Pharmaceutical Validation: The Challenge of Outsourcing Manufacturing

By Christopher Abbott and Christian Phillips

What to look for in a CMO for process scale-up

Selecting a contract manufacturing organization (CMO) to outsource parenteral product manufacturing to should rely on much more than the CMO's ability to fill a product aseptically. Consideration should be given to whether or not the CMO has had experience in the formulation of similar products.

Drug companies often experience unexpected challenges with formulation scale-up. As Richard Pariza, PhD, chief scientific officer of Cedarbug Pharmaceuticals (Grafton, Wis.), said in an interview, "Only the simplest of reactions behave the same way on both small and large scale. There are always some engineering problems. However, an experienced medicinal chemist will have seen enough processes go to larger scale to design the chemistry, from the start, to avoid many issues. There is no substitute for the wisdom that comes from experience."¹ It is imperative that a drug company select a CMO with experience and expertise in its specific type of formulation.

This article is written from a process engineer's perspective. By looking at some of the challenges and solutions involved in process scale-up and tech transfer, it provides some criteria to consider when selecting a CMO.

LIPOSOMES

Challenge: Targeted drug delivery via lipid encapsulation is a cutting edge technology that employs the use of a phospholipid to suspend hydrophobic and hydrophilic components in an aqueous phase. Typically, the active pharmaceutical ingredient (API) is a soluble small molecule encapsulated within the lipid bilayer. This novel drug delivery mechanism is gaining momentum and popularity, as more drug companies come up with unique strategies for phospholipid formulation and targeted delivery.

Successful liposomal formulation is often marked by a specified particle size or distribution, percent encapsulated drug, and/or the adequate removal of the organic phase. Upon scale-up, the latter can be particularly challenging from an operational perspective due in part to equipment size and footprint.

Other critical parameters that should be considered include the infusion rate of the organic phase containing the lipid, the aqueous phase, the pH, and the temperature. There are a variety of different techniques that will achieve success. For example, a process may utilize an extrusion method versus homogenization via high shear mixing or high-pressure nozzle homogenization versus direct-stream infusion. These techniques dictate particle size and percent drug encapsulation.

Solution: Process risk can be mitigated by investing in development and by performing engineering and demonstration runs. Liposomal formulation often involves so many critical process parameters with narrow tolerances to control, a situation requiring meticulous and gradual scale-up efforts, that it is wise to seek out industry expertise from experienced sources to devise an informed plan for development and scale-up. Because liposomal drug delivery technology is complex and relatively new, it may take some time to find someone experienced in the nuances of formulation.

By the time a lipid formulation technology is transferred to a CMO, it has typically undergone extensive development at the bench prior to scaling up to pilot or clinical scale. Because these types of formulation do not scale in a linear manner, sponsors often need to invest in feasibility studies "at scale" to render worthwhile data.

PROTEINS, OTHER LARGE MOLECULES

Challenge: Therapeutic proteins are often used in enzyme replacement therapies for the correction of a clinical deficiency in the body and as antibodies to target harmful cells and substrate such as cancer cells and cytokines. Peptides are another macromolecule manufactured for a number of indications, including adjunct therapies. Large molecules, as these are called, can present unique challenges in their parenteral formulation and often include an array of excipients, including buffer, surfactant, and various forms of glycol, aimed at supporting the stable configuration of the molecule. Large molecules are sensitive to degradation and may have limited stability; strict instructions concerning proper storage conditions need to be followed.

Unprocessed bulk API often arrives frozen at the CMO and might require freezing as a final product to maintain stability. This necessity can present further challenges. Both freezing and thawing must be done carefully to avoid gradients from forming in the bulk; these may lead to protein rearrangement and subsequent inactivation. Disposable biobags are often used to store bulk. Biobag polymer layers become susceptible to tearing upon freezingor thawing; precautions must be taken to prevent this problem.

Often, there is a "time of exposure limitation" with respect to how long bulk product can be left at ambient room temperature. The window of exposure can be as little as 12 hours, a limit that can present complex logistical challenges for executing formulation and fill. Care must also be taken to limit solution surface-to-volume ratios, because protein aggregation and rearrangement may occur at the liquid-gas interface.

Finally, large molecules, in the form of recombinant proteins, take on a different, more challenging registration process compared to other drugs, because they are governed by unique regulations in both the United States and Europe. Choosing a CMO that has the infrastructure and experience to support the compliant manufacture of biologics is critical.

Solution: Proteins, while complex in their formulation, work well with disposable technology due to their overall compatibility with disposable product contact layers, including low-density polyethylene, ethylene vinyl acetate, silicone, polypropylene, and others. Disposable technology is more amenable to the tech transfer process when working with a CMO that operates a multi-product facility. Additionally, disposable technology allows for greater flexibility and even scalability because the disposable industry has widely recognized the need to provide scaleable formulation and compounding solutions.

