1. Purpose
The purpose of this document is to provide minimum mandatory requirements in the validation of processes for the commercial manufacture of formulated products to demonstrate the effectiveness and reproducibility of a process and being suitable for the intended purpose. The purpose is also to outline recommendation on how to achieve compliance.
2. Scope and Applicability
This Guideline is applicable to all Operations, functions and departments undertaking work, or providing support services, required to meet Good Manufacturing Practice(GMP) or, in the absence of a GMP standard, International Organization for Standardization (ISO) standards.
3. Definitions
3.1 Process Validation
Establishing documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.
3.2 Prospective Validation
Establishing documented evidence that systems do what they purport to do prior to the commercial distribution of a new product or an existing product made by anew or modified process.
3.3 Concurrent Validation
Validation carried out during routine production of products intended for sale.
3.4 Retrospective Validation
Validation of a process for a product, which has been marketed, based upon accumulated manufacturing, testing and control data.
3.5 Validation Protocol
A written protocol or plan stating how validation, testing and sampling will be conducted, defining roles and responsibilities, and defining acceptance criteria.
3.6 Validation Report
A written report that summarizes the raw data and evaluates the validation work against the acceptance criteria defined in the Validation Protocol. It includes clear conclusion as to whether the validation has been completed and successful or not.
3.7 Worst Case
A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, that pose the greatest risk of process or product failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.
4. Responsibilities
It is the responsibility of the manufacturing site to ensure that all manufacturing processes used for commercial products are validated.
5. Guideline
5.1 General
Process validation itself is one of the many elements of validation required in providing an organized approach to satisfy the GMP requirements.
The proof of validation is obtained through rational experimental design and the evaluation of data, preferable beginning from the process development phase and continuing through the commercial production phase.
5.2 Validation Master Plan
For more complex validation activities, a Validation Master Plan, VMP, should be produced to describe the approach to be followed for each element of validation.
A VMP is a strategic document, which must be approved at an early stage in the project and which identifies the elements to be validated.
5.3 Prerequisites for Process Validation
At the time of commencing process validation, other related elements of validation must be in place. The elements that must be in place and the requirements for those should be defined in the Validation Protocol. E.g.:
– Qualified and calibrated facilities, systems, services and equipment
– Validated testing methods
– Established specifications, batch records, materials and suppliers
– Trained personnel taking part in the validation work
– Current SOPs encompassing the process activities
5.4 Activities Prior to Process Validation of Commercial Process
Process validation should be an activity that originates within the development process for a product and is extended into commercial manufacturing, using technology transfer systems and procedures.
The development activities should gain sufficient process related information, as for example about the behaviour and the physical and chemical properties of the drug substance, the composition and the manufacturing process, to be able to clearly define the critical process parameters and controls.
Collection of process monitoring data during the process development can provide useful information to enhance process understanding. The evaluation of the process during this phase should provide proof of feasibility of the process at the commercial scale.
The site that will manufacture the product should be involved during the process development phase, prior to Technology Transfer, to gain knowledge about the product and the process, as well as around scale-up and commercial scale manufacture.
5.4.1 Setting the Manufacturing Process to Work
When a new or modified product or process is being established there is invariably a period of experimental manufacture during which processing conditions may be adjusted until optimization of the process is achieved. This experimental “setting to work” should be carried out in accordance with a protocol that should specify the objectives, methods and criteria for completion of the work.
When all experimental work has been successfully completed and the product or process can be considered established, validation is ready to begin.
5.5 Validation of Commercial Process
The Process Validation must ensure by testing that a process is capable of repeatedly and reliably produce a formulated product of the required quality. Information from R&D must be used to identify the critical process parameters to be tested during Process Validation in order to ensure batch reproducibility.
A risk assessment approach should be used to determine the scope and extent validation’s predefined number of validation batches (also called conformance batches) should be manufactured to demonstrate that, under normal conditions and defined ranges of operating parameters, the commercial scale process appears to make an acceptable product. It should normally cover the manufacture of at least three consecutive batches of material.
Validation should be performed under conditions to be used for routine manufacture. The batch size should be the same as or representative of the intended commercial scale batches.
Sampling and testing should be carried out to ensure compliance with the most stringent requirements. If the validation batches are intended for commercial use, the conditions under which they are prepared and manufactured must comply with them requirements.
