AAPS PharmSci 2002; 4 (2) article 7 (http://www.aapspharmsci.org).
`Assuring Quality and Performance of Sustained and Controlled Release
`Parenterals: Workshop Report
`Submitted: March 17, 2002; Published: April 17, 2002
`
`Diane J. Burgess1, Ajaz S. Hussain2, Thomas S. Ingallinera 3 and Mei-Ling Chen2
`
`1Department of Pharmaceutics, University of Connecticut, 372 Fairfield Road, Storrs, CT 06269
`
`2Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, 1451
`Rockville Pike, HFD-350, Rockville, MD 20857
`
`3InfiMed Therapeutics, Inc., 8 Lantern Rd Framingham, MA 01702
`
`* This report may contain statements of opinion that are those of the author(s) and do not necessarily reflect the opinions of AAPS or its members, the
`Food and Drug Administration, or the United States Pharmacopoeia.
`
`PLANNING COMMITTEE
`
`Diane J. Burgess, Ph.D., University of Connecticut, Co-
`Chair
`Ajaz S. Hussain, Ph.D., Food and Drug Administration,
`Co-Chair
`Thomas S. Ingallinera, Ph.D., InfiMed Therapeutics, Inc.,
`Co-Chair
`Mei-Ling Chen, Ph.D., Food and Drug Administration
`Yuan-yuan Chiu, Ph.D., Food and Drug Administration
`Larry A. Gatlin, Ph.D., Biogen, Inc.
`Barbara B. Hubert, United States Pharmacopeia
`Funmi Johnson, Ph.D., Alkermes, Inc.
`Marilyn Martinez, Ph.D., Food and Drug Administration
`Eyal S. Ron, Ph.D., eNOS Pharmaceuticals, Inc.
`Arthur J. Tipton, Ph.D., Southern BioSystems, Inc.
`Lawrence Yu, Ph.D., Food and Drug Administration
`Roger L. Williams, M.D., United States Pharmacopeia
`Melvin H. Weinswig, Ph.D., University of Wisconsin-
`Madison, Continuing Education
`
`SPEAKERS AND DISCUSSION LEADERS
`
`Diane J. Burgess, Ph.D., University of Connecticut, Co-
`Chair
`Ajaz S. Hussain, Ph.D., Food and Drug Administration,
`Co-Chair
`Thomas S. Ingallinera, Ph.D., InfiMed Therapeutics, Inc.,
`Co-Chair
`Hae-Young Ahn, Ph.D., Food and Drug Administration
`Mei-Ling Chen, Ph.D., Food and Drug Administration
`Yuan-yuan Chiu, Ph.D., Food and Drug Administration
`Todd Darrington, Ph.D., Pfizer, Inc.
`Eric Duffy, Ph.D., Food and Drug Administration
`Thomas H. Ferguson, Ph.D., Eli Lilly and Company
`Larry A. Gatlin, Ph.D., Biogen, Inc.
`
`Correspondence to:
`Diane Burgess
`Telephone: 860-486-3760
`Facsimile: 860-486-4998
`E-mail: diane.burgess@uconn.edu
`
`Anthony Huang, Ph.D., Alza Corporation
`Barbara B. Hubert, United States Pharmacopeia
`Andrew Janoff, Ph.D., The Liposome Company
`Funmi Johnson, Ph.D., Alkermes, Inc.
`Kofi Kumi, Ph.D., Food and Drug Administration
`Johnny Lau, Ph.D., Food and Drug Administration
`Patrick Marroum, Ph.D., Food and Drug Administration
`Frank Martin, Ph.D., Alza Corporation
`Marilyn Martinez, Ph.D., Food and Drug Administration
`Mehul Mehta, Ph.D., Food and Drug Administration
`Chien-Hua Niu, Ph.D., Food and Drug Administration
`Kanaiyalal R. Patel, Ph.D., Monsanto Company
`Atiqur Rahman, Ph.D., Food and Drug Administration
`Moo-Jhong Rhee, Ph.D., Food and Drug Administration
`Eyal S. Ron, Ph.D., eNOS Pharmaceuticals, Inc.