By the time a lipid formulation technology is transferred to a CMO, it has typically undergone extensive development at the bench prior to scaling up to pilot or clinical scale. Because these types of formulation do not scale in a linear manner, sponsors will often need to invest in feasibility studies "at scale" to render worthwhile data.

Mixing systems like the disposable LevTech line offered by Sartorius-Stedim are good examples of this type of disposable technology. These systems allow for effective mixing, bulk sampling, and aseptic fluid transfer capability, while offering tight control over mixing profile to accommodate proteins sensitive to shear. An additional advantage is the ability to minimize the frothing or foaming at the liquid-gas interface that can lead to protein rearrangement and subsequent deactivation of API.

While the compatibility profiles of large molecule formulations are often excellent for the use of disposables, a careful assessment must still be rendered. For example, there are simple, small-scale filterability studies performed with 45 mm filter membrane discs of various material types, including polyvinylidene fluoride, polyethersulfone, nylon, and cellulose acetate. This approach can help you to identify a filter membrane type that supports adequate flux and exhibits excellent chemical compatibility.

Before making the decision to scale up to a disposable capsule that utilizes this membrane type, take into consideration the construction materials in the capsule housing. Taking this precaution can help you to avoid a situation in which the filtration, at scale, is working fine until the polycarbonate housing begins to crack due to incompatibility with the excipients being used.

Special storage units are available for keeping and transporting frozen bulk in biobags. While these range in price and complexity, some of the higher end units offer not only protection for the frozen bulk but also uniform freezing and thawing to minimize gradient formation. For frozen bulk that arrives in bottles or carboys, you can establish procedures that provide a gentle swirl to the bulk periodically throughout the thawing event.

Limiting exposure of bulk product to ambient requires careful consideration on the planning and scheduling end of production. But in order to be in a position to make informed decisions on orchestrating formulation/fill activities, engineers and operators must first gain experience with the formulation/fill process using bulk product-often provided as a placebo-via demonstration and engineering runs. CMOs have different facilities, with unique personnel and material flows, that need to be carefully evaluated by the engineer and project manager in order to meet expectations for exposure limits.

Contract a CMO with proven experience manufacturing biologics in order to avoid not just technical problems but also the unique current good manufacturing and regulatory pitfalls that are associated with biologic product registration. A competent CMO will provide direction to the client with regard to quality control sampling plans-for example, the need for bulk sterility testing post sterile filtration but pre-fill-that support biologics manufacturing. This guidance will demonstrate awareness of the identification, qualification, and receipt of raw materials that go into that formulation.

Because the lower concentrations required in large molecule formulations result in volume dosages that tend to be larger than that of small molecule products, give careful consideration to endotoxin specifications for raw materials entering the formulation. This can prove challenging, because some of the common excipients included in large molecule formulations include carbohydrate solutions such as sucrose that can be difficult to source with a highly limited endotoxin specification. Again, a CMO experienced in these areas can best address such challenges, either by sourcing the right raw material or by utilizing technology and experience-including ionic filtration, ultrafiltration, and other, more complex, techniques-for polishing endotoxin from the raw material.

SMALL MOLECULES

Challenge: While large molecules are often used to target the surface of cells, small molecules typically use diffusion to enter the cell for therapeutic effect. While the small molecule bulk product formulation itself-excipient and API recipe-is often less complex than that of large molecules, the compounding and formulation may still involve a rather complex process, depending upon the characteristics of the small molecule API. Molecules that are oxygen sensitive, photosensitive, or hygroscopic need special handling processes and procedures that protect against product degradation. Furthermore, small molecules, which require formulations comprised of organic solvents, are not compatible with disposable technology.

As a result, stainless steel or glass vessels and potentially expensive Teflon tubing may be required. Fixed and/or reusable vessels typically add complexity and scope to a project. Procedures for equipment cleaning, sterilization, and changeover must be developed and adhered to, as do specific validations for equipment cleaning and sterilization. Training and instructions for vessel assembly may also add complexity to the batch record.

Solution: Experienced process engineers can custom design vessels to protect product integrity, optimize yield, and simplify handling and processing. Glove boxes can be used under dry inert gas sparge (i.e., nitrogen or argon) to weigh out hygroscopic powders. Head-space and the liquid bulk can be sparged with inert gas to displace dissolved oxygen. Processing areas can be lit with special lighting to prevent photodegradation.

