By Shawn Shirzadi
As peptide-based therapies become increasingly viable drug discovery and development targets, the industry is paying more attention to the quality concerns that underlie peptide-manufacturing processes. Peptide synthesis for pharmaceutical manufacturing can be tedious and time-consuming, given the complexity of the product and the lengthy, intricate synthesis process. Regulatory compliance, quality control, and assurance efforts are critical for the successful development and manufacture of peptides as active pharmaceutical ingredients.
As a key element in the peptide production process, quality should be built into every step and should be considered a process parameter, not a process outcome. This will assure the purity of the final product and effectively satisfy regulatory oversight.
Elements of Quality
Achieving product quality and purity requires a meticulous quality-centric approach from discovery to the final product release. Although quality encompasses all activities designed to ensure adequacy of manufactured products, pharmaceutical industry protocols are usually divided into two separate functions: quality assurance (QA), which oversees the entire manufacturing process and is responsible for the final release and disposition of the product, and quality control (QC), which is responsible for analytical testing and characterization of raw materials and finished products.
Essentially, QC monitors the endpoints of a production run: what comes in and what goes out. QA, by contrast, is responsible for quality throughout the entire manufacturing process.
The analytical chemists responsible for QC also ensure that analytical methods are developed and subsequently validated. Their assessment of the structural integrity and purity of the peptide is critical during the development stages of a product. Without rigorous analytical characterization and evaluation of potential impurities at the start of each manufacturing project, problems can be missed that will resurface as product recalls at a later point in the process, sometimes with devastating effects on patient health and safety.
Quality System Is the Sum of Its Parts
A quality system in a pharmaceutical manufacturing environment is composed of several components, including but not always limited to facilities and equipment, laboratory controls, materials, packaging, and labeling. These components should be designed to incorporate redundancies and fail-safes, because failure of one component can mean failure of the entire operation.
The facility and equipment component is a critical part of overall quality management, requiring consistent monitoring, maintenance, validation, and possibly calibration. Regular evaluation of the humidity, ventilation, air control system, compressed gases, and water systems is key. These facility- and equipment-specific considerations should be addressed during facility design and continually improved as needs evolve.
For example, a quality standard operating procedure should mandate regular cleaning and maintenance procedures, contamination prevention, and regular testing and monitoring of the controlled environment. Lighting, flooring, potable water, and sanitary facilities, as well as sanitization and pest control, are also important considerations.
Equipment and facility assets, such as a pharmaceutical-grade water system and emergency power supply systems, must be validated prior to use (installation qualification, operational qualification, and performance qualification). Cleanroom and all other controlled areas must be qualified prior to use.
Achieving Compliance with a Focus on Quality
A focus on quality must have regulatory compliance as its ultimate goal. Adherence to current good manufacturing practices (cGMPs) and a robust documentation program can ensure reproducible, verifiable quality procedures that not only stand up to regulatory scrutiny but also guarantee a high-purity final product.
The U.S. Food and Drug Administration (FDA) mandates cGMPs, obligatory prerequisites to establishing a robust and reproducible manufacturing process. Apart from general guidelines, including the Code of Federal Regulations (CFR) and International Conference on Harmonisation (Q7) Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, there is only one guideline specifically dedicated to peptides. The FDA’s Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls Information for Synthetic Peptide Substances, issued in 1994, stipulates that the lot-release specifications—a set of tests and acceptance criteria that must be met before a product is released—must be sufficient to ensure the identity, purity, strength, and/or potency of the peptide and to demonstrate lot-to-lot consistency.
Every product manufactured under cGMP must undergo a battery of analytical tests. Each batch should be provided with a lot-specific certificate of analysis (COA) documenting specifications, test methods, and results. A typical COA contains information on appearance, solubility, purity by gradient high-performance liquid chromatography, and molecular weight, as well as peptide counter ion, water, and residual organic solvent content.
Documentation and Quality System
Documentation of manufacturing processes, along with all related in-process and final-release testing, is essential for maintaining compliance with regulatory oversight. Extensive documentation is required of production, change control, vendor audits, qualification process, and raw materials testing and release.
Specifically, documentation demonstrates compliance not only with cGMPs but also with 21 CFR 211, part 211.42: Design and construction features, which stipulates that “any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction, and location to facilitate cleaning, maintenance, and proper operations.” Firms must also prove compliance with 21 CFR 211, part 211.63: Equipment design, size, and location, which indicates that “equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.”
An important step in the documentation process is the focus on accurate labeling and label accountability. Lack of strict controls in this area can spell disaster, because issues with mislabeling often lead to recalls.
Implementing Quality
Based on customer needs for a specific peptide manufacturing project, the product manufacturer develops a basis for a manufacturing project design scheme. From there, a conscientious peptide manufacturer will help define the parameters for the engineering function that include operational and compliance requirements. Along with guided tours of facilities, engineering the project involves assisting with the client’s preparation of regulatory documents, including chemistry, manufacturing, and controls and drug master files, all while discussing any and all discrepancies, product testing, and technical support. This dialogue should be ongoing, starting at the beginning of the project, before the initial design, and continuing after product release.
With an approved production batch record, the process begins with the qualification of raw materials as well as equipment used in the process. The manufacturer must ensure that the in-process testing and verification of critical steps are documented within the production batch records.
Systems Approach to Quality
Bearing all these elements in mind in a holistic fashion is critical for implementing a sound quality system. Indeed, the key word for any effective approach to quality outcomes is “system.” Because every component of a manufacturing process contributes to the quality of the final product, moving forward without a comprehensive systems approach to the entire process means that even a minor misstep can compromise final outcomes. The approach that considers every miniscule aspect of the manufacturing operation—from documentation to capital equipment—is the surest way to guarantee final quality.
Shirzadi is vice president of quality at American Peptide Company. Reach him at (408) 733-7604; for more information e-mail sales@americanpeptide.com or go to www.americanpeptide.com.
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