CMC analytical servicesFrom discovery to finished product

pharmaceutical development • regulatory submission • cG

MP

• a nalytical quality • chemical measurement • bioanalysis • standardsLGC in drug development

Operating from state-of-the-art facilities to GLP, GCP and cGMP standards, LGC has leading analytical capabilities to support Chemical Manufacturing and Control (CMC) with significant experience in the physical and chemical characterisation of compounds.

We work on behalf of clients from all over the world and our consultative, science-driven approach ensures our clients receive the highest quality data. Our flexible and tailored services follow the same rigorous principles for all experimental work, so whether you require non-regulated discovery or full regulatory studies, you know that your samples are in safe hands.

Reliable with the routine and exceptional with the unexpected

Discovery Pre-clinical Phase I/IIa Phase II-IV Post marketing

Bioanalysis (small and large molecules)

Biomarkers

Microbiology and molecular biology

CMC

Central lab services

LGC has a dedicated team of scientists focused on providing laboratory services to help accelerate the development of new medicines. We offer comprehensive analytical solutions to meet the requirements for the regulatory compliance of your drug substance and drug product. Our comprehensive expertise and capabilities provide support to the complex challenges faced in drug development and in solving issues at all stages of manufacture.

LGC provides regulatory compliant analytical testing for a range of dosage forms:

• Solid oral dose

• Inhaled and nasal

• Parenteral

• Topical/creams

• Ophthalmic.

Batch release and import testing

We work with many manufacturers and distributors importing products that have been manufactured outside of the EU and must therefore be tested within the EU at an accredited facility prior to release to the market. We provide a cGMP analytical service to test and batch release your samples in a timely manner to ensure that your product reaches the end user without costly delays.

Development and validation of analytical methods

LGC develop fit for purpose methods across a wide range of technologies in support of stability testing. i. Forced degradation studies Accelerating degradation of the product using acid, base, oxidation and photo stability (in accordance with ICH Q1(B) guidance) gives an all round appraisal of any potential degradation products that are likely to be seen during stability testing. This allows the development of stability indicating methodology to ensure these are monitored during the programme.

ii. Method validation Methods validated in accordance with ICH Q2(R1) guidance to provide confidence in data

produced for Quality Control, batch release and during the life or your stability programme to ensure conformance with regulatory guidance and expectation. Stability storage and programme management

LGC have on-site cGMP stability storage to standard ICH conditions, we will manage your stability programmes and provide all of your analytical needs for long term assessment of products.

• Protocol design

• Accelerated and long-term stability testing

• Drug substance stability testing

• Marketed product stability testing

• Comparator testing and bioequivalence studies

• Photostability (ICH Q1B)

• Temperature cycling studies.

Under your control, in our care

Chemistry, manufacturing and control (CMC) testing, stability storage and programme management

Extractables and leachables

Impurities resulting from contact surfaces in the manufacturing process or in the final container closure system are referred to as leachables. These compounds can have a significant impact on the drug product’s safety and efficacy. Understanding the potential sources of these compounds and the analytical tools to detect them can be vital to a development programme. Designing and implementing an extractables and leachables programme can save significant time and cost in development and potentially avoid pitfalls, which may increase time to market.

Extractables assessment:

LGC has pre-developed screening methodology for the assessment of volatiles, semi-volatiles, non-volatiles and inorganic extractable components, and have years of experience in putting together bespoke protocols. All work is carried out using the Product Quality Research Institute (PQRI) industry guidance.

Leachables analysis:

LGC validates methods specifically for use with your product following the extractables analysis, and supports the storage of your samples and leachables assessment in parallel with the stability testing as part of a larger CMC package.

Change of packaging studies and product/packaging interaction studies

Using our expert knowledge in the field of extractables and leachables, LGC will work with a sponsor to minimise risk associated with change in packaging components. We have designed bespoke protocols to assess a change in contact material with pharmaceutical

products, and provide our clients with confidence that their product is safe within its new packaging material.

Bioassays For biopharmaceuticals, bioassays are developed, validated and performed to the relevant regulatory guidelines of cGMP, GLP and GCP. We have state-of-the art instrumentation in our dedicated biopharmaceutics laboratories offering pharmacokinetic, immunogenicity and biological product assessment:

• Cell-based assays

• Electrochemiluminescence

• Luminescence

• Absorbance.

