Batch release is the final step of a pharmaceutical product's manufacturing process, where a defined batch or lot is confirmed to meet all regulatory requirements and pre-defined quality specifications before it is released to the market. Several analyses are typically performed on the finished product as part of batch testing, covering physical, chemical, biological, and microbiological parameters. In addition, tests performed on raw materials and intermediates at different stages of the manufacturing process can provide data to support batch release.
Regulatory framework for batch testing in the EU
All human medicinal products placed on the EU market must comply with Directive 2001/83/EC and be manufactured in accordance with good manufacturing practices (GMP), as outlined in Directive (EU) 2017/1572.1 Together, these directives provide the legal basis for batch testing and batch release in the EU, with the following articles being particularly relevant:
Article 51 of Directive 2001/83/EC requires each batch of a medicinal product to be certified by a qualified person (QP) to ensure it has been manufactured and checked in compliance with its marketing authorization and EU pharmaceutical legislation.
Article 11 of Directive (EU) 2017/1572 requires manufacturers to maintain an independent quality control system capable of testing starting materials, packaging materials, intermediates, and finished products. It also states that analytical results and manufacturing conditions must be considered as part of the final control and release of each finished product batch.
How is batch testing conducted?
The exact product specifications that pharmaceuticals must meet for batch release are determined on a case-by-case basis and described in the product-specific marketing authorization. However, at least the following aspects are generally considered:
Identity and purity of raw materials, including but not limited to active pharmaceutical ingredients (APIs), excipients, manufacturing solvents, and API precursors
In-process controls and monitoring of relevant chemical, physical, and microbiological parameters of intermediates at different stages of production
Composition, strength, and purity of the final product
Stability of the product throughout its intended shelf-life
Individual tests are typically conducted according to European Pharmacopoeia (Ph. Eur.) monographs, which set the official quality standards for pharmaceuticals and their ingredients in Europe.2 When justified in the marketing authorization, corresponding monographs in other pharmacopoeias, such as the United States Pharmacopoeia (USP) or the British Pharmacopoeia (BP), may also be used.
Testing of pharmaceutical raw materials
Before a batch of a medicinal product is manufactured, all starting materials must comply with their approved specifications, which are typically based on the applicable pharmacopoeial monograph. Ph. Eur. monographs define the required qualitative and quantitative characteristics of hundreds of substances used in the manufacture of medicinal products, together with the corresponding test methods and acceptance criteria, thereby establishing harmonized quality standards for pharmaceutical ingredients in Europe.
Many pharmacopoeial monographs are ingredient-specific and define the requirements for individual APIs or excipients, such as pharmaceutical-grade water or microcrystalline cellulose. These monographs cover several attributes, including identity, appearance, solubility, and typical impurities.
Other monographs apply across multiple materials and are used to assess a particular quality parameter. Common examples include Ph. Eur. 5.1.4, which defines the microbiological quality criteria for non-sterile pharmaceutical preparations and substances, and Ph. Eur. 2.6.12 and 2.6.13, which describe validated analytical methods for the determination of total aerobic microbial count (TAMC) and total yeasts and moulds count (TYMC), and for testing for the presence of specified microorganisms, respectively.
In-process controls
In-process controls are used to monitor critical steps during manufacturing to ensure that processes remain within validated parameters and consistently produce intermediates that meet predefined specifications. The purpose is to detect deviations as early as possible, before batch completion, to minimize waste and reduce the risk of non-conforming products.
Under certain conditions, data generated through in-process controls and monitoring can be used as an alternative to routine end-product testing for batch release. This approach is referred to as Real Time Release Testing (RTRT). For example, in the case of some terminally sterilized medicinal products, it may be possible (or even preferable) to monitor the bioburden of intermediates and other key sterilization parameters throughout the manufacturing chain instead of conducting sterility tests on the finished product. This form of RTRT is known as parametric release.3
In addition to bioburden and sterility, critical quality attributes measured during in-process monitoring can include a range of physico-chemical, biological, and microbiological parameters. Examples of European Pharmacopoeia methods that may be applied include:
Osmolarity and osmolality according to Ph. Eur. 2.2.35
Particle size distribution by laser diffraction according to Ph. Eur. 2.9.31
Viscosity by capillary viscometry (Ph. Eur. 2.2.9) or rotating viscometry (Ph. Eur. 2.2.10)
Final product analyses for batch release
Batch release testing of the finished drug product is performed to confirm that the product, as presented for use within its packaging, complies with predefined quality specifications for identity, strength, purity, safety, and performance. Some specifications and analytical methods are defined in pharmacopoeial monographs or ICH/EMA guidance, while others are specified by the manufacturer and approved as part of the marketing authorization.
Impurity control is a central part of finished product testing, as EU regulatory guidance and ICH standards define toxicologically based limits for several classes of impurities. Examples include:
Bacterial endotoxins according to Ph. Eur. 2.6.14 – Bacterial endotoxins are common pyrogenic contaminants that may pose significant risks to patient safety, particularly in parenterally administered medicines. This is why endotoxin testing, most commonly using a Limulus Amebocyte Lysate (LAL) assay, is a routine part of batch release for applicable products. Compliance limits are set in product-specific Ph. Eur. monographs.
Elemental impurities according to ICH Q3D – The guideline establishes harmonized Permitted Daily Exposure (PDE) levels for 24 elements, including several heavy metals.4 Compliance testing is typically performed using high-performance ICP methods, such as ICP-MS.
Nitrosamine impurities according to EMA guidelines – Maximum Acceptable Intake (AI) levels for 200+ nitrosamines are specified in a periodically updated Appendix to an EMA Q&A document. Various types of finished pharmaceutical products can require screening for small-molecule nitrosamines as part of batch release testing, while products containing APIs known to be susceptible to nitrosamine formation should also be analyzed for the relevant nitrosamine drug substance-related impurities (NDSRIs) using targeted methods.5
Because final product matrices are unique and the required quantification limits are often low, analytical protocols typically require detailed method development and appropriate validations according to GMP before routine analyses can be performed.
The role of stability testing for batch release
While not directly part of the release process of every batch, stability testing runs in parallel to batch release as part of an ongoing stability program. According to ICH and EU GMP guidelines, at least one batch per year of each API and finished product should be included in such an ongoing programme to confirm that the storage conditions and retest or expiry dates established through initial stability testing still hold.6
Parameters analyzed as part of stability testing often overlap with those assessed for batch release (e.g., dissolution characteristics, impurities), but the tests are conducted after the product has been maintained at the intended storage conditions for the applicable retest or shelf-life period. As degradation of packaging materials and possible contamination resulting from this are key concerns, extractables and leachables (E&L) studies can also be incorporated into the stability testing program. These are often performed according to the principles outlined in USP <1663> and USP <1664>.
Measurlabs’ solutions for pharmaceutical batch testing
Measurlabs offers a broad range of GMP-compliant analyses for raw materials, intermediates, finished medicinal products, and pharmaceutical packaging, supporting manufacturers at every step of the batch release process. The following are examples of popular services:
We can also offer practically any other test specified in the European Pharmacopoeia. Do not hesitate to ask for more information or a quote using the form below.
References:
1 Directive 2001/83/EC on the Community code relating to medicinal products for human use and Directive (EU) 2017/1572 as regards the principles and guidelines of good manufacturing practice for medicinal products for human use. See also EudraLex, Volume 4, for the European Commission’s GMP guidelines, which provide detailed guidance on how compliance with good manufacturing practices should be demonstrated. Annex 16 (Certification by a Qualified Person and Batch Release) is particularly relevant for batch release.
2 European Pharmacopoeia, 12th edition
3 See Annex 17 (Real Time Release Testing and Parametric Release) of EudraLex, Volume 4. Section 4 of the document, titled “Parametric release and sterilization”, states that in-process monitoring of sterilization parameters “can provide more accurate and relevant information to support sterility assurance” than end-product tests.
4 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH): Guideline for elemental impurities Q3D(R2)
5 European Medicines Agency (EMA): Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products. See also Appendix 1 for the list of nitrosamine AI limits.
6 See section 11.5 “Stability Monitoring of APIs” in ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients & the section titled “On-going stability programme” in Chapter 6: Quality Control of EudraLex, Volume 4.