Drug product formulation and process

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Chapter: Pharmaceutical Drugs and Dosage: Protein and peptide drug delivery

Most proteins and peptides are not absorbed to any significant extent by the oral route.


Drug product formulation and process

Most proteins and peptides are not absorbed to any significant extent by the oral route. Therefore, most commercially available protein pharmaceu-ticals are administered by parenteral routes. Parenteral protein formula-tions are typically administered by IV, IM, or SC injection. In addition, some protein drugs, for example, insulin, can also be delivered by inhala-tion for absorption through the alveolar mucosal membrane.

Parenterally administered proteins are rapidly cleared from circulation by the reticuloendothelial systems (RES). Proteins are metabolized by pep-tidases, leading to rapid loss of their biological activity. Pharmacokinetics of proteins after parenteral administration can be improved by covalent conjugation with a hydrophilic polymer such as PEG (PEGylation), as dis-cussed earlier. Protein bioavailability from the SC route is generally low (~30%–70%). In addition, immunogenicity potential of proteins is higher when administered by the SC route. At the same time, SC administration is preferred because it allows for patient self-administration—as compared to IV administration, which must be carried out by a health care provider.


Route of administration

Selection of the appropriate route of administration for a protein drug depends on several factors, including the disease state, the desired onset and duration of drug absorption/action, drug dose, frequency of administration, patient compliance, and the physicochemical properties of the drug. For example:

·           IV route is preferred for rapid onset of administration, whereas the SC route can be used for sustained drug delivery devices. Thus, sustained drug delivery devices such as poly(lactide-co-glycolide) (PLGA)-entrapped drugs are often designed for SC administration.

·           Compared to the SC route, IM injection is exposed to much greater blood supply and, thus, faster absorption.

·           Higher injection volumes may be administered by the IM (2–5 mL) than the SC (up to 1 mL) route.

·           In cases where patient self-administration of a drug is required, IM or SC injections are needed over IV.

In terms of formulation requirements, the needed volume of injection is deter-mined by the drug dose and solubility. If solubility is inadequate, solubilization approaches may be needed. Preparation of concentrated protein solutions can, however, lead to high viscosity—which could make deaeration upon agitation and injectability through a syringe difficult. For example, SC injections typically use lower diameter (25–30G) needles compared to IM injections (20–22G).


Type of formulation

Selection of the type of protein formulation depends on several factors, such as follows:

·           Disease condition: For example, requirement of patient self-administration (SC route preferred) versus administration by a health care professional in a hospital setting (IV route preferred) might depend on whether typically the patients are hospitalized or outpatients. The SC formulation typically has limitations on the number of injections per dose and per day as well as on the volume per injection. IV injection or infusion in a hospital setting generally does not have such a limitation.

·           Drug half-life: Rapidly cleared drugs must be administered as an IV infusion to obtain sustained plasma concentrations.

·           Patient population: Age of the patient may determine the kind of deliv-ery devices that may be the most suitable. For example, slow infusion pump or autoinjector may be preferred for a geriatric population for drug self-administration over vial of lyophilized drug and syringe due to the dexterity required to reconstitute the lyophilized powder and fill the syringe from a vial before injection.

·           Route of delivery, such as IM, IV, SC, intraperitoneal, topical, inha-lation, or nasal. IV formulations can further be IV bolus or IV infu-sion. Inhalation formulations can be dry powder based or solution based.

·           Drug dose, solubility, stability, and other physicochemical properties.

Proteins and peptides for parenteral administration are typically formu-lated as ready-to-use aqueous solutions or as lyophilized solid mass that is reconstituted into a protein solution by dilution with water, isotonic dextrose solution, or isotonic sodium chloride solution immediately before administration. Proteins and peptides for inhalation and nasal routes of administration are typically formulated as dry powders. The details of dry powder formulations will not be discussed in this chapter.


Formulation components

The development of a suitable pharmaceutical formulation of a protein usually involves the screening of a number of physiologically acceptable buffers, salts, chelators, antioxidants, surfactants, cosolvents, and preser-vatives (Table 25.4). Formulation components are selected to address one or more requirements for protein formulations, such as follows:

Table 25.4 Typical excipients in protein formulations


Abbreviations: EDTA, ethylenediamine tetraacetic acid; DTPA, diethylene triamine pentaacetic acid; EGTA, ethylene glycol tetraacetic acid.

·           Increasing protein solubility by the use of surfactants and/or cosol-vents and pH adjustment.

·           Using pH of optimum stability by the use of buffering agents. Selection of an appropriate buffer type and strength is carried out to minimize specific/general acid/base degradation of the protein.