Glass vessels can be used for small-to medium-scale processes when disposable technology is not compatible. For larger scale processes involving more than 30 liters, however, stainless steel reusable vessels are often necessary. It's vital to choose a CMO with experience in stainless steel skid assembly, steam in place (SIP), clean in place (CIP), and general associated process flows. In addition, the facility itself needs a footprint that is compatible for large vessel mobility, transport, and cleaning. The use of stainless reusable vessels necessitates a great deal of validation; the CMO's ability to provide comprehensive validation protocols that fully support the process is critical.

MICRONIZED EMULSIONS

Challenge: A system of two immiscible liquids in which droplets of one are dispersed in the other is considered an emulsion. Typical emulsion processes require the use of either high-shear mixers with a rotor stator head or a high-pressure nozzle or valve homogenizer that uses extremely high pressure to force solutions through a small orifice to form the emulsion. The formulation of an emulsion is complex; it consists of formulating two phases, one aqueous and the other organic.

The use of stainless reusable vessels necessitates a great deal of validation; the CMO's ability to provide comprehensive validation protocols that fully support the process is critical.

Often, large homogenizers and tanks are used to create the emulsion after the two immiscible solutions are introduced within a single vessel. Large equipment may come with significant floor space and facility infrastructure requirements. Large valve or nozzle type microfluidizer processors, such as those manufactured by Microfluidics Corp. (Newtown, Mass.), require the plumbing and installation of cooling loops and have significant electrical requirements. As tanks and equipment sizes increase, CIP and SIP systems are the only practical means to sterilize and clean them. Batch sizes can be limited by the receiving vessel's capacity.

Solution: A large amount of effort is required, depending on process scale, to coordinate both the installation of the microfluidizer processor and the operation of the equipment. Because the scale-up of microfluidization processes leads to large footprints, a CMO should be assessed for its ability to meet utility requirements. The necessity of build-outs and expansion will mean that the facility and organization should be evaluated for flexibility and expertise in this area. The CMO will need strong facilities engineering and process engineering groups for managing both the facility and process design scope of the project. Large-scale micronization processes may demand operation in a grade A environment. A cleanroom may need to be fully dedicated to the process, or the CMO may opt to design a space around the equipment.

Often, in development phases, homogenization processes are defined by a number of serial passes through the system to produce the desired particle size. On a larger scale, discrete passes are not easily obtained, because transferring the large volume bulk becomes cumbersome, requires multiple large holding vessels, and introduces areas of concern around potentially compromising the aseptic integrity of the system. Continuous pass homogenization is therefore opted for in large scale; because continuous pass is not as efficient as discrete, however, significantly longer processing times may result.

HANDS-ON EXPERIENCE

When it comes to formulation/fill/finish operations that will successfully carry clients from early clinical through commercial registration, it is imperative to select a CMO with a wealth of hands-on experience in the particular formulation being processed. Because of the complex and dynamic nature of these formulations and the way they are processed, an abundance of experience in just one particular formulation or process will likely not be adequate for taking on new formulations, even those that seem similar.

This article has attempted to elucidate a number of tech transfer challenges, particularly with respect to scale-up, in the areas of lipid, small and large molecule, and micronized formulations. The CMO that is a multi-product facility will need effective procedures and a design for handling other formulations to protect personnel and control cross-contamination.

Viscous product processing requires a CMO with specialized formulation and filling equipment and experience with both Newtonian and non-Newtonian fluids. Proper equipment and experience assist in overcoming technical challenges such as sterile filtration, in maximizing product recovery, and in maintaining adequate filling speed. There are dozens of nuances and unique challenges that accompany almost any new project, especially when it comes to scale-up. A CMO that can anticipate these types of challenges can make the difference between timely success or missed timelines and failure.

A CMO should be assessed on its facility/infrastructure, its experience within a particular category of formulation, and an academic knowledge of the formulation chemistry and critical attributes. It is also critical to look at experience from an operational and quality standpoint. A CMO with both can overcome technical hurdles and ensure that all decisions are made in the context of current good manufacturing processes and overall compliance. This will support client objectives for successful manufacturing and product registration of their therapeutic product. ¦

Abbott is supervisor and Phillips is director of process engineering at Hyaluron Contract Manufacturing. Reach them at (781) 270-7900, ext. 165, or cabbott@hyaluron.com or at (781) 270-7900, ext. 181, or cphillips@hyaluron.com.

REFERENCES

1. Roth G. Engineering and quality: process development. A CMO talks about scale-up issues [interview]. Contract Pharma. March 2007. Available at: http://www.contractpharma.com/articles/2007/03/engineering-quality. Accessed September 26, 2008.

Pharmaceutical Validation

Wednesday, January 27, 2010

The Challenge of Outsourcing Manufacturing