How can stability studies and expiration dates be waived after oral solid drugs are repackaged into a single dose?

It is very convenient for medical institutions and patients to repack oral solid drug products in single dose packaging, which will make the drug have better compliance Therefore, in the past decades, the demand for repacking oral solid drugs into single doses has been increasing But single dose repacking leads to the problems of stability study and expiration date of these repackaged drugs In view of this, on August 8, 2017, FDA issued the guidance on the expiration date of unit dose repackaged solid oral solid dosage form drug products (final guidance) Unlike the previous USP general rules chapter 1178 "good repacking practice (GPP)" recommendations for determining the shelf-life of single dose repackaged oral solid drugs, this guideline describes the stability studies required by FDA to exempt these repackaged products and the designation of shelf-life based on these conditions The author will concentrate on the essence of this guide and share with readers Due to the limited ability of the author, there may be biases in the understanding of the contents of the guide Please also ask relevant experts and readers to correct Note: this draft replaces the 2005 edition of expiration day of unit dose repackaged drugs: compliance policy guide 1、 The scope of products to which this guide applies 1 The guide covers prescription drugs and OTC drugs that are repackaged into unit dose containers These drugs shall be registered with FDA in accordance with section 510 of the federal food, drug, and Cosmetic Act (FD & C act) and shall comply with the cGMP requirements of 21 CFR 210 and 211 Note: the regulated repackaged production or processing process includes repackaging or otherwise changing the container, package or label of any drug packaging to further distribute the drug from the initial production site to the personnel who ultimately deliver or sell the drug to the final consumer 2 The guidelines do not cover repacking of the following products: ● other dosage forms (e.g sterile, liquid, local) ● repackaged products at state licensed pharmacies, federal facilities and outsourced facilities as defined in section 503B of the FD & C act Note: repacking of state licensed pharmacies, federal facilities, and outsourced facilities will be addressed by separate guidelines For example, refer to pharmacy and outsourcing facility guidelines for Industry repackaging of human drugs 2、 Requirements before the introduction of this guideline 1 According to the cGMP requirements of FDA for finished drugs Each drug should have a suitable expiry date determined by stability test The date must be related to any storage conditions specified on the label as determined by the stability study (§ 211.137 (a) and (b)) The validity period of single dose packaged drugs shall be placed on the main container unless it is not feasible 2 The sample used for stability test must have the same sealed container system as the commercial drug product (§ 211.166 (a) (4)) This is to ensure the safety and effectiveness of the drug within its expected shelf life, and to ensure that data representing the products on the market can be obtained in case of quality problems during the expected shelf life of the drug 3 Chapter 7 of the general principles of the United States Pharmacopoeia (USP) stipulates that "the label of the official drug shall contain the expiration date" For unit dose repackaged products, the validity period recommended in Chapter 1178 "good repackaging management practice (GPP)" of USP general rules shall not exceed (1) 6 months from the date of repackaging; or (2) the validity period specified by the manufacturer; or (3) 25% between the repackaging date and the validity period of drugs shown on the bulk product container of the manufacturer who is repackaging Whichever is earlier 3、 The specific requirements of this guideline are that FDA does not intend to perform the requirements of §§ 211.137 and 211.166 (i.e., determine the validity period through stability study) for oral solid preparations repackaged into single dose packaging, i.e., exempt these repackaged products from stability study and specify the validity period according to these conditions But it needs to meet certain conditions There are two cases: case 1 If the expiry date of these products is not longer than the shorter of the following two conditions: (1) 6 months from the date of repacking; (2) 25% between the repacking date and the expiry date of the drug shown on the manufacturer's bulk product container being repacked For example (the author's own understanding of this guide is not the main body of the guide) case 1 also needs to meet the following conditions: (1) the single dose container meets the class A or class B standards described in the USP general chapter container performance test "single component container and solid oral dosage form single dose container packaging system classification" However, vessels meeting USP class C and D standards do not meet this condition In this case, only if (a) there are appropriate data on the moisture permeability of class B materials and the moisture sensitivity of the drug product; and (b) a risk assessment of these data has been carried out to ensure that the use of such containers will not damage the quality of the product throughout the specified validity period, so that containers conforming to class B standards can be used (2) If, as indicated by the manufacturer, the drug product is sensitive to light (e.g "off light" on the label), the single dose repackaging container sealing system shall provide light protection equal to or greater than that of the product's original packaging container sealing system (3) The original containers of drugs have not been opened before and all repackaged at one time (4) Repacking and storage should be in an environment consistent with the conditions described in the original drug label If the temperature and humidity are not specified in the original label, the product shall be kept at "controlled room temperature" and "dry place" (as defined in USP packaging and storage requirements) during the repackaging process, including storage (5) It is not allowed to repack the drug without warning on its label For example, the instructions clearly state that "the tablet should be kept in the original container" and "repacking is not allowed" Case 2 If the expiry date specified for these products exceeds the shorter of the following two conditions: (1) six months from the date of repacking; (2) 25% between the date of repacking and the expiry date of the drug indicated on the manufacturer's bulk product container being repacked For example (the author's own understanding of this guide is not the main body of the guide) case 2 also needs to meet the following conditions: (1) meet the five conditions in case 1 above (2) Supporting data from a suitable study using a sufficient number of samples show that the container sealing system used for repacking provides at least the same protection for the drug as the original packaging The comparison of container sealing system can be carried out by several methods, such as testing the situation of blocking water, oxygen and light as required; comparing the performance of the original container sealing system with the new system through pressure test, including product test after storage under extreme conditions (such as high temperature and high humidity) and degradation test after long-term or accelerated storage Appropriate research should be based on sound science and risk-based assessment to ensure product quality is maintained to the expiry date (3) The validity period of the repackaged products shall not exceed that of the original products.