Introduction
This document provides guidance for qualification and validation activities that take place as a result of the Technology Transfer for approved commercial Active Pharmaceutical Ingredient (API) and Drug Product (DP) processes. Other aspects of Tech transfers such as regulatory changes, stability impact, etc must also be considered as described in relavent guidance, but these other activities are outside the scope of this guidance.
While overall Technology transfers often include many aspects (e.g. validation, stability, regulatory, safety considerations), this guidance focuses on the validation aspects of technology transfers. Qualification and validation requirements for processes, cleaning, analytical methods, and systems (equipment, facilities, utilities etc) should be documented in Site Quality Standards.
Guidance for qualification and validation activities necessary at the receiving site is described in the following sections.
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 Validation Master Plan should also be updated accordingly.
Recommendations & Rationale
General:
It is recommended that the transferring facility compile a knowledge information package to set the foundation for knowledge transfer to the receiving facility. An overall Technology Project Plan is typically utilized to define what information is needed, by whom, and at what point in the transfer process.
Validation personnel at the receiving site should be represented in initial interdisciplinary knowledge sharing meetings to assess the scope of work and estimate time requirements and plans.
Typical contents of a knowledge information package include or reference:
– Regulatory Process Description
– Process Flow Diagrams
– Equipment List
– Bill of Material
– Master Batch Records or Manufacturing Instructions
– Cleaning Procedures or Instructions
– Raw Material Specifications (where appropriate)
– Intermediate Specifications (where appropriate)
– Product Specifications
– In-process testing methods and limits
– Cleaning Agents used, including solubility data.
– Qualification and Validation Documents specific to the transferred process
– Change History for the process
– Access to Regulatory Documents
– Analytical Methods
– Stability Requirements
– EH&S requirements
– Critical Quality Attributes and Critical Process Parameters
– Annual Product Review reports
– Cleaning Evaluation Reports (inc. appropriate limits and cleaning methods)
Where information suggested in this guidance is not available to provide to the receiving site, an evaluation should be performed to determine the significance of the missing information. This may be more common with older processes. If the information that is not available is considered to be critical to the technology transfer, then it is recommended that the necessary data be generated/obtained.
Depending upon the type of missing information, some tech transfer activities may be able to proceed in parallel with the collection/generation of the missing information. If the information is determined to not be critical, then the tech transfer may be able to proceed without obtaining it.
Considerations for System Validation (e.g. Equipment, Facilities, Utilities, Automation, Computers)
Considerations related to Systems Validation may include:
– A documented risk analysis should be performed comparing the requirements of the transferred process with the existing systems such as facilities and equipment. Validation requirements for systems such as facility modifications, qualification of new equipment, or equipment transferred from the originating facility can be outlined in a revision to the existing facility validation master plan, or in a Tech Transfer Validation Project Plan.
– A System and Component level impact assessment, if necessary, to determine Direct Impact Systems and Critical Components that may require qualification as a result of the incoming process.
– Changes, if any, that may be necessary to existing System Validation status and documentation as a result of the incoming process (e.g. ranges of equipment operation). This includes a review and revision, where appropriate, of existing system(s) validation and qualification documents.
– Additional requirements of the incoming process that impact supporting systems.
– Specific product environmental/facility requirements (e.g. temperature, relative humidity control), including Dispensary, Manufacturing, Pack-out areas and Product and Stability Sample storage areas.
– Specific product utility requirements (e.g. water or compressed gas quality).
– Specific product Process Automation recipes, where common Process Control systems are used.
Cleaning Procedure Validation Considerations:
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.
