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Trace elements in raw materials may impact the quality and safety of the finished biologic product, according to industry experts.
Raw materials used in bioprocessing must be free from any elements that may potentially affect the quality and safety of biopharmaceuticals. The nature of upstream processing presents an environment that may increase the potential for these elements to interact with target cells during bioprocessing.
BioPharm International spoke with Nandu Deorkar, vice-president of research and development at Avantor, and Brian Follstad, director of upstream process development at Catalent Biologics, Madison, about standards and best practices for ensuring the purity of raw materials used in upstream processing.
BioPharm: What standards must be met when sourcing raw materials for bioprocessing?
Deorkar (Avantor): Several organizations define sourcing and manufacturing best practices for the global biopharmaceutical market. Major regulatory agencies, such as FDA and UK Medicines and Healthcare products Regulatory Agency (MHRA), are tightening regulations and pushing for stricter norms for biopharma companies, not only in terms of manufacturing practices, but also where they source their ingredients or components.
For example, Avantor has focused on compliance efforts for the International Council for Harmonization’s (ICH) Q7 (for APIs) and International Pharma Excipients Council (IPEC) (for bulk pharmaceutical excipients) guidelines to continuously improve our systems and ensure quality, safety, and functionality of biopharmaceutical excipients.
In addition, raw materials suppliers are making an effort to better understand and control the purity and consistency of materials sourced and manufactured for bioprocessing.
New investigations into areas such as trace metals in cell-culture media, and carbohydrate sources and materials used to regulate pH factors in bioreactors, are being made so we can better determine how trace metal levels and the lot-to-lot consistency affect upstream and downstream bioprocessing.
Follstad (Catalent Biologics): ICH requirements for pharmaceuticals for human use serve as the basis for any bioprocessing raw materials standards. For upstream processes, chemically defined and animal component-free components should be used for all process raw materials, with the minimal addition of components that require clearance testing such as recombinant insulin and antifoam.
Extractables and leachables (E&Ls) should be assessed for process raw materials as well, particularly those that contact the culture for an extended period of time. Also, we require a commitment from the supplier to support GMP-grade material for large-scale GMP manufacturing for clinical and commercial batches. This approach lowers both the regulatory and supplier risk for our clients.
BioPharm: What practices/strategies are used to ensure that one has a stable supply of quality raw material for bioprocessing?
Follstad (Catalent Biologics): We typically get a written commitment from the supplier to support GMP-grade material for large-scale GMP manufacturing for clinical and commercial batches; this documentation is particularly important if the raw material is currently not a commercial product. We are also in regular contact with the suppliers to ensure that their manufacturing lead times and our production run schedules are aligned.
Additionally, we validate multiple suppliers for the same raw material, where possible. Finally, adopting a platform approach to raw materials across multiple projects helps tremendously in reducing the effort required to manage the logistics of handling project-specific custom components.
Deorkar (Avantor): Current good manufacturing practices (cGMPs) are being implemented globally to ensure that biopharmaceutical products can be safely and consistently manufactured and tested to meet strict levels for quality and safety before they reach the marketplace.
For biologic-drug manufacturers, securing well-characterized raw materials that consistently meet quality standards in every lot is also critical to safeguard their global supply chains.
Given these needs for well-characterized raw materials, bioprocessing materials suppliers are responding to developments in cGMP manufacturing and supply chain management with expanded production and supply chain footprints to key regions around the globe.
Having local manufacturing sites, however, is not enough. Globalized and standardized quality systems at production facilities, no matter where they are located, help ensure consistency and continuity.
Raw materials suppliers should implement systems and processes to achieve consistent quality, uninterrupted supply, and availability of necessary documentation to support transparency efforts.
Facility audits and product quality monitoring are an important part of supplier quality management, too.
Avantor has installed Master Control QMS software across many of our cGMP manufacturing sites across the globe to manage documents, quality training, corrective and preventive actions, and other operations. ICHQ7 and IPEC guidelines helped shape the company’s change management process.