`Arthur J. Tipton, Ph.D., Southern BioSystems, Inc.
`David Young, Pharm.D., Ph.D., GloboMax USA
`Lawrence Yu, Ph.D., Food and Drug Administration
`Roger L. Williams, M.D., United States Pharmacopeia
`Helen Winkle, Food and Drug Administration
`Sui-Ming Wong, Ph.D., Novartis Pharmaceutical
`Corporation
`Jeremy C. Wright, Ph.D., Alza Corporation
`Liang Zhou, Ph.D., Food and Drug Administration
`
`ABSTRACT
`
`This is a summary report of the American Association of
`Pharmaceutical Scientists,
`the Food and Drug
`Administration and the United States Pharmacopoeia co-
`sponsored workshop on
`"Assuring Quality and
`Performance of Sustained and Controlled Release
`Parenterals." Experts from the pharmaceutical industry,
`the regulatory authorities and academia participated in
`this workshop to review, discuss and debate formulation,
`processing and manufacture of sustained and controlled
`release parenterals and
`identify critical process
`parameters and their control. Areas were identified
`where research is needed in order to understand the
`performance of these drug delivery systems and to
`assist
`in
`the development of appropriate
`testing
`procedures. Recommendations were made for future
`workshops, meetings and working groups in this area.
`ALL 2200 AAA
`PROLLENIUM V. ALLERGAN
`IPR2019-01505, et al.
`
`1
`
`

`

`AAPS PharmSci 2002; 4 (2) article 7 (http://www.aapspharmsci.org).
`
`
`
`INTRODUCTION
`
`This report summarizes the outcome of the workshop on
`"Assuring Quality and Performance of Sustained and
`Controlled Release Parenterals," which was held in April
`2001 in Washington, DC. This workshop was sponsored
`by
`the American Association of Pharmaceutical
`Scientists (AAPS), the Food and Drug Administration
`(FDA) and the United States Pharmacopoeia (USP). The
`overall goal of this workshop was to identify future
`directions for regulatory activity and public standards in
`the rapidly emerging area of controlled release (CR)
`parenteral products. Presentations focused on dispersed
`systems
`(microspheres,
`liposomes,
`gels
`and
`suspensions) as well as implants of small molecule and
`protein/peptide therapeutics for human and animal use.
`The objectives of the workshop were to:
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`and
`processing
`formulation,
`Review
`manufacture of CR parenterals. Identify and
`discuss critical process parameters and their
`control.
`
`Identify new and emerging methods of in vitro
`release testing for CR parenterals and their
`ability to predict product performance.
`
`Discuss accelerated stability and in vitro release
`testing methods for CR parenterals.
`
`Discuss bioavailability, bioequivalence and
`pharmaceutical equivalence for CR parenterals.
`
`for
`the opportunity
`Explore
`correlation of CR parenterals.
`
`in vitro-in vivo
`
`Identify future directions for regulatory activity
`and public standards in this area.
`
`the
`from
`together experts
`This workshop brought
`pharmaceutical industry, the regulatory authorities and
`academia to discuss and debate issues pertaining to
`assuring the quality and performance of sustained and
`controlled
`release parenterals. The workshop was
`divided into formal presentations in the morning and
`parallel breakout discussion sessions in the afternoon.
`The breakout sessions served
`to
`identify
`future
`directions for regulatory activity and public standards in
`this rapidly emerging area. At the close of each breakout
`session
`the moderators were asked
`to prepare a
`summary of the key points discussed in their session.
`This report represents a compilation of these summaries
`together with background information explaining the
`need for regulatory activity in this area. Since many of
`the same concerns and issues were raised in different
`parallel sessions, this report is not divided by the
`breakout sessions, but rather by
`the key
`issues
`discussed.
