One of the major differences between research-use only (RUO) and current good manufacturing practice (CGMP)-manufactured raw materials is the quality systems in place to ensure consistency. Raw materials are reagents and/or ancillary materials used in the manufacturing of drug substances or active pharmaceutical ingredients. Because of the strong link to the final drug product, it is critical these materials meet appropriate quality standards and specifications to increase productivity, process recovery and patient safety.
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Drugs in commercial production must be manufactured under conditions and protocols required by CGMP regulations to assure quality is built into the design and manufacturing process at every step. However, the need for CGMP supplies could begin as early as phase 1 clinical trials. Therefore, it is never too early to consider CGMP requirements during R&D or process development phases.
Set regionally, CGMPs are based on guidelines developed by the International Conference on Harmonization (ICH), Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme (PIC/S) and regulatory agencies.&#;
These regulations are meant to assure the identity, strength, quality and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations. They focus on preventing cross contamination and keeping environmental contaminants out of the product in all aspects of production &#; from starting materials and facilities to staff training and hygiene practices. There is no CGMP certification; they are standards to maintain quality and purity characteristics in pharmaceutical development.
Some of the most frequently referenced regulatory statements and guidelines include, but are not limited to:
It is essential to consider CGMP compliance early in development rather than waiting until late clinical trials and/or large-scale production. Using well-characterized, high quality and CGMP raw materials and reagents earlier in the transition to large-scale commercial manufacturing makes for a seamless transition &#; maintaining quality and viability while avoiding additional costs, potential process re-development and lost production time.
When you identify suppliers of higher quality reagents ahead of time &#; chemicals that have been extensively tested and documented &#; you gain heightened supply chain security and assurance of regulatory compliance. Use CGMP raw materials during development to:
The reagents needed for clinical manufacturing must meet additional regulatory requirements to validate sterility, consistency and efficacy. This includes quality control testing of incoming raw materials, increased documentation to show manufacturing control and robust process validation.
Key challenges that early use of CGMP may address include:
It is important to note that any change in materials at a late stage in development, even one so benign as salt, can lead to delays, added expenses and possible process redevelopment. So, while there is increased cost in using CGMP materials early, the greater danger lies in potential scale-up issues or batch failure.
Aside from the regulatory requirement to ensure personnel authorized to release a batch have the information necessary to make decisions, it ensures all personnel connected with manufacturing know what to do and when to do it. When it comes to producing commercial biopharmaceuticals, if it&#;s not documented, it didn&#;t happen.
Documentation serves as a traceable record that a supplier&#;s manufacturing facility, processes and operators are fully qualified, providing a complete account of the manufacturing activities of each batch of biological product. Further, it provides an audit trail which allows for investigation should deviations occur and must allow for another person to be able to accurately reconstruct what transpired.
Starting materials may require additional documentation on source, origin, supply chain, method of manufacture and controls applied to ensure an appropriate level of control, including of microbiological quality, if applicable.
Key challenges that early use of CGMP materials may address include:
Documentation must reflect not just varying regional requirements but detail the strict procedural and environmental controls necessary for regulatory filings. The manufacturing of biologics drugs across regions governed by different regulatory bodies necessitates multi-compendial classification. Manufacturers must try to strike a delicate balance between speed and quality to meet deadlines. Proper documentation serves as a strong foundation for effective technology transfer.
It is not a box to be checked, but should be a systematic approach&#;to acquiring, analyzing, storing and disseminating information related to products, manufacturing processes and components. As regulatory guidance continues to evolve in a climate of accelerated and compressed timelines, risks related to process development and manufacturing increase.
Collaborative planning, smart forecasting and sales and operations planning are needed to keep your CGMP materials in stock to hit your manufacturing goals. This is particularly critical in the transition to commercialization, as the volume of raw materials needed will increase significantly. The importance of clear and transparent communication with suppliers cannot be understated.
Establishing a comprehensive supply chain strategy, as well as a robust management of change program, as early as possible mitigates risk.
Key challenges that early use of CGMP may address include:
Business continuity and redundant manufacturing are also key parts of supply chain control. Dual sourcing can eliminate late changes in material or scale. The caveat here is to make sure both contracted suppliers get materials from truly different sources and to not use two companies that source from the same place.
Geographic redundancy is another large risk that many companies underestimate. Specialized and proprietary materials are often located in one place, leaving them vulnerable to catastrophic events such as power outages coupled with generator failure. Any of these critical proprietary reagents should be in multiple locations for true redundancy; ideally with one version at a biorepository.
Selection of a globally established material supplier that also has a biorepository service offers the necessary redundancies and supply chain security, such as multiple sites qualified for materials, access to new sources of materials and the ability to hold inventory in strategic geographic localities.
Using CGMP materials earlier in development simplifies technology transfer, making the transition less demanding. Developing vendor partnerships early in the design phase will improve process efficiency and minimize future errors, especially regarding quality and regulatory compliance.
