What are Bulk Ingredients and Why are they Necessary for Compounding?

When a medical practitioner determines that a medication needs to be compounded to meet the needs of a patient ...

it is because the practitioner has determined that there is no commercially available, FDA-approved medication to meet that patient’s medical need. While there may be commercially available FDA-approved medications containing the active ingredient being prescribed, the dosage form, strength or flavor of the manufactured product may be inappropriate for the patient. In other cases, commercially available medications may contain excipients such as fillers and preservatives that cannot be tolerated by the patient because of sensitivities or allergies to these substances.

Because of these issues, when a drug is customized, or compounded, to meet the identified needs of patients or groups of patients, it is common practice to use only ingredients necessary to achieve the prescribed compounded medication. This means starting with the active pharmaceutical ingredient (API) in its purest form, and then adding only the excipients necessary to achieve the prescribed dosage-form, strength and, where specified, flavor. APIs are the essential ingredients that make the medicine what it is, and are commonly referred to as bulk ingredients. Using bulk ingredients in a compounded medication is the surest, safest way of satisfying the prescriber’s request for medication to meet the special, customized needs of the patient.

The use of finished product, such as a tablet or capsule, as a source of API has the potential for serious health problems for those patients using that medication, for two main reasons. First, because the active ingredient makes up only a small portion of the overall ingredients used in commercial tablets or capsules, it is impossible to separate the active ingredient from the other excipients (fillers, binders, dyes, flavorings, preservatives and other materials). Because these excipients cannot be separated, they would be incorporated into the finished compounded medication.

For example, if there were the need to remove red dye in a commercially available tablet because of patient intolerance to red dye, using the commercial tablet as the source of the active ingredient in the compounded medication means the patient would still end up ingesting the red dye with a potential adverse reaction. In other instances, a medical practitioner may determine that the patient requires a compounded medication in a completely different dosage-form from what is commercially available. This might include the need to convert the medication to a sterile injectable. The use of a commercial tablet or capsule rather than bulk API would be completely unacceptable, as excipients such as corn starch, talc, or cellulose would be incorporated into the injection, and could result in serious adverse events. The need to convert the dosage form to transdermal creams, suspensions and other forms also requires the use of API in order to remove unnecessary and potentially harmful excipients.

The second main reason for using bulk API in a compounded medication rather than manipulating a finished product is the need for accuracy. Individual finished products are allowed a considerable amount of variance in the actual active ingredient, and the use of a finished product introduces an unacceptable and possibly dangerous element of inaccuracy into the compounded medication.

To fully appreciate the issue of accuracy, it is important to understand the allowed variances in individual dosages that are allowed in manufactured finish product. The USP Monographs for finished dosage forms will typically allow an average variance of ± 5% to 10% of the stated dosage on the label. This variance, however, applies to multiple doses (e.g., if all finished capsules in a bottle are averaged). But for individual dosage units, the allowed variance under USP’s “Uniformity of Dosage Units” has a variance value of 25%. This means that an individual dosage unit could depart from label claim by up to ± 25%.

If a compounded prescription were to be made from a single dosage unit (e.g., from crushing a pill), having such a wide variation in the active ingredient would mean that the compounded preparation could have a variation of up to ± 35%. This is way outside the range of acceptable quality assurance under USP guidelines of ± 10%. Having a finished compounded preparation with an active ingredient strength that is ± 35% of the strength that was prescribed could result in the patient being over medicated or under medicated, either of which could have a significant impact on that patient’s health.

There are other reasons that make compounding from bulk API both necessary and desirable. For example, compounding from finished tablets or capsules would require the incorporation of unknown excipients into the compounded preparation. This can alter the texture, taste and palatability of the compounded preparation, making it more difficult to dose the human or animal, and can also be an issue with patients with known and unknown allergies. Additionally, utilizing a commercial tablet or capsule in an ophthalmic or optic preparation may be pharmaceutically unacceptable because the excipients would, at a minimum, irritate the eye.

And where do compounding pharmacies get their bulk ingredients? They get them from the same sources that pharmaceutical companies get their bulk ingredients. They are purchased from suppliers who get them from FDA-registered facilities. They just don’t purchase them in as large a quantity as a manufacturer. When they are purchased, the compounding pharmacy receives a certificate of analysis verifying the purity and quality of the ingredients. Often, additional testing is also done by the compounding pharmacy before making the customized medication.