`
`
`
`formulation,
`the workshop,
`first day of
`the
`On
`development and manufacture of the different products
`were reviewed and critical process parameters were
`identified. The breakout sessions focused on chemistry,
`manufacturing, and control issues and were divided by
`product (liposomes, microspheres, gels, suspensions
`and
`implants). The
`second day
`centered on
`biopharmaceutics issues, including physiology of the
`parenteral routes, bioavailability and bioequivalence, in
`vitro release testing and the possibility of in vitro-in vivo
`correlation.
`
`BACKGROUND
`
`Controlled release drug delivery systems are used to
`improve the therapeutic response by providing blood
`levels that are more consistent and stable compared to
`immediate release dosage forms. They can result in a
`reduction
`in adverse reactions since
`less drug
`is
`required and since the drug may be targeted to the site
`in vivo avoiding high systemic levels. As a consequence
`of targeted and controlled release, patient compliance
`may be improved due to lower dosing frequencies and
`simpler dosing regimens. With
`targeting and more
`sustained, predictable levels, efficacy may also be
`enhanced. CR parenteral drug delivery systems include:
`suspensions,
`liposomes, microspheres, gels and
`implants. Tiny microspheres and
`larger
`implantable
`devices can be used to modify release over periods of
`months to years. Suspensions, liposomes and gels may
`not achieve quite as long durations of action; however,
`they can be localized at the site of action in vivo and
`liposomes may achieve
`targeted delivery both by
`passive and active means
`following
`intravenous
`administration. These delivery systems are becoming
`increasingly utilized by the pharmaceutical industry to
`deliver drugs for treatment or prevention of a variety of
`diseases.
`
`Not all drugs are candidates for controlled delivery via
`the parenteral route. The candidate drug should be
`potent with known toxicity and pharmacokinetic profiles.
`A CR parenteral dosage form is usually selected when
`there are problems associated with oral delivery (e.g.
`gastric irritation, first pass effects or poor absorption)
`and a need for extended release or targeted delivery
`(e.g. rapid clearance). Both systemic and localized
`delivery can be achieved using CR parenterals. In
`addition,
`the drug must be compatible with
`the
`manufacturing process, which may be fairly harsh for
`some of
`these products. Examples of disease
`applications for CR parenteral delivery include: fertility,
`hormone therapy, protein therapy, infections (antibiotics
`and antifungals), cancer therapy, orthopedic surgery and
`post-operative
`pain,
`chronic
`pain,
`CNS
`vaccination/immunization,
`disorders,
`and
`immunosupression. Approved CR parenteral products
`are listed in Table 1.
`
`
`
`2
`
`

`

`AAPS PharmSci 2002; 4 (2) article 7 (http://www.aapspharmsci.org).
`
`Table 1 - Approved CR Parenteral Products
`
`?
`
`Trade Name Active Ingredient
`
`Approval
`Date
`
`?
`
`Suspension Products
`
`Depo-Medrol Methylprednisolone
`
`pre-1982
`
`Depo-Provera Medoxyprogesterone pre-1982
`
`Celestone
`Soluspan
`
`Insulin
`
`?
`
`Betamethasone
`
`pre-1982
`
`Lente
`NPH
`
`Unltralente
`
`pre-1962
`
`Microsphere Products
`
`Lupron Depot Leuprolide
`
`Sandostatin
`LAR
`
`Octreotide
`
`Nutropin Depot Somatropin
`
`Trelstar Depot Triptorelin
`
`?
`
`Liposome Products
`
`Doxil
`
`Daunorubicin
`
`Daunoxome
`
`Daunorubicin
`
`Ambisome
`
`Amphotericin B
`
`Depocyt
`
`Cytarabine
`
`?
`Lipid Complex Products
`
`Ambelcet
`
`Amphotericin B
`
`Amphotec
`
`Amphotericin B
`
`Visudyne
`
`Verteporfin
`
`?
