The complex nature of peptides makes the purity and identity of the final product a critical issue. Shawn Shirzadi, vice president of quality, American Peptide Co, describes the main quality systems that should be in place for peptide synthesis
As peptide-based therapies increasingly become 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 (APIs). As a key element in the peptide production process, quality should be built into every step and thought of as process parameter, rather than a process outcome. This is required to assure the purity of the final product and effectively satisfy regulatory oversight.
quality-centric system
Achieving product quality and purity requires a meticulous quality-centric approach from discovery to the final release of the product. While the notion of quality encompasses all activities designed to ensure adequacy of manufactured products, the protocols for the pharmaceutical industry 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 characterisation of raw materials and finished products. Essentially, QC monitors the endpoints of a production run: what comes in and what goes out. QA, in contrast, is responsible for quality throughout the entire manufacturing process.
The analytical chemists who are responsible for QC also ensure that analytical methods are developed and subsequently validated. Their assessment of structural integrity and purity of the peptide is critical during the development stages of a product. Without rigorous analytical characterisation and evaluation of potential impurities at the start of each manufacturing project problems may be missed, only to resurface at a later point in the process - often as product recalls and sometimes with devastating consequences for patient health and safety.
A quality system in a pharmaceutical manufacturing environment is comprised of several components including, but not always limited to, facilities and equipment, laboratory controls, materials, packaging and labelling. These components should be designed to incorporate redundancies and fail-safes, for 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 and validation, and possibly a need for calibration. Regular evaluations of the humidity, ventilation, and air-control (HVAC) system, compressed gases and water systems are key.
These facility- and equipment-specific considerations should be addressed during facility design and continually improved upon as needs evolve. For example, a quality SOP should mandate regular cleaning and maintenance procedures and to prevent contamination, it should call for regular testing and monitoring of controlled environment. Lighting, flooring, potable water and sanitary facilities, as well as sanitisation and pest control, are also important considerations.
It is required that equipment and facility assets, such as a pharmaceutical-grade water system and emergency power supply systems, be validated prior to use (Installation Qualification, Operational Qualification, and Performance Qualification). Cleanroom and all other controlled areas need to be qualified prior to use.
A focus on quality must have as its ultimate goal regulatory compliance. Adherence to current good manufacturing practices (cGMPs) and a robust documentation programme can ensure reproducible, verifiable quality procedures that stand up to regulatory scrutiny as well as guarantee a high purity final product.
The US FDA mandates cGMPs, obligatory pre requisites to establishing a robust and reproducible manufacturing process. Apart from general guidelines, including the Code of Federal Regulations (CFR) and ICH (Q7A) Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, there is only one guideline specifically dedicated to peptides. 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 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 HPLC and molecular weight, along with peptide counter ion, water, and residual organic solvent content.
accurate documentation
Documentation of manufacturing process along with all related in process and final release testing is essential to maintaining compliance with regulatory oversight. This involves extensive documentation of production, change control, vendor audits and qualification process and the 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 will also prove compliance with 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 labelling and label accountability. This is where the lack of strict controls can spell disaster, as issues with mislabelling can often lead to recalls.
Quality also needs to be implemented into Project Engineering and Process Flow. 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 includes operational and compliance requirements.
Along with guided tours of facilities, engineering the project involves assisting clients with the preparatopm of regulatory documents, including Chemistry, Manu-facturing, and Controls (CMCs) and Drug Master Files (DMFs), all the while discussing any and all discrepancies, product testing, and technical support.
This dialogue needs to be ongoing, starting at the beginning of the project, before the initial design, and continuing after the release of the product.
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 make sure that the in-process testing and verification of critical steps are documented within the production batch records.
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..
Given that every component of a manufacturing process contributes to the quality of the final product, without a comprehensive systems approach to the entire process, even a minor misstep could compromise final outcomes. The approach that takes into account every miniscule aspect of the manufacturing operation - from documentation to capital equipment - is the surest way to guarantee final quality.