AAPS PharmSciTech, Vol. 11, No. 3, September 2010 ( # 2010)
`DOI: 10.1208/s12249-010-9521-x
`
`Review Article
`Theme: Sterile Products: Advances and Challenges in Formulation, Manufacturing, Devices and Regulatory Aspects
`Guest Editors: Lavinia Lewis, Jim Agalloco, Bill Lambert, Russell Madsen, and Mark Staples
`
`Considerations in Developing a Target Product Profile for Parenteral
`Pharmaceutical Products
`
`William J. Lambert1,2
`
`Received 16 April 2010; accepted 25 August 2010; published online 15 September 2010
`Abstract. A target product profile (TPP) describes how a product will be utilized by the end user. A
`systematically developed TPP can ensure alignment of objectives across company departments,
`accelerate development timelines, minimize development risks, and eventually lead to an optimal
`product. A TPP is particularly important for parenteral products due to the need for administration
`devices, the variety of possible end users (nurses, patients, pharmacists, and physicians), and require-
`ments specific to sterile products. This manuscript describes key components of a TPP from a formulation
`development perspective and provides guidance on practical issues common to parenteral products.
`KEY WORDS: freeze dried; injectable; lyophile; quality by design; sterile product; target product profile.
`
`INTRODUCTION
`
`Before work begins on the development of a new
`product,
`it
`is critical
`that
`the development scientist or
`engineer clearly defines the critical attributes of the product.
`In the popular Six Sigma approach, defining the design goals
`for a product is the first of the five phases (1). In the
`pharmaceutical industry, these product attributes are referred
`to as the target product profile (TPP). Ideally, the TPP
`describes how the product will be utilized by the end user. For
`the company, the TPP will help identify project goals and
`potential risks. It can serve as the basis for discussions
`between various groups within the company (clinical, devel-
`opment, drug safety, manufacturing, marketing, regulatory,
`research, and quality) before and during development. These
`discussions should occur from the candidate nomination stage
`through and after marketing approval. The development of
`pharmaceutical products is a lengthy and expensive exercise,
`often taking 10 years and costing over $1 billion (2). Given
`this time and expense, it is critical to ensure that the right
`product is being developed. The TPP is a key tool to help
`ensure the eventual product meets all expectations. In
`addition, the TPP document can be used for discussions
`between the company and the Food and Drug Administration
`(FDA) and, in fact, is considered a “critical path” tool by the
`agency (3).
`The absence of a well-defined TPP can lead to a host of
`problems. For example, without a TPP, one group within a
`company may make certain assumptions about how the
`
`function, only to find out at a later and
`product will
`inopportune moment that the product does not meet that
`group’s expectations. This can lead to inefficiencies in time
`and resources and may even result in failure of the product
`from a medical or commercial standpoint. A well-planned
`TPP can also be used to guard against unnecessary changes as
`new members are assigned to project teams. Ultimately, the
`TPP helps ensure that all parties are clear on what is and is
`not being developed.
`The use of a parenteral pharmaceutical product has a
`number of considerations which may not apply to orally
`administered dosage forms. For example, administration
`generally requires a device such as a syringe, injection pen,
`catheter, etc. In addition,
`formulations often must meet
`specific requirements (e.g.,
`the use of an antimicrobial
`preservative in a multi-use container). Finally, there are a
`variety of end users for parenteral products. These include
`self-administration by the patient, preparation by a pharma-
`cist, and administration by a nurse or physician, all of whom
`can introduce a variety of preferences. The use of a TPP for
`pharmaceutical development has previously been described
`(4,5). The purpose of this manuscript was to focus on those
`considerations that are specific to sterile products from a
`formulation development perspective. The importance of the
`customer’s requirements and preferences is stressed. An
`example TPP will be provided in order to provide useful
`guidance to the reader.
`
`KEEP THE CUSTOMER IN MIND
`
`1 Pacira Pharmaceuticals, Inc., Pharmaceutical Development, 10450
`Science Center Dr, San Diego, California 92121, USA.
`2 To whom correspondence should be addressed. (e-mail: BillL@
`pacira.com)
`
`Development of the TPP must start with consideration of
`the end user’s needs. How will they use the product? Are
`they already using a similar product? Product sales can be
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`impacted if an unfamiliar device or technique is forced on
`hospital staff. If the company is entering a therapeutic area
`where it has limited experience, it may be useful for the
`marketing group to perform focus group studies with
`appropriate nurses and/or physicians to better understand
`their needs. If this is done,
`it is a good idea that the
`development scientist be involved so that technically relevant
`questions are asked and so the scientist can receive useful
`input.