`Implant Products
`
`Norplant
`
`Levonorgestrel
`
`Gliadel
`
`Zoladex
`
`Viadur
`
`
`Carmustine
`
`Goserelin
`
`Leuprolide
`
`1989
`
`1998
`
`1999
`
`2000
`
`1995
`
`1996
`
`1997
`
`1999
`
`1995
`
`1997
`
`2000
`
`1990
`
`1996
`
`1998
`
`2000
`
`Although CR parenteral products are relatively low
`volume in sales compared to oral products, they offer
`significant and distinct therapeutic advantages for certain
`types of drugs and consequently their use is becoming
`more
`prevalent. CR
`parenterals
`are
`complex
`formulations and thereby present significant challenges
`in regulation and the development of standards. In
`addition, they are considered ?high risk? products since
`they are complex, are designed for prolonged and
`targeted release and, in the case of dispersed system
`CR parenterals, are almost impossible to remove from
`the body once administered. Consequently, there is a
`
`
`
`3
`
`pressing need to open a public dialog between industry,
`FDA and USP on how best to assure the quality and
`performance of these products. This workshop served to
`initiate this public dialog.
`
`Of paramount importance is to identify any gaps in our
`scientific understanding of CR parenteral products and
`determine regulatory policy issues that need to be
`addressed. Critical formulation and process variables for
`individual products must be identified in order to develop
`the necessary characterization studies that undergird the
`substance, excipient, and product specifications that
`allow batch release. Key
`issues discussed
`in
`this
`workshop include: in vitro drug release testing (need for
`quality assessment as well as in vivo relevance), the
`possibility of in vitro-in vivo correlation, stability testing to
`ensure that specifications are met during shelf-life, as
`well as in vivo stability, sterility assurance, sterility
`testing, foreign particulate matter, particle size analysis,
`bioavailability
`and
`bioequivalence
`assessments,
`qualification of new biopolymers, residual solvent levels,
`reconstitution of parenteral products, and nomenclature.
`
`issues and recommendations
`The major
`workshop are summarized below.
`
`from
`
`this
`
`IN VITRO RELEASE METHODS
`
`Because the issue of in vitro release testing was raised
`at many of the breakout sessions, attendees generally
`agreed that an immediate need for guidance in this area
`exists. This guidance should focus on regulatory and
`compendial approaches with respect
`to acceptable
`apparatus, media and sampling methods, test intervals,
`and total percent release. Attendees also requested
`guidance on the method development process for in vitro
`tests for quality control purposes as well as on how to
`ensure the in vivo relevance of these tests. A need for
`guidance on accelerated in vitro testing for routine
`quality control purposes was also expressed. The issue
`of in vitro - in vivo correlation was discussed.
`
`Although workshop attendees did not want a single
`approach to be set for in vitro release testing given the
`wide range of CR parenteral products, they noted a need
`for general guiding principles and encouraged research
`to ensure a scientific basis for the development of
`different tests, procedures (to include apparatus) and
`acceptance criteria. These general approaches could
`then be modified, as appropriate, for specific products.
`For example, a given product may have specific
`requirements with respect to media, sampling interval or
`temperature.
`
`Apparatus
`
`Current USP apparatus for in vitro release testing are
`designed for oral and transdermal products and may not
`be optimal for controlled release parenteral products.
`USP apparatus 1 (basket) and 2 (paddle) were designed
`
`

`

`AAPS PharmSci 2002; 4 (2) article 7 (http://www.aapspharmsci.org).
`
`for immediate- and modified-release oral formulations.
`USP apparatus 5 (paddle over disc), 6 (cylinder) and 7
`(reciprocating holder) were designed for the transdermal
`route. USP apparatus 3 (reciprocating cylinder) and 4
`(flow through cell) were designed for extended-release
`oral formulations. These latter two methods may be the
`most relevant to CR parenterals and may be suitable
`following appropriate modification. Alternative apparatus,
`such as small sample vials and vessels, with and without
`agitation, are currently used
`for CR parenterals.
`Problems that may be associated with these alternative
`apparatus include: lack of sink conditions and sample
`aggregation.
`
`Research is required to determine the scientific basis for
`the
`tests, procedures,
`including apparatus
`(e.g.,
`geometry and hydrodynamics), and acceptance criteria
`for CR parenterals. The apparatus and media used
`should take into account the release mechanism and the
`physical properties of
`the product (e.g. size and
`stability). In addition, in vitro release tests must also
`discriminate between
`the performance of different
`formulation variants and
`ideally should have bio-
`relevance.
`
`Method development
`
`Attendees considered the purpose of in vitro release
`testing since method design may vary according to the
`purpose of the test. Current uses of in vitro release
`testing include: 1) formulation development, to include
`assessment of dose-dumping and in vivo stability (e.g.,
`Stealth-type liposomes, which should remain stable
`without significant drug release until uptake at the target
`site in vivo); 2) quality control to support batch release,
`3) evaluation of the impact of manufacturing process
`changes on product performance, 4) substantiation of
`label claims; and 5) compendial testing.
`
`Although in vitro release testing of CR parenterals is
`primarily utilized for quality control purposes, many
`attendees agreed that in vitro release tests should be
`developed with
`regard
`to clinical outcomes
`(bio-
`relevance). The rationale for this understanding is that
`the ultimate purpose of quality control testing is to
`ensure the clinical performance, i.e., efficacy and safety
`of the product. In order to achieve in vivo relevance,
`physiological variables at the site need to be considered
`including: body temperature and metabolism (both can
`significantly affect blood
`flow), muscle pH, buffer
`capacity, vascularity, level of exercise, as well as volume
`and osmolarity of the products. Any tissue response,
`such as inflammation and/or fibrous encapsulation of the
`product may need to be considered. In vitro release
`methods should be designed based on in vivo release
`mechanisms. With this understanding, attendees noted
`the following general approaches for in vitro test method
`design: 1) identification of release media and conditions
`that result in reproducible release rates; 2) preparation of
`formulation variants that are expected to have different
`
`
`
`4
`
`biological profiles; 3) testing of formulation variants in
`vitro as well as in vivo; and 4) modification of in vitro
`release methods
`to allow discrimination between
`formulation variants that have different in vivo release
`profiles.
`
`relevance of sink
`the
`Attendees also discussed
`conditions in in vitro test design for CR parenterals,
`considering that sink conditions may not exist at a
`particular in vivo site. General agreement was that sink
`conditions should be used for in vitro testing for quality
`control purposes provided that the study design allowed
`for discrimination between formulation variants with
`different in vivo release profiles. However, participants
`argued that non-sink conditions may be necessary if the
`purpose of the in vitro test is to establish in vitro-in vivo
`correlation (IVIVC). Although IVIVC is not utilized at
`present for CR parenterals, with sufficient bio-relevance
`built into the in vitro tests to support an IVIVC it may
`allow subsequent waiver of in vivo studies (see the
`IVIVC section below).
`
`Attendees also considered other issues, including the
`percent total release required (e.g., 70%, 80%) and the
`value of physical/chemical properties in lieu of release
`data for some quality control purposes (e.g., for stable
`liposomal formulations that are designed for no release
`until uptake at the site).
`
`Development of IVIVC for CR parenterals
`
`for all CR
`IVIVC may not be possible
`Although
`parenteral products, many attendees agreed that this is
`an important area for research. The principles used in
`IVIVC of oral extended-release products may be applied
`to parenterals with appropriate modification, justified on
`a scientific basis. IVIVC modeling and measurements
`may be different for different types of products (e.g.
`targeted release versus extended release products).
