RUO to GMP—Considerations for Biotech Companies

RUO to GMP, upstream and downstream impacts
 

Small and medium-sized biotech companies often must make difficult decisions regarding whether the quality level of materials and processes should be for research use only (RUO) or compliant with good manufacturing practice (GMP). The numerous challenges and pitfalls to navigate when developing biologics manufacturing processes for therapeutic or diagnostic products range from sourcing of raw and starting materials to implementing quality management systems.

At Thermo Fisher Scientific, our aim is to be a reliable partner to biotech firms as you plan your strategy for usage of RUO and GMP materials and products in your biologics process development and seek to understand how your choices may have downstream impacts. Here we suggest considerations to help you make decisions that improve your downstream outcomes.

What does GMP mean?

GMP stands for Good Manufacturing Practices. In general, it is a system of ensuring that any product is made in a way that ensures quality and traceability. For biotech companies, it refers to the set of guidelines and regulations that govern the way that drugs and other therapeutic modalities are manufactured in a way that is controlled, reproducible, and meets quality standards. GMP defines best practices for a company to follow in product development and manufacturing.

There are GMP guidelines for different types of products—from food and beverage production to cosmetics, medical devices, and drugs. Besides GMP guidelines that are followed in the pharmaceutical and medical device industries, there are similarly named guidelines in the health sector and other industries, like GCP (good clinical practice), GDP (good distribution practice), and GAP (good agricultural practice). These have been implemented to set certain minimum standards for quality and provide safe products to end users.

What are GMP guidelines?

Each country or region has its own sets of GMP guidelines. For example, companies operating in America have different GMP guidelines than companies operating in Europe. The diverse range of guidelines has led to the formation of global organizations like the International Council for Harmonisation (ICH) and International Organization for Standardization (ISO) to drive harmonization. In practice, a company must follow general ICH guidelines in addition to specific, regional GMP guidelines.

The first draft of the international GMP guidelines for pharmaceuticals was submitted to the World Health Organization in 1967 and published with some amendments into the international pharmacopoeia in 1971. Since then, more and more countries have adopted these guidelines into national law, which has led to an internationally recognized quality standard for the manufacturing of medicine and medical equipment.

In some countries, a GMP certificate is awarded by an official agency after a thorough inspection. In the US, no certificate is issued—full responsibility for compliance remains with the company. When required by law, governments ensure compliance through review of new product submissions and facility inspections. For example, American GMP guidelines (also referred to as cGMP, for current good manufacturing practice) are enforced by the FDA through regular inspections. Short notice of approximately one week is given for routine inspections. In the European Union, the European Medicines Agency (EMA) is responsible for ensuring compliance to the EU GMP guidelines.

Why is GMP so important?

The main purpose of GMP is to guarantee the safety and effectiveness of a product in its intended use. Without proper quality control and monitoring, human error, equipment failure, mix-ups, and other manufacturing failures will occasionally lead to mistakes in product purity or wrong declaration. The regulatory term commonly applied to a poor-quality product is “adulterated product.” This term indicates the product was not made in compliance with GMP guidelines. In some cases, the consequences are small. However, sometimes adulterated products cause serious impairment or even a major loss of life.

Before the implementation of GMP for example, in a 1937 incident, cough medicine containing impure sulfanilamide led to over 100 deaths in the United States. Another example is the early polio vaccine, which was insufficiently processed and gave many children polio.

The first draft of the international GMP guidelines was submitted to the World Health Organization in 1967 and published with some amendments into the international pharmacopoeia in 1971. Since then, more and more countries have adopted these guidelines into national law, which has led to an internationally recognized quality standard for the manufacturing of medicine and medical equipment.

However, development of international GMP guidelines hasn’t completely prevented the production and sale of dangerous products or otherwise substandard drugs. For example, in 2009, a teething medication containing toxic diethylene glycol went on sale in Nigeria, causing at least 84 infant deaths; in 1999, an incorrectly labeled infusion led to two deaths in Germany. Prevention of mistakes like these by having quality controls in all procedures and processes is why GMP guidelines are so important.

State-of-the-art quality management systems

The overarching theme of GMP is a robust quality management system (QMS), with organizational management behavior being the driving force of compliance. This includes all the processes and systems a manufacturer puts in place to ensure the product’s quality is consistently high. Similar to GMP, the International Organization for Standardization (ISO) has defined a series of quality management norms (e.g., ISO 9000 and 9001), to which companies can certify voluntarily. Because the principles underlying GMP and ISO guidelines are the same, there is considerable overlap between them.

