21st Century Validation Strategies For Drug Products

By Anil Doshi, R.Ph.,Ph.D., President, Infinity Pharmaceutical Consulting

Dr. Janet Woodcock of the Federal Drug Administration (FDA) once said that a mutual goal of the pharmaceutical industry and regulatory agencies would be to have a "desired state" which is an efficient, agile flexible pharmaceutical manufacturing sector. This sector would be one that would reliably produce high quality drug products, without extensive regulatory oversight.[1]  The desired state would be achieved based upon the risk based implementation of Quality by Design (QbD) outlined in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance's: Q8 (Pharmaceutical Development), Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System)[2].  

Any pharmaceutical company that initiates and implements QbD (ICH Q8, Q9, and Q10)  will effectively and efficiently fully leverage a competitive advantage in 21st century. The prudent implementation of this strategy based on good science and an accurate grasp of the available regulatory knowledge will create transformational value by providing high product quality assurance for patients, more efficient regulatory oversight and cost savings for the company. In this article, I will give an overview on how QbD relates to process validation, as well as outline the three stages to the lifecycle approach to process validation.[3]

QbD Helps Maintain The Validated State Of Your Process

 Process validation of pharmaceutical dosage forms is the process of establishing documented evidence of a drug product's quality.  This evidence provides a high degree of assurance that a specific manufacturing process will consistently produce a drug product meeting pre-determined quality attributes when operated within its critical process parameters ranges (CPPs). Once a drug product manufacturing process has been validated, the validated state must be maintained through implementation of operating procedures, preventive maintenance, calibration programs, atypical investigation procedures, annual product review programs, and change control procedures. Any changes to the process must be evaluated through the process change request (PCR) system as outlined by each corporation's quality policy, procedure, guidelines, and procedures for change control to determine if the validated state will be compromised.

Designing a process validation requires the demonstration of process controls. For example, a company must define upfront the necessary critical process parameters (CPPs) as well as the in-process and finished product critical quality attributes (CQAs) that it intends to achieve with each run of the manufacturing process.  A CPP is an input process variable that is maintained within a specified range to ensure that an intermediate or final product will be within the CQA limit. A CQA is a measured property of the intermediate or final product that is considered critical for establishing the intended purity, efficacy, safety, and bioavailability of the drug product. The demonstration of consistency of the CPP and CQA is ultimately consolidated to represent a validated process for manufacture of a pharmaceutical dosage form.  

A Quality Management System Is Crucial For Process Validation Stages

All systems have to be in compliance with the current regulatory guidelines prior to conducting any validation studies. A big part of this is establishing a quality management system (QMS). QMS is defined by the American Society for Quality (ASQ) as a formalized system that documents the structure, responsibilities and procedures required to achieve effective quality.[4]  These systems also represent a set of interrelated processes that, working together, assure product safety, strength, identity, purity, and quality.  In developing quality management systems, FDA recommends six core quality systems on which companies should base their QMS: 1) quality, 2) facilities and equipment, 3) materials, 4) production, 5) packaging and labeling and 6) laboratory control. These core systems are vital to assuring that a system is well developed and worthy of being validated. These FDA recommendations are broad enough to encompass the main aspects of a system that must be considered in creating a QMS. Performing validation studies on a poorly designed system is a waste of a company’s resources and time. Therefore, companies must be in compliance with these six core systems prior to conducting any process validation studies.

All pharmaceutical products manufactured worldwide are to be prospectively validated. A life cycle approach to process validation should be comprised of three stages over the life of the product and process.

Stage 1 - Process Design

The process design stage is the activity of defining the commercial manufacturing process that can consistently deliver a product that meets its CQAs. Process design activities should include the following:

• Identify potential CQAs of the drug product, based on target product profile (TPP);
• Determine relevant CQAs of the drug substance, excipients, and packaging in order to deliver drug product of the desired quality; and
• Define the manufacturing process to be qualified and the appropriate control strategy.

Stage 2 - Process Qualification

During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.  Process Qualification is proof of process knowledge and control. This stage has two elements. The first is the design of the facility and qualification of the equipment and utilities.  The second is the process performance qualification (PPQ).

Process re-qualification is proof of knowledge and control after a planned (e.g. significant process change, API source change, etc) or unplanned (e.g. process drift, atypical event) change in the manufacturing process. The proof is demonstrated via technical justification & supporting documents and Qualification study defined by a process performance qualification protocol.

Stage 3 - Continued Process Verification   

Ongoing assurance is gained during routine production that the process remains in a state of control. Once stage two process qualifications are completed, processes are monitored via the continued process verification and annual review process. Significant deviation from desired process performance uncovered through continued process verification, annual review or via a typical event, warrants consideration for process requalification. It is required that the data generated is continually documented into the process design knowledge of the product (i.e. controlled strategy, design space, and risk assessment documents).

With the FDA's guidance document providing these general stages, each pharmaceutical company should implement a QbD approach specific for each manufacturing process of a drug product. Each process should be tailored on a case-by-case basis to the specific drug product. These validations strategies could facilitate continual improvement and innovation throughout the product life cycle. Additional product and process understanding can lead to enhanced manufacturing efficiency and regulatory flexibility, thereby providing the availability of safe, effective and high-quality drug products.

In my subsequent columns, I will address validation strategies with respect to solids and controlled release dosage forms; liquids, suspension and semisolid dosage forms; and sterile dosage forms (small and large molecules).

About The Author:

Anil is the president of Infinity Pharmaceutical Consulting, which provides product and process development, technical transfer, manufacturing, regulatory, and management strategies to the life science industries. For any questions, please contact anilinfinity@optonline.net, or call 973-538-1725