The receiving site must evaluate how the cleaning requirements of the transferred process fit into the existing cleaning regime. It is recommended that the following information be provided to the receiving site:
– Existing cleaning validation documents (protocols, reports, cleaning evaluation reports, other supporting documents) from the sending site
– Cleaning procedures, including: cleaning agents, mechanical methods ( e.g. spray devices, flooding, power washing); cleaning parameters and applicable ranges (e.g. concentrations, temperatures, contact times); and sampling procedures (including technique and location)
– Residues to be removed
– Stain logs, if applicable to a given residue related to the process
– Analytical sampling and test method(s) and recovery data for verification of cleanliness, including methods for swab and rinse analysis, and limits used for analytical method validation
– Solubility of residues in cleaning agents
– Cleaning agent specifications, raw material test methods (if applicable), vendor related docs (if applicable)
– Toxicology info and proposed dosage data of each residue to be tested, if applicable.
– Potential for degradation by-products or conversion products, if applicable
– Stability of materials being cleaned under the proposed conditions
– Evaluation of campaign length
– Acceptance criteria and rationales for interval cleaning
– Visually detectable quantities, if available.
– Suitability of cleaning agents to surface finish.
– Relevant information regarding the materials of construction of product contact surfaces from which the transferred product has been cleaned previously, including surfaces that are more problematic than others to clean.
– Evaluation of cleaning limits for the transferred product at the receiving site against existing cleaning limits matrices for receiving site, if applicable
– Information on cleaning deviations related to the cleaning process and resulting investigations at sending site, if relevant to the cleaning procedure used at the receiving site.
– Cleaning Process change control reports / documentation, if relevant to receiving site
– Whether cleaning validation for Biopharma products will occur prior to, or concurrently with process validation batches.
Analytical Method Qualification and / or Validation Considerations:
When transferring analytical sampling and test methods, it should be determined what the analytical method is utilised for (e.g. quality of product, EHS purposes, etc.), as well as the current validation status.
Some methods (e.g. related to operational efficiency only) may not require validation. One can then prioritise which methods may require a more formalised analytical transfer and/or validation. A comparison of the originating and receiving laboratory instruments and capabilities would likely need to be performed.
The following information should be provided to the receiving site:
– The analytical sampling and test method, including description of method, reagents and instrumentation used at the sending site laboratory.
– Method development and validation documentation and reports. If methods require validation and there is no validation documentation available, or the method was not originally validated to current standards, the method may need to be revalidated.
– Information about critical analytical method parameters and / or procedural steps, deviations related to the method, and resulting investigations at the sending site.
– Procedures to prepare analytical standards that are not readily available, for example, API Impurities or Intermediates.
– Microbiological method validation (e.g. Endotoxin, Bioburden) if applicable.
Process Validation Considerations:
Processes used in the manufacture of API or Drug Product require validation. The timing and strategy for validating the process at the receiving facility will typically be influenced by the following factors:
– Prerequisite activities such as facility, equipment, and system qualification, cleaning validation strategy and analytical method validation requirements.
– The number of pre-validation (e.g. engineering or demonstration) lots (if required) and the intended use and disposition of this material.
– The extent to which existing supporting studies and matrixing and bracketing approaches can be used to reduce the validation workload. Rationale for utilizing existing information to cover requirements of a validation should be documented.
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.
– Process Instructions with detailed description of process.
– Laboratory, small scale studies, and / or risk assessment documents supporting the identification and rationale for Critical Process Parameters (CPPs) and Quality Process Parameter designations, acceptable operating ranges, and probable adverse consequences of deviation.
CPPs for some processes may not have been defined consistent with current expectations, or may be modified for the receiving site depending on equipment control capabilities. Therefore, a review of the Critical Process Parameters and Critical Quality Attributes of the transferred process, versus the receiving sites’ system capabilities may be necessary. The designation and selection of process parameters may therefore need examination with respect to impact on critical quality attributes of the API.
– IProcess validation documents (protocol, reports, supporting documents) from the sending site.
– In process sampling plans, testing requirements, and specifications specific to the process validation.
– Studies supporting in process hold times, if applicable. This is particularly relevant to Biopharma products where hold times are typically validated. An assessment should be performed to determine the strategy for confirmation or determination of hold times, if necessary, at the receiving site. The strategy for revalidation of hold times for Biopharma products should be assessed. The rationale for the strategy should be documented.
