PFQ 48:FQfmpgs1-16 1 11/22/09 8:23 PM Page 1
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`P O S T- D I S C OV E RY D E V E L O P M E N T VA L I D AT IO N
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`Volume 11 Number 6
`OCTOBER/NOVEMBER 2009
`
`PLUS
`
`PHARMATOOLS
`SERIES II: MASS
`SPEC EVOLUTION
`RAPID
`MICROBIOLOGY
`SYSTEMS
`RTUs PART II
`HPLC ANALYSIS
`
`MakeWay
`for the
`
`Modular
`Cleanroom
`
`Companies adopt quicker-to-build
`facility and cleanroom designs
`
`www.pharmaquality.com
`
`Hospira, Exh. 2016, p. 1
`
`

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`should be included in stability submis-
`sion packages.2 In this article, we discuss
`considerations in designing stability
`studies, data evaluation, and expiration
`dating for parenteral products—with an
`emphasis on intravenous RTU drug prod-
`ucts in plastic containers.
`
`Stability Study Design
`For U.S. new drug applications, typically
`three batches per drug product configu-
`ration are required with data through 12
`months of long-term (25°C/60% relative
`humidity [RH]), six months of accelerated
`(40°C/75% RH), and 12 months of inter-
`mediate (30°C/65% RH) storage condi-
`tions, if applicable. Two of the three
`
`Stability study results
`help set or refine
`appropriate
`specifications and
`establish the shelf life
`applicable to all future
`batches.
`
`batches placed on stability should be
`manufactured at “not less than 10%” of
`the intended commercial batch size (at
`least at pilot scale); the third batch may
`be smaller.
`Using multiple active pharmaceutical
`ingredient lots and exposing some
`batches to worst-case processing condi-
`tions such as maximum hold times and
`sterilization temperature and time should
`be considered when manufacturing sta-
`bility batches. The batches should be
`manufactured at the proposed site for
`commercial production, using equipment
`equivalent to commercial use.
`For proposed products with multiple
`presentations, manufacturers may con-
`sider a matrixing or bracketing design
`approach described in ICH Q1D.3 Both
`designs offer potential cost savings, either
`by decreasing the need for testing or re-
`ducing the number of batches needed.
`These designs are amenable to products
`with the same constituents, the same con-
`tainer materials, and similar attributes.
`A bracketing study design involves
`testing only samples from the extremes of
`the proposed product configurations, with
`the assumption that the extremes repre-
`
`October/November 2009
`
`PFQ 48:FQfmpgs1-16 1 11/22/09 8:23 PM Page 2
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`Formulation
`
`RTU DRUG PRODUCTS: PART II
`
`Ensure Safety, Efficacy of
`Ready-to-Use IV Drug Products
`
`Stability considerations are key | BY PAU L A YO U N G B E R G W E B B , MS ,
`A N D R AO C H I L A M K U RT I , P H D
`
`Editor’s Note:This is the second in a three-part series on ready-to-use parenteral products. The first
`part appeared in our September issue, and the third part will be posted on our Web site, www.phar-
`maquality.com, when our December/January issue goes online in late December.
`
`R eady-to-use (RTU) intravenous drug products are pre-mixed solutions of
`
`drug and intravenous diluents that are typically packaged in 50 mL to 1,000
`mL flexible plastic containers. Key considerations in the development of
`intravenous RTU drug products have been described previously.1 After the
`formulation and the container system have been selected and the analytical methods
`validated, the manufacturer must conduct registration stability studies to demonstrate
`the product’s acceptability over its intended shelf life. These study data are included
`in the regulatory filing.
`In addition, stability study results help set or refine appropriate specifications and
`establish the shelf life applicable to all future commercial batches. The International
`Conference on Harmonisation of Technical Requirements for Registration of Pharma-
`ceuticals for Human Use (ICH) Q1A (R2) guidance document offers guidance on stabil-
`ity testing for new drug substances and products and provides directions on what
`
`ISTOCKPHOTO.COM
`
`Hospira, Exh. 2016, p. 2
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`

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`PFQ 48:FQfmpgs1-16 1 11/22/09 8:23 PM Page 3
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`FORMULATION RTU Drug Products: Part II
`
`sent the stability of the intermediate config-
`urations. Table 1 (see below) provides an
`example of a bracketing approach for 12
`product presentations, reducing the num-
`ber of registration batches from 36 to 12.