`The importance of understanding how the end user will
`want to utilize the product cannot be overstated. Consider the
`use of an anesthetic agent such as bupivacaine in a hospital
`operating room. It would be easy to assume that the surgeon
`takes a vial and removes the desired dose with a syringe.
`However,
`it
`is common practice for the stopper to be
`removed from the vial and the vial contents poured into a
`sterile surgical bowl containing a volume of saline appropriate
`for the given surgery. The bowl is then utilized to replenish
`the syringe used as the surgery proceeds. This insight might
`lead the development scientist to consider alternative pack-
`aging. For example, a tear-off seal could be utilized for the
`vial (rather than a traditional “flip-off” seal) in order to
`facilitate emptying of the vial.
`In addition to the patients, pharmacists, nurses, and
`physicians, the needs of internal customers must also be
`considered. Pharmaceutical products generally have multiple
`internal customers, and often, each has certain requirements
`to ensure success for the product. The internal customers
`include groups such as marketing, clinical, legal, regulatory,
`quality, and manufacturing.
`
`COMPONENTS OF A TPP
`
`The TPP as described by the FDA (3) can encompass a
`fairly broad range of topics which may lead to inclusion in the
`product labeling. Topics can include dosage and administra-
`tion, clinical studies, adverse reactions, and contraindications.
`For the present document, the focus will be on those aspects
`of the labeling which directly impact how the product should
`be developed from a formulation development standpoint.
`TPP topics such as indications and adverse reactions are
`outside the scope of this manuscript and are not addressed,
`except as they might impact the formulation. A list of product
`attributes which should be considered for inclusion in the
`TPP is provided in Table I. Many of the attributes relate to
`what
`the product will be used for and how it will be
`administered to the patient. Other attributes address the
`specifics of the product, its components, and how it will be
`packaged. Some address potential intellectual property issues.
`Finally, attributes which impact the manufacturing site are
`addressed.
`
`“MUSTS” AND “WANTS”
`
`During the development of the TPP, people will often
`describe what they feel are product “requirements.” For
`example, “The product must be isotonic and formulated at
`pH 7.4” or “It must have a 2-year shelf-life.” It is critical to
`differentiate what are minimally acceptable requirements
`(musts) from what are desired attributes (wants). Some
`companies may indeed have a commercial policy on having
`
`a 2-year shelf-life, and this is probably a reasonable require-
`ment for many low-volume products in order to ensure
`stability through distribution and storage. However, if launch-
`ing the company’s next blockbuster with only an 18-month
`shelf-life is preferred over stopping development from a
`corporate standpoint, then a 2-year shelf-life is not a must.
`The TPP can be used to clarify such considerations.
`It is generally useful to put quantifiable ranges on the
`musts and wants. The development scientist should make use
`of the literature to assist other project team members with
`regards to what product attributes are acceptable. For
`example, significant evidence exists that injectable products
`do not need to be formulated at pH 7.4, but rather, a fairly
`broad range of pH is found to be well tolerated in commercial
`use (6–10). Thus, one might define a pH range of 5–8 as
`preferred for a given product, with the stipulation that the pH
`must not be <3.5 or >9.5. When attributes are quantified in
`this manner, the development scientist has a clear direction
`how to proceed.
`
`EXAMPLE TPP
`
`An illustrative example of a TPP is provided in Table II.
`For this example, a hypothetical antifungal agent about to
`enter Phase 1 studies was used. Being an early stage
`compound, the final dose is yet to be determined. For the
`development scientist, this leads to uncertainty as to what the
`eventual
`formulation concentration will be and possibly
`whether the compound is sufficiently soluble. The TPP will
`aid in addressing these considerations.
`instances where the
`The example contains several
`desired product attribute differs from the true requirement.
`For example, it may be desirable for marketing to launch in
`both a plastic bag and a bottle. However, the TPP captures
`the true requirement, which in this case is just one package
`type.
`Flexibility has also been built in to the TPP. For example,
`this stage in development,
`it may not be clear if a
`at
`solubilizing agent such as a cyclodextrin is required. Since
`the use of a cyclodextrin could require a technology license,
`the potential
`impact of the license on cost of goods sold
`(COGS) is noted under “Freedom to Operate.”
