Qualification and Validation

INTRODUCTION

In the pharmaceutical environment, qualification and validation are required for any good manufacturing practices (GMP) facility, utility, equipment, or process. The intent of qualification and validation activities is to provide documented evidence that the facility, utilities (for example, water, gases, air), and processes are designed and operate in accordance with GMP requirements. An infinite amount of detail can be provided in each phase of the validation life cycle. Regulations are vague when determining specific requirements for what constitutes a qualification or validation document. Industry standards have provided content and activities of the qualification and validation documentation.

To ensure that the facility, utilities, and equipment have been designed, built, and installed properly, and operate as intended, proper qualification and validation activities must occur. The foundation of a successful qualification and validation program begins with design. During the design phase, the specifications, requirements, and critical aspects are developed and documented. Specifications are prescribing attributes that are required to provide a quality of work for something to be built, installed, or manufactured. Requirements are detailed necessities for the item being built, installed, or manufactured. Requirements can be defined as user requirements or as functional requirements. Critical aspects are specification and design requirements that focus on those attributes that are critical to product quality and patient safety, and these aspects may be outlined within the specification and requirements documents. Another document that is required to outline and plan the requirements for the life cycle process is a validation master plan (VMP).

The VMP document or a suitable equivalent defines the overall structure, philosophy and approach of the phases of the validation life cycle. The VMP should define the structure and required documentation for design, qualification, and validation activities, to include prerequisites, and stage-gate requirements to move on to the next phase in the validation life cycle. The VMP should detail key criteria within each stage and phase, and other qualification and validation requirements and considerations, including lists of products, processes, and systems to be validated, documentation format, required standard operating procedures (SOPs), and planning and scheduling.

The facility, utilities, and equipment should be designed to predetermined requirements and specifications. The critical aspects are used to create and document the design requirements and specifications. The design is documented through design qualification (DQ).

DESIGN QUALIFICATION

DQ should establish and provide evidence that the equipment is designed in accordance with the requirements of GMP. DQ is a formal document that requires quality assurance (QA) oversight. This document uses critical aspects from approved requirements (user and functional requirements) and other approved specifications as the source documents. Typical items that may be found in the scope of a DQ document include verification that:

The design will achieve the user requirements

The design is GMP and will conform to applicable national standards and guidelines

The utility services are appropriate and are qualified or will be qualified

All the required support documentation is specified

The system will be able to be calibrated

The system will be able to be maintained

Personnel training requirements will be met

At the completion of the design phase, the project moves to the next phase—the commissioning and installation phase.

COMMISSIONING AND QUALIFICATION

Once the facility, utility, or equipment has been designed, built, and/or installed, a commissioning program should encompass the additional testing to establish a qualified state, which can be performed through factory acceptance testing (FAT), testing that is performed at the vendor’s factory before shipping the equipment. This task is important, as equipment that does not meet the requirements of design should not be shipped to the manufacturing facility until it does meet the necessary specifications and requirements. Once the equipment or system is at the manufacturing site and its final destination, as part of a commissioning, a site acceptance testing (SAT) exercise may be conducted. These activities as part of commissioning are prerequisites to site qualification exercises.

The commissioning program should encompass as much testing as possible to include, but not be limited to, testing the vendor or manufacturer’s functional and operational requirements, the design requirements and other aspects that are critical to quality, business continuity, and safety. This testing ensures that the systems and equipment are challenged to test the full functionality and operational ability in a noncommercial environment to avoid any potential impact to GMP equipment, areas, and/or product. Qualification activities may be introduced in the commissioning program as long as the program is well documented and QA oversight exists. The commissioning program requires good documentation practices (GDP) and good engineering practices (GEP) to ensure that the testing activities that are conducted are properly documented and can be used for qualification activities.

Many regulatory guidance documents, such as European Union (EU) Annex 15, United States Food and Drug Administration (FDA) process validation guidance (Process Validation: General Principles and Practices), and Pharmaceutical Inspection Convention and the Pharmaceutical Inspection Co-operation Scheme (PIC/S) P006-3, require and discuss the elements of installation qualification (IQ) and operational qualification (OQ). Some additional publications in the last few years include installation and operational qualifications. ASTM E2500-7 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment introduced concepts of streamlining the traditional IQ and OQ program to eliminate some of the formal documentation requirements and QA oversight that are typically required for formal validation programs. The ASTM E2500 standard proposes the concept of verification, where traditional qualification activities are conducted as verification exercises. The QA oversight is acceptable during the development and approval of requirements, specifications, and critical aspects. The commissioning and verification test requirements and acceptance criteria are defined in a verification plan. QA is not involved at the implementation level of protocol writing and test plan execution as long as the approved verification plan has not been deviated from. Although new standards and publications exist with the intent of providing guidance on performing and documenting commissioning, qualification, and/or verification activities, the relevant intent of installation and operational qualification is that the facility, utility, and equipment/systems are designed properly, installed properly, and operate as intended by design and as per GMP requirements.

It is a requirement of the regulatory guidance documents and GMP that the documentation provided by each pharmaceutical company proves a state of control in that the “drug meets the requirements of the Act as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess.” The commissioning and qualification program must have adequate QA governance.