BioPharm: How does the quality of the raw materials impact the quality and therapeutic efficacy of the end biological product?
Deorkar (Avantor): Biologic-based therapeutics are produced using systems that are known to be inherently variable, a feature which has important consequences for the reproducibility, safety, and efficacy of the resulting biologics.
Slight changes in the raw materials used in bioprocessing, such as the presence of trace metals or reactive impurities, can affect product quality, safety, and efficacy. It is crucial to ensure that all clinically active attributes of the biotherapeutic, including protein posttranslational modifications (PTMs), are accounted for and confirmed.
One such PTM is protein glycosylation, where carbohydrates attach to a protein structure. It’s been recognized that glycosylation can be a critical quality attribute for proteins as therapeutic molecules. Protein glycosylation often plays a key role in the efficacy, safety, stability, and functionality of the protein, which is why minimal changes-at the parts-per-billion levels of certain elemental impurities like trace metals-can impact glycosylation patterns and reduce target cell growth.
Although the impact of low levels of trace metals has been researched extensively, the focus has usually been on how those trace metal levels affect protein expression and process yield. New attention is now being given-and Avantor is conducting multiple studies-to assessing the impact of lot-to-lot variability of trace metal impurities in upstream processing and protein glycosylation.
Follstad (Catalent Biologics): The scientific literature is full of examples linking upstream raw materials to product quality attributes (PQAs). Media trace elements such as copper and manganese can impact glycosylation and other PQAs even at the trace contaminate concentration level; this is important since media suppliers still have difficulty sourcing high purity trace elements. Also, raw materials such as single-use bioreactors (SUBs) should be assessed for E&Ls in accordance with the use of the materials (process time, temperature, and materials used such as culture medium). Some SUB manufacturers provide options for the SUB contact layer if a cell line is particularly sensitive to a particular E&L profile. Given these process sensitivities, a raw material risk assessment is a requirement for late-stage process development during process characterization as well as post-approval lifecycle management to assess the impact of any changes in raw material specifications on the process.
BioPharm: Concerns over product purity remain a major issue in bioprocessing; what challenges do particular raw materials present to product purity (e.g., E&L, trace metal contamination, etc.)?
Deorkar (Avantor): Quality and consistency of raw materials is critical for managing the quality of biopharmaceutical product discovery and development. Based on research, the most common elements that impact the glycosylation pattern include zinc, aluminum, manganese, molybdenum, and iron. An additional group of trace metals include copper and nickel.
Avantor has studied the impact of variations of trace iron levels, examining a range of levels between 100 to 300 parts-per-billion. For example, in the molecule we studied, if iron levels exceeded 300 ppb, we observed a change in glycosylation in an antibody particle within the molecule.
Further study into the impact of changes in lot-to-lot-consistency of trace metal levels will be valuable given what is already understood about how low levels of trace metals can affect glycosylation patterns. However, all elemental impurities must be closely monitored in all incoming raw materials.
Also, biopharmaceutical manufacturers and raw materials suppliers should be aware that upstream process conditions can affect how trace metals interact with the target cell during bioprocessing.
Factors such as cell environment, outside media, and media temperature can all affect trace element uptake and how they metabolize in the cells.
Biopharma manufacturers and raw material suppliers need to have a broader appreciation of the avenues by which trace metals are introduced into upstream processing. This includes cell culture media, carbohydrate energy sources like sucrose and glucose, and pH control agents such as sodium bicarbonate. In addition, some biopharmaceutical producers have determined that introducing mineral elements as supplements can aid in achieving targeted yields; however, if these elements are already present as trace metals from other sources, the bioprocessing results may not achieve desired targets.
Vol. 31, No. 9
When referring to this article, please cite it as S. Haigney, "Elements in Raw Materials May Impact Product Quality," BioPharm International 31 (9) 2018.