– Studies supporting registered reprocessing and rework procedures, if applicable. An assessment should be performed to determine the strategy for revalidation of reprocessing and rework, if applicable. The rationale for the strategy must be documented.
– Information on concurrent studies to be performed, if applicable.
– A review of Annual Product Quality Reviews from the sending site may be useful for the transferred process.
– Noteworthy deviation information related to the process and the outcome of investigations at the sending site.
– Technical reports from the sending site related to the process.
– Process Impurity profile and historical lot data for equivalency comparison
– Normal or expected API particle size distribution, relating to specific Drug Product needs or agreements, if applicable
– Right First Time and / or Statistical Process Control data if available.
– Solvent Recovery practices, processes and validation, if applicable
– Process Change Control records / documentation
– Vendor Information (certifications, audits, other vendor-related records for API starting materials and Primary Packaging).
– Product packaging information (e.g. components, specs), if applicable.
Validation Project Plan (VPP) Summary
Information typically included in a Validation Project Plan for a Technology Transfer is the following:
– Approvals – The Plan should be reviewed and approved by representatives from stakeholder functions (e.g. Engineering, IT, etc) involved with validation activities related to a given product transfer. The plan must be approved by site Quality Team and System Owner.
– Introduction – A summary statement covering the particular validation objectives. This may reference project information such as project plans, milestones, schedules and transfer target date.
– Responsibilities – Define or reference responsibilities of the Transfer Validation Project Team or equivalent site Validation team members and the organizational structure and responsibilities for qualification and validation activities at the receiving site. This should include a description of activities that will be performed by contractors and suppliers.
– The Tech Transfer Validation Plan should include a summary section for each type of validation that is impacted by the technology transfer (e.g. process validation, cleaning validation, analytical validation and system qualification) as outlined in the previous sections of this guidance. Each of these summary sections should describe:
– An assessment determining which systems and processes or process steps require validation and the extent of validation activities required.
– Scope of validation and qualification activities, including boundaries, exemptions and the reasons for exemption of systems and processes to be qualified or validated. This should include a description of the facilities, systems, processes or process steps requiring qualification and/or validation. Associated or related plans that are outside the scope of the VP should be referenced. The scope should also include whether a given validation is an initial validation or a re-validation due to a change.
– A list of deliverables planned for each type of validation __ Description of, or reference to, the qualification and/or validation policy, program or approach to be used at the receiving site, including documentation requirements, general acceptance criteria and deviation handling.
– When required information is contained in other GMP documents (e.g. site Validation Master Plan, SOPs, etc) it does not have to be repeated in the VP. The other documents may simply be referenced in the relevant section of the VP. Where additional detail specific to the project is required, this information should be discussed in the VP.
– Confirmation that critical inter-related systems at the receiving site, such as utilities, environmental control systems, equipment, etc are qualified, or are identified as requiring qualification or validation.
– Schedule of critical validation activities, which may be by reference to a separate document, plan, or schedule
– The sequence of validation of different systems and processes, along with any interdependencies should also be outlined. If some activities must be completed before a given validation can be initiated these should be identified.
– Reference to programs that support validation and qualification activities, such as: change control, SOPs, document retention, calibration, preventative maintenance, periodic review and training.
– The VP should specify what activities may be needed outside of the normal quality systems that are specific to support a given tech transfer validation. For example, if special training is required to execute a given tech transfer validation, this may be specified in the plan.
– Related document references, such as procedures, the site Validation Master Plan and/or guidelines used in the validation and qualification activities of the technology transfer.
Validation Project Plan Report
Upon successful completion of the validation and on approval of the supporting validation reports, a Validation Project report may be written and approved by the signatories of the plan (or their designee).
This report summarises conclusions from:
– Process validation batches and references the process validation report.
– Systems Qualification and respective report references
– Cleaning Validation Strategy as outlined in the protocol
– Analytical Method Qualification and / or Validation and reference to the reports
The report should also state whether or not the process is acceptable for regulatory submission and commercialisation.