The Hidden Inactive Ingredient: Biological Products in Recombinant Pharmaceuticals

INTRODUCTION

Pharmaceutical products have long been prepared with various inactive ingredients to enhance pharmacokinetics, stability, and pharmaceutical elegance. In an age where the use of recombinant technologies is rapidly increasing and consumers are more aware of inactive ingredients in food and cosmetic products, there remains a paucity of centralized information to help medical professionals counsel their patients about recombinant technologies. Although patient-specific factors such as race, age, and weight are considered when prescribing and dispensing medications, oftentimes religion and dietary habits are left out of the conversation. The increasing array of biopharmaceuticals on the market and in production creates an opportunity for healthcare providers and patients to enhance their knowledge of these issues. The purpose of this review is to create a centralized resource for healthcare providers that describes some common dietary restrictions of select faith and ethnic groups and to identify FDA-approved medications of biologic origin.

RECOMBINANT PROCESS

A biopharmaceutical is “any active agent biological in nature and manufactured using living organisms.”¹ Since the 1980s, scientists have been harnessing the power of single-cell organisms to create unique proteins that can be used to treat a wide range of disease states ranging from diabetes to hematologic disorders. The recombinant process enhances scientists’ ability to modify and manipulate protein structure and function to produce a targeted agent for therapeutic purposes. Now, almost 40 years later, recombinant technologies are on the rise using a wider range of bacterial, fungal, and animal cell lines.^1,2

Original biopharmaceuticals were replacement proteins such as insulin, hormones, and antibodies. Advancements in the field have widened the scope of indications to hematologic and oncologic disorders. Recombinant products for use in oncology have been expanding over the past two decades, with a focus on monoclonal antibody production. The area of targeted drug delivery within oncology is a rapidly growing field, with promise for new agents or enhancements to existing agents that can improve antitumor cytotoxicity while reducing adverse effects. As this technology continues to advance, scientists are experimenting with alternative ways to produce biopharmaceuticals by way of transgenic organisms and animal cloning.³

The process of creating a recombinant product involves transferring the specific genes responsible for creating the protein into a bacteria, yeast, or animal cell. Historically, Escherichia coli was the prominent cell line that was used, and even today is the cell line used to manufacturer medications such as insulin and filgrastim. Over time, scientists explored the use of yeast cells, namely Saccharomyces cerevisiae, and other mammalian cells such as Chinese hamster ovary (CHO) cells.

The use of mammalian cell lines has increased in recent years because of the cell systems’ ability to produce glycosylated proteins.² Glycosylation is one of the most complex post-translational modifications that occurs to a protein but it offers certain pharmaceutical advantages, such as increased plasma half-life.⁴ Many antibodies that were formed as a result of recombinant technology combine fragments from two different species. Often, these are combined with human fragments to form chimeric antibodies. Most commonly, murine antibody fragments have been fused with human fragments to produce an antibody that is more human-like. This differs from a humanized antibody, which may contain elements of nonhuman origin but maintains essentially the same amino acid sequence that can be found in the human antibody.⁵ Irrespective of drug development, a pharmaceutical manufacturer’s choice of cell line is balanced by the complexity of protein folding and post-translational modifications with a cell line that is easy to maintain and simple to culture.

The nomenclature of recombinant products is regulated by the World Health Organization (WHO)’s International Nonproprietary Names (INN). Names awarded an INN are selected by WHO on the advice of experts from the organization’s Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations.

The product names can assist health practitioners in understanding how the products are manufactured based on the pre-stems and stems of the names.⁶ It is beyond the scope of our review to discuss all the nomenclature, but monoclonal antibody medications are a good example of this practice. Previously, two infixes denoted the target of the drug as well as the source. In 2015, the INN together with the United States Adopted Name (USAN) Council agreed that to simplify drug naming, the source infix would be dropped.⁵ The name now consists of a prefix, a target infix, and the suffix “-mab” (Table 1).

Availability of Recombinant Drug Information

Often the most convenient source of information on how a drug is manufactured is the package insert. However, information about the recombinant process and the cell line from which the pharmaceutical product is made frequently isn’t relayed to the patient during counseling. To compile a compendium of medications from animal origin, we undertook an extensive review of all Food and Drug Administration (FDA)-approved medications using a data set of 15,797 entries based on the National Drug Code (NDC) from the FDA website, on December 2, 2016.⁷ Duplicate entries based on nonproprietary names were deleted. We also initially excluded entries whose marketing category included cosmetic, over-the-counter (OTC) drug monograph, unapproved homeopathic, or unapproved medical gas, and entries whose product type was a standardized or non-standardized allergenic extract. The remaining 666 records we reviewed manually, and we also reviewed package inserts for possible inclusion. Table 2 is organized by the type of cell line used in the manufacturing process, listed alphabetically by generic name.

