Excipients labelling

Excipient labels are typically either printed on demand or purchased preprinted. Where labels are purchased, the Quality Unit should approve their receipt by matching the incoming label content against an approved reference label. Where labels are printed on-demand, the Quality Unit, or their designate, should compare a printed label against the approved reference label to assure the printed content is correct. The approved reference label is one that has been carefully reviewed by the organization responsible for label content and design. The initials and date of the responsible individual affixed to the reference label provide confirmation that the label is an approved reference. 

Assay 90-110% of label claim (pick 20 tablets at random grind and mix weigh an amount of powder corresponding to five tablets dissolve compound sample and centrifuge excipients run a HPLC analysis on an aliquot of the supernatant), and... 

Because acid excipients can be used to achieve rapid polymer erosion, the possibility of preparing devices useful for oral delivery was investigated (31). In one such system, 2 wt% phthalic anhydride was incorporated into a polymer prepared from the diketene acetal, trans-cyclohexanedimethanol and C-labeled 1,6-hexanediol and polymer erosion followed in a pH 7 buffer and in pH 1.5 canine... 

The possibility of container-closure interactions should be considered, taking into account any admixture and dilution of products. Sorption of active ingredients and excipients should be considered as should leaching of container-closure components over the shelf life. Studies should extend to simulation of use. Pack components, administration devices (e.g., giving sets), and label adhesives should be considered. 

If an excipient had been observed, it would need to be identified. In Fig. 13.34, the drug substance standard is applied on lane 1 next to the extracted tablet. The remaining lanes labeled 2-12 are individual excipients in this particular tablet. Only one excipient, number 6, appears and it does in fact have the same R value as the band observed in the tablet. This confirmatory test is commonly used to identify interfering excipients. Now this band can be labeled appropriately, rather than mistakenly labeled as a degradant or impurity. 

Purified drug substances are mixed with excipients into finished dosage forms sohds, liquids, parenterals, inhalants, and ointments and creams, then packaged and labeled and shipped for distribution. 

To demonstrate the ability to evaluate intersample variations, an over-the-counter (OTC) pain relief medication from two different manufacturers was compared. The samples contain three APIs each acetaminophen, aspirin and caffeine. Pure acetaminophen, aspirin and caffeine samples are obtained in either tablet form or powder compact and included within the same FOV as the tablets to provide simultaneous reference materials for the tablet samples. The tablets and pure components were arranged as shown in Plate 8.1a. Measurements on all samples were collected simultaneously. Tablet A samples from one manufacturer have a reported label concentration of 37%, 37%, and 10%, for the three API components, respectively. Tablet B samples from the second manufacturer contain the same three APIs, at label concentrations of 39%, 39%, and 10 %, respectively. In addition to these samples, tablet C samples are included in the array of tablets. These samples contain only acetaminophen as the API with a reported label concentration of 79%, and are made by the manufacturer who produces tablet A. The remaining mass of all three tablet types represents the excipient (binder, disintegrant, and lubricant) materials. 

The concentrations of the active ingredients as reported from the manufacturer s label are 37% acetaminophen, 37% aspirin, and 10 % caffeine. The remainder of the tablet mass represents the excipient (binder, disintegrant, and lubricant) materials. Pure acetaminophen, aspirin and caffeine samples are obtained in either tablet form or powder compact and used to obtain reference specua of pure components. 

There are other components in the tablet, composing the remaining 16% of the tablet. These excipients were not included in the initial model, so the results for the three API components need to be normalized to then-expected contribution to the whole tablet. When normalized to a total contribution of 84%, the abundance estimations are 36% for acetaminophen, 37% for aspirin and 11% for caffeine. These valnes compare favorably with the manufacturers label claim of 37% for acetaminophen, 37% for aspirin, and 10 % for caffeine. 

The Tandem system (Bruker Optics) is available for use during tablet production to measure tablet weight, thickness, hardness, and diameter, as well as online NIR content uniformity. The system can provide online analysis for drug substance uniformity, moisture content, and excipients. The advantage of systems like this is that the necessary data are available immediately to make adjustments to the production parameters in order to improve product rmiformity. Therefore, adjustments can be made to tablet weight in real time in order to achieve 100% of the label claim. 

These percentages are based on the assumption that the drug substance in the finished product is formulated to 100% of labeled potency. The total additive effect of all excipient changes should not change by more than 10%. 

The inactive ingredients are updated quarterly, by the fifth working day of April, July, October, and January. To search for the excipient, one can enter any portion of the name of an excipient, of at least three characters. Search results are displayed alphabetically, sorted first by ingredient, then by the route of administration and dosage form. Routes of administration and dosage forms are derived from current approved labeling. Refer to the IIG query search results column headers for data field definitions. 

Raw materials must always be approved by the Quality Unit before use by production. Each lot of raw material should be sampled and the laboratory should perform at least an identity test in addition to verifying from the supplier Certificate of Analysis (COA) that the lot test results conform to the excipient manufacturer s specification. Upon approval, the status of the lot is changed from unapproved or quarantine to approved or available. The raw material lot status can be identified by use of approval labels on the container or pallet, movement of the raw material lot to the approved section of the warehouse, or by changing the lot status in a computerized inventory system. 

When the specification for a compendial excipient differs from the compendial monograph (e.g., additional tests, different analytical methods, or different acceptance criteria) the test results will be accepted from the excipient manufacturer s COA. However, the excipient should still conform to the monograph in an official compendium if there is such a monograph otherwise, justifications must be provided, and labeling needs to be changed to state plainly that the article does not meet the compendial requirement. 

While the COA is the excipient manufacturer s responsibility, once the material is received, it is the drug product manufacturers responsibility to verify the product and ensure that it is properly tested, handled, and stored. Upon receipt of a shipment, each lot of excipient will be withheld from use until the lot is sampled, tested, or examined according to the written procedures. The quality control (QC) personnel will examine each container for (i) manufacturer s name, (ii) manufacturer s lot number, (iii) leaks or spills, (iv) contamination, (v) breached containers, (vi) proper labeling, and (vii) material safety data sheet and determined material hazards. 

To ensure safe and effective finished drug products, the excipients must be stable. Some excipients may be stable and may not require extensive testing, while others may be less stable and require more scrutiny. A retesting or expiration date should be identified on the container label and the COA of the raw material at the time of use. Expiration or retest dates should relate to any storage conditions stated on the label and should be supported by appropriate stability studies. 

Analytical reagents used in testing the excipients should be prepared and labeled following established procedures. Retest or expiration dates should be used, as appropriate, for analytical reagents, or standard solutions. Analytical methods should be validated unless the method employed is set forth in the current revision of the United States Pharmacopeia/National Formulary, Association of Official Analytical Chemists (AOAC), Book of Methods, or other recognized standard references, or detailed in the Drug Master File or approved New Drug Application and are used unmodified. 

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