Validation
Validation is necessary to ensure that a process, system, material, method, product, piece of equipment, or personnel practice meets its intended purpose and function or allows it to function reliably and consistently. A company gains little if the complete understanding of validation remains solely within the validation department.
After four decades of existence, validation is little better understood now than when it was first understood, beyond the concept of “requiring a minimum of three runs”. The term “validation” may differ in meaning from company to company. Validation is proving and documenting that something does (or is) what it is supposed to do (or be).
Auditor Role Challenge
Resources to support validation may not be the best to adhere to compliance procedures. Start by understanding the relevant SOPs for validation, and specifically process validation. The role of the auditor will be to examine the protocols and reports executed against internal SOPs and external regulations. In addition to the SOPs that govern Process Validation, the auditor needs to know if there have been any other commitments against which Process Validation should be checked.
o Previous internal audit commitments
o Client audit commitments
o Internal program initiative commitments (e.g., GMP program)
o FDA Commitments (presentation or inspection)
When are Process Validations (or Revalidations) required?
During R&D, physical and chemical performance characteristics must be defined and translated into specifications, including acceptable ranges, which must be expressed in measurable terms. The validity of these specifications is verified by tests and challenges during development and initial production.
Validation of such processes is not required prior to Regulatory Submission (ie NDA, ANDA). Validation commitments can be included in the regulatory filing. The Validation Master Plan must include a periodicity (for example, every six months) and specify the revalidation when the equipment, or other relevant element, changes.
FDA regulations for process controls are included in Part 211: Current Good Manufacturing Practices for Finished Pharmaceutical Products, Subpart F: Production and Process Controls, Section 211.100 Written Procedures; deviations
In part, these regulations require written production and process control procedures designed to ensure that pharmaceutical products have the identity, potency, quality, and purity that they purport to have. These written procedures, including changes, must be drafted, reviewed and approved by the corresponding organizational units and reviewed and approved by the quality control unit. Written production and process control procedures shall be followed in the performance of the various production and process control functions and documented at the time of performance. Any deviation from the written procedures must be recorded and justified.
Validation Types
There are several different types of validation approaches. The best is “Propsective” as it is planned and therefore most favored by the FDA.
oRetrospective:
evaluates historical performance; traditionally requires more data, not allowed in some companies, but may be required for products that have been in production for a long time and predate current validation requirements.
oCompetitor:
collects data as executions run; less than ideal due to lack of advance planning
o Forecast:
planned protocol, guaranteed pre-validation tasks; FDA Favored
Process Validations (Process Qualifications)
Process validation is the establishment of documented evidence that provides a high degree of assurance that a specific process will consistently produce a product that meets its predetermined specifications and quality characteristics. The intent is to demonstrate that a process repeatedly produces a product of acceptable quality. A minimum of 3 consecutive successful cycles, on a given piece of equipment using a specific process, constitutes validation of the process and equipment. Not only is the process under scrutiny, but also the equipment used to deliver that process. The operating limits of the process should be tested, but not the edge of failure. “Robustness” and “worst case” are common goals.
Activities that occur before process validation
Analytical methods must be validated. Processing parameters and conditions must be specified and approved. Clear and detailed SOPs and manufacturing lot instructions should be available that avoid the use of subjective criteria and wide processing ranges (eg, mix gently for 10 to 60 minutes).
Pre-tasks to minimize variability
Check to make sure tasks that could add variability to validation are completed, such as:
-Employee training
-IQ, OQ, Calibration and Maintenance Equipment
-Component Specifications
-Environmental requirements (temperature, humidity, controlled air quality)
-Qualification of key production materials.
Importance of the Protocol
It is a commitment established by the parties involved with the activity. It involves a description of the activity, the proposed and agreed way to achieve that goal, the number of runs required to achieve that goal, and the acceptance criteria. It is an expectation of the FDA that all validation protocols be approved prior to execution. Typical sources of approval are the department responsible for preparing the protocol, the department where the equipment will be installed, and the quality group.
Protocol and Acceptance Criteria
The quality attributes of the product must be detailed in the protocol. The “acceptance criteria” are often the stated product specifications. Validation should not be used to establish or optimize processing parameters and specifications. Acceptance criteria can be more stringent, but should never be less stringent than product specifications. Beware of subjective statements as they cannot be validated. Example: …continue adding water until you have a proper granulation…”
Test conditions should encompass the upper and lower processing limits that put the most stress on the system. Key process variables must be monitored and documented. The data analysis must establish the variability of the process parameters.
FDA perception of the role of the Quality Unit
Those involved in validation must understand what responsibilities the FDA has to the quality unit. Ensure that the performed validation has met any additional quality unit requirements, especially additional testing, questionable retesting, and further justification.
Included are FDA regulations for sampling and testing Part 211: Current Good Manufacturing Practices for Finished Pharmaceutical Products, Subpart F: Production and Process Controls, Section 211.110 Sampling and Testing of In-Process Materials and Drug Products
In part, these regulations require that written procedures be established and followed that describe in-process controls and tests or examinations to be performed on appropriate samples of in-process materials from each batch. Said control procedures will be established to monitor the output and validate the performance of those manufacturing processes that may be responsible for causing the variability in the characteristics of the material in process and the pharmaceutical product. Said control procedures will include, among others, the following, when applicable: variation of the weight of the tablets or capsules; decay time; adequacy of the mixture to ensure uniformity and homogeneity; dissolution time and rate; clarity, integrity, or pH of solutions.
Failure to meet acceptance criteria
Unless the acceptance criteria are met, or there is a strong justification for not meeting them, the goal will not be achieved and the validation will have failed. When a protocol failure occurs, it is customary to conduct an investigation. The investigation must: identify the assignable cause, identify corrective actions and restart the activity. The importance of this investigation and identification of corrective actions cannot be overstated. If the investigation does not identify an assignable cause for the failure, validation should be restarted.
Validation of a transferred process
In the age of multinational corporations, it is not uncommon for an R&D unit to be located in one part of the nation (or world) and a manufacturing unit in another. Thus, when a process is transferred from one place to another, a series of technology transfer points and documents are generated as prospective validation to proceed with the validation through the different steps of product development. There are many departments involved and they are generally isolated units. Confusion results unless communication is good. Often a project management team approach will make it easy to include all affected units and identify all steps involved.
Validation of Transferred Technology
Audit checklists can be used to ensure that important elements of the transferred process are not overlooked or misunderstood. The appropriate participants should have approved the protocol and also the final report. If it’s not clear to the auditor, it won’t be clear to the FDA.
Frequently asked questions during technology transfer
Raw Materials
Are there specifications?
They have senses?
Are the test methods reliable?
Are specifications necessary?
What should be specified but is not specified?
What is the origin of the raw materials?
Are there more sources?
What is the degree to use?
Are the degrees interchangeable?
Team
Does the plant have adequate equipment?
Do the lot size and equipment match?
Is there an alternative provider?
Can the plant equipment be used, although the working principle is not yet specified?
Process parameters
Are the setpoints too narrow?
Are the setpoints too wide?
How were the set points determined?
Sampling
How do I take samples?
What do I try?
Where do I try?
Why should I sample?
How much sample should I take?
What does the data mean once obtained?
Final product
How were the specifications established?
Are the tests reliable?