·           Physical stability improvement by the addition of polyhydric alcohols, carbohydrates, and amino acids. Addition of these components to aqueous solutions of proteins leads to their hydrogen bonding on the protein surface, thus stabilizing the native protein conformation.

·           Stabilization of protein conformation by the addition of cosolvents such as glycerol or PEG, which may decrease the protein surface area in contact with the solvent.

·           Electrostatic interactions in proteins may be modulated by the altera-tion of the solvent polarity and dielectric constant to change protein electrostatic interactions in solution, which may reduce the associa-tion tendency of a protein.

·           Antimicrobial agents may be added to large volume parenteral (LVP) solutions or multidose vials where repeated puncturing for dose with-drawal is expected to preserve aqueous solutions of proteins against bacterial and fungal growth.

·           Chelating agents and antioxidants may be added to prevent metal and/or oxidation-induced chemical instability.

·           Osmolarity control is required for parenteral formulations. This is often achieved by the use of salts, buffers, and sugars.


Manufacturing processes

1. Protein solution

A typical manufacturing process of protein solution involves

1.        Freeze ad thaw of the bulk drug substance (therapeutic protein).

2.        Formulation (dilution and addition of excipients).

3.        Filtration for removing any particulate matter and/or sterilization.

4.        Filling of drug product in vials or syringes.

5.        Inspection of filled vials or syringes for the presence of any particulate matter.

6.        Labeling and packaging.

7.        Storage and shipment of drug product.

8.        Use of a delivery device for drug administration to the patient.

Many of these processes may affect formulation stability. For example:

·       Exposure to light and shear during inspection and transportation can lead to the formation of microbubbles in the formulation, which can increase the propensity for aggregation and oxidation.

·           Protein may interact with the silicone oil typically used in syringes for smooth barrel movement, leading to instability of syringe-filled protein formulations.

·     Protein loss may occur due to adsorption to manufacturing equipment and filter membranes. In addition, leaching of metal ions from manufacturing vessels into the protein formulation can lead to protein instability. Modern day manufacturing practices utilize single-use plas-tic liners in process tanks to avoid the risk of metal leaching and also to eliminate cleaning verification needs and cross-contamination risk.

2. Lyophilization

Many proteins are very unstable in solution and may not yield accept-able shelf life, even under refrigerated (2°C–8°C) storage conditions. In such cases, freeze-drying or lyophilization is often employed to minimize the kinetics of degradation processes that occur in solutions. Many vari-ables impact the stability of lyophilized drug product. For example, high concentration of reacting species in the protein microenvironment can be detrimental. Further, careful optimization of residual water and protein-binding sugar concentration is required to ensure cake integrity and rapid reconstitution.

The role of residual moisture in the lyophilized formulations on proteins stability can be complex. The amount of moisture adsorbed on each protein as a monolayer can be determined by the Brunauer–Emmett–Teller (BET) method. Lyophilized protein product needs closely bound water layer on the protein to shield its highly polar groups, which would otherwise be exposed leading to aggregation and cause opalescence upon reconstitu-tion. High moisture content, on the other hand, could increase plasticity in the system leading to high reactivity and compromise the physicochemical stability. For example, insulin, tetanus toxoid, somatotrophin, and human albumin aggregate in the presence of moisture, which can lead to reduced activity, stability, and diffusion.

Formulation components that stabilize the protein during and after lyoph-ilization depend on the particular protein. For example, polysorbate 80, hydroxypropyl β-cyclodextrin, and human serum albumin-stabilized human IL-2. Mannitol in combination with dextran, sucrose, and trehalose reduced aggregation in lyophilized TNF-α. Sugars stabilize most proteins during lyophilization by protecting against dehydration. Polyvinylpyrrolidone (PVP) and BSA protect some tetrameric enzymes, such as asparaginase, lac-tate dehydrogenase, and phosphofructokinase, during lyophilization and rehydration by preventing protein unfolding.

Lyophilization is a high cost, long (several days), batch unit operav-tion that requires careful formulation and process cycle development.

Lyophilization process involves freezing of a protein solution to a very low temperature (such as −40°C), followed by primary drying (removal of water from the frozen state) under vacuum at a higher temperature (such as −30°C) and then secondary drying at an even higher temperature (such as −20°C). Sometimes, an annealing step is inserted before primary drying and after initial freezing of solution. Annealing involves short-term increase of product temperature to allow reorientation of polymeric proteins and other components with excipients and provides better cake performance. Completion of each drying stage of lyophilization is ascer-tained through changes in the humidity in the lyophilization chamber (which indicates the rate of evaporation of water), change in the con-densate weight or volume at the vacuum pump (which indicates amount of water removed), and/or change in product temperature through tem-perature probes inserted in vials (which indicates changes in the heat of sublimation).

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