Guidance Summary 041 - 050
Guidance 041 Summary - Release For Commercial Use of Drug Product Validation Batches
Batches of product manufactured prior to completion of PV activities may be released for commercial use following verification of acceptable results for all tests, verification that the acceptance criteria have been satisfied, the critical process parameters, ranges and materials used are the same as the proposed commercial manufacturing process and fulfillment of other site requirements for product release as necessary. Release for commercial use will require satisfactory completion of the validation study for that process, ensuring that the recommendations described in this bulletin are met for these pre-validation batches.
Product batches manufactured prior to completion of PV activities may include Demonstration (demo) batches, sometimes called ‘proof of concept’ batches, pre-validation batches, or engineering batches. These are typically manufactured for the purpose of examining a new process or a process with a significant planned change that requires revalidation, to insure that the process operations are understood and work as planned before beginning production of validation batches.
The process used must be within processing conditions allowed by the approved product registration, unless the validation activities include, or are as a direct result of changes to registered processing conditions. The requirements for Product Change Management system should be followed. Once registration approval has been received, the recommendations of this guidance can apply to the new manufacturing process.
The scope of a validation project can vary in many ways. The decision to approve and release
product batches prepared for the validation study should be made only after review of relevant data and verification that the required acceptance criteria have been met. Depending on organization of validation protocol(s) prepared for a process, there may be different points in the production process where evaluation of data and verification of meeting acceptance criteria are needed.
Guidance 042 Summary - Selection of Critical Process Parameters for Validation
Two objective criteria must be met for a process parameter to be considered a potential critical process parameters (CPP):
- Running the process outside the proven acceptable range (PAR) for the parameter results in a significant risk of producing material of unacceptable quality;
- The difference in quality is carried through the process to the finished product (intermediate for sale, API or DP) where it results in the product not meeting one or more pre-determined Critical Quality Attributes.
For new processes, CPPs are identified during Co-Development. The CPPs are typically identified by Technical Support site personnel, if not previously identified during process development. For many processes, a recommended approach to identifying the CPPs for validation is to begin with identifying the product’s CQAs and the process parameters that directly and indirectly impact these CQAs.
A process parameter may affect a CQA in either a univariate (single variable effect) or multivariate manner (multiple variables each having an impact). Some CQAs may have no specifically related process controls or parameters. Assessing the criticality of a process parameter should include consideration of all of these potential situations.
In a given API process, control of a process-related impurity is primarily determined by controlling reaction temperature within the identified PAR and by preventing an extended reaction time. Additionally, the conditions under which the
API is crystallized influence the ability to diminish the presence of this impurity. Reaction conditions (e.g., temperature and duration) and crystallizations conditions (e.g., solvent composition and temperature) should all be evaluated when determining which parameter(s) should be identified as critical.
Risk assessment of parameters should include evaluation of any process parameters impacting product quality, either directly or indirectly. The risk assessment provides the justification to explain why lower risk is associated with the quality-related parameters that are not identified as CPPs. Parameters that have a reduced risk of affecting product quality are sometimes described as Key Process Parameters, in manufacturing of small molecule APIs.
When evaluating the potential impact of a change (e.g., to the manufacturing instructions, equipment, manufacturing site, product specifications, or addition of a new product to existing equipment), the associated risk analysis of the parameters that impact product quality should be re-examined
Guidance 045 Summary - Solvent Recovery Validation Example
This guidance provides an example of the contents that may be found in solvent recovery validation documentation, including appropriate acceptance criteria for solvent recovery validation. The processing addressed by this type of validation includes the recovery of used solvent to provide solvent that is acceptable for use.
If the potential for significant variability in the feed stock of used solvent exists, it is recommended that validation batches be prepared over a significant period of time to encompass the likeliness for variability in the used solvent feedstock. A good practice that has been used is to include validation batches made with an intervening time interval between each, as shown in the example provided later in this guidance (see acceptance criteria section). The increased risk introduced by potential variability in feedstock is therefore addressed by evaluating more validation batches over a longer time period.
The remainder of this guidance provides one example of validation of a batch solvent recovery process that of the recovery of tetrahydrofuran (THF) from a used THF/toluene mixed solvent . The used THF may be derived from multiple process streams and the recovered THF will be available for mult-process use. While this example includes the use of computer simulation to predict when to make cuts for collection of distillate fractions, validation of the process may also be achieved with appropriate in-process monitoring.
In preparation for the final distillation, information on the composition of each batch of used solvent to be distilled is needed. For THF recovery, the computer simulation does not account for isopropyl alcohol (IPA) in the stream, so it is critical that the amount of IPA is NMT 0.1 vol-%. Feed composition that is higher in IPA will negatively impact the quality of recovered THF by being unacceptably high in the total alcohols (C1-C4) specification.
Used THF/toluene streams with higher amounts of IPA should be directed through the optional processing step for removal of alcohols.
To validate this solvent recovery process, THF will be recovered from three sets of at least three consecutive batches of used THF. The time period between the beginning of the last batch in a set and the first batch of the next set will be at least one month. The total number of batches will therefore be no less than nine.
Guidance 046 Summary - Test Deviations during Validation
This guidance provides recommendations for investigation and reporting of test deviations during a validation exercise.
Deviations may be identified by the tester during execution of the protocol or by a reviewer.
Where a protocol error is identified, it is recommended that the deviation procedure makes a clear distinction between typographical and other minor errors where the intent of the protocol is still clear, and errors that require correction to allow the test to be executed. It is considered acceptable to hand-amend (per applicable site documentation practices) typographical and other minor errors that have no impact on the test method or acceptance criteria. Where correction is required to allow the test to be executed, including determining whether the test passes or fails, then a deviation should be raised.
Where the deviation and any corrective actions do not impact the intent of the original validation test, then testing should be allowed to proceed.
If corrective actions identified impact ongoing validation activities (including moving to the next phase of validation), validation testing should be stopped, the actions should be implemented and confirmed and the deviation should be closed before continuing testing.
Where testing that has already been completed is impacted, consideration of the repetition of those tests should be included in the corrective actions.
An out-of-specification (OOS) result generated by the laboratory is a deviation and should be investigated according to applicable procedure and procedures for laboratory OOS results. Another common deviation is missing or lost data. The impact of the missing or lost data should be evaluated to determine the criticality of the unavailable information and its impact on providing evidence of validation or qualification of the system or process.
Guidance 047 Summary - Validation Activities during Technology Transfers
Technology transfers of existing APIs or DP processes to a different site often involve a change in registration documentation for the product, to include the new location. This will likely prompt a regulatory inspection at the receiving site and/or regulatory scrutiny (e.g. of analytical methods, critical process parameters, etc) of the registration documents. Therefore, validation requirements for production and support systems at the receiving site should be considered at an early stage of the technology transfer process. The Site Master Validation Plan should also be updated accordingly.
- Regulatory Process Description
- Process Flow Diagrams
- Product Specifications
- In-process testing methods and limits
- Qualification and Validation Documents specific to the transferred process
- Change History for the process
- Analytical Methods
- Stability Requirements
- Critical Quality Attributes and Critical Process Parameters
- Annual Product Review reports
- Cleaning Evaluation Reports (inc. appropriate limits and cleaning methods)
Multi-product facilities may consider the potential benefits of single use consumables to reduce the burden of cleaning and the risk of cross contamination. This may be especially relevant for products manufactured using Biopharmaceutical and classical fermentation processes. The receiving site should perform an assessment to determine what equipment may be dedicated and what will be designated for multi-product use.
Providing the documentation of key information relating to the process is fundamentally important to the successful transfer of the process. In addition to the documents provided as part of the knowledge information package, the following list of documents and considerations are typically needed for the receiving site to successfully validate the incoming process:
- Existing Regulatory documents, including Annual Product reviews and change supplements.
- Raw material, reagents, solvents, Intermediate and Final product specifications. The validation impact (if any) of changes in raw material suppliers. For example, if a critical drug product raw material such as the API is changed, this may prompt revalidation of the DP process.
