5.1.2 - Cleaning Validation
The Maximum Allowable Residue for Therapeutics (MART) and Residue Acceptability Limit for Therapeutic Dose (RALT) should be calculated based on each product that is to be processed in a specific equipment train and determined by the formulas and equations provided in Appendix A. A common default MART is not more than ten (10) ppm.
This document provides guidance in selecting the type of routine verification sampling method to use for particular types of API equipment and recommends locations for where to perform swab and / or visual inspection conducted during cleaning validation and during subsequent routine verification.
The ability to group products or equipment for the purpose of reducing the amount of sampling and testing during cleaning validation is dependent on scientific, documented rationale. Similarly, scientific, documented rationale is also required when determining a worst-case product for the purposes of cleaning validation of API and DP manufacturing equipment.
The area to be swabbed must be defined, typical areas range from 5cm x 5cm to 4” x 4”. It shall include special requirements and/or calculations for specific areas or equipment. It should be constant and well defined at each site to ensure consistency.
If visual inspection is the only verification of a changeover cleaning process on minor equipment, the limit of detection using visual inspection techniques should be quantified in the laboratory or referenced from recognized literature.
Comparison of an unknown peak to the RAL determines if an investigation is initiated. There are multiple Safety Factors typically applied in the RAL calculations. Therefore, the risk of having an unknown peak present that is significant to toxicity or dose limits is relatively low considering the conservative approach chosen to calculate the RAL.
The cleaning program requires that cleaning is conducted and the cleaning activities documented following written instruction-records, or SOPs with attached checklists.
An understanding of the concept and relationship between normal operating range and proven acceptable range is necessary in establishing the range for a critical process parameter. Rationale for the determination of a parameter as critical must be documented.
5.1.3 - Other Validation
Critical process parameters should be determined by a review of available historical data generated during development and/or manufacturing, or by experimentation. Each critical step is evaluated by observing the effect that potential critical process parameters have on quality attributes. .
A Cleaning Evaluation should be conducted, documented, and approved by the Site Quality and Production Team. This evaluation may be a single report or several reports and may be equipment centric or process centric and document or reference the required information.
Demonstrating equivalence is needed in all API validations, but this guidance is applicable to APIs prepared by chemical synthesis. Additional analysis (not described here) may be needed to evaluate physical attributes of the API, where requirements are defined for the corresponding Drug Product.
A new or modified drug products should be demonstrated to be equivalent to previously produced product. Comparisons must be done as part of process validation studies for new product and significantly modified processes that require validation.
This guidance describes considerations and risks for determining if the establishment of clean equipment hold times for equipment producing drug product and Active Pharmaceutical Ingredients (API) are required
This guidance outlines considerations and risks associated with hold times between equipment use and cleaning. The recommendations to evaluate if the time between equipment use and cleaning needs to be established and controlled are described for Active Pharmaceutical Ingredients (APIs) and Drug Products. When they are determined to be critical, recommendations on how to establish and extend existing hold times are also described.
This guidance provides recommendations and examples for evaluating the process validation impact of changes to manufacturing processes used for manufacture of API, Drug Products and packaging processes.
This guidance addresses recommendations for good sampling practices. Validation sampling plans must be specified or referenced in the protocol.
This guidance provides recommendations related to the selection and application of swab sampling and visual inspection for various types of Drug Product equipment.
This Guidance sets out guidelines for the determination and validation of in-process and bulk product holding times.
This guidance provides information on demonstrating batch homogeneity of final APIs (small and large molecules) and critical intermediates.This procedure provides guidance for performing a homogeneity evaluation in support of API process validation. The following components of the evaluation are described: Materials to be tested, Selection of test methods for examining homogeneity, Sampling plan – when to collect samples, from what locations, and the number of samples, Selecting acceptance criteria for evaluating homogeneity test results.
This guidance provides an example of documentation to support the use of Continuous Quality Verification for demonstrating that a manufacturing process is in a validated state.
This guidance describes the documentation needed to support the use of Continuous Quality Verification to demonstrate that a drug product or active pharmaceutical ingredient process is in a validated state. It also describes some similarities and differences between Continuous Quality Verification and traditional process validation using three discrete lots.
This guidance provides points to consider when selecting Dosage and Toxicity data for use in the Cleaning Limits calculations.
This procedure provides examples and guidance on classification of defects for packaged non-sterile drug products.
This procedure provides guidance in the qualification of simple, moderate, and complex laboratory equipment that is used in an analytical laboratory in a Good Manufacturing Practices (GMP) environment associated with products in or intended for the market place.
Bracketing and matrixing allow a ‘most appropriate challenge’ condition to be defined for a process or drug product family (the same drug product with different dosage strengths). This risk-based approach can allow the validation to be focused on the most challenging circumstances, or “worst cases.” Use of this approach can provide a significant benefit to reduce the overall validation effort.
Examples of primary and secondary packaging validation, both manual and automated operations are provided in this guidance. This also provides guidance on aspects to consider for packaging validation. Explanations of factors to consider for acceptable packaging validation and lot size are provided with various practical examples.
This guidance is to address environmental control for existing, new, and modified non-sterile API processing areas used for the manufacture of commercial materials. This includes non-sterile API manufacturing areas where the API will subsequently be used to produce sterile Drug Product.
