Pharmaceutical Process Validation: Emplication of New FDA Guidelines

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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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