`
`EVOLUTION OF THE TPP OVER THE PRODUCT
`LIFE CYCLE
`
`The first version of the TPP may be a key document used
`in the decision process for taking a drug from research into
`development. TPPs have even been used at the discovery
`stage to help set research goals (11).
`The TPP is considered the initial step in the “quality
`by design” approach to pharmaceutical development
`(12,13). As the formulation and process are developed
`and critical quality attributes are identified, the TPP should
`be revisited to ensure consistency. The TPP should be
`considered a living document. It should be updated
`throughout development as knowledge of
`the product
`increases or as new information becomes available (e.g.,
`knowledge of a competing product, changes in hospital use
`patterns).
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`Drug-related
`Indication
`
`Table I. Critical Components of a TPP from a Formulation Development Standpoint
`
`Attribute
`
`Comments
`
`Lambert
`
`Route of administration
`
`Dose range
`Dose frequency
`Expected duration of treatment
`Infusion or injection rate/duration
`Volume per dose
`Drug concentration(s)
`Pharmacokinetic profile
`
`Drug products which may be mixed or co-infused with this product
`
`Product-related
`pH
`Tonicity
`Excipients compendial, precedented, contain low levels of endotoxin?
`Need to dilute/reconstitute and with what?
`Single or multiuse container?
`Packaging type(s)
`
`Storage conditions
`
`Shelf-life
`Shipping requirements
`
`Legal-related
`Freedom to operate
`Product intellectual property
`
`Manufacturing-related
`Cost of goods sold
`Equipment needed for manufacture
`Product processing time
`
`Note if target population may have restrictions (e.g., glucose
`and diabetics)
`May impact acceptability of excipients (e.g., intraspinal injections),
`deliverable volumes, etc.
`
`The volume, duration of treatment, and dosing frequency may
`impact the use of some excipients (are these outside the
`precedented use levels?)
`
`Is toleration or activity associated with the plasma concentration
`or total exposure? For controlled release formulations, what is
`the desired profile?
`Are there potential incompatibilities?
`
`If more than one, will all be available at launch? Does the
`packaging work with existing equipment? Will there be a kit
`(with a diluent, device, etc.)? Are there disposal considerations
`(may vary from region to region)? Is functional labeling needed
`(e.g., freeze indicators, able to be hung from an IV pole,
`anti-counterfeiting measures)?
`Include in-use stability requirements and constraints (e.g., “do not
`freeze”, need for secondary packaging to protect from light).
`
`Are there unusual constraints (temperature excursions,
`susceptibility to shaking, etc.)?
`
`Does the product or process infringe any patents and applications?
`The ability to patent the product, process, or method of use may
`be a critical attribute for drugs near the end of their patent life
`
`Include any royalties as appropriate
`Will the process match existing equipment?
`May be an issue for some processes (e.g., freeze drying). Also,
`need to consider sterility assurance.
`
`The development scientist should be aware of how new
`knowledge of the product will impact the TPP. For example, if it
`is discovered that the hydrochloride salt of a basic drug has
`limited solubility, it behooves the scientist to assess the solubility
`product constant (Ksp) of the salt and determine if this will
`impact its ability to be diluted in normal saline. If the ability to
`dilute with saline is considered a must in the TPP, the low
`solubility of the chloride salt needs to be communicated to the
`team. Thus, the TPP can be a useful tool for the scientist to use
`when communicating technical issues which might impact the
`use of the product.
`It may also be useful to develop separate TPPs which
`are appropriate for products utilized in specific stages of
`development (having said this, the eventual commercial
`TPP must always be kept in mind). Thus, in the preclinical
`stage, it will be important to have a TPP describing the
`
`product to be used in the various drug safety studies. In
`this case, the dosing and administration may vary signifi-
`cantly from the human product. Other considerations may
`include the desire to introduce potential degradation
`products into the formulation in order to qualify these
`compounds. Likewise, the TPP for the clinical product may
`have more or less stricter requirements than the commer-
`cial TPP. As noted in the compatibility section above,
`administration sets can introduce a large number of
`variables. For this reason, one may wish to limit
`the
`number of administration sets which will be used for Phase
`1 and 2 clinical studies, and the TPP for the clinical drug
`product may be used to effectively achieve this.