This Guidance provides a tabulation of potential critical process parameters and quality attributes of typical steps of primary solid drug product (i.e. dry products) packaging processes. It also includes packaging validation items such as evaluation of equipment, protocol and report contents, amount of data (e.g. number of runs) and if warranted, microbiological studies.
This guidance provides Process Validation Sampling guidelines for non-sterile liquid (solutions and suspensions) and semi-solid (ointments, creams, pastes, gels and lotions) drug product dosage forms.
This guidance provides Process Validation Sampling guidelines for non-sterile solid dose drug product dosage forms. The purpose of this guidance is to provide the general principles and approaches that should be considered for sampling non-sterile solid dosage forms.
This guidance compares and contrasts Performance Qualification (PQ) to Process Validation (PV). This guidance describes the differences between PQ and PV. It clarifies how the PQ term is applied to systems and to processes. As applied to processes, PQ batches are used to demonstrate the robustness of a process and PV batches are intended to demonstrate the reproducibility of the process. As applied to systems, PQ testing is intended to verify that integrated systems function together as required
This guidance addresses the application of a risk-based approach to: Prioritize the systems and processes for periodic review (PR); Justify frequency and schedule of PR (if applicable); Routine revalidation of processes.
This guidance addresses considerations for commercial release of batches of product manufactured prior to completion of process validation (PV) activities, and considerations for release of batches associated with performance qualification (PQ) and PV activities.
This guidance discusses the term critical process parameter and considerations are described for identifying the term CPP that need validation. It is applicable to the manufacture of commercial intermediates, API, Drug Products and packaging.
This guidance provides an explanation of the semi-solid Drug Product dosage form and recommendations for analysis of the manufacturing process critical process parameters. Semi-solids come in a variety of dosage forms, yet significant steps and equipment used for the manufacturing processes share commonality. The critical process parameters will often be the same from process to process.
This guidance provides an overview of potential critical process parameters for the manufacturing of solid oral dosage forms. Solid oral drug products come in a variety of dosage forms frequently with common steps and equipment. The potential critical process parameters are often the same from process to process. This guidance provides an overview of process steps and typical equipment involved in manufacturing of solid oral dosage products and notes what might be critical process parameters associated with these process steps and equipment.
This guidance provides an example of the documentation for validation of a solvent recovery process. Solvent recovery validation is needed in some situations such as where the recovered solvent is intended for general site wide reuse into suitable manufacturing processes, including other API manufacturing processes than those from which the used solvent originated
Out-of-specification (OOS) results and any other deviations that may impact the acceptability of the qualification/validation should be documented, investigated, root cause determined, corrective action taken and reported. Several examples are included.
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 Produc processes. Other aspects of Tech transfers such as regulatory changes, stability impact, etc must also be considered as described in relevant guidance, but these other activities are outside the scope of this guidance.
This document provides guidance to determine if validation of re-work and/or re-processing steps are 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
This guidance provides recommendations for the content of the planning, testing and reporting types of validation documentation.
The risk of compromising biopharmaceutical materials in shipping is relatively high, as these materials are particularly vulnerable to degradation when exposed to various environmental and handling conditions. The risks can be managed effectively through qualification of packaging, handling, and transport procedures.
This document explains how the Commissioning and Qualification System Level Impact Assessment template can be used for Information Systems. To classify Information Systems as Direct, Indirect or No impact systems, only one question is applicable for Information Systems. By means of three typical examples, this guidance explains how system classification could be performed, based on the use of the system and its data.
This document recommends sampling locations, frequencies and testing activities associated with the commissioning and qualification of new installations or major revisions of Clean/Pure Steam Systems (e.g. the addition of new subloops or other system wide retrofitting). This guidance defines the sampling location, frequency, and testing activities utilizing a risk based approach for supporting the commissioning and qualification for a clean/pure steam system.
The classification of Information System components as critical or non critical can be performed using a Component Level Impact Assessment in order to determine which components need qualification. This guidance also gives guidance on how to identify components in applications and includes examples of component level impact assessments for three typical software applications.
There are three elements to achieving successful validation of a freeze drying cycle: 1. A well defined and understood formulation, 2. A qualified freeze dryer and a freeze drying cycle that provides the link between a specific formulation and 3. A specific freeze dryer.
Test results should be documented in a manner permitting objective pass/fail decisions to be reached. The following represents the objectives of good test documentation practices. The degree to which these are achieved should be based on the criticality of the function being tested.
This procedure provides guidance for allowing Vendor’s Material of Construction (MOC) documentation, such as Certificates of Analysis (C of A) and other record documents, to be accepted as confirmation that a specified material has been used for new systems or components that come into direct contact with product.
This document provides guidance on the transfer of documents during the activities that take place as a result of the Technology Transfer for approved commercial packaged Drug Product (DP) processes.
This guidance recommends sampling locations, frequencies and testing activities associated with the commissioning and qualification of Purified Water (PW) and Water for Injection (WFI) Systems.
This guidance provides recommendations when developing specifications for the design of Direct Impact Compressed Air, Pressure Swing Adsorption (PSA) and Cryogenic Nitrogen Systems used in the manufacture of Active Pharmaceