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.
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.
CGMPS: The bedrock of quality
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:
- The U.S. Current Good Manufacturing Practices for Finished Pharmaceuticals regulations (U.S. CGMPs)
- The Guide to Good Manufacturing Practice for Medicinal Products of the European Union (EC GMP Guide)
- MHRA Medicines and Healthcare Products Regulatory Agency
- ANVISA Agencia Nacional de Vigiloncia Sanitaria
- The Ministry of Health, Labour & Welfare (MHLW) Standards for Manufacturing Control and Quality Control for Drugs and Quasi-Drugs
- The ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
- The World Health Organization (WHO) good manufacturing practices
CGMP compliance during developmentIt 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:
- Develop characterization analytics for key quality attributes (e.g., potency, purity) to ensure product consistency
- Minimize risk of contamination or aberrant results due to a less controlled manufacturing process of the raw materials
- Provide material traceability to support regulatory compliance
- Eliminate requalification of material due to unavailable grade and quantity of material after technology transfer
- Evaluate reliable sources of supply and global regulatory requirements
Challenges of early CGMP use
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:
- Lot release testing. RUO raw materials do not include comprehensive (and time-consuming) quality control (QC) testing, specifically for bacterial endotoxin and particulates leading to patient safety concerns.
- Sterility validation. With the change to GMP products, this is not a one and done test validation; dose audits must be done regularly to prove sterility per ANSI/AAMI/ISO 11137 (VDmax25).
- Clinical comparability studies. After a raw material or process change, testing can demonstrate that there is no difference in quality of the product that could adversely impact the safety and efficacy of a product. By making the change early, manufacturers save this time-consuming process and get less chance of variants or out of specification results leading to Process Performance Qualification (PPQ) batch failures.
- Personnel. Using CGMP reagents and equipment from the beginning builds familiarity and gets staff qualified early, reducing risk of error.
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.
Perils of lack of documentation
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:
- Process validation: Supporting documentation should be in place for scale-up, providing documented proof that correct procedures are consistently followed at each step in the manufacturing process, every time a product is made. If you wait to implement CGMP materials later in the manufacturing life cycle, any variations from the validation protocol should be documented with appropriate justification.
- Traceability: Raw materials at this level must be documented and traceable. For example, the FDA recommends keeping a record with all relevant information on all materials; including the receipt date, quantity of the shipment, supplier’s name, material lot number, storage conditions and corresponding expiration date. This ensures any issues with the end-product or process can be adequately investigated and ruled out. The traceability, proper use and storage of reference standards should be ensured, defined and recorded.
- Certified quality systems: Documentation is not a stand-alone deliverable. Requirements for quality control sampling and testing procedures change with the transition from RUO to CGMP, as do corrective/preventative actions (CAPA). Due to the inherent variability of biological processes and starting materials, all analytical methods used in quality control should be well characterized, validated and documented to a satisfactory standard to yield reliable results.
- Standard Operating Procedures (SOPs): Detailed, written procedures for each process that could affect final product quality are essential. Putting consistent SOPs in place takes time. Start early with CGMP materials to help maintain critical quality attributes.
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.
Tackling supply issues
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:
- Change control: Provides traceability to ensure changes were made using established processes and were evaluated for impact to the product. Changes to raw materials must be communicated from the supplier usually in the form of change management. Changes on the supplier’s side may require additional testing or revalidation of the raw materials to confirm they meet specifications. Unknown changes to critical raw materials can cause serious delays, at best.
- Limited raw materials list: Key to building a diverse and large approved raw material parts list ahead of time, so a stable supply chain is in place with qualified secondary suppliers in case a reagent is discontinued.
- New production/distribution sites: Moving manufacturing can disrupt a previously secure supply of CGMP reagents; facilities must be certified and in compliance with regional regulatory standards. Changing the source of supply of critical raw materials requires adherence to a formal change control system.
- Supplier auditing: A system for evaluating suppliers of critical materials as necessary; all CGMP production materials must be traceable. This provides proactive, risk-based audits that enable manufacturers to understand the capabilities of new suppliers and collaborate effectively to promptly address CAPA, if needed.
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 9001 and ISO 13485 quality systems and animal origin-free or EMA/410/01 compliant materials.
Key challenges that early use of CGMP may address include:
- Supplier evaluation and monitoring. Assess their ability to meet CGMP material needs, now and in the future. Set clear expectations for product quality, including specifications for identity and purity. Make sure they have the proper analytical procedures and quality controls in place, then monitor via routine audits.
- Multi-compendial compliance. Material portability, using standardized materials, processes and products across facilities and geographic boundaries, reduces the risk of variable quality and supply disruptions as well as program management time savings.
- Changing environmental regulations. Manufacturers should carefully evaluate raw materials regarding regulations for environmental safety or toxicity. As compliance can vary by country or region, proactively remove or avoid at-risk chemicals to future-proof against regulatory constraints.
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.