`A matrixing study design includes
`all samples being tested at the initial
`and final time point, with only a subset
`of samples tested at any given time point
`in between; the assumption is that the sta-
`bility of the tested samples represents the
`stability of all of the samples at a given
`time point. Table 2 (see below) provides an
`example of a matrixing test design. This
`design can be risky: If results indicate
`a difference among the configurations
`
`tested, then the untested configurations
`will be assigned the shortest dating deter-
`mined until actual configuration testing
`confirms what is appropriate.
`Manufacturers must evaluate aque-
`ous-based drug products packaged in
`semi-permeable containers, such as flexi-
`ble plastic containers, for potential water
`loss, in addition to the physical, chemical,
`biological, microbiological, and func-
`tional attributes of the container. These
`products must demonstrate the ability to
`withstand low relative humidity environ-
`ments. We describe the storage conditions
`for room temperature products packaged
`in semi-permeable containers in Table 3 ,
`
`Table 1. Example of a Bracketing Study Design
`
`100mL
`
`200mL
`
`400mL
`
`500mL
`
`1.0 mg/mL
`Ø
`
`2.0 mg/mL
`O
`
`3.0 mg/mL
`Ø
`
`O
`
`O
`
`Ø
`
`O
`
`O
`
`O
`
`O
`
`O
`
`Ø
`
`(O) Represents proposed products
`(Ø) Represents proposed products to be placed on study
`
`Table 2. Example of a Matrixing Study Design
`
`Batch
`
`Size (mL)
`
`Schedule
`
`0
`
`1
`
`2
`
`3
`
`10 20 50 10
`
`20
`
`50 10 20 50
`
`1
`
`Ø
`
`2
`
`Ø
`
`3
`
`Ø
`
`2
`
`Ø
`
`O
`
`3
`
`Ø
`
`O
`
`1
`
`Ø
`
`Ø
`
`3
`
`Ø
`
`O
`
`1
`
`Ø
`
`Ø
`
`2
`
`Ø
`
`O
`
`along with the typical test intervals for
`each condition and the minimum amount
`of data required for the submission.
`The duration of the storage period at
`room temperature (25°C) and correspon-
`ding test schedule must cover the intended
`shelf life of the proposed product and
`demonstrate its stability profile. Testing in-
`tervals should be at a sufficient frequency
`to characterize the degradation profile ade-
`quately. Typically, samples stored at the
`intermediate condition are not tested un-
`less a significant change is observed at ac-
`celerated conditions. (See reference 2 for
`the definition of significant change.)
`If significant change is observed, the
`manufacturers should conduct an interme-
`diate storage condition study. For frozen
`products, the long-term storage condition
`is –20°C. Short-term thawed testing, which
`generally consists of storage at 5°C for up
`to 30 days or for up to three days at 25°C
`after thawing, is also performed at various
`long-term frozen intervals. Due to the na-
`ture of frozen products, the length of the
`study at each storage condition will be
`specific for each drug product.
`
`Tests Performed During Studies
`Selection of specific tests/assays is based
`on the technical understanding of the so-
`lution product and the container system.
`The test schedule should focus on the
`parameters controlling shelf life or those
`parameters likely to change, in addition to
`meeting regulatory requirements regard-
`ing test type. The typical tests performed
`on parenteral drug products include ap-
`pearance, color, potency, degradation
`products, pH, particulate matter, sterility,
`pyrogenicity, and container leachables.
`For products in semi-permeable flexible
`plastic containers, it is essential to moni-
`tor water loss as well.
`The critical product attributes or
`those likely to change, such as potency,
`degradants, pH, and water loss should be
`monitored at each test interval. Attributes
`expected to remain stable, such as excipi-
`ents or sterility, may be tested less fre-
`quently, perhaps every six or 12 months
`during the course of the study. To charac-
`terize the stability profile of a particular
`parameter, it may be necessary to sched-
`ule additional intervals (e.g., one, three,
`five, six, seven, or nine months) depend-
`ing on its rate of change.
