Quality Assurance not only requires increasing resource but also needs to be introduced at an increasingly early stage of development. Susan Birks reports on trends, regulatory changes and issues affecting quality programmes
Quality Assurance (QA) is all about safeguarding the patient’s well-being, by assuring that operations associated with the production of a medicinal product are of a standard that ensures that the patient’s expectations of safety and efficacy are met. In practice, it is about checking the small print and making sure that what has been declared to have happened, did in fact happen in the manner detailed in the record and produced consistent results.
The scope of QA has steadily increased and today it cuts across all areas – development, quality control, production and distribution. The principles of current Good Manufacturing Practice (cGMP) have been extended to clinical trials operation (Good Clinical Practice) and safety and toxicology studies (Good Laboratory Practice). QA requirements are also extending ever further down the supply chain from active ingredients to excipients and intermediates.
It is a constantly moving target as standards are updated and increasingly couched in terms such as ‘using appropriate methods’, ‘to the extent possible’ and ‘state-of-the-art techniques’. In the past couple of years, the industry has seen new USP chapters drafted on metal impurities; the EU FMD directive introduced requiring oversight of the supply chain; while the growth in biologicals has also led to a raft of new quality issues.
The presence and control of particulate matter has grown in importance
The 2012 outbreak of fungal meningitis in the US, traced to contamination in three lots of a medication used for epidural steroid injections, packaged by the New England Compounding Center in Framingham, MA, saw the introduction in the US of the Compounding Quality Act, which calls for large-scale entities in the compounding industry to voluntarily register with the FDA and comply with guidelines, under section 503B of the FD&C Act. Prior to the new Compounding Quality Act, the fundamental regulation was USP <797> and guidance was provided by state pharmacy boards. The new law expanded the FDA’s role in providing guidance for compounding pharmacies.
Meanwhile, the presence and control of particulate matter has grown in importance. To this end, USP is also developing General Chapter <1790>, Visual Inspection of Injections. This standard is designed to give a comprehensive life-cycle approach for understanding particulate matter, where it can come from and how to control it. In early 2015, it is proposed that a version of General Chapter <1790> will be posted for feedback on Pharmacopeial Forum, the USP’s free-access online resource for posting standards and receiving comments.
As quality requirements have become stricter and monitoring and inspections tougher, more companies have recalled products at short notice, leading in some cases to drug shortages. Some companies have simply been unable to afford the facility upgrades needed to meet the tougher standards. With the number of patients affected by drug shortages rising, the has FDA introduced initiatives, such as Quality by Design (QbD), with the aim of changing the way companies think about quality, moving from a ‘quality by inspection’ (an after-the-event scenario) to building quality into the system from the design stage. While it has taken time to filter through, QbD is now being adopted in numerous areas of drug development and manufacture.
While it has taken time to filter through, QbD is now being adopted in numerous areas of drug development and manufacture
More recently and responding to the drug shortage issue, the International Society for Pharmaceutical Engineering (ISPE) released its Drug Shortages Prevention Plan. Based on responses to a 2013 ISPE Survey, the plan was created in a collective effort by industry experts and US and EU regulatory agencies, and suggests that companies carry out more investigations into the root causes of drug shortages and create a better quality culture to ensure a reliable supply of drugs.
The development of new, better targeted medicines based on biopharmaceuticals, such as monoclonal antibodies (mAbs) or antibody-drug conjugates (ADCs), has brought with it a need for greater product characterisation. The complexity of biologically-based products has led to the suggestion by some in the industry that the monographs for biotherapeutic products need more flexibility than those for a chemically-defined substance or even that biotherapeutics should not have the same monographs as medical products but rather have general recommendations and requirements for their characterisation.
MAbs are one of the fastest growing classes of biopharmaceuticals. These highly complex recombinant proteins are now being used successfully as therapeutics in various disease indications. A myriad of analytical techniques are required, however, to characterise and control the quality of these molecules during their clinical development and commercial production.
Compared with traditional small molecule-based therapies, ADCs create a much greater analytical testing burden, simply because they are made up of an ADC, plus a drug, and a linker.
QA is moving down the supply chain to encompass excipients and intermediates
At a recent biopharmaceuticals quality seminar organised by SGS Life Science Services, speaker Richard Easton (SGS M-Scan Team Leader in Carbohydrate Analysis) explained that ‘all parts of the drug have to be looked at – intermediates, extractables and contaminants’. As a result, drug developers need to know as early as possible what the degradation products are, said Easton, and because what works for one molecule won’t necessarily work for another, a tailored approach is required.