Cell based potency assays

Cell-based potency assays are challenging and require an in-depth understanding of the biology of the system under investigation. LGC has a highly provide expertise capable of supporting candidate selection. We develop and validate methods to satisfy the requirements of ICHQ6B and for product release and stability using the following assay types:

• Ligand binding

• Cell signalling

• Cell migration

• Cell inhibition and proliferation

• Receptor binding

• Receptor activation.

Designing and implementing an extractables and leachables programme can save significant time and cost in development, and potentially avoid pitfalls, which may increase time to market.

Troubleshooting and process support to keep you on trackUSP <232> and <233> heavy metals analysis

The United States Pharmacopeia (USP) has announced the new required methodology proposed to replace the general chapter for heavy metals. This update moves the testing from a colorimetric ‘limit’ test for all metals, to quantitative assessment for individual metals in the test sample. This also includes looking for trace levels of inorganic impurities within your sample.

In an effort to improve and modernise the USP General Chapter for Heavy Metals <231>, United States Pharmacopeia has proposed the addition of two new General Chapters and one Supplemental General Chapter.

• <233> Elemental Impurities – Procedure

• <232> Elemental Impurities – Limits

Many companies are now preparing for the mandatory introduction of the chapter, and LGC is well placed to provide support for your transition to the new methodology required, both in terms of method development and validation, and also on-going batch testing as required. We have vast experience in preparing samples from a wide range of matrices and a detailed understanding of the importance of sample preparation.

Case studyAnalysis of final products for elemental impurities to the limits detailed in ICHQ3D and USP<232><233>

Challenges:• Rapid assessment of multiple products in preparation

for regulatory changes to avoid non-compliance and product withdrawal.

• Simultaneous analysis of 27 elemental impurities in multiple dosage forms using one sample preparation at target concentrations between 0.037ug/g to 39000ug/g.

Science:• Microwave assisted digestion of oral products, pMDIs

and Parenterals followed by ICP-MS analysis.• Screening of elemental impurities at 30% PDE limits

followed by full quantitation of those found above >30% PDE.

• Identified need for targeted sample preparation in some products to obtain Ag and/or Os quantitatively.

• Flexibility to assess elemental impurities using actual maximum dose values ranging between 40mg (parenterals) to over 12g (oral doses) per day.

Solutions and output:• Product specific elemental impurity data based

on actual dosage levels complying with latest ICHQ3D limits.

• Customer is fully compliant with impending new regulations.

Residual solvent analysis

Residual solvents in pharmaceuticals are defined as organic volatile compounds, which are used or produced in the manufacture of drug substances or excipients, or in the preparation of pharmaceutical drug products. Drug manufacturers have to ensure that these impurities are removed or are present only in limited concentration for toxicological concerns. The acceptable level to avoid residual solvents has been established by the International Conference on Harmonisation (ICH Q3C). Using Gas Chromatography (coupled with a Headspace auto sampler) LGC will ensure that your sample is tested to industry recognised guidelines, for example, USP<467> or equivalent and provide assurance on the levels within your sample.

Unknown impurity identification and structural elucidation

Unknown impurities can come from numerous sources, including:

• Process contaminants

• API and/or non-active component degradation during stability trials

• Oxidative polymer additives

• Un-reacted monomers/oligomers

• Extractables and leachables.

Impurities (above 0.1% (ICH Q3A)) that are previously unknown have to be identified and characterised so that their potential toxicological effect can be assessed. LGC has many years of

experience in adapting HPLC methodologies for use with our state-of-the-art mass spectrometry instrumentation to ensure that we can structurally elucidate your unknown compound.

USP <1600> glass delamination studies

Also known as ‘the evaluation of the inner surface durability of glass containers’, this has become a real issue for the pharmaceutical sector following a series of very costly and high profile product recalls. LGC has the necessary experience and a range of state-of-the-art analytical techniques to assess your product in glass vials. We provide protocols for the assessments of your glass containers, artificially stressing and simulating long term use to evaluate and provide reassurance that your product and container will be safe.

Contamination studies

There is an increasing regulatory requirement for the characterisation and counting of visible and sub-visible foreign particles in pharmaceutical products from a safety, quality and efficacy perspective. We understand that the turnaround times are often critical to our clients due to the nature of the requirement of this testing. LGC has a team dedicated solely to providing rapid analysis of your samples, using a selection of microscopic and spectroscopic techniques.

• Optical microscopy

• Scanning electron microscopy with EDX

• FTIR spectro-microscopy.

