This article is part of PharmTech's supplement "API Synthesis and Formulation 2009."
Drug development is an arduous, financially risky process that has been estimated to cost pharmaceutical firms an average
of $802 million for each therapeutic gaining marketing approval (1). To maximize return on the initial investment, companies
look to strengthen their market position and extend product life cycles through reformulations, new routes of administration,
and use of the latest technology.
(BRAND X PRODUCTS/GETTY IMAGES)
For injectable therapeutics, one way to accomplish this goal is to move a product's presentation from a vial to a prefilled
syringe. A prefilled syringe helps to increase dosing accuracy, convenience, and safety; enhance patient quality of life;
and reduce patient time in the clinic. While the introduction of prefilled syringe presentations varies among drug classes
and therapeutic categories, the overall market for prefilled syringes is expected to grow by 12.8% per year (see Table I)
Table I: Partial list of injectable therapeutics and vaccines available in prefilled syringes in the US.
This article presents a project manager's perspective on the rationale and timeline for moving an injectable therapeutic to
a prefilled-syringe format. The author also discusses a regulatory strategy that can facilitate a smooth transition to the
new dosage form.
Rationale and timeline
The natural first question is, "Why change a drug's presentation to a prefilled syringe?" For many companies, the decision
to change to a prefilled-sryinge format is strategic because it meets the demands of physicians and patients looking for easier
modes of administration and it helps further differentiate the product from competing drugs in the same therapeutic category.
Data from Frost and Sullivan, a global market-research firm, demonstrate the importance of product presentation to physicians
and patients. Three of the top five factors influencing a physician's choice of a drug-delivery type—ease of use by patients
(16%), convenience (11%), and comfort (9%)—are affected by the presentation of the product. Physicians also commonly view
patient satisfaction (14%) and a minimum of side effects (9%) as important factors in their choice of drug-delivery methods
When selecting a drug-delivery device for their patients, 46% of physicians take into account whether it easily enables self-administration
(3). Patients who have a choice between drug-delivery devices also judge the ease of self-administration (37%) and whether
the product has been recommended by the physician (24%) (4).
Prefilled syringes also present economic advantages for pharmaceutical companies marketing injectable therapeutics. Because
the devices meet customer demands for increased safety and convenience, companies often are rewarded with premium pricing
for prefilled syringes compared with vials (5). Moreover, prefilled syringes help increase the saleable yield of active pharmaceutical
ingredient (API). Filling API in prefilled syringes enables the required dose to be delivered precisely. Consequently, only
trace amounts of API remain in the needle of the prefilled syringe after injection. In contrast, single- or multi-use vials
require overfilling the API to ensure that an accurate dose is pulled into the syringe each time.
The question of when to move an injectable therapeutic into a new presentation is as significant as the rationale for why.
Speed to market is a critical factor for the development of new pharmaceuticals, as well as for producing reformulations or
improved delivery devices. Injectable drugs typically are introduced in a vial, because vials enable a faster pathway to regulatory
approval, particularly when individual patient dosing varies according to factors such as age or weight.
Once the product is on the market, a reasonable timeline for developing improved packaging depends on whether the initial
product presentation is liquid or lyophilized (see Table II) (6). Moving from a liquid vial to a prefilled syringe can be
accomplished within 6 to 18 months in most cases.
Table II: Differentiation of an injectable therapeutic throughout its life cycle.
The timeline is a bit longer for molecules introduced to the market as lyophilized powder. As a consequence, movement to a
prefilled syringe from a dry vial typically is considered a mid-term life-cycle strategy. The process of developing a stable
liquid formulation and gaining regulatory clearance for the formulation and enhanced packaging may require 18–36 months, and
occasionally longer depending on clinical-trial results.
Teva Pharmaceuticals (Petach Tikva, Israel) employed a mid-term strategy in 2002, when it changed the lyophilized vial presentation
of Copaxone (glatiramer acetate) into a stable liquid offered in a prefilled syringe. Before reformulation, market share of
Copaxone was declining. Yet, the new presentation achieved rapid acceptance in the market; 64% of patients switched to the
prefilled syringe version within the first three months of availability. The remainder switched within six months of the new
product's launch (6).
The Copaxone prefilled syringe had measurable advantages for patients on chronic therapy for multiple sclerosis, particularly
the amount of time required for self-administration. The average time a patient spent preparing for a Copaxone injection was
reduced from the 235 s it took to reconstitute the product and draw it into a syringe to 38 s with a prefilled syringe. Consequently,
the reformulated version saved a typical patient more than 20 hours over the course of a year. For Teva, increased patient
convenience was rewarded with premium pricing, compared with the original formulation. In 2002, the premium started at 5%
and rose to 48.6% by 2005 (6).
Similarly, in 2004, Amgen (Thousand Oaks, CA) changed the presentation of Enbrel (entanercept), a treatment for rheumatoid
arthritis, from a dry-vial prefilled diluent-syringe kit to a single-use prefilled syringe. In 2006, the company launched
Enbrel in an autoinjector, which further differentiated the product and added value. Although unit sales of Enbrel have remained
stable, sales revenue has increased because of the price premium associated with the prefilled syringe and autoinjector formats
(see Figures 1, 2) (6).
Figure 1: Unit sales of Enbrel following movement from a dry-vial prefilled diluent-syringe kit to a prefilled syringe and
autoinjector (5). (FIGURE COURTESY OF THE AUTHOR)
For most companies, the process of moving an injectable therapeutic to a prefilled syringe can be fairly complex because of
sterility and stability issues associated with small and large molecules in addition to challenges related to the size and
structure of biologic molecules. To facilitate a smooth path to regulatory approval, companies must establish a strategy that
carefully evaluates proposed changes in manufacturing, packaging, and shipping processes and that ensures the company can
validate the effect of these changes on the therapeutic molecule.
Figure 2: Growth in worldwide and projected sales for Enbrel following introduction of a prefilled syringe and autoinjector
format in 2004 and 2007, respectively (5). ROW is rest of world. (FIGURE COURTESY OF THE AUTHOR)
The US Food and Drug Administration requires that any change in the manufacture of a drug product, whether major or minor,
be put into place only after the license holder assesses the effect of the change on the identity, strength, quality, purity,
and potency of the molecule, because these factors will influence the safety and effectiveness of the pharmaceutical (7).
In addition, FDA has stringent requirements for changes that may affect parenteral drug product. These requirements pertain
to moving a therapeutic to a prefilled syringe from another container–closure system; silicone treatments in the closure systems
such as in elastomeric closures or the syringe barrels; and changes in the size or shape of a container that holds a sterile
drug product (8). Any such change is considered to be "major" by FDA and must be documented in a prior approval supplement.
Stability and clinical testing for parenterals depend on a multitude of factors, including the formulation, indication, mode
of administration, size and functionality of packaging, and the introduction of new materials. Any potential need for clinical
or stability data must be noted and planned for at the outset, and included in the stability protocol.