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Quality considerations for peptide manufacturing processes.

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 in the pharmaceutical manufacturing environment 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 (API s). As a key element in the peptide production process, quality should be built into every step, and thought of as a process parameter, not a process outcome. This is required to ensure the purity of the final product and effectively satisfy regulatory oversight.

The Elements of Quality

Achieving product quality and purity requires a meticulous quality-centric approach from discovery to the final release of the product. Although the notion of quality encompasses all activities designed to ensure the adequacy of manufactured products, 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 the 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 the entire process along the way. The analytical chemists who are 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 the 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.


The Sum of its Parts

A quality system in a pharmaceutical manufacturing environment comprises 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, as the failure of one component can mean the 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 heating, ventilation and air conditioning (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 to prevent contamination; it should call for the regular testing and monitoring of controlled environments. Lighting, flooring, potable water and sanitary facilities, as well as sanitization and pest control, are also important considerations. It is required that equipment and facility assets, such as pharmaceutical-grade water systems and emergency power supply systems, should be validated prior to use (Installation Qualification, Operational Qualification and Performance Qualification). Cleanrooms and all other controlled areas need to be qualified prior to use.

Compliance with a Focus on Quality

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 Food and Drug Administration mandates cGMPs, obligatory prerequisites 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.

Documentation and Quality Systems

The documentation of the manufacturing process, along with all related in-process and final release testing, is an essential aspect of maintaining compliance with regulatory oversight. It involves the extensive documentation of production, change control, vendor audits and qualification process and raw materials testing and release. Specifically, this documentation not only demonstrates compliance 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 should 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 a lack of strict controls can spell disaster, as issues with mislabelling can often lead to recalls.


Implementing Quality 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 to 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 preparing regulatory documents, including CMCs (Chemistry, Manufacturing and Controls) and DMFs (Drug Master Files), all the while discussing any and all discrepancies, product testing and technical support. This dialogue needs to be ongoing, which starts at the beginning of the project, before the initial design and continues after the release of the product. With an approved production batch record, the process begins with the qualification of raw materials as well as the 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.

A Systems Approach to Quality

Bearing all these elements in mind--in a holistic fashion--is critical for implementing a reliable 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 the final outcome. 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.

For more information

Shawn Shirzadi

Vice President, Quality

American Peptide Company

777 E. Evelyn Avenue

Sunnyvale, California 94086, USA.

Tel. +1 408 733 7604


(1.) J.T. Busfield, "Facility and Equipment Quality System Outline--Presentation Transcript,"

(2.) FDA website ( cmc4.pdf).

(3.) American Peptide Company website ( QA_102_092508.pdf).
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Title Annotation:quality control
Author:Shirzadi, Shawn
Geographic Code:1USA
Date:Sep 1, 2009
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