Many physical properties of a material such as form, solubility, colour, particle shape and size, hardness, flow, density, melt temperature and hygroscopicity are crucial attributes that can determine a product’s stability, manufacturability, handling, and importantly, formulation and bioavailability. We believe in taking a fundamental approach when it comes to materials characterisation to develop a meaningful set of critical quality attributes that define a material. We offer bespoke analyses tailored to meet your development needs including:

• Full solid state characterisation of API, excipients, raw materials and API in formulation for phase identification and quantification using PXRD, FTIR, NIR, DSC, TGA, DVS.

• Surface properties assessment using gas adsorption and iGC, optical and scanning electron microscopy to provide surface area and energy and particle shape/morphological information.

• Bulk powder properties evaluations such as bulk and tapped density measurements and laser diffraction and image analysis using wet and dry dispersion methods for size.

Accelerated stability assessment programme (ASAP)

A humidity-corrected arrhenius equation provides reliable estimates for both temperature and humidity effects on degradation rates for API and drug product stability. Chemical degradation analysis coupled with solid form assessment helps to ensure that shelf life predictions are accurate as possible based on a two week, product specific protocol. This can be advantageous during early stage formulation development, allowing for a product and packaging strategy to be developed.

Excipient compatibility

Assessment of any compatibility issues between the active ingredient and chosen excipients is an essential aspect of drug product development. We have in-house protocols to assess and screen a wide variety of excipients and actives in parallel, with a range of cutting edge analytical instruments and techniques, reducing the time required for development.

Materials characterisation, for the story beneath the surface

We offer bespoke analyses tailored to meet your development needs.

Medical devicesWe work with many of the world’s top medical device design teams to develop and test pharmaceutical medical and delivery devices. From novel inhaled products through to blood monitoring devices, we have the analytical resources to help you.

Packaging selection studies

LGC will work with you to select the correct polymer or product contact materials from the start of your development, often saving a potential problem further into the development process when timelines will be critical. We have temperature and humidity chambers and also light cabinets to assess the longer term suitability of the packaging to environmental factors.

Design verification testing (DVT)

Product registration requires rigorous testing to simulated conditions of use and the requirements of the end user. Design verification testing is carefully carried out using a range of simulated test conditions to mimic the use over the life of the device and product.

Case studyDelivering the best product to the patient requires the right quality attributes for all components in your drug formulation

Challenges:• Overcoming poor bioavailbility from a capsule

formulation.

Science:• Parallel assessment of physical and chemical

characteristics.• Development of a dual detection method

(HPLC-UV-ELSD).• Evaluation of API, excipients and capsules.• Interpretation of complex secondary and tertiary

structure through structural elucidation using X-ray crystallography and electron microscopy.

Solutions and output:• Provided qualitative ranking of preferred excipients

and capsules based on comprehensive chemical and physical testing to ultimately aid drug product formulation.

The smooth running of your outsourced project is dependent upon the skill and experience of the people you are working with. Above all, however, the success of the collaboration relies on great communication. At LGC, we are committed to ensuring that you have a great experience working with us and this, we believe, is a major factor in maintaining our excellent record of repeat business. Our goal is for 100% of our customers to return to us where they have a need for our services.

With a dedicated team of scientists working on your project, you benefit from open channels of communication with a project manager who is close to the experimental work. In the challenging world of drug development, things don’t always go as planned, so everyone at LGC is encouraged to be open and honest about problems as they arise and proactively offer solutions.

LGC is an international science-based company and market leader in the laboratory services, measurement standards, genomics, reference materials and proficiency testing marketplaces. LGC operates in a variety of markets – including, but not confined to, Food & Agriculture, Government, Pharmaceuticals and Biopharmaceuticals and Sports - which underpin the safety, health and security of the public and the regulation of industry, for both private and public sector clients.

With headquarters in Teddington, South West London, LGC employs over 2,000 staff, operating out of 22 countries worldwide. Its operations are extensively accredited to international quality standards such as ISO/IEC 17025.

Set up in 1842 as the Laboratory of the Government Chemist, for more than 100 years LGC has held the unique function of the Government Chemist in the UK. LGC was privatised in 1996 and is now majority-owned by funds managed by Bridgepoint.

Your team at LGC

About LGC

We offer comprehensive analytical solutions to meet the requirements for regulatory compliance of your drug substance and drug product.

Science for a safer world For more information about LGC – our latest results, news, details of our products and services,

please visit the Group’s website at www.lgcgroup.com

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