`Additional studies may be needed
`once the product is removed from the
`overpouch, because the water loss rate
`
`3
`
`6
`
`9
`
`12
`
`18
`
`24
`
`Ø
`
`O
`
`Ø
`
`O
`
`O
`
`Ø
`
`O
`
`Ø
`
`O
`
`Ø
`
`Ø
`
`Ø
`
`O
`
`O
`
`Ø
`
`O
`
`Ø
`
`Ø
`
`Ø
`
`O
`
`Ø
`
`Ø
`
`Ø
`
`O
`
`Ø
`
`O
`
`Ø
`
`Ø
`
`O
`
`Ø
`
`O
`
`O
`
`Ø
`
`O
`
`Ø
`
`O
`
`Ø
`
`Ø
`
`O
`
`Ø
`
`O
`
`O
`
`Ø
`
`Ø
`
`O
`
`Ø
`
`Ø
`
`Ø
`
`(O) Represents all possible testing points
`(Ø) Represents planned testing
`
`P F Q
`
`www.pharmaquality.com
`
`Hospira, Exh. 2016, p. 3
`
`

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`PFQ 48:FQfmpgs1-16 1 11/22/09 8:23 PM Page 4
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`Table 3. Storage Conditions for Solutions in Semi-Permeable Containers
`
`Storage Condition* Typical Test Intervals
`Study
`Long Term 1
`25ºC/40%
`0, 3, 6, 9, 12, 18, 24 months, then yearly until expiry
`Intermediate 2 30ºC/35%
`Accelerated
`40ºC/NMT 25%
`*Temp = +/- 2ºC; RH = +/- 5%
`1The applicant decides whether to use 25ºC ± 2ºC/40% RH ± 5% RH or 30ºC ± 2ºC/35% RH ± 5% RH
`2If 30ºC ± 2ºC/35% RH ± 5% RH is the long-term condition, there is no intermediate condition
`
`0, 1, 3, 6 months
`
`0, 6, 9, 12 months** (**Only if significant change observed) 12 months
`
`Min. Data at Submission
`12 months
`
`6 months
`
`(Ref. 3 - ICHQ1A)
`
`may increase with the overpouch. Or, in
`the case of oxygen-sensitive products,
`rapid ingress of oxygen into the container
`may result. Manufacturers should conduct
`a photostability study per ICH Q1B to
`demonstrate the product’s stability when
`exposed to light and the effectiveness of
`the packaging system, as appropriate.4
`Manufacturers should also conduct tem-
`perature cycling studies to demonstrate
`the effects of temperature variation that
`the product might undergo during ship-
`ping and distribution. The number of
`replicates per test depends on the variabil-
`ity of the method and the expected change
`over time of the attribute. Typically, three
`samples are scheduled: one for potency,
`one for degradants, and pH testing to
`facilitate statistical analysis.
`
`Using statistics to establish
`shelf life provides a
`higher degree of confi-
`dence that all future
`batches will meet the
`acceptance criteria.
`
`Data Evaluation
`Once available, the stability data are eval-
`uated to set the appropriate expiry date.
`The ICH Q1E guidance document provides
`direction on how to assess stability data,
`including the use of statistics to estimate
`product shelf life.5 To ensure that the drug
`product will remain within acceptance cri-
`teria through its shelf life, product expira-
`tion dating must consider the following:
`stability data from registration batches,
`formulation development data, manufac-
`turing process data, analytical variability,
`release and stability specifications, and
`stability data supporting in-use condi-
`tions. Each attribute should be evaluated
`separately—and an overall assessment
`
`used—to propose a shelf life. The shelf life
`should not exceed that predicted for any
`single attribute.
`As indicated in ICH Q1E, chemical at-
`tributes, such as potency or degradants,
`generally follow zero-order kinetics during
`long-term storage. Zero-order kinetics can
`also estimate water loss for products pack-
`aged in semi-permeable containers. Using
`statistics to establish shelf life provides a
`higher degree of confidence that all future
`batches will meet the acceptance criteria.