`As intravenous formulations move into later stage
`clinical studies, the clinical sites will often want to co-
`administer the drug of
`interest with other medications,
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`Table II. Commercial TPP for a Hypothetical Antifungal Agent About to Enter Phase 1 Studies
`
`Product attribute
`
`Wants
`
`Musts
`
`Drug-related
`Indication
`
`Route of administration
`Dose range
`Dose frequency
`Expected duration of treatment
`Volume per dose
`Drug concentration(s)
`
`Product-related
`pH
`Tonicity
`Excipients compendial, precedented,
`contain low levels of endotoxin?
`Need to dilute and with what?
`
`Single or multiuse container?
`Packaging type(s)
`
`Storage conditions
`Shelf-life
`
`Treatment and prophylaxis of systemic
`candidiasis
`IV
`50–100 mg
`Once per day
`1 week
`100–200 mL
`0.25–1 mg/mL
`
`Treatment of systemic candidiasis
`
`IV
`<300 mg daily
`No more than three times per day
`2 weeks
`<500 mL
`>0.17 mg/mL
`
`pH 5–8
`Isotonic
`Yes
`
`No (ready to use solution)
`
`Single
`Glass bottle and plastic bag with
`ability to be hung
`Room temperature
`3 years or more
`
`Greater than pH 3.5 and less than pH 9.5
`Isotonic ±50%
`If not, will need endorsement by project team
`
`Dilution or reconstitution only if necessary; normal
`saline and D5W
`Single
`Glass bottle or plastic bag with ability to be hung
`
`Room temperature (long term and in-use)
`2 years or more; 24 h following dilution or
`reconstitution
`
`Legal-related
`Freedom to operate
`
`Yes
`
`Product intellectual property
`
`Formulation/process patent if possible
`
`Will need to meet COGS requirements if a proprietary
`solubilizing agent is necessary
`Formulation/process patent not necessary
`
`Manufacturing-related
`Cost of goods sold
`Equipment needed for manufacture
`
`Product processing time
`
`<30% of sales price
`<10% of sales price
`Standard equipment in facilities X and Y If not standard equipment, will need endorsement by
`project team
`To be determined
`
`Compound to fill in <16 h
`
`often through a “Y-site” or by direct addition of two or
`more of the drugs in one bag or bottle. There are many
`examples in the literature where the co-administration may
`lead to physical and/or chemical incompatibilities (14–16).
`Thus, it is critical to understand what drugs might be co-
`administered and capture these in the TPP in a phase-
`appropriate manner.
`Project teams should review the commercial TPP at
`various milestones during development to ensure that all
`parties are still in agreement with the profile. Tebbey and
`Rink (17) have appropriately addressed the issue that
`given the fact that the TPP is dynamic, it is critical for the
`project
`team to assess how the current product being
`developed compares to the original vision of the product.
`They note that without such an evaluation, a company may
`unwisely invest
`in a drug product
`that does not meet
`marketing needs.
`Following the product launch, the TPP can be utilized to
`assess life cycle management and product extension oppor-
`tunities. Often, the product which is launched may meet the
`“musts” but fall short of the “wants,” possibly as part of a
`strategic decision to shorten the development timeline. A
`second-generation product which can address these unmet
`desired attributes might lead to significant product value.
`
`Fig. 1. Theoretical number of days dose released in an initial burst
`for a sustained-release dosage form as a function of the intended
`duration and the percent of the total drug content released in a
`“burst”; 5% (◆), 10% (◼), 20% (r), and 30% (X) burst percent
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`SPECIAL CONSIDERATIONS
`
`As described above, parenteral formulations are unique
`in that they must be administered to the patient using some
`type of administration device. These devices as well as the
`primary packaging used for the product must be thoroughly
`considered when developing the TPP. In addition,
`if the
`product is a sustained-release formulation, the TPP should
`address attributes critical
`for such dosage forms. These
`considerations are discussed below.
`
`Packaging. The primary packaging used for parenteral
`products should be considered integral with the formulation
`and thus deserves significant attention. Furthermore, how the
`product is packaged can provide a competitive advantage
`over existing or soon to be marketed products. It is important
`to address end user preferences, particularly for products
`entering a well-established therapeutic area. It must also be
`acknowledged that not all end users are alike, and thus, there
`may be a need to provide multiple packaging options.
`Consider an infusion product that will be used in the hospital
`setting. Not all hospitals are alike. Purchasing at a community
`hospital may look at the bottom-line cost per unit and may
`prefer simple vials. On the other hand, a busy teaching
`hospital might prefer prefilled bags or Add-Vantage® vials as
`a means to reduce pharmacy and nursing staff labor. The
`marketing strategy for these varying preferences needs to be
`factored into development timelines and the TPP.
