1. Purpose
The purpose of this document is to provide guidance on the validation of processes for the manufacture of bulk drug i.e. those synthetic stages from introduction of the defined API Starting Materials into the process up to and including the physical processing of the API (Active Pharmaceutical Ingredient). Validation should extend to those operations determined to be critical to the quality and purity of the API. The validation of stages prior to the API Starting Materials is not mandatory. A risk assessment may deem it necessary.
2. Scope and Applicability
All functions, departments and manufacturing sites or their contractors. The manufacture of intermediates post API starting materials up to and including final API, for onward sale external to the site or for use in site formulated products.
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 Validation Protocol
Written plan stating how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters/operating ranges, product characteristics, sampling, test data to be collected, number of validation runs, and acceptable test results. Note: for process validation, the protocol would identify the number of validation batches.
3.3 API Starting Material
A raw material, intermediate, or an API that is used in the production of an Apian that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-housemaids Starting Materials are normally of defined chemical properties and structure.
3.4 Critical Parameter
Process parameter that must be controlled within an established range to ensure that the Active Pharmaceutical Ingredient or intermediate will meet specification.
3.5 Critical Activity
An activity that will prevent the Active Pharmaceutical Ingredient or intermediate from meeting its specification when omitted or carried out incorrectly.
3.6 Quality Assurance Agreement Coordinator (QAAC)
The team which is to co-ordinate the GMP related interactions and issues between an established contractor and the sponsor site, including auditing and the establishment of the Quality Assurance Agreement. QAAC can be coming from the receiving site if only one site is involved. (This concept can be applied when the contractor supplies different materials assigned to more than one Lead Site)
3.7 Lead Sites
The site that is accountable for conducting specified QA activities, notably Analysis and release, and Stability Studies, as recorded in the QA agreement between the Lead Site and the Receiving Site. Lead site can be a receiving site if only one site is involved.
4. Responsibilities
It is the responsibility of each site to validate bulk drug processes (API and intermediates) undertaken at that site. In the case where third party contractors are used to manufacture an intermediate or API it is the responsibility of the QAAC/ Lead site to ensure that the processes at the contractor are validated in line with receiving site requirements.
5. Guideline
5.1 Wider Elements of Validation
Process Validation itself is only one of the many elements of validation required to provide an organized approach to satisfy GMP requirements.
For more complex validation activities, a Validation Master Plan should be produced to describe the approach to be followed for each element of validation.
At the time of commencing Process Validation, the other related elements of validation should be in place, e.g.:
– Qualified and calibrated equipment, services and validated computer systems.
– Validated analytical methodology and established specifications, materials and suppliers. Critical in-process tests should also be established/validated.
– Cleaning validation plan and related validated analytical methodology.
– Trained personnel.
– Current SOPs encompassing the activities.
These requirements should be confirmed in a ‘Statement of Readiness to Proceed to Validation ‘In a multi-step synthesis, the intent is to Validate all steps identified as Critical steps from process development and/or historical data and Control (routinely test) other steps.
Critical steps are those containing Critical Parameters and/or Critical Activities. Process validation is therefore required from the first API intermediate stages containing critical steps, through to the stage producing the final API. For consistency of operation, some sites choose to validate all registered stages.
For outsourced registered stages, it is recommended that at least the final outsourced stage be validated, even if it does not contain identified critical steps.
5.2 Types of Validation
New or modified processes should be prospectively validated. In all cases, Process Validation activities should follow a pre –prepared Validation Protocol which highlights the rationale for the work being carried out and clear acceptance criteria against which the outcome will be assessed.
5.2.1 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. This should be based on a pre-planned protocol (normally a minimum of 3 consecutive batches). Prospective process validations performed when a manufacturing process has been established or following significant change.
5.2.2 Concurrent Validation
The validation carried out during routine production of products for sale. In exceptional circumstances it may not be acceptable to complete a prospective validation program before routine production starts. Performed when the frequency of manufacture is insufficient to satisfy prospective validation requirements.
Batches may be individually released, subject to meeting the requirements of the protocol. Whilst valid action of the process may not be formally complete during concurrent validation, there should be sufficient assurance that each batch was thoroughly monitored and tested. Concurrent validation may also apply to modified processes and where the product has a short “shelf life”.
5.2.3 Retrospective Validation
The validation of a process for a product that has been marketed based upon accumulated manufacturing, testing and control batch data. It may be used as the basis to support (but not in lieu of) prospective/concurrent validation activities.
5.2.4 Prior to Commercial Process
Process validation activities during product development are the responsibility of the development function. Development reports provide a repository of product knowledge that the processing and testing are understood. In addition, they helping setting process parameters by providing information on worst case testing carried out on small-scale laboratory batches.
5.2.5 Commercial Process
It is the responsibility of the manufacturing site to ensure that all manufacturing processes used for commercial materials are validated. Prospective validation, follows a pre-prepared validation protocol that derives any critical parameters/activities and acceptance criteria from the product development/scale up/optimization experiences for new products, and/or from historical manufacturing information on existing processes.
Validation should be undertaken under the fixed process conditions to be used for routine manufacture using appropriately trained individuals.
5.3 New and Modified Products and Processes
For new or modified product or processes, it is now frequent practice to derive parameter ranges from Factorial Experimental Design (FED) work in the laboratory, then to establish the process on the plant using Established Parameter Ranges (EPR).
There is invariably a period of experimental manufacture on plant, during which processing conditions may be adjusted until optimization of the process is achieved. This experimental work should be carried out in accordance with program, which 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, it still requires validation to provide assurance that it satisfies its intended purpose, that is, to consistently yield product of the required quality. Validation should be carried out after completion of the experimental or establishment phase and should normally cover the manufacture of three consecutive batches nominated in advance.
Minor changes are allowed between establishment and validation but critical process parameters must remain unchanged. An example of processing steps normally covered in a validation program are shown in the table in appendix 1, together with examples of objectives, sampling& testing and acceptance criteria for each step.
This information should be used only as a guideline, however, and appropriate programs should be produced to meet the requirements of the particular product or process to be validated. It is important to demonstrate equivalence of impurity profiles for validation of existing products.
5.4 Validation Documentation
All documentation and raw data generated during validation activities is GMP documentation for retention/archiving purposes. It should be retained in a manner that permits traceability and ensures that it is readily retrievable.
Validation Protocols should be clear written programs approved and issued in advance of the work, describing how the validation is to be done -including; detailed objectives, process and equipment to use, critical parameters/activities to evaluate, sampling and testing procedures, number and identify of batches, acceptance criteria and responsibilities.
In addition to the critical parameters, data for the EPR parameters can provide information beneficial during future manufacture. Validation Reports should summaries the raw data, review deviations, evaluate the work against the acceptance criteria and conclude with a clear conclusion as to the validation status. Approval of all protocols and reports by manufacturing and QA personnel should be undertaken.
Systems should be in place to provide continued assurance that the validation status is being maintained.
Change control and deviation reporting systems should assess all proposed changes and deviations for potential implications on the validated state, and in each case consider the need for any revalidation. The extent of revalidation may vary with the situation.
A periodic evaluation of the need for revalidation should also be undertaken e.g.by Annual Product Reviews.
5.5 Product Distribution The manufacturing site undertakes the validation of all APIs and appropriate synthetic stages before product is distributed to the market. See also 5.2.2.6 Appendices
6.1 Appendix 1 : API and Intermediate Sampling and Testing.
B, M, E = Beginning, Middle and End
Note 1: Typically, would take top, middle and bottom samples from the discharge process and compare with the blend using pre-defined acceptance criteria, which are based on scientific knowledge and quality attributes of the process.
The aim is to minimize variations.
Note 2: Critical process parameters must be operated within their proven acceptable range during validation Critical activities must be carried out correctly.
Batch homogeneity must be proven by analysing and comparing a minimum of 3 samples (typically beginning, middle and end). One suggested approach is to compare the results (beginning, middle, end and routine), together with their associated analytical variability, such that all ranges should have a value in common with the routine sample.
The range can be calculated as the analytical result for the sample +/- method MAD (maximum acceptable deviation).
As a minimum this should be done for strength but can also be done for impurity specification limits and other numerical limits.
The impurity profile must be proven to be comparable or better than historical data and, where applicable, the profile demonstrated for batches used in pivotal clinical and toxicological studies.
For established products the suggested criteria are
– All results within specification- No new imp >0.1%
– Values for each imp should lie below the historical mean + 3 stud deviations
– No two out of three consecutive validation batch results should lie further than 2 deviations above the historical mean
For new products (where limited batch data exists) suggested criteria are
– All results within spec
– No new impurity > 0.1%
– If sufficient data is available The Upper Control Limit (UCL) for each related substance, calculated using relevant data from process development and data from establishment and Validation, should be no higher than the specification limit, or be no higher than the
Uncalculated using the relevant data from process development and establishment, whichever is the greater. Critical in process tests shall pass acceptance criteria Yields shall be within the predicted range (make an allowance for filter heels where appropriate)