Inactive Ingredients

Additional ingredients involved in the preparation of pharmaceutical products also may be derived from animal products. Gelatin is a substance of bovine or porcine origin that is commonly used for commercially made capsules.⁸ A WHO memo from 2001 addresses a ruling that allows Muslims to accept gelatin because it has been transformed from its original source,^8,9 although not all Muslims accept the ruling. Specialized compounding centers may offer vegetable-based capsules for those who refuse gelatin-based products.

Lactose is a common sugar that is found as a filler in many capsules and tablets and is derived from cows’ milk. In addition, lactulose can be synthetically produced in large quantities in the laboratory. Lanolin is a fat extracted from sheep’s wool that is used as an ingredient and base in many ointments and topical medications. It is important to consider all ingredients within a pharmaceutical preparation, including all the inactive ingredients.⁸

Faith and Ethnic Restrictions

It is well known within the medical community that Jehovah’s Witnesses patients abstain from blood products. This issue often comes to a head when a patient is critically ill and in need of a transfusion. Many hospitals have developed policies and standard procedures for approaching these situations to respect the autonomy of the patient while continuing to offer appropriate and excellent medical care. Although this restriction is widely known, providers might not be so familiar with other, less common restrictions.

Even within a faith or ethnic group there can be differences about dietary restrictions, but having a general sense of what these restrictions are will enable providers to provide a patient-centered care approach. A lack of communication might lead to distrust and decreased patient satisfaction if a patient subsequently learned how a particular medication is processed and handled.

The decision to adhere to strict dietary restrictions is an individual choice. Through conversations with the patient, a provider can identify the personal dietary beliefs that might affect their therapy selection. Certain religious organizations have thus made formal statements to relieve their followers of strict dietary considerations as they relate to medicine and health. For example, Muslims are permitted to ingest gelatin capsules because the product is believed to be transformed in property and in character. Shariah law also allows for the use of insulin products in case of necessity.⁹ Table 3 lists common religious and faith-based groups that follow specific dietary restrictions.^8,12–15 It is important to note that within these general classifications, there are also various practices arising from individual beliefs.

Alternative Options

There is no consensus on how to deal with patient refusal based on faith or ethnic beliefs. Because adherence to diet that is based on religion is personal to the patient, it requires a personal response from the provider. Oftentimes, a patient’s refusal to use a specific product can be met with misunderstanding and frustration by the provider. Sometimes a conversation about the risks and benefits can persuade the patient to adhere to a medication while at other times, frank refusal can lead to patient morbidity and mortality. In certain situations, it would be appropriate to routinely solicit information regarding religious or personal prohibitions in order to identify potential conflicts with the treatment plan. Maintaining open communication with the patient can prevent such conflicts. In the authors’ experience, patients also may be misinformed about specific pharmaceuticals as a result of their own Internet searches; this can make them hesitant to trust the healthcare team, who can provide them with well-researched information. When confronted with these situations, the goal of healthcare professionals should be to provide their patients with treatment options and sound medical advice while simultaneously respecting patients’ autonomy when they make their decisions.

Consider the following example of an individual who abstains from pork products. Patients receiving dialysis must have their hemodialysis catheter flushed and locked with an anticoagulant solution to maintain the catheter’s patency. Normally, heparin locks are the anticoagulant of choice for this indication, but patients who strictly adhere to pork restrictions may refuse these. Heparin in central venous lines is more effective than normal saline at reducing the amount of line occlusions.¹⁰ Sodium citrate might be another option but it will present additional challenges because of procurement and availability.¹¹ Additional options and their risks and benefits can be discussed with the patient to ensure a solution is found that meets everyone’s needs.

CONCLUSION

As technological advances enhance the ability of researchers and healthcare professionals to provide medications that target specific receptors, the challenge will be to provide consistent and relevant information to the patient. Providers may encounter the need to discuss a patient’s personal beliefs and opinions of medication-manufacturing processes while they are administering health care. A regularly updated, centralized resource that is easily accessible to providers at the point of treatment is necessary to help inform patients about their healthcare decisions. Although patients’ decisions and beliefs can be misunderstood by and prove frustrating for providers, this knowledge will help to prepare and facilitate a productive discussion regarding patients’ desired outcomes.

Disclosure: The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria.