Almac’s extensive expertise in performing release testing includes API, drug product, medical devices and biologics. We have provision in place to handle highly potent and controlled substances.
Release testing covers a variety of tests to address the purity, concentration, consistency, identity and safety of the product. Typical testing would comprise of appearance, assay and impurities, dissolution and microbial testing. It is essential that the methodology involved is robust, to ensure the products’ safety and integrity, and reproducible, in order to minimise out-of-specification or out-of-trend repeats .
As well as release testing, we perform method development and validation, and often transfer methods from client and third party sites. We also have an extensive library of in-house methods, and significant experience working with pharmacopeial methods. We routinely work on NCEs and set specifications in line with ICH guidelines.
Typical release testing methods include:
U(H)PLC – Ultra (High) Performance Liquid Chromatography testing is the most widely used analytical technique in the pharma industry. U(H)PLC is flexible, reliable and applicable across multiple product types and dosage strengths.
This technique helps determine the assay value (purity) of compounds, and the nature and level of any impurities present. These methods can also be used to monitor the degradation of products to support stability data. U(H)PLC is a powerful technique and can be used in tandem with MS and MS/MS detectors to provide full characterisation of a range of drugs.
Almac has significant capacity for U(H)PLC testing with a mix of UPLC and HPLC instruments from both Agilent and Waters with a range of detectors including:
- Ultraviolet Visible (UV)
- Refractive Index (RI)
- Fluorescence Intensity (Fl)
- Evaporative Light Scattering Detector (ELSD)
- Charged Aerosol Detector (CAD)
- Mass Spectrometry – Triple Quad (MS-TQ)
- Mass Spectrometry – Quadrupole Time of Flight (MS-QTOF)
ID by NMR testing
Nuclear magnetic resonance (NMR) testing is a powerful tool in pharmaceutical drug development. By producing molecular structure information, impurities and other substances can be identified and confirmed. This technique is also widely used in biologic development. NMR is a quick and simple technique used primarily to confirm or elucidate the identity of organic compounds. It is also useful to determine potency values where no suitable reference standard is available.
Almac have two GMP NMR instruments (400MHz and 500MHz) allowing full structural elucidation of small molecules and peptides. We have recently invested in a state-of-the-art broadband cryoprobe which offers enhanced sensitivity over ambient temperature probes and allows us to observe 1H & 19F, as well as NMR active nuclei in the resonance frequency range of 15N-31P. We also have a range of 2D NMR capabilities and a highly trained technical team to support interpretation of data.
As well as ID by NMR, we support qNMR for assaying compounds and have experience developing and validating these methods.
Residual solvent analysis
Residual solvent analysis is undertaken to identify traces of solvents remaining from the manufacturing process. This technique is critical to ensure product purity and safety.
Residual solvents must be detected to low ppm levels to ensure the safety of products. The level of scrutiny required will depend on the manufacturing process and the class of solvents that are used. Our team supports our in-house manufacture of NCEs so has extensive experience in setting specifications for class 1, 2 and 3 solvents in line with ICH guidelines. Our Laboratory has the flexibility to use direct injection GC or headspace GC testing as required.
Drug product dissolution testing is a regulatory requirement and is routinely performed for quality control and development purposes to ensure batch-to-batch consistency, for product release and stability testing.
Almac supports dissolution testing for a range of different drug product formulations including tablets, capsules and softgels utilising USP apparatus 1 (basket) and 2 (paddle). We routinely perform comparative dissolution testing for over-encapsulated products. We can also support disintegration testing if required.
Moisture content analysis
Moisture content analysis is an essential testing element throughout the drug development lifecycle for quality control purposes. The level of moisture content can significantly influence the physical properties and quality of nearly all substances and materials at all stages of development and within the final product. High moisture content can also lead to faster degradation of drugs and as such needs to be carefully monitored and controlled.
Almac perform water determination by Karl Fisher testing:
- Stromboli Oven
Our physical sciences group can also investigate hygroscopicity of samples and formation of different hydrates. Their crystallisation team can look deep into the crystal structure for embedded water, and develop new methods of crystallisation to ensure robust and reproducible crystal formation.
Analytical Method Transfers are performed between two or more testing laboratories – it’s a documented process that qualifies a new laboratory to use an analytical method developed by another laboratory. This could be between laboratories at different companies organisations or between two laboratories within the same company organisation.
A formal Analytical method transfer will streamline the testing process, ensuring the method performs well efficiently in the new laboratory, and minimising deviations in results. It is important to have validated analytical methods available at more than one testing site to secure continuity of supply.
Almac can also act as a contingency laboratory to safeguard the continuity of commercial products.
Microbiology: Pharmaceuticals, biopharmaceuticals, biologics and medical devices need to be produced in accordance to the strictest cGMP requirements and must have release testing packages carefully designed to demonstrate compliance. Microbiology testing provides knowledge and understanding any microorganisms and toxins in raw materials, intermediates, finished products, etc. The objective of microbiology testing is to ensure the safe manufacture of pharmaceutical and healthcare preparations and medical devices which involves risk assessment analysis and environmental monitoring.
Clinical trial supply support
Clinical supply: Before a drug can be used in a clinical trial, extensive analytical testing must be performed to ensure its safety and effectiveness, often in comparison to a standard treatment already offered. Almac is unmatched in its ability to manufacture clinical trial supplies and provide analytical support, with fully integrated sites in the UK, EU and US.
Pharmacopoeial / Raw material analysis
Raw material testing is an essential activity to ensure that every ingredient used to formulate a drug fully meets the required specifications and requirements.
We perform GMP testing of raw materials, APIs, excipients and drug products for compliance with appropriate standards, according to pharmacopoeial monographs and client methods.
Our scientists have over 10 years’ experience and detailed knowledge of methods in a range of pharmacopoeias, including EP, USP, BP and JP which enables us to provide dedicated support for pharmacopoeial testing.
A full suite of analytical equipment allows us to offer chemical and physical analysis covering all pharmacopoeial monographs.
In addition to monograph testing, Almac has the ability to develop and validate new methods or transfer existing methods from our clients. We can work with your QC department to provide reliable test results quickly.
Impurities such as N-Nitrosodimethylamine (NDMA) have been highlighted by the US FDA, EMA and other regulatory authorities as an area for concern as they are probable human carcinogens. We have responded to regulatory guidance and offer laboratory drug testing to detect levels of NDMA and related impurities within our mass spectrometry laboratory. Our expert team have successfully performed testing on a number of APIs and Finished Products as per FDA method FY20-006-DPA-S_LCMSMS 10/17/2019 to establish levels of NDMA. Read our paper to find out more.
Reference standard management
Reference standards are a vital element within pharmaceutical drug development at every stage of analytical support. Typical reference standard management includes techniques such as characterisation, expiry dating, re-certification, and storage and distribution. A comprehensive reference standard management program is critical to ensure there are no avoidable delays within the drug development process.
Our highly organised and proficient team enable prompt recertification. We also manage resupply of standards when stocks run low via our synthetic chemistry group, who can manufacture standards and by/degradation products of API and drug product. This can be done via total synthesis or isolation from manufacturer supplied mother liquors or enriched waste streams. We have significant knowledge on best practice in this area and have been managing the standard portfolio of a big pharma partner for >15 years.
Full reference standard management
Each reference standard must be qualified prior to use. This comprises a range of analysis to demonstrate compound characterization and purity including batch aliquoting, purification and isolation for by degradation products. Upon isolation, characterisation (typically by orthogonal methods, both chromatographic and spectroscopic) is necessary to confirm structure and purity. As part of qualification, a specification is issued for each standard which includes details on shelf-life and retest date.
Reference standards are typically stored under controlled conditions to prevent degradation. Depending on the nature of the compound this could be controlled ambient, chilled, or frozen. As well as temperature, the storage conditions may have limitations around oxygen, air or water exposure, and each standard will come with specific storage instructions.
Standards are typically used in small quantities by several different parties. For example, both the API and drug product manufacturers require access and for commercial drugs with large volumes there could be multiple suppliers for each worldwide. Typically, the reference standards are provided in bulk to a supplier where they are aliquoted into smaller vials and shared with sites that require them. This vialling prevents waste as once the standard is expired it can no longer be used.
Once the standards have been portioned out, they need to be sent to the appropriate facility. This shipping exercise includes preparation of GMP paperwork (including certificates of analysis and custom forms) to ensure that the vials are received in a timely fashion. The location of these standards is especially important if vendors are spread over different continents.
Depending on the nature of the standard, recertification may be required annually, or every 2-3 years. Almac’s lab management system can track expiry dates, inventory and stock levels to ensure standards are always ready and available to use.
Almac’s labs have the capacity and capability to perform full management of reference standard programs on behalf of our clients. We have more than 20 year’s experience in this area with long standing relationships with a number of key partners. Almac’s flexible approach makes us the partner of choice for reference standard programs.