring the quality of the new drug substance and new drug product
`at release and during shelf life. Specifications are an important component of quality
`assurance, but are not its only component. All of the factors listed above are
`considered necessary to ensure consistent production of drug substances and drug
`products of high quality.”
`And
`Section 2.3 “It may be possible to propose excluding or replacing certain tests on this
`basis. Some examples are:
` Microbiological testing for drug substances and solid dosage forms that have been
`shown during development not to support microbial viability or growth (see Decision
`Trees #6 and #8).”
`
`It is my interpretation that the accomplishment of section 2.3 is dependent on meeting the requirements of
`sections 1.2 and 1.3. The authors assumed that those requirements discuss in 1.2 and 1.3 had been fulfilled
`when they wrote section 2.3.
`And
`Section 3.3.1 Drug Substance (g) “The type of microbial test(s) and acceptance criteria
`should be based on the nature of the drug substance, method of manufacture, and the
`intended use of the drug product.”
`And
`Section 3.3.2 New Drug Products:
`“(f) Microbial limits: Microbial limit testing is seen as an attribute of GMP, as well
`as of quality assurance. In general, it is advisable to test the drug product unless its
`components are tested before manufacture and the manufacturing process is known, through
`validation studies, not to carry a significant risk of microbial contamination or
`proliferation. It should be noted that, whereas this guidance does not directly address
`excipients, the principles discussed here may be applicable to excipients as well as to
`new drug products. Skip testing may be an appropriate approach in both cases, where
`permissible (see Decision Tree #6 for microbial testing of excipients).”
` “Acceptance criteria should be set for the total count of aerobic microorganisms,
`the total count of yeasts and molds, and the absence of specific objectionable bacteria
`(e.g., Staphylococcus aureus, Escherichia coli, Salmonella, Pseudomonas aeruginosa).
`These should be determined by suitable procedures, using pharmacopeial procedures, and
`at a sampling frequency or time point in manufacture that is justified by data and
`experience. The type of microbial test(s) and acceptance criteria should be based on the
`nature of the drug substance, method of manufacture, and the intended use of the drug
`product. With acceptable scientific justification, it should be possible to propose no
`microbial limit testing for solid oral dosage forms.”
`
`It is this last section that has not been addressed in this submission.
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`Deficiency for the applicant:
`
`ICH Q6a states “it is advisable to test the drug product unless its components are tested before
`manufacture and the manufacturing process is known, through validation studies, not to carry a
`significant risk of microbial contamination or proliferation.” Adequate information has been provided that
`the finished dosage form will not support growth but the introduction of contaminants during the
`manufacturing process has not been adequately addressed. The product specification should state that the
`product meets the requirements of USP <61>, <62>, and <1111> if tested. The batch release criteria should
`identify the specific manufacturing process tests and criteria used to assess the finished product as
`microbiologically suitable for release. These tests and criteria should include, for example:
`
` •
`
` Microbial limits data for critical raw materials,
`• Microbiological environmental monitoring data for critical processing steps, and
`•
`In-process control parameters
` that may affect product quality
`microbiology.
`
`
`
`
`
`END
`
`2
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JAMES L MCVEY
`10/05/2010
`Still need a microbial limits test or reasonable evidence of microbial control.
`
`STEPHEN E LANGILLE
`10/05/2010
`
`Reference ID: 2845611
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF PHARMACEUTICAL SCIENCES
`NEW DRUG MICROBIOLOGY
`
`
`
`
`
`
`M E M O R A N D U M
`
`19 August 2010
`
`Craig Bertha, DARRTS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Date:
`
`TO:
`
`FROM:
`
`Cc:
`
`SUBJECT: NDA 201655 Oxyorpone HCl
`
`The applicant does not propose any microbial limits testing for the drug product. The reason for
`not doing so is reproduced below.
`
`"Oxymorphone hydrochloride
`product.
`
`James L. McVey, Team Leader, New Drug Microbiology
`
`David Hussong, Ph.D., Associate Director, New Drug Microbiology
`
`extended-release tablets
`
` extended-release tablets are a non-sterile oral
`
`Research studies demonstrate that the final drug product does not promote microbial growth. Not
`less than 2, 7, 0.7 and 3, 7, 0.7 log reduction from the initial count of the bacteria Staphylococcus
`aureus, Pseudomonas aeruginosa, and Bacillus subtilis, respectively, was observed after 14 and
`28 days of incubation. For the mold Aspergillus niger, no increase from the initial count was
`found after 14 and 28 days.
`
`Therefore, it is deemed appropriate not performing microbial test for the release and stability
`monitoring of the drug product."
`
`Also from the application:
`“Oxymorphone hydrochloride, a semi-synthetic opioid analgesic, is supplied in 5 mg, 7.5 mg,
`10 mg, 15 mg, 20 mg, 30 mg, and 40 mg
` extended-release tablet strengths for
`oral administration. The tablets contain the following inactive ingredients: hypromellose,
`polyethylene oxide, polyethylene glycol, α-tocopherol, citric acid, polyvinyl alcohol, titanium
`dioxide, macrogol and talc. In addition, the 5 mg, 7.5 mg, and 30 mg tablets contain iron oxide
`red. The 7.5 mg tablets contain iron oxide black, and iron oxide yellow. The 10 mg tablets
`
`1
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Memoranda
`
`contain FD&C yellow No. 6. The 20 mg tablets contain FD&C blue No. 1, FD&C yellow No. 6,
`and D&C yellow No. 10. The 40 mg tablets contain FD&C yellow No. 6, and D&C yellow
`No. 10.
`
`The manufacturing process steps include
`
`
`
`Reviewer comments:
`
`
`
`
` No bioburden
`information is provided for the excipients used. Although the data summary provided demonstrates that the
`compendial organisms do not grow in the product, there is no evidence of the extent of microbiological
`contamination before or after manufacturing. The growth capabilities of the indigenous microorganisms may
`be more significant than the compendial testing demonstrates.
`
`Recommended Comment to Applicant.
`
`Include a test for microbial limits (USP<61>, <62>) in the release specifications for this product. USP
`<1111> provides recommendations for acceptable limits. The information provided does not address
`the microbiological load or in-process control. It is recommended that the appropriate ingredients also
`be tested for bioburden as part of the microbiological control of this manufacturing process.
`
`Over time it is possible that the product may take on water and support growth. This issue should be
`addressed in the stability plan. Annual testing is recommended.
`
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Memoranda
`Memoranda
`
`
`
`END
`END
`
`
`
`

`

`Application
`Type/Number
`--------------------
`NDA-201655
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`ENDO
`PHARMACEUTICA
`LS INC
`
`------------------------------------------
`Oxymorphone HCl
` extended-release tablet
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JAMES L MCVEY
`08/19/2010
`Needs a microbil limits release test.
`
`STEPHEN E LANGILLE
`08/19/2010
`
`(b) (4)
`
`