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Pharmaceutical Process Validation: Emplication of New FDA Guidelines

About Author:
Ashutosh Gupta
B.Pharm, kanpur university

This summary represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance.

Reference Id: PHARMATUTOR-ART-1397

The lifecycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production. This guidance supports process improvement and innovation through sound science.

This guidance covers the following categories of drugs:
· Human drugs
· Veterinary drugs
· Biological and biotechnology products
· Finished products and active pharmaceutical ingredients (APIs or drug substances)
· The drug constituent of a combination (drug and medical device) product

This guidance does not cover the following types of products:
· Type A medicated articles and medicated feed
· Medical devices
· Dietary supplements
· Human tissues intended for transplantation regulated under section 361 of the Public Health Service Act.

FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

In the Federal Register of May 11, 1987 (52 FR 17638), FDA issued a notice announcing the availability of a guidance entitled Guideline on General Principles of Process Validation (the 1987 guidance). Since then, we have obtained additional experience through our regulatory oversight that allows us to update our recommendations to industry on this topic. This revised guidance conveys FDA’s current thinking on process validation and is consistent with basic principles first introduced in the 1987 guidance. The revised guidance also provides recommendations that reflect some of the goals of FDA’s initiative entitled “Pharmaceutical CGMPs for the 21st Century ? A Risk-Based Approach,” particularly with regard to the use of technological advances in pharmaceutical manufacturing, as well as implementation of modern risk management and quality system tools and concepts.


A. Process Validation and Drug Quality
Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. This principle incorporates the understanding that the following conditions exist:
Quality, safety, and efficacy are designed or built into the product.
Quality cannot be adequately assured merely by in-process and finished-product inspection or testing.

B. Approach to Process Validation
For purposes of this guidance, process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process. This guidance describes process validation activities in three stages.
Stage 1 Process Design:The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.
Stage 2 Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
Stage 3 Continued Process Verification:Ongoing assurance is gained during routine production that the process remains in a state of control.

A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control of the manufacturing process that result in products with the desired quality attributes. Manufacturers should:
· Understand the sources of variation
· Detect the presence and degree of variation
· Understand the impact of variation on the process and ultimately on product attributes
· Control the variation in a manner commensurate with the risk it represents to the process and product

Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product. Focusing exclusively on qualification efforts without also understanding the manufacturing process and associated variations may not lead to adequate assurance of quality. After establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.

Implementation of the recommendations in this guidance for legacy products and processes would likely begin with the activities described in Stage 3.

Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement as following:
A drug . . . shall be deemed to be adulterated . . . if . . . the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.

FDA regulations describing current good manufacturing practice (CGMP) for finished pharmaceuticals are provided in 21 CFR parts 210 and 211. 

In summary, the CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process materials and the finished product meet predetermined quality requirements and do so consistently and reliably.

In the following sections, we describe general considerations for process validation, the recommended stages of process validation, and specific activities for each stage in the product lifecycle.

A. General Considerations for Process Validation
In all stages of the product lifecycle, good project management and good archiving that capture scientific knowledge will make the process validation program more effective and efficient. The following practices should ensure uniform collection and assessment of information about the process and enhance the accessibility of such information later in the product lifecycle.

We recommend an integrated team approach to process validation that includes expertise from a variety of disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance). Project plans, along with the full support of senior management, are essential elements for success.



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B. Stage 1 ? Process Design
Process design is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.

1. Building and Capturing Process Knowledge and Understanding
Generally, early process design experiments do not need to be performed under the CGMP conditions required for drugs intended for commercial distribution that are manufactured during Stage 2 (process qualification) and Stage 3 (continued process verification). They should, however, be conducted in accordance with sound scientific methods and principles, including good documentation practices. This recommendation is consistent with ICH Q10 Pharmaceutical Quality System. Decisions and justification of the controls should be sufficiently documented and internally reviewed to verify and preserve their value for use or adaptation later in the lifecycle of the process and product.

2. Establishing a Strategy for Process Control
Process knowledge and understanding is the basis for establishing an approach to process control for each unit operation and the process overall. Strategies for process control can be designed to reduce input variation, adjust for input variation during manufacturing (and so reduce its impact on the output), or combine both approaches.

FDA expects controls to include both examination of material quality and equipment monitoring. Special attention to control the process through operational limits and in-process monitoring is essential in two possible scenarios:
1.      When the product attribute is not readily measurable due to limitations of sampling or detectability (e.g., viral clearance or microbial contamination) or
2.      When intermediates and products cannot be highly characterized and well-defined quality attributes cannot be identified.

C. Stage 2 ? Process Qualification
During the process qualification (PQ) stage of process validation, the process design is evaluated to determine if it is capable of reproducible commercial manufacture. This stage has two elements: (1) design of the facility and qualification of the equipment and utilities and (2) process performance qualification (PPQ). During Stage 2, CGMP-compliant procedures must be followed. Successful completion of Stage 2 is necessary before commercial distribution. Products manufactured during this stage, if acceptable, can be released for distribution.

1. Design of a Facility and Qualification of Utilities and Equipment
Proper design of a manufacturing facility is required under part 211, subpart C, of the CGMP regulations on Buildings and Facilities. It is essential that activities performed to assure proper facility design and commissioning precede PPQ. Here, the term qualification refers to activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly. These activities necessarily precede manufacturing products at the commercial scale.

Qualification of utilities and equipment generally includes the following activities:

·         Selecting utilities and equipment construction materials, operating principles, and performance characteristics based on whether they are appropriate for their specific uses.

·         Verifying that utility systems and equipment are built and installed in compliance with the design specifications (e.g., built as designed with proper materials, capacity, and functions, and properly connected and calibrated).  

2. Process Performance Qualification
The process performance qualification (PPQ) is the second element of Stage 2, process qualification. The PPQ combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. A successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected.

Success at this stage signals an important milestone in the product lifecycle. A manufacturer must successfully complete PPQ before commencing commercial distribution of the drug product.16 The decision to begin commercial distribution should be supported by data from commercial-scale batches. Data from laboratory and pilot studies can provide additional assurance that the commercial manufacturing process performs as expected.

3. PPQ Protocol
A written protocol that specifies the manufacturing conditions, controls, testing, and expected outcomes is essential for this stage of process validation. We recommend that the protocol discuss the following elements:

  • The manufacturing conditions, including operating parameters, processing limits, and component inputs.
  • The data to be collected and when and how it will be evaluated.
  • Tests to be performed and acceptance criteria for each significant processing step.
  • Criteria and process performance indicators that allow for a science- and risk-based decision about the ability of the process to consistently produce quality products. The criteria should include:
  • A description of the statistical methods to be used in analyzing all collected data.
  • Provision for addressing deviations from expected conditions and handling of nonconforming data. Data should not be excluded from further consideration in terms of PPQ without a documented, science-based justification.
  • Design of facilities and the qualification of utilities and equipment, personnel training and qualification, and verification of material sources (components and container/closures), if not previously accomplished.
  • Status of the validation of analytical methods used in measuring the process, in-process materials, and the product.
  • Review and approval of the protocol by appropriate departments and the quality unit.

4. PPQ Protocol Execution and Report
Execution of the PPQ protocol should not begin until the protocol has been reviewed and approved by all appropriate departments, including the quality unit. Any departures from the protocol must be made according to established procedure or provisions in the protocol. Such departures must be justified and approved by all appropriate departments and the quality unit before implementation.

A report documenting and assessing adherence to the written PPQ protocol should be prepared in a timely manner after the completion of the protocol. This report should:

  • Discuss and cross-reference all aspects of the protocol.
  • Summarize data collected and analyze the data, as specified by the protocol.
  • Evaluate any unexpected observations and additional data not specified in the protocol.
  • Summarize and discuss all manufacturing nonconformances such as deviations, aberrant test results, or other information that has bearing on the validity of the process.
  • Describe in sufficient detail any corrective actions or changes that should be made to existing procedures and controls.
  • Include all appropriate department and quality unit review and approvals.

D. Stage 3 ? Continued Process Verification
The goal of the third validation stage is continual assurance that the process remains in a state of control during commercial manufacture. A system or systems for detecting unplanned departures from the process as designed is essential to accomplish this goal. Adherence to the CGMP requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow detection of undesired process variability. Evaluating the performance of the process identifies problems and determines whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control.

An ongoing program to collect and analyze product and process data that relate to product quality must be established. The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.

In most cases, the PPQ study needs to be completed successfully and a high degree of assurance in the process achieved before commercial distribution of a product. In special situations, the PPQ protocol can be designed to release a PPQ batch for distribution before complete execution of the protocol steps and activities, i.e., concurrent release. FDA expects that concurrent release will be used rarely.

Concurrent release might be appropriate for processes used infrequently for various reasons, such as to manufacture drugs for which there is limited demand or which have short half lives (e.g., radiopharmaceuticals, including positron emission tomography drugs). Concurrent release might also be appropriate for drugs that are medically necessary and are being manufactured in coordination with the Agency to alleviate a short supply.

Documentation at each stage of the process validation lifecycle is essential for effective communication in complex, lengthy, and multidisciplinary projects. Documentation is important so that knowledge gained about a product and process is accessible and comprehensible to others involved in each stage of the lifecycle.

The degree and type of documentation required by CGMP vary during the validation lifecycle. Documentation requirements are greatest during Stage 2, process qualification, and Stage 3, continued process verification. Studies during these stages must conform to CGMPs and must be approved by the quality unit in accordance with the regulations. Viral and impurity clearance studies, even when performed at small scale, also require quality unit oversight.

Process knowledge depends on accurate and precise measuring techniques used to test and examine the quality of drug components, in-process materials, and finished products. Validated analytical methods are not necessarily required during product- and process-development activities or when used in characterization studies. Nevertheless, analytical methods should be scientifically sound (e.g., specific, sensitive, and accurate) and provide results that are reliable. There should be assurance of proper equipment function for laboratory experiments. Procedures for analytical method and equipment maintenance, documentation practices, and calibration practices supporting process-development efforts should be documented or described. New analytical technology and modifications to existing technology are continually being developed and can be used to characterize the process or the product.



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Capability of a process:
Ability of a process to produce a product that will fulfill the requirements of that product. The concept of process capability can also be defined in statistical terms. (ISO 9000:2005)

Commercial manufacturing process: The manufacturing process resulting in commercial product (i.e., drug that is marketed, distributed, and sold or intended to be sold). For the purposes of this guidance, the term commercial manufacturing process does not include clinical trial or treatment IND material.

Concurrent release: Releasing for distribution a lot of finished product, manufactured following a qualification protocol, that meets the lot release criteria established in the protocol, but before the entire study protocol has been executed.

Continued process verification: Assuring that during routine production the process remains in a state of control.

Performance indicators: Measurable values used to quantify quality objectives to reflect the performance of an organization, process or system, also known as performance metrics in some regions.

Process design: Defining the commercial manufacturing process based on knowledge gained through development and scale-up activities.

Process qualification: Confirming that the manufacturing process as designed is capable of reproducible commercial manufacturing.

Process validation: The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products.

Quality: The degree to which a set of inherent properties of a product, system, or process fulfils requirements.

State of control: A condition in which the set of controls consistently provides assurance of continued process performance and product quality.

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