QMS includes various elements such as:

• Documentation requirements, including storage of information
• Standard operating procedures (SOPs)
• Qualification procedures for equipment and materials
• Qualification and training of people performing work
• Validation of processes and test methods
• Audits

QMS often implements the Plan-Do-Check-Action (PDCA) cycle:

• Plan: In this phase, a company sets goals for an action and ensures all necessary preparations and precautions are taken and documented.
• Do: This phase refers to implementation. For a new product, this may include testing on a small scale to minimize potential damage.
• Check: Data from implementation or testing are analyzed. If there are any unexpected outcomes, changes must be made.
• Action: In this phase, the system is refined to work as intended and all documentation is updated. However, the PDCA cycle does not end there (hence the word “cycle”), and continual improvement is achieved by repeating all steps within the cycle.

There are numerous quality techniques that focus on one or more segments of the PDCA cycle. Such techniques include Kaizen improvement events, GEMBA reviews of work areas, 5 Why questioning, error-proofing practices, and implementation of computer-controlled error detection systems.

FDA Guidelines for vendor qualification

Producers of biotherapeutics must make sure that every component in the manufacture, processing, and storage of the product is supplied by a qualified vendor. To that end, the vendor selection and qualification process requires:

• Specification- Indicate clear expectations for a QMS and any certifications. Documenting specifications for product quality, including product identity and purity, are critically important; also include specifications for production volume and delivery times.
• Verification- Conduct an audit and/or site visit to ensure that the vendor is capable of complying with the specifications and other terms of the contract. The detail level of the audit, and whether a site visit is necessary, will depend on the criticality of the vendor’s component product to your sellable biopharmaceutical product.
• Monitoring- Schedule routine audits throughout the contract period to monitor performance and adherence to the vendor agreement with respect to the QMS.

RUO- vs. GMP - compliant biologics and starting materials

In addition to the broader GMP guidelines, there are also more specific rules when dealing with products made from biological sources. The WHO defines a list of biological substances to which different GMP quality criteria should be applied. These biologicals differ by their source and include:

• Products from non-transgenic animal or plant sources (e.g., heparin or insulin)
• Products from transgenic animal, plant, or bacterial sources (e.g., recombinant proteins)
• Products made from bacterial cell lines or viruses (e.g., vaccines, enzymes)
• Products from human sources (e.g., stem cell lines)

An examples of a GMP-compliant biologics production process is culture of a GMP-compliant cell line used in production of a recombinant protein that will become part of the biopharmaceutical product.

Important terminology for pharma GMP

For biotech companies developing pharmaceutical or diagnostic products, it is important to understand some key terms. Both the ICH Guideline for Common Technical Document (CTD) Quality Sections and the FDA Guidance for Industry M4Q distinguish between raw materials, source or starting materials, and excipients.

• Raw materials are components or reagents that are used during the manufacture of the therapeutic product.
• Source or starting materials are intended to become part of the active biological substance in the final therapeutic product.
• Excipients are intended to be inactive and include everything that is used in the final formulation of the therapeutic product, except for the active substance and the labeled container closure.

Guidelines that apply to source or starting materials may be straightforward, but their application is often complicated. Raw materials require qualification and assessment of risk with respect to safety and performance.

For source or starting materials like donor cells or viral vectors, the guidelines can help companies to focus on understanding the purity profile or early characterization of the biological activity, for example, many viral vectors have their own starting materials. When working with plasmid DNA, it is important to have a complete understanding of its identity. For cell banks, a good understanding of a cell line’s history is key, and viral safety information is critical.

Materials of animal origin

One of the key questions related to source is whether it is acceptable to use raw materials that may contain human or animal-origin components. These could be present at the product level or at the production level. Companies should aim to avoid animal-origin components when possible. If avoidance is not possible, a risk-based approach for the selection of raw materials is important. It pays off to give some consideration to the country of origin, source of material, viral testing and inactivation, grade of material, upstream vs. downstream use, possible alternatives, and supplier traceability.

When assessing risk associated with the use of a material of animal origin, it is often important to investigate multiple levels of processing. Most vendors who provide such materials to the cell and gene therapy industry have an animal policy statement. By having a certified animal origin-free product, the need to prove viral safety of biologically derived components is removed.

How to qualify raw materials and assess their risk

• Consider raw material risk early in product development.
• Develop a material qualification program.
• Use a structured risk assessment strategy to evaluate the overall safety of using a raw material in the manufacturing process.
• Consider overall quality with respect to identity, purity, and biological safety profiles, including exposure to adventitious agents when evaluating risk related to raw materials.
• Have mitigation strategies in place.
• Evaluate business and supply chain risks.

When sourcing any material, it is crucial to understand where the material is coming from, look beyond the marketing information, and ask the right questions—marketing terms may not mean what you think. “GMP” grade, for example, is not a “grade” but a quality system (a grade is a set of test methods and acceptance criteria that sufficiently characterize the material). No general legal requirement for GMP exists for raw materials; they are not regulated by government agencies but controlled by the company using the raw material.

There are several quality claims different suppliers make, such as medicinal, clinical device or clinical grade, pharmacopoeia grade, EDQM certificate of suitability, cGMP/GMP grade, research use only, or lab use only. Key characterization tests for raw materials include identity, purity and impurities, content, biological activity, and other similar parameters. Traceability and documentation also play a big part in raw material risk assessment and are demonstrated by certificates of analysis, origin, and compliance; safety data sheets; and regulatory support files. Master files can be useful in countries that support master file processes for raw materials, such as the US, Canada, and Japan. Finally, a robust supply chain is important to ensure continuity.

Small-molecule chemical materials can be fully characterized by physicochemical methods. For many, a common pharmaceutical quality can be defined. The term “chemically defined” comes with some caveats, though. For example, highly purified and homogeneous recombinant proteins are included despite biologically derived materials being inherently heterogenous. Recombinant proteins still pose adventitious risks, depending on their expression system and other materials used in manufacture. They should not be assumed to be inherently safer.

To avoid common regulatory hurdles and pitfalls when dealing with raw and starting materials, due diligence is crucial before raw materials are used for clinical manufacturing. This can be done by looking at all the supplier documentation that comes with the product, comparing it to the regulatory guidance, and checking to see if there are any gaps or if further evidence from the supplier is needed.

If possible, choose solutions that have been successfully validated and implemented into a manufacturing process similar to yours.

Producing GMP-compliant cells

The following aspects are important when producing GMP-compliant cells:

• The source, origin, and suitability of active substances, starting materials (like cryo-protectants and feeder cells), buffers and media (reagents, growth media, sera, enzymes, cytokines, growth factors, amino acids, etc.), and other components of the finished product should be clearly defined and controlled according to the WHO GMP guidance for pharmaceutical products. This again emphasizes the importance of high-quality starting materials to ensure the GMP status of the product.
• Manufacturers should retain information about the source and quality of the source biological materials for at least one year after the finished product’s expiry date. They should also comply with local regulations concerning biological products. All starting material suppliers should be initially qualified based on a risk-evaluation approach with documented criteria. Regular assessments of their status should also be carried out.
• The contamination risk of the starting materials during their passage along the supply chain should be assessed, with particular emphasis on the potential of the presence of adventitious agents such as those causing transmissible spongiform encephalopathies (TSEs).
• The production of certain biological products like vaccines starts with microbial cultures, cell cultures, or propagation in embryos and animals. However, repeated subcultures and multiple cell generations can cause unwanted drift of genetic properties.
• To prevent genetic drift, labs should use a system of masters and working seed lots and/or cell banks. The number of generations, expressed as passages or doublings, between the seed lot or cell bank and the finished product should be consistent with the marketing authorization dossier.

In addition to these requirements, there are many more rules a manufacturer of GMP-compliant cell materials must follow. Achieving GMP status can take time and expertise—it’s definitely not an easy task. To get an idea of the steps and requirements for GMP-compliant biologicals, consult the official WHO document.

Downstream considerations: RUO vs. GMP

Some materials and chemicals are labeled “for research use only” (RUO). This means that the products are intended by the manufacturer to be used only for research and not for manufacturing or product testing. RUO materials probably have not been produced according to GMP standard. RUO also indicates that the materials are not to be used to manufacture any products for human use without validation. RUO product can be used for medical applications, but this requires significantly more effort to ensure that the RUO material is suitable and effective for the intended use. Validation and qualification of RUO materials can lead to significant additional costs, so it is advisable to use GMP-compliant materials from the start to make sure the end- product is compliant.

Obviously, it is much easier and more cost-effective to use RUO materials. For some applications, it would be far too expensive to use only GMP-compliant starting materials, unless they are absolutely required. Therefore, both types of materials have their place in product development and manufacturing.

When should you take the leap from RUO to GMP during the discovery phase?

GMP guidelines are often formulated in general terms, so the real value lies in knowing how to interpret them. How do these guidelines relate to your specific work and the decisions you need to make early on to ensure getting to clinical trials and manufacturing is easier?

When exactly should you make that switch? Among other factors, it depends on your risk sensitivity and your cost sensitivity. For biotech companies specifically developing a therapeutic or diagnostic, switching from RUO to GMP often makes sense as soon as you have identified your target.

By choosing reagents, components of your process, media, etc., early on that will meet the most rigorous regulatory expectations that will come later in development, it is possible to avoid the need to make changes, justify those changes and go through the change control process as you get closer to the clinical and commercial stages.

Working with suppliers and partners to implement or transfer GMP processes

If an assay is transferred to external partners, for example, they would need to decide whether they must develop it again from scratch or if they can do a technology transfer. In this case, it also depends on the type of assay that is developed from RUO to a validated system. Some are easy, others are difficult. Consequently, choosing a supplier that offers a wide range of products in both RUO and GMP categories increases flexibility.

For biotech companies transitioning from RUO to GMP-compliant processes, it pays to contact an expert to help. Implement processes step by step, make sure you get the official GMP certificates, and maintain product quality, as unannounced inspections can happen on short notice. Think about what you must communicate ahead of time so your partner of choice can give you the most relevant advice. Be aware that there are different regulations to consider; the devil is in the details.

Some useful questions to ask yourself while seeking help from experts at suppliers and regulatory authorities are:

• What are the challenges of unique new raw materials and technologies?
• What are the regulatory considerations?
• What are the key differences between EMA and FDA regulatory requirements we need to be aware of?
• When should our company or process be “GMP ready”?
• Do we need to consider a global raw material approach early on?
   

Example: Cell Therapy Systems (CTS) products

Biotech companies that are manufacturing state-of-the-art cell and gene therapies are transforming lives by making better therapies more accessible. To realize these advances on a larger scale, ensuring the safety and availability of these medicines is crucial. The Cell Therapy Systems (CTS) line of products is manufactured in accordance with GMP and ISO standards, providing you assurance that these products meet high quality standards and can be used as you transition your process from RUO to GMP.

As you move from basic cell therapy research to the clinic, high-quality GMP-manufactured cell therapy ancillary materials and proper documentation are essential. Thermo Fisher Scientific offers both RUO and CMP products to support the research, development, and manufacturing of cell and gene therapies. Our CTS products carry specific use statements and regulatory documentation to facilitate regulatory filings, so you can transition your therapy to the clinic with confidence.

What does GMP mean at Thermo Fisher Scientific?

Supply companies often use GMP as an umbrella term to describe the manufacturing controls they have in place to help their customers make products that fulfill their regulatory obligations. Supply companies often aren’t using GMP to say their materials meet a government’s regulations and their manufacturing facility has been audited by the regulatory authority.

Here is what we mean when we say a Thermo Fisher Scientific product complies with GMP. It is a product manufactured under a quality management system that is certified to the ISO standard of ISO 9001 or ISO 13485 and ensures the following GMP guidelines are met:

• Documented processes and change control
• Personnel training programs
• Materials management
• Vendor qualification/monitoring
• Equipment, processes, test methods are validated
• Facility maintenance, safety programs, and pest control
• Batch release by QA
• Product shelf life established

Thermo Fisher Scientific GMP products can support your efforts to produce products that function consistently as intended. We follow quality standards in manufacturing, testing, documentation, and proven use. Our -CTS products, intended for use in GMP production, are manufactured at sites that are FDA registered, ISO 13485 certified, and regulatory audited. We provide traceability documentation and certificates of origin, upon request. To help ensure product safety, we test for sterility and the presence of endotoxins and mycoplasma for media and reagents. Our CTS products have been used in over 200 clinical trials.

Conclusion

Companies developing a therapeutic or diagnostic product must navigate countless regulatory challenges and make strategic decisions about when to switch from RUO to GMP products. Assessing how the transition from RUO to GMP impacts upstream and downstream decisions is no trivial task.

At Thermo Fisher Scientific, we work with our customers to navigate the complex questions along the way. Regarding the qualification strategy for raw materials, key areas we focus on include materials sourcing, the quality of the manufacturing, the characterization testing, and the traceability documentation.

Our mission is to help you with decisions in the discovery phase so that downstream steps are more streamlined. Our global regulatory affairs team continually monitors the regulatory landscape for new and emerging regulations and assesses the impact of these on our products and services.

Thermo Fisher Scientific supports biotherapeutic development from discovery to commercialization.
Learn more at - thermofisher.com/biotech

Resources

1. Thermo Fisher Scientific Cell Therapy Systems: a proven choice for clinical cell therapy manufacturing
2. Thermo Fisher Scientific on-demand webinar: Regulatory FAQs and common concerns for cell and gene therapy raw and starting materials