`Similarly, in vitro release methods and media are likely
`to vary depending on the product and should be
`developed based on in vivo relevance. For example, in
`vitro cellular tests may be acceptable as long as they are
`reproducible and can be validated. Similarly, in vivo
`measurements may vary and may
`include plasma
`concentrations, efficacy/safety data, surrogate endpoint
`data, as well as tissue concentrations. Discussions
`stressed that both in vitro and in vivo measurements
`must be justified scientifically. In the case of some
`products, such as liposomes, it may be necessary to
`measure
`in vivo concentrations of both
`free and
`encapsulated drug. Models
`that represent multiple
`processes (e.g., physical and biological) should be
`considered, as appropriate.
`
`The use of animals was considered to be acceptable to
`prove that an in vitro release system is discriminating.
`However, the use of animal models was considered
`inappropriate to prove an IVIV C for regulatory purposes.
`Instead, bio-relevance should be developed using
`
`

`

`AAPS PharmSci 2002; 4 (2) article 7 (http://www.aapspharmsci.org).
`
`clinical data. Nevertheless, IVIVC modeling using animal
`data would be suitable for "proof of principle" for initial
`research purposes. Research in this area should be
`encouraged, possibly coordinated
`through Product
`Quality Research Initiative (PQRI).
`
`The issue of data variability with respect to IVIVC was
`discussed and the following potential solutions were
`suggested:
`
`•
`
`•
`
`•
`
`the number of dosage units or
`Increase
`individuals.
`
`Variability may be acceptable as long as its
`source can be estimated and a valid IVIVC is
`obtained.
`
`If the source and importance of the variability
`can be determined,
`it may be possible
`to
`minimize it.
`
`Attendees noted that tissue responses, such as fibrous
`encapsulation, may affect release in vivo and this needs
`to be considered in establishing an IVIVC. However,
`these types of tissue response may be difficult to
`simulate in vitro.
`
`Use of animal models in release testing
`
`In the development of in vitro release methods, animal
`data may be used to obtain tissue distribution and
`pharmacokinetic information. Plasma levels may not be
`the best measure of in vivo behavior for CR parenteral
`products intended for local delivery or targeted release,
`and therefore, discussion in some sessions centered on
`the use of animal models to investigate in vivo product
`performance. More extensive bio-data can be obtained
`using animal models, including tissue levels at the local
`site. Animal models were considered to be invaluable
`and serial tissue samples might be used to compare
`product performance before and after manufacturing
`changes for CR parenterals with tissue-specific delivery.
`Although data will be useful in initial development,
`ultimately human data must be used to establish an
`IVIVC.
`
`Selection of an appropriate animal model was discussed
`and it was suggested that comparative studies be
`performed between
`injection sites
`in humans and
`animals in order to establish interspecies differences in
`drug release. Larger animals such as sheep and dogs
`may be more representative of humans with regard to
`interspecies differences than would small laboratory
`animals. This may be particularly important with regard
`to issues such as injection volume. Since inter-subject
`variability significantly
`impacts
`in vivo data,
`inbred
`animals may be useful in identifying variables that affect
`the drug release and absorption processes. Extensive
`inter- and intra-subject variability may mask critical
`formulation and manufacturing variables unless very
`
`
`
`5
`
`large human populations are utilized. The identification
`of an appropriate animal model for CR parenteral
`products was recommended as a research project,
`possibly for investigation through PQRI. The initial step
`of
`this research project should be a retrospective
`literature review of parenteral bioavailability data to
`develop initial correlation predictions between humans
`and animals. This research study should
`include
`different animals as well as different sites and should
`attempt to establish correlations between human and
`animal data
`relating
`the
`findings
`to physiological
`parameters. Different dosage forms and drugs should be
`investigated to determine whether the results are drug-
`and/or dosage form-dependant.