5.5.1 Worst Case and Challenge Tests
The process should be challenged by making deliberate changes to demonstrate its robustness and to define its limits of tolerance. In challenging a process to assess its adequacy, the conditions should simulate those that could be encountered during actual production.
These tests should be repeated enough times to assure that the results are meaningful and consistent. Such worst case or challenge tests should preferably be performed prior to manufacture of validation batches. Typically, they are done during the Operational or Performance Qualification stage of a validation program.
5.5.2 Types of Validation
Depending on when the validation is performed in relation to production, it can be prospective, concurrent or retrospective. For new or modified processes, prospective validation must be the default method or approach. The rationale and justification for using concurrent or retrospective validation approach must be documented in the Validation Protocol and in the VMP (if applicable).
5.5.2.1 Prospective Validation
Prospective validation is carried out prior to the commercial distribution of a new product or an existing product made by a new or modified process. It is carried out when a manufacturing process has been established, or following significant change.
5.5.2.2 Concurrent Validation
Concurrent validation is carried out during routine production of products for sale. In exceptional circumstances it may be acceptable not to complete all validation activities before routine production starts.
Concurrent validation can be performed when the frequency of manufacture is insufficient to satisfy prospective validation requirements. The batches may be individually released, subject to meeting the requirements of the Validation Protocol.
There should be sufficient assurance that each batch was thoroughly monitored and tested. Concurrent validation may also be applied to modified processes and where the product has a short “shelf life”.
5.5.2.3 Retrospective Validation
Retrospective validation must never be used as the general routine approach and can only be considered under unusual circumstances.
Retrospective validation can only be acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment.
Retrospective validation is part of a validation process for a product already in distribution based upon accumulated production, testing and control data.
It includes a review of key historical data including analytical results, processes used and equipment used during a relevant period of review. It may be used as a basis to support (but not in lieu of) prospective/concurrent validation activities.
5.5.3 Matrix or Family Approach to Process Validation
The general principle is to validate a manufacturing process and the “same” process can typically be used for several related products. Rather than to develop a plan for each product manufactured by a process, it can be possible to develop a plan for that process instead.
There are two general principles that could be applied. “Matrix approach” generally means a plan to conduct process validation on different strengths of the same product. “Family approach” describes a plan to conduct process validation on different, but similar products.
Either approach must demonstrate that the process is consistent for all the strengths or products involved. The plan should be designed to evaluate all likely sources of variation in the products manufactured by the process.
Each plan should be evaluated on a case-by-case basis. For significant differences in equipment or process this approach would not be applicable and render each strength or product to be validated separately.
5.6 Timing of Process Validation
Process validation must be completed, evaluated, documented and approved before commercial distribution.
It is normally not expected that process validation be completed at the time of submission of a new product application to authorities. However, where the manufacturing process utilizes a non-standard method of manufacture, data demonstrating the validity of that method should be submitted in the EU marketing authorization dossier.
These data should be submitted from all sites where productions intended to take place.
5.7 Validation Documentation
All documentation and raw data generated during validation activities is considered MP documentation for retention/archiving purposes. It must be retained in a manner that permits traceability and ensures that it is readily retrievable.
The Validation Protocol, describing how the validation activities are to be executed, must be clearly written with defined acceptance criteria. It must be approved by Amassed in advance of the work and be version controlled. Where deemed appropriate, rationales and justifications for the scope and strategy should be documented.
The validation protocol should include, but not be limited to the following:
– Detailed objectives
– Process description
– List of products/product strengths
– List of process, facilities, systems and equipment to use
– Summary of critical parameters and activities to evaluate Number and identity of runs/batches
– Release specification/s and list of analytical methods
– Acceptance criteria
– Proposed in-process controls
– Additional testing to be carried out
– Sampling plan and testing procedures
– Methods for recording and evaluating results
– Functions and responsibilities
– Proposed timetable
The Validation Report must summaries the raw data and evaluate the work against the acceptance criteria.
A clear conclusion needs to be written as to whether the validation has been completed and successful or not. The report should also include summary of the acceptance criteria to be used in routine manufacture, and conclusions regarding future sampling and revalidation plans.
It should also include a review of deviations, their impact on the results and actions to correct them. Validation protocols and reports must be approved by manufacturing and QA.
5.8 Revalidation Requirements
Systems for review of the validation status should be in place to provide continued assurance that the validation status is being maintained.