Host cell proteins are the biggest protein contaminant in biopharmaceuticals derived by recombinant DNA-technology. Such proteins are often immunogenic and pose risks to both the efficacy of a drug and also to patient safety and so require protein recovery processes to minimise their content in a final product. Host cell DNA levels are also a contaminant and, as a result, the regulatory bodies have set maximum levels that they consider safe in products.
Viruses pose a threat at all stages of the biopharmaceutical manufacturing process
In addition, biologically-derived materials may be contaminated with infectious agents such as viruses, bacteria and mycoplasmas. Viruses pose a threat at all stages of the biopharmaceutical manufacturing process, from raw materials to cell lines and cell culture, through bulk harvests and biomanufacturing. The precise testing requirements depend on: the origin and nature of the biopharmaceutical material; the intended use of the product; and the requirements of the regulating authorities.
‘During the development of biopharmaceutical products, the threat of cell culture contamination by adventitious agents such as mycoplasma, endotoxins and viruses should not be underestimated,’ said Richard Adair, Virology Manager, SGS Virology, a division of SGS Life Science Services which offers adventitious agent and mycoplasma testing among its services.
Today, drug manufacturers must have an in-depth knowledge and understanding of any new drug substance in terms of its physiochemical properties and structural conformation, and not just the protein therapeutic but also small molecules, excipients, extractables and leachables. The manufacturer also needs to be able to measure both product-related and process-related impurities.
The testing equipment and reagent suppliers are moving quickly to simplify, improve and automate complex but routine testing regimes
Eurofins, which is active in the pharma, food and environmental testing markets, estimates the size of the global pharma and biotech testing market currently to be worth around €5bn.1 While many biopharmaceutical companies outsource such specialised testing, the testing equipment and reagent suppliers are also moving quickly to simplify, improve and automate complex but routine testing regimes. For example, advances in high performance liquid chromatography (HPLC) have improved the analysis of intact mAbs for the determination of low levels of aggregates, variants, and impurities.
In the area of biological molecule purification, Sartorius Stedim Biotech (SSB) has just introduced Denarase endonuclease, a genetically engineered endonuclease from Serratia marcescens. Because of its high activity and ease of use, Denarase is often used in production of viruses and virus-like particles. The enzyme can be added to the cell lysate to rapidly reduce the large amounts of host-DNA and decrease viscosity, thereby rendering subsequent unit operations, such as column chromatography and membrane filtration, much more economical. Denarase is exclusively licensed to SSB by c-LEcta. Its manufacture is based on recombinant expression in Bacillus sp. production bacterium strain and is free of animal-derived compounds.
Clarisolve depth filters from EMD Millipore provide a fast and efficient way to clarify high-density pre-treated feed streams. The filters are specifically tuned to the particle size distribution of various pretreatment methodologies enabling not only fast clarifications but also easy to transfer processes from upstream to downstream without the use of centrifugation. Clarisolve depth filters were designed for high cell density/titre mammalian cell culture feed streams for mAb production. There has also been early success in microbial and vaccine applications.
A shift in emphasis to testing in earlier phases, increasing efforts to reduce cost, stricter regulatory guidance, and a reduction in animal usage is driving the demand for more predictive in vitro ADME and Tox assays and services
According to Paul Brooks, Head of Discovery Research Services at Sigma-Aldrich Corporation: ‘A shift in emphasis to testing in earlier phases of drug discovery and development, increasing efforts to reduce cost, stricter regulatory guidance, and a reduction in animal usage is driving the demand for more predictive in vitro ADME and Tox assays and services.’ Designed to meet the growing demand, BioReliance, Sigma-Aldrich Corporation’s biologics and early-development services business, has introduced selected in vitro ADME (absorption, distribution, metabolism and excretion) and toxicology testing services for pharmaceutical, chemical and other products.
The predictive assays use a novel suite of genetically-modified cell lines created with Sigma-Aldrich’s proprietary CompoZr zinc finger nuclease technology. They help customers predict outcomes by determining levels of permeability, transport, metabolism and toxicity in a drug product. Each cell line is tested for functionality, which means that customers in discovery phases can more easily isolate any compounds that may affect product development before it can affect the safety or efficacy of a possible drug product.