`
`in
`Animal models could potentially be utilized
`pharmaceutical development. For SUPAC-type changes,
`attendees
`recommended
`that an animal-human
`correlation be established so that animal models can be
`used (along with
`in vitro specifications)
`in
`lieu of
`extensive post-approval human trials. To achieve this,
`out of specification batches would be used to test the
`sensitivity of the animal model. Tests should also
`examine the sensitivity of the animal model to changes
`in product performance when the duration of testing is
`truncated (e.g., 3-month release testing for a one-year
`release product).
`
`Concerns were raised with respect to animal lifespan as
`well as physiological and metabolic differences between
`species. Animal lifespan may be a concern for extended
`release dosage forms with unusually long durations of
`action. Metabolic differences were considered not to be
`of importance for formulation comparisons. However,
`such differences may be very significant if animal
`models were to be used as a surrogate for efficacy.
`Another potential problem area is antibody production
`when using human derived proteins. Since immuno-
`suppression may be a possibility, the impact of this on
`pharmacokinetic and pharmacodynamic
`responses
`needs to be considered.
`
`Accelerated in vitro release testing
`
`The need for accelerated release testing was discussed,
`particularly for extended release products. Accelerated
`release testing is desirable for routine quality control
`purposes. Attendees generally agreed that these tests
`should have relevance to "real time" in vitro release tests
`conducted under conditions that simulate the in vivo
`situation as closely as possible. "Real time" in vitro tests
`for the full product duration should be conducted during
`product development and are essential for validating
`accelerated release rate tests. Accelerated tests should
`be bio-relevant and the mechanism of drug release
`should not be altered in accelerated tests, rather it
`should only be speeded up. For example, in the case of
`PLGA microspheres that release drug primarily via
`polymer erosion the accelerated test should speed up
`the polymer erosion process.
`In
`the design of
`
`

`

`AAPS PharmSci 2002; 4 (2) article 7 (http://www.aapspharmsci.org).
`
`factors such as polymer
`test,
`in vitro
`accelerated
`transition and degradation
`temperature should be
`considered to avoid any change in the mechanisms of
`drug release.
`
`release
`"burst"
`initial
`the
`Attendees discussed
`associated with some CR parenterals. When a CR
`parenteral delivery system produces an initial burst
`release, accelerated release tests should be augmented
`by an initial "real time" study that allows adequate
`assessment of this burst. Specifications for accelerated
`release
`tests should be
`tied
`to safety and
`to
`manufacturing experience. For example, significant
`deviation from the expected result may indicate a
`manufacturing problem. Attendees expressed the view
`that mathematical modeling to predict long-term release
`from accelerated release is useful.
`
`Labeling requirements for release rates
`
`that
`Attendees were concerned about products
`displayed an initial rapid burst release followed by a
`second slower release rate. Total drug cont ent and in
`vivo release rate are label requirements for CR products.
`Agreement was reached that inclusion of the initial burst
`release on the label should be handled on a case-by-
`case basis. Provided the initial burst rate is supported by
`clinical safety/efficacy data and
`is covered by
`specifications, it may not need to be included. However,
`if there are safety implications, this rate must be
`included. Given that regulatory guidance is not available
`on how much burst release is acceptable, attendees
`note
`that
`this performance
`factor should also be
`assessed on a case-by-case basis, depending on the
`drug and the safety/efficacy implications. Attendees
`discussed eliminating burst release from products where
`it did not provide a clinical benefit, but agreed that this
`might be prohibitively expensive.
`
`STABILITY
`
`Attendees considered both shelf life and in vivo stability
`for CR parenterals.
`In addition
`to drug stability,
`attendees noted the importance of "inactive" ingredient
`stability and product stability for CR parenterals.
`
`Shelf life stability
`
`The initial shelf life stability of entrapped drug is a
`concern because manufacturing conditions for some CR
`parenterals (e.g. some microsphere products) may be
`harsh. In the case of protein drugs, documentation of
`lack of chemical breakdown only is insufficient because
`conformational changes may have occurred that can
`affect activity. Therefore, activity must be demonstrated
`as
`part
`of
`the
`stability
`testing
`utilizing
`a
`pharmacodynamic method. Stability testing of many of
`these products requires extraction of the drug. The
`method of extraction (e.g., solvent system) should be
`selected to avoid any potential alteration in drug stability.