`When statistics are performed, if the rates
`from different batches meet the criteria for
`poolability, a mean rate is used to establish
`shelf life. If the rates cannot be pooled
`or cannot be considered statistically the
`same, then the worst-case rate predicts
`the expiration date.
`Intravenous RTU products that sur-
`vive terminal sterilization and exhibit
`minimal change in potency and degrada-
`tion products over time often have their
`shelf life based on water loss. The water
`loss rate through the semi-permeable con-
`tainer system is linear over time. In some
`cases, dating may be determined by pH,
`which may change due to lack of formula-
`tion buffer or due to low levels of con-
`tainer-related leachables.
`For aseptically filled room tempera-
`ture products, the level of degradation
`products is often the shelf life-limiting pa-
`rameter. For aseptically filled frozen prod-
`ucts, manufacturers must evaluate the
`change in potency, pH, and degradants
`on frozen storage stability as well as on
`thawed stability at 5°C and room tempera-
`ture to determine the appropriate expira-
`tion dating for the product.
`Extrapolation to extend shelf life be-
`yond the period covered by the available
`long-term data can be proposed if no sig-
`nificant change is observed at the acceler-
`ated storage condition. A proposed shelf
`life based on extrapolation should always
`be confirmed by additional real-time
`long-term stability data as soon as the
`
`data become available. The post-approval
`commitment batches should be tested at a
`point in time that corresponds to the ex-
`trapolated shelf life.
`In the end, the key to a successful
`RTU pre-mix drug stability program is
`developing and implementing study de-
`signs based on scientific understanding
`of the formulation stability and container
`properties—specifically flexible plastic
`containers—along with applicable ICH
`guidelines. Stability study data are evalu-
`ated to establish appropriate expiration
`dating periods for the products. Well-de-
`signed studies fully characterize the sta-
`bility profile of the RTU pre-mixed product
`and ensure that it is safe and efficacious
`and will meet its requirements through
`expiry while in the market. n
`Youngberg Webb is senior director, stability operations,
`and Dr. Chilamkurti is senior director, pharmaceutical
`technology, at Baxter Pharmaceuticals & Technology. Reach
`Dr. Chilamkurti at rao_chilamkurti@baxter.com.
`
`REFERENCES
`1. Chilamkurti R, Youngberg Webb P. The keys to
`RTU parenterals. Pharm Formulation Quality.
`2009; 11(5):40-42.
`
`2. International Conference on Harmonisation of
`Technical Requirements for Registration of
`Pharmaceuticals for Human Use. ICH Guide-
`line Q 1 A (R2): Stability testing of new drug
`substances and products. Geneva, Switzerland;
`2003. Available at: www.ich.org/LOB/media/
`MEDIA419.pdf. Accessed September 29, 2009.
`
`3. International Conference on Harmonisation of
`Technical Requirements for Registration of
`Pharmaceuticals for Human Use. ICH Guide-
`line Q 1 D: Bracketing and matrixing designs
`for stability testing of drug substances and drug
`products. Geneva, Switzerland; 2002. Available
`at: www.ich.org/LOB/media/MEDIA414.pdf.
`Accessed September 29, 2009.
`
`4. International Conference on Harmonisation of
`Technical Requirements for Registration of
`Pharmaceuticals for Human Use. ICH Guide-
`line Q 1 B: Stability testing: photostability test-
`ing of new drug substances and products.
`Geneva, Switzerland; 1996. Available at:
`www.ich.org/LOB/media/MEDIA412.pdf.
`Accessed September 29, 2009.
`
`5. International Conference on Harmonisation of
`Technical Requirements for Registration of
`Pharmaceuticals for Human Use. ICH Guide-
`line Q1 E: Evaluation of stability data. Geneva,
`Switzerland; 2004. Available at:
`www.ich.org/LOB/media/MEDIA415.pdf.
`Accessed September 29, 2009.
`
`Reprinted with permission from PFQ Magazine October/November 2009.
`
`Hospira, Exh. 2016, p. 4