The U.S. FDA recommends a written and approved contract or formal agreement between a company and its contractors that defines in detail the GMP responsibilities, including the quality measures, of each party. This is the safest way to ensure CGMP compliance, as well as Certified ISO and ISO quality systems and animal origin-free or EMA/410/01 compliant materials.
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Key challenges that early use of CGMP may address include:
To completely manage supply chain risk, choose a partner with extensive experience in manufacturing biological products and access to a broad portfolio of quality products, from multiple qualified sources. They should be able to provide all elements required for CGMP; from a qualified and trained staff and approved procedures to sterile premises and suitable storage and transport.
Through ongoing collaboration and clear communication, developers can achieve a seamless transition to commercialization. Designing for full GMP production at the pilot scale helps to identify and eliminate potential hurdles later and ensures quality of the product throughout its lifecycle. The upfront costs are overcome in the long term, as changes in materials can lead to process variability and potential rework of your facility, equipment and process steps. &#;The product is the process&#; holds true.
Before the ratification of regulatory guidelines from The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q8&#;Q11 (1&#;4) &#; whose scope includes raw materials for biopharmaceutical production &#; many drug manufacturers chose the most cost-effective and readily available raw materials sourcing options without specifically considering the provenance of those materials. Depending on the chosen supply chain, such materials could be of widely varying quality and not necessarily suitable for a destined application. Raw-material sourcing for bioprocesses is not a one-size-fits-all operation.
Why Source Matters
When sourced materials exceed quality standards, excessive cost is the main issue. However, in the case of substandard materials, patient-health risks become the primary cause for concern. Perhaps the most well-known example of the detriment that substandard materials can cause is the heparin incident. A contract laboratory sourced what it thought was adequate-quality porcine heparin from China. It turned out to be contaminated with oversulfated chondroitin, which was not identified until it was too late. The laboratory&#;s client had already used the ingredient in formulated drug product administered to patients. The end result was 80 patient deaths and hundreds more patients reporting adverse health effects.
The heparin incident (and other contamination incidents) led to more stringent regulations to prevent such sourcing-derived problems from reoccurring. Those requirements are enshrined in the ICH Q11 guideline (4), which biopharmaceutical manufacturers are now striving to implement for their manufacturing processes.
By extension of the ICH Q11 requirements and stipulations placed on drug manufacturers, raw materials suppliers should provide a number of data points to support risk-management and control strategies. Such data include whether a material is of biologic or synthetic origin, in which facility a material was made, how it was handled and packaged, and any change- control elements. Suppliers also should include information about any potentially toxic substances that were used during their manufacturing processes, such as heavy metal catalysts and solvents. This list is not exhaustive; any other information that could affect a raw material&#;s quality also should be included.
Do: Determine What Level of Quality Is Required
There is a misconception that every raw material used in a biopharmaceutical process must be US Pharmacopeial (USP) or good manufacturing practice (GMP) verified, or both. Although requesting prices for GMP material might seem simple when contacting potential suppliers, providing all documentation demanded for a GMP ingredient may be unnecessary, particularly for certain raw materials used in early stages of fermentation. This is why a careful risk assessment of the entire process is essential.
Don&#;t: Assume That &#;GMP&#; Means the Same to All Suppliers
GMP is a generic term applied to many different industries, not all of which may meet the needs of a bioprocess. To a supplier whose business is focused on the production of active pharmaceutical ingredients (APIs) and late-stage intermediates for small-molecule drugs, GMP would mean something very different than it does to a company specializing in ingredients destined for the food-manufacturing sector. API GMP standards usually far exceed what is necessary for bioprocess raw materials &#; and thus add unnecessary cost. By contrast, food- grade (or other grade) materials are unlikely to come with the supply chain traceability that is necessary for a bioprocess. Although no general definition yet describes exactly what level of raw material traceability and control is suitable for a bioprocess, the GMP standards demanded for excipients are being recognised as broadly appropriate. The joint International Pharmaceutical Excipients Council &#; Pharmaceutical Quality Group (IPEC-PQG) GMP guidelines for excipients are the most useful set of rules to reference.
Don&#;t: Assume That &#;USP Quality&#; Will Be Suitable or Even Available
USP also can have different meanings. An ingredient should claim to meet USP requirements only if it has met the analytical standards laid out within the USP compendium and has been processed under conditions that meet GMP standards. Yet some suppliers omit those processing conditions and claim USP compliance if an ingredient meets the analytical criteria alone. Some suppliers provide no indication about the conditions in which their ingredients were made, handled, and packaged. So a given ingredient actually might not be suitable for a bioprocess. Demanding that USP standards be met for all raw materials is pointless, because many ingredients used in biopharmaceutical manufacture are not listed in the USP compendia or other compendial listings and thus cannot (by definition) be supplied in USP or other compendial quality.
Do: Find Out Whether a Supplier Has Internal Bioprocess-Specific Standards
Many big chemical suppliers that are active in the biopharmaceutical sector already have developed a set of internal standards for raw materials destined for bioprocesses. Those suppliers will cherry-pick the most relevant parts of GMP, USP, IPEC, and other quality systems organizations while omitting those parts that are unnecessary. The result is a set of cost- effective raw materials that are designed for bioprocessing. In such cases, a supplier can help you determine whether a material indeed will be suitable for a specific bioprocessing step. If it is not, the supplier can suggest what might be acceptable to balance quality and cost.