`
`
`6
`
`life stability should be conducted at room
`Shelf
`temperature as occurs for other products.
`
`In vivo drug stability
`
`In vivo drug stability is an issue for controlled release
`parenterals, especially those intended for long term
`extended release. In the case of large implants, drug
`stability could be determined by analyzing the drug
`remaining in explanted systems. This method could only
`be feasible for dispersed system CR parenterals by
`utilizing an appropriate animal model where tissue
`samples could be excised. An alternative approach that
`might be acceptable would be an in vitro test that
`simulated
`in vivo conditions
`(e.g., 37? C and
`approximately 100% humidity). Attendees agreed that
`some in vivo drug degradation might be acceptable for
`extended release products, provided that the product
`was demonstrated to be safe and effective. A typical in
`vivo degradation profile should be established together
`with safety and efficacy data. Immunologic response
`may require assessment, since protein degradation may
`occur with prolonged in vivo residence time.
`
`In vivo product stability
`
`Attendees agreed that in vivo product stability is equally
`as
`important
`as
`drug
`stability
`since
`degradation/alteration of the product as a whole or
`unwanted tissue response to the product may affect
`performance and bioavailabilty. For example, fibrous
`encapsulation of an implant or microsphere product will
`reduce/eliminate blood
`flow and consequently affect
`drug
`release
`and
`bioavailability.
`Attendees
`recommended that in vivo evaluation of CR parenterals
`include evaluation of product stability and
`tissue
`response to the product as well as drug stability. This is
`another area where animal models may be useful.
`Further discussion of this issue is required and/or a
`research project should be
`initiated
`to determine
`appropriate animal models.
`
`In vivo integrity of targeted products
`
`Another in vivo stability issue is the integrity of products
`that are intended to remain stable without significant
`drug release until uptake at the target site. An example
`of this type of product is "Stealth-type" liposomes. There
`was no consensus as to how to determine in vivo
`integrity of such products. Attendees discussed a
`proposal to conduct a single-dose study over a sufficient
`time period, with measurement of both encapsulated and
`unencapsulated drug. However, there was no prevailing
`opinion as to what percentage/ratio of unencapsulated to
`encapsulated drug should remain in the circulation for a
`liposomal drug product to be considered stable.
`
`

`

`AAPS PharmSci 2002; 4 (2) article 7 (http://www.aapspharmsci.org).
`
`PARTICLE SIZE
`
`Attendees requested guidance/clarification on particle
`size specifications for dispersed system CR parenterals.
`Particle size may affect release rates of extended
`release products, such as microspheres. It may also
`affect targeting ability and reticuloendothelial system
`(RES) uptake of liposome products. Acceptable particle
`size ranges may vary
`for different CR parenteral
`systems. For example, a liposome system intended for
`targeted release, where
`targeting
`is particle size-
`dependent, may require more stringent particle size
`specifications
`than some other dispersed systems.
`Attendees noted the importance of a specification for
`particle size range as well as average particle size since
`a few large particles may have a significant effect on
`product performance as well as safety. Larger particles
`can
`cause
`capillary
`blockage when
`injected
`intravenously. Particle size may also affect syringability
`of the product. Attendees requested guidance on particle
`sizing instrumentation and techniques, particularly when
`more than one instrument is necessary to measure the
`entire size range. Concluding, attendees generally
`agreed that a workshop to address particle size issues
`would be useful.
`
`STERILIZATION, STERILITY ASSURANCE AND
`FOREIGN PARTICULATE MATTER
`
`Sterilization and sterility assurance
`
`CR parenterals are complex products usually containing
`polymers and/or lipids with glass transition temperatures
`below the temperature required for hea