`
`Compatibility with Administration Devices. For intrave-
`nous (IV) formulations, it must be recognized that IV access is
`necessary. The product will generally not be given directly into
`the vein with a syringe and needle, but instead will generally
`involve the use of a catheter, placed either peripherally or into a
`larger central vein such as the subclavian vein. Some catheters
`are intended for long-term use and, in this case, may have
`antimicrobial substances such as antibiotics, silver sulfadiazine,
`or chlorhexidine on the lumen surface. If the product will be
`infused rather than given as a bolus, it may be placed in a bag or
`bottle and delivered through an IV set. The IV set may or may
`not utilize an in-line filter.
`The development scientist must consider the potential
`for incompatibilities with all of these administration device
`materials. Common incompatibilities include loss of potency
`due to adsorption to or permeation into polymeric admin-
`istration devices, loss of particulate-based systems to in-line
`filters, and electrostatic interactions between charged colloi-
`dal systems and charged administration set surfaces which
`may lead to aggregation of the product.
`
`Sustained-Release Formulations. Sustained-release for-
`mulations necessitate significant discussion as to what is the
`preferred and required pharmacokinetic profile. Is there a
`goal of remaining above a certain therapeutic level in the
`plasma while remaining below a level which leads to
`undesirable side effects? Is there a maximum ratio of plasma
`concentration at its highest point to the average over the
`intended duration (Cmax/Cavg ratio)? How will duration be
`defined? Given the complexity of developing-sustained
`release formulations, it is imperative that all interested parties
`agree on the desired pharmacokinetic profile.
`
`Lambert
`
`Since many sustained-release systems are to be self-
`administered by the patient, a prefilled syringe or pen-type
`injector may be utilized. This added level of complexity with
`these devices might lead to a TPP just for the device itself. One
`item which does require attention is the gauge of needle.
`Advances in needle design in the last decade or two have led to
`narrow-diameter needles which do an excellent job of eliminat-
`ing or minimizing pain. However, not all sustained-release
`formulations are compatible with needle gauges of 27 G or
`more. For example, the inside diameters of 27- and 31-G needles
`are typically 0.19 and 0.11 μm, respectively. Lumens in this size
`range will often clog with many microparticulate systems and
`present an impractical resistance for many viscous systems. This
`must be addressed early in development.
`Finally, the preferred dosing frequency also needs to
`be considered. Superficially,
`it might appear that a once
`every 2-week formulation would be preferred over a once
`a week formulation. However, twice as much drug must be
`loaded in the former, which can lead to a variety of issues.
`First, the release characteristics of most sustained-release
`dosage forms are impacted by drug loading. In addition, an
`initial “burst” of release is often observed in the first 24 h.
`Such a burst of drug may result in undesirable side effects,
`particularly for drugs with a small therapeutic index. The
`longer the duration (requiring a higher total dose present
`in the dosage form), the more likely it is for this burst to
`become significant. This concept is exemplified in Fig. 1. If
`the burst releases 20–30% of the total dose, the patient will
`receive the equivalent of approximately 3–8 days of drug in
`the first 24 h for a formulation intended to be given every
`2–4 weeks. For many drugs, this would not be an accept-
`able situation. On the other hand, a dosage form designed
`to be administered once weekly can have a 20% burst and
`yet only release a little over 1 day’s worth of dose.
`Furthermore, patients have trouble remembering to take
`a drug every other Saturday versus just every Saturday.
`Thus, a once a week formulation may be preferred over
`one with a longer duration. This is an issue that
`the
`marketing group should consult on.
`
`CONCLUDING REMARKS
`
`The use of a TPP during development of the product
`provides a formal mechanism to ensure that the various
`disciplines needed to bring a drug to the market are
`communicating and working toward a common goal. When
`a project
`is initiated,
`the development scientist should
`schedule informal meetings with colleagues in key depart-
`ments to begin development of the TPP. Often, project
`team members come away with a greater understanding of
`the challenges that their colleagues face during product
`development by going through the process of generating
`the TPP. Thus, the TPP should be viewed as a helpful tool
`for development team members. It is also critical to ensure
`that the TPP undergoes periodic review to verify that no
`changes in project direction have occurred which might
`impact the TPP. In the end, effective use of the TPP will
`benefit the project team, the company, and, eventually, the
`patient.
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