[Stability Testing related News – vol.63]

◆  In 2022 again Numerous FDA 483s due to Deficiencies in the Stability Program (07-Dec-22 ECA)

Observations made by the inspector during an FDA inspection are listed on the FDA Form 483. Spreadsheets summarizing the areas of regulation cited on FDA’s system-generated 483s are available by fiscal year on the FDA’s homepage in the subsection on “Inspection Observations“. These spreadsheets represent the area of regulation and the number of times it was cited as an observation on a Form FDA 483.

Stability studies of pharmaceuticals are a well-established discipline and, of course, an important regulatory requirement. Nevertheless, as you could read in provious articles, deficiencies in the stability program were mentioned in numerous FDA 483s in fiscal years 2019 to 2021.

The FDA has now published the data for the fiscal year 2022 (October 2021 to September 2022). 466 FDA 483s were issued in the area of “Drugs”. The evaluation shows that deficiencies in the stability program are again mentioned in numerous forms.

Regulatory Requirements
Requirements for stability studies are defined in the Code of Federal Regulations, mainly in 21 CFR Part 211.166:

Sec. 211.166 Stability testing
(a) There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include:
(1) Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability;
(2) Storage conditions for samples retained for testing;
(3) Reliable, meaningful, and specific test methods;
(4) Testing of the drug product in the same container-closure system as that in which the drug product is marketed;
(5) Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted.

(b) An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained. Accelerated studies, combined with basic stability information on the components, drug products, and container-closure system, may be used to support tentative expiration dates provided full shelf life studies are not available and are being conducted. Where data from accelerated studies are used to project a tentative expiration date that is beyond a date supported by actual shelf life studies, there must be stability studies conducted, including drug product testing at appropriate intervals, until the tentative expiration date is verified or the appropriate expiration date determined.

(c) For homeopathic drug products, the requirements of this section are as follows:
(1) There shall be a written assessment of stability based at least on testing or examination of the drug product for compatibility of the ingredients, and based on marketing experience with the drug product to indicate that there is no degradation of the product for the normal or expected period of use.
(2) Evaluation of stability shall be based on the same container-closure system in which the drug product is being marketed.

(d) Allergenic extracts that are labeled “No U.S. Standard of Potency” are exempt from the requirements of this section.

In addition, stability testing is also mentioned in 21 CFR Part 211.194:

Sec. 211.194 Laboratory records
(e) Complete records shall be maintained of all stability testing performed in accordance with § 211.166.

In the area of “Drugs”, the following number of reports have been issued in the past years:

  • Fiscal year 2019: 779 FDA 483 forms
  • Fiscal year 2020: 349 FDA 483 forms
  • Fiscal year 2021: 215 FDA 483 forms
  • Fiscal year 2022: 466 FDA 483 forms

◆  USP-NF Stimuli Article on Quality by Design (QbD) Principles in Method Development (18-Jan-23 ECA)

In the Pharmacopeial Forum, PF 49(1), a stimuli article entitled “A Novel Approach Using Quality by Design to Develop and Implement Flexible Methods in Non-Application Over-the-Counter Monographs” was published.

The article starts with an introduction highlighting the importance of nonprescription drugs (over-the-counter drugs, OTC), which are useful for the treatment of symptoms of minor, self-limiting conditions. It is pointed out that “products marketed under the FDA OTC Monographs do not go through FDA’s premarket approval process and frequently lack specific drug product compendial standards.” Therefore, “the US Pharmacopeia (USP), US Food and Drug Administration (FDA), and Consumer Healthcare Products Association (CHPA) have committed to work collaboratively to develop and implement a path forward on establishing product-specific compendial standards”.

Creating such a compendial standard for an OTC product can be a challenging task. In the article, “a proposed approach for generating flexible compendial organic impurity methods for drug products where multiple versions of products exist or that undergo frequent changes in formulation with respect to flavor, color, and excipients striving to meet consumer preferences in a fast-moving, competitive marketplace” is discussed.

In the following section, the concept of Design Space is explained. “Design Space” in the context of the stimuli article is defined as follows: “The multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality. The analytical method is identified by a range of operating conditions that are defined by the analytical design space.”

To develop such a multidimensional space, a logical stepwise approach is followed:

  • Primary Design Space: It denotes the conditions that resolve the API, degradation products, and process impurities as defined in the analytical target profile (ATP);
  • Secondary Design Space: It resolves the ingredients within the primary design space with the addition of the most common excipients;
  • Tertiary Design Space: It resolves all components of a drug product within a specific formula.

The main part of the article provides the method and development process for diphenhydramine oral solutions. This was agreed to be the first test case product. With this example, the procedure is explained in detail. The results are illustrated by several figures and tables.

The full article is available on PF Online via the USP Website Access Point. The deadline for submitting comments is 31 March 2023.

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