Guidance 048 Summary - Validation Considerations for Re-work and Re-process of API
This document provides guidance to determine if validation of re-work and / or re-processing steps is required for Active Pharmaceutical Ingredient (API) processes.
This guidance provides recommendations for evaluating the potential impact on product quality to determine if a given re-work or re-process step requires validation.
Compliance with regulatory filings, consideration of impact on product stability, and To clarify validation considerations for re-processing and re-work steps, definitions of these terms are listed below:
Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process, and not re-processing.
It may be necessary to extend evaluation of the product to its performance in subsequent steps of the process, including the drug product manufacturing process. This evaluation can be conducted via change control and doesn’t automatically require a validation exercise.
Batches that have different reasons for re-processing or re-work may be combined to perform the proposed remediation, if there are data and/or rationales (such as blend uniformity) available to support that the re-processing or re-work would be effective on each individual batch. Validation considerations for these combined batches can be determined using the flow-chart provided. Per ICH Q7A, “Out of specification batches should not be blended with other batches for the purposes of meeting specifications”.
Example:
Batch B of a final API is found to contain an unacceptable amount of a known process-related impurity. Investigation of the incident reveals the root cause of the problem, and the corrective action for Batch B relies on process knowledge that indicates an elevated amount of this impurity cannot be removed by the normal product purification procedure. During process development, an alternate crystallization solvent mixture was shown to effectively control elevated amounts of this impurity. Use of this procedure did not become part of normal processing because of poor product yield from the solvent mixture. This re-work procedure has not been used before during commercial-scale manufacturing and therefore has not been previously validated.
Guidance 049 Summary - Validation Documentation
This guidance provides recommendations for the content of the planning, testing and reporting types of validation documentation.
Typically documented in a Validation Master Plan or similar policy-level document.
This may also be considered as the validation strategy for a site or Center function and is typically documented in a Validation Master Plan or similar policy-level document.
The documentation should be based on the scope of the site or Center function’s operations and/or functional areas. The program / strategy documentation may reference other documents addressing various aspects of validation, for example, different facilities within a site or different validation types.
A validation planning document should be considered for use for larger scale projects that encompass multiple systems and processes. A planning document may be a separate document or combined with other documents such as testing or change control documents.
Documentation, such as protocols or test scripts, should be developed that specifies how the validation study will be conducted. Testing documentation should contain or reference the following information, as applicable:
Test documentation should be reviewed and approved prior to execution. Completed testing documentation should contain or reference the following information, as applicable:
Reports should describe the results from the planning and testing and should be approved by QA and the process/system owner, at minimum. The content of the report should include, or reference, the following:
Guidance 050 Summary - Shipping Validation for Biopharmaceutical Materials Derived from Biotech Processes
This document describes the qualification studies required to validate product specific shipping procedures for biopharmaceutical materials derived from biotechnological processes, including:
- Bulk Intermediates
- Bulk Drug Substance
- Drug Product bulk vials
- Fully packaged sample kits in commercial packaging.
- Samples for analytical testing
Temperature excursions can occasionally occur as a result of inadequate thermal protection under unexpected or unusual circumstances in routine shipments. Temperatures outside of the allowable shipping range can often be attributed to shipment delays, unanticipated temperature extremes during shipment, or incorrect shipping methods. In addition, the position of primary containers within the shipping container should be carefully considered to prevent unintended warming or freezing as a result of proximity to external conditions or cooling source.
Proteins may be susceptible to shear or formation of aggregate caused by shaking or rough handling. Vibration may cause foaming and turbidity of liquid solutions shipped under refrigerated conditions. While motion in shipment is obviously inevitable, the packing configuration should be designed so that the primary containers are secured and cannot move in the container interior. Securing primary containers also minimizes the risk of damage to the primary or shipping containers.
Concurrent studies may be conducted with shipments of actual material if sufficient experience with similar containers, materials, batch sizes and shipments justifies the risk.
The acceptable temperature range (supported by stability data) is defined. This temperature range is often wider than the recommended storage temperature under normal conditions, but the range specified must be supported by data. A description of the calibrated monitoring device that will log interior temperatures during temperature and transport should be included.