Don&#;t: Assume That All Raw Materials from China Should Be Avoided
The heparin incident has led to a misconception that Chinese suppliers should not be trusted to supply quality raw materials and that supply chain problems will vanish if China is avoided. This is simply not the case. Although a great deal of small molecules are easy to source from multiple suppliers in many countries, some specific raw materials (e.g., sugars, salts, amino acids, and trace metals) are predominantly produced in China. An internal blanket-sourcing ban would leave very few options, if any, for those essential components.
Do: Identify Reliable Chinese Suppliers
With so many Chinese companies offering raw materials to the biopharmaceutical industry, ostracizing an entirely competent segment of suppliers would be counterproductive to finding a solution. In some cases, a company selling ingredients might also be the original manufacturer, but it is more likely that a third- party exporter (providing no clue about where materials were made) is selling them. Carrying out visits and audits to check whether production standards meet requirements is an expensive and onerous task. Often, the best way forward is to engage a trusted supplier based in the United States or Europe that has the resources to identify potential sources in China and carry out audits through its own Chinese procurement and audit specialists. That supplier should also be able to provide important traceability documentation and, if necessary, reprocess sourced material in its own facility so it meets correct quality standards.
Don&#;t: Assume That if It&#;s Made in the West, Then It Will Be Safer
Conversely, there is a similar misconception that anything sourced from one of the big Western chemical conglomerates is guaranteed to meet quality requirements. That is not the case. Big chemical companies make the vast majority of their money selling large volumes of chemicals into sectors such as oil exploration or plastics manufacture. Even if one of their products happens to be required in a bioprocess, it is unlikely to meet the stricter quality standards for pharmaceutical manufacturing. Worse, because biopharmaceutical manufacturing could represent such a minuscule proportion of sales for that chemical, the company is likely to be unwilling to put in the effort to complete the necessary paperwork and analytical work to satisfy biopharmaceutical regulators. A Western chemical supplier also may have insufficient microbiological control in the handling and packaging processes or a lack of appropriate change-control systems.
Do: Use a Pharma-Dedicated Third-Party Supplier
All of the above drawbacks can be prevented if you use a trusted third-party supplier. Such a supplier can have several customers looking for bioprocess-specific materials, and their combined volume demand puts those customers in a much better position to persuade big chemical companies to meet all additional requirements of the biopharmaceutical sector. Such suppliers also can process materials further (e.g., by using distillation, recrystallization, or salt formation) to reduce levels of contaminants such as heavy metals or solvent residues and to meet targeted biopharmaceutical specifications. A trusted third- party supplier also can carry out all analytical testing the original manufacturer is unable to perform.
Don&#;t: Assume Materials Must Be Sourced from Original Manufacturers
A recent update to the European Union&#;s (EU&#;s) GMP guidelines (6) states that, when possible, raw materials should be procured from the original manufacturer. Although the reasoning behind that statement is sound, in practice it is not feasible to purchase every chemical component directly from myriad manufacturers. The intent of the guideline is to ensure full traceability of all materials back to where they were actually made and to prevent complex supply chains of traders where the identity of the original source is obscured. The guideline should not be interpreted to dictate that all third parties are to be avoided. When dealing directly with an original manufacturer, a biopharmaceutical manufacturer that wants to purchase only a few grams of a substance can find it very difficult to extract the necessary documentation and to gain audit access. As with sourcing from chemical conglomerates, using an experienced large third-party supplier will facilitate such tasks, because the increased purchasing power gives the supplier greater weight to request information. It also can significantly expedite the entire process, both for materials manufacturers (that now need deal with only one customer) and for biopharmaceutical companies (that will now not waste months verifying that the material meets all FDA and EMA requirements).
Safety First
Sourcing all individual components that go into a bioprocess and ensuring that such materials meet quality requirements is a huge task. By preventing the pitfalls and misconceptions (and using a trusted third-party supplier where appropriate), you can make that task more manageable while keeping costs down. All of this contributes to the development of a safe and efficient product, backed up by a reliable raw materials supply chain.
References
1 ICH Q8(R2) Pharmaceutical Development. Fed. Reg. 71(98) .
2 ICH Q9 Quality Risk Management. Fed. Reg. 71(106) : &#;.
3 ICH Q10 Pharmaceutical Quality System. Fed. Reg. 74(66) : &#;.
4 ICH Q11 Development and Manufacture of Drug Substances. Fed. Reg. 77(224) : &#;.
5 The Joint IPEC &#; PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients ; http://ipec-europe.org/UPLOADS/IPEC_PQG_GMP_Guide_(1).pdf.
6 EU Guide to GMP for Medicinal Products, Part 1, Chapter 5; http://www.ecv.de/leseproben/.pdf
Douglas Bowman is a program manager of PharmaGrade at SAFC; [ protected].
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