INSTALLATION QUALIFICATION

Elements of the traditional IQ may be incorporated into the commissioning program. The regulatory guidance documents such as EU Annex 15 and FDA process validation guidance require IQ and OQ. Although the installation verification may have occurred during the commissioning stage, the regulatory expectation is that an IQ protocol and report documents that the facility, utilities, and/or equipment were installed properly. The intent of commissioning and/or the IQ is to verify that the facility, utilities, and/or equipment are installed properly. The IQ program includes, but is not limited to:

Verification of components and parts

Identification and verification of serial numbers and model numbers

Identification and documentation of software versions and correct level of installation

Verification of calibration

Verification that installation is as specified per appropriate drawings and specifications (including sloping, dimensions, and so on)

Verification that support utilities conform with national standards and other guidance documents

OPERATIONAL QUALIFICATION

OQ is the documented evidence that the system operates as designed and for its intended use. Commissioning activities can include operational testing, which should include the full range of parameters for which the equipment was designed. The OQ testing may be reduced if the full testing was conducted in commissioning, and may include only challenging the ranges or parameters of the intended use of the system. The OQ program includes, but is not limited to:

Verification of integrated loop testing

Testing of alarms

Testing of interlocks and permissive conditions

Testing of data storage integrity

Verification of the functionality of the equipment

Testing of security levels to prevent unauthorized access or changes

Testing to verify and document power loss recovery

Verification of procedures (operation, preventive maintenance, and calibration)

Challenge of the system by stressing the equipment or system to the edge of failure to determine proven acceptable ranges

Once the equipment is qualified, the equipment can be released for performance qualification (PQ) and commercial manufacturing. The facility, utility, and equipment will be under a formal change control system and GMP environment. The OQ must be successfully completed before beginning PQ.

PERFORMANCE QUALIFICATION

PQ ensures that the equipment or integrated systems function under normal operating conditions to confirm that the equipment/system functions as intended. During the PQ phase, systems, processes, and utilities are challenged at nominal operating characteristics. This process includes studies that ensure the system properly functions under various conditions, such as evaluating seasonal changes for the water system, evaluating a circuit or piping/equipment configuration for steam in-place validation, or evaluating load patterns for sterilization in autoclaves. The PQ program includes at least three consecutive successful runs or qualifications within the study. The definition of a run or qualification can be designated and predetermined by a description and definition of the run or qualification in the protocol or VMP.

The PQ program is a confirmatory exercise of verification of predefined critical aspects and critical quality attributes. Elements traditionally in a PQ include, but are not limited to:

Definition of performance criteria and test procedures

Identification of critical control parameters, critical quality attributes, and key process parameters (for example, predefined specifications and acceptance criteria)

Determination of the sample size and test intervals (including the rationale to support these requirements)

Definition of corrective actions if the system does not meet the established criteria

Upon completion and successful verification of PQ, validation of the commercial manufacturing process may begin. The PQ may not be entirely completed but may be released for commercial manufacturing or process validation activities. Stage II PQ for utilities may not be completed (due to required seasonal testing); however, stage I of utility PQ must be completed. The system has demonstrated the required performance characteristics at the end of stage I.

PROCESS VALIDATION

The traditional term process validation under the FDA process validation guidance document covers all elements of the validation life cycle (Figure 31.1). The FDA document refers to that activity as a process performance qualification (PPQ). For the purposes of this chapter, the term “process validation” will be retained as its traditional activity where the verification of the manufacturing process is completed. 

Cleaning validation may be conducted during the PQ phase or the tradi-tional process validation phase in parallel with the manufacturing of the validation batches. The details of the philosophy and approach for process and validation activities must be detailed in the site’s VMP. Validated laboratory test methods are required for the execution of process and cleaning validation studies.

After successful completion of the process validation batch campaign, the next stage in the validation life cycle approach is operational phase or continuous monitoring/sustaining of operations, also termed continued process verification. During routine manufacturing, continuous monitoring of the critical quality attributes provides a continuous loop of information. The continuous monitoring aspect of the validation life cycle creates a feedback mechanism that is used to improve the process. Any proposed changes to improve the process must be formally documented in the change control system. Information gained during the continuous monitoring program is feedback into various systems, including updating and improving calibration and preventive maintenance systems.

VALIDATION LIFE CYCLE

Validation is a prospective and confirmatory exercise. The difference between qualification and validation is that equipment is individually qualified, and the system or process is validated. The intent of validation activities, including PQ and process validations, is to confirm the knowledge gained during design, development, installation, and challenge exercises, and as a confirmatory exercise of a process that is already known and in control. A few types of validation are discussed in some regulatory guidance documents, which include prospective, retrospective, and concurrent. The chapter has discussed and outlined prospective validation. Prospective validation is the most preferable and defendable nature of validation. This type of validation aligns with the validation life cycle approach and provides the most confidence in the documentation generated that the drug is produced as required by GMP.

Retrospective validation is a look-back approach to validation and an attempt to justify legacy systems based on a retrospective gathering of documentation. Retrospective validation is not normally considered acceptable. There is an expectation of understanding and documenting processes, including the site’s legacy processes and equipment. Retrospective validation is difficult to document as the data gathered must be statistically based and analyzed.

Concurrent validation occurs when manufactured batches are released one lot at a time before the completion of the three or designated number of batches for the process validation campaign, and should only be used when drugs are medically necessary and an approved plan that outlines the nature of concurrent release is approved by required regulatory agencies.

Qualification and validation are regulatory guided programs for GMP pharmaceutical companies. Although these programs are mandated by various regulatory bodies, the intent of a robust qualification and validation program is to ensure that facilities, utilities, equipment, systems, and processes are designed with the end in mind. Requirements are tested and verified to predetermined specifications, and there is verification that the facilities, utilities, or equipment are installed and operate properly. These programs provide documented evidence that what was purchased meets expectations and produces a drug product that meets the requirements of 21 CFR 210.1.


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