Introduction and Background
The storage of a bulk drug product is defined by the European Medicines Agency (EMA), with main reference to oral solid dosage forms (e.g., tablet cores before coating or packaging), but also to liquid dosage forms, as “any stage in the manufacturing process of any pharmaceutical product where bulk is held in storage prior to further processing“ (Ref. 1a).
Stability studies to support the storage of bulk drug products (e.g., before tablet coating or packaging or before filling a liquid dosage form) are not described in the ICH Q1A(R2) stability guideline (Ref. 2).
This topic is mentioned very briefly in the World Health Organization (WHO) stability guideline with the recommendation to generate stability data if a bulk product, e.g., coated tablets before final packaging, “may be stored for a period exceeding 30 days before being packaged and/or shipped from a manufacturing site to a packaging site” (Ref. 3).
WHO has also published a short and specific guideline on hold-time studies (i.e. bulk stability studies), which includes e.g., criteria for choosing the type of stability pack and the parameters to be tested in the stability study (Ref. 4).
EMA has prepared a short, but well-structured guidance on bulk stability studies within a Questions and Answers (Q&A) section for Quality of Medicines, published on its website (Ref. 1). The guidance given by EMA on bulk stability studies in the cited document, as well in another guideline, will be summarized in this blog.
EMA guidance on stability studies for bulk product storage
Information to be included in a marketing application for a bulk pack for stability related aspects
EMA recommends that the maximum storage period for the bulk product or, alternatively, the maximum storage time of the product batch from the start of manufacturing to the completion of the packaging of the primary container for marketing, should be declared in the dossier for marketing authorization application (MAA, Ref. 1b).
When the storage of a bulk product is prolonged (i.e., more than 30 days for solid oral dosage forms), EMA recommends that evidence of the suitability of the bulk container-closure system, proposed for storage and transportation, should be included in the MAA (Ref. 1b).
Within this suitability support of the chosen bulk packaging, there is an EMA expectation that stability data will be provided in the dossier on at least two batches, manufactured at least at a pilot scale. If stability data are generated on pilot scale batches in a bulk pack, these stability data should also be confirmed for commercial scale batches, e.g., with data in the MAA or during the post-approval phase with a specific commitment in the MAA (Ref. 1b).
It should also be reported in the MAA if the bulk product will be stored (and if relevant, transported) under controlled or uncontrolled storage conditions (Ref. 1c).
Bulk stability study storage conditions
The long-term storage condition applied for this stability study on bulk drug products, according to the EMA Q&A guidance, should “…. reflect real storage conditions in the standard container foreseen at the manufacturing site” (Ref. 1d).
In this regard, the EMA Q&A guide states that it is not necessary to conduct stability studies on bulk packs according to ICH recommendations for temperature or humidity (Ref. 1d).
The EMA’s “Guideline on manufacture of the finished dosage form” specifies that stability studies to support holding times longer than, e.g., 30 days for solid oral dosage forms, should be performed at the relevant temperature and humidity with respect to the intended storage conditions for the bulk product. These storage conditions should be indicated in the MAA, i.e., at what temperature and humidity (T / RH%) the bulk product will be stored. If the T/RH% range during bulk product storage does not correspond with the ICH stability storage conditions, other conditions should be used (Ref. 5).
When transportation of a bulk drug product is planned between manufacturing sites, the stability studies should also consider the duration and conditions during transport (Ref. 1d). The impact of excursions outside of the labeled bulk pack storage conditions during transport should be discussed. The discussion should be supported, if necessary, by stability data at an accelerated storage condition (Ref. 1b and 5).
In summary, the storage conditions used to support the stability studies for a bulk product should be carefully selected, taking into due consideration the actual storage conditions at which the bulk pack will be stored in the warehouse and during transport, and must be properly justified in the MAA.
Start of shelf-life for a product stored in a bulk pack
For a product to be stored in a bulk pack prior to final packaging for marketing, the shelf-life should start from the date of batch release, or of manufacturing date (DoM), if the release is made beyond 30 days after the DoM (Ref. 1e). Exceptions are explicitly allowed by EMA (e.g., shelf-life starting from date of packaging), if supported by data from an adequately designed stability study. For this support, stability data should be generated on batches that have been stored for the entire proposed bulk product holding period before being placed in the stability program, as final packaged product (Ref. 1e).
Stability data should be generated according to EMA recommendations, to support a prolonged storage of the bulk drug product (e.g., more than 30 days for solid oral dosage forms), on at least two batches. The storage conditions for this stability study on the bulk drug product should be appropriately chosen to reflect the conditions under which the drug product will be stored and, if relevant, transported between sites.
About the Author
Piero De Filippis is the StabilityHub EU Regional Contributor, based in Italy. His e-mail address is firstname.lastname@example.org.
- European Medicines Agency (EMA) Quality of Medicines Questions and Answers: Part 2 –Section “Stability – Stability issues of pharmaceutical bulk products use in manufacture of the finished product” – a) Question 1 – b) Question 5 – c) Question 3 – d) Question 7 – e) Question 6. https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/qa-quality/quality-medicines-questions-answers-part-2#stability—stability-issues-of-pharmaceutical-bulk-products-use-in-manufacture-of-the-finished-product-section (Last accessed 31 October 2021)
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline Q1A(R2). Stability Testing of New Drug Substances and Products – Section 2.2.7. Storage Conditions (2003)
- World Health Organization (WHO) Technical Report Series, No. 1010 – Annex 10 ‘Stability Testing of Active Pharmaceutical Ingredients and Finished Pharmaceutical Products’ – Section 2.2.11 In-use and hold time stability (2018)
- WHO Technical Report Series, No. 992 – Annex 4 ‘General guidance on hold-time studies’ (2015)
- EMA guideline EMA/CHMP/QWP/245074/2015 ‘Guideline on manufacture of the finished dosage form’. Section 4.4. ‘Controls of Critical Steps and Intermediates’ – ‘Storage of intermediate and bulk products’ (2017). https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-manufacture-finished-dosage-form-revision-1_en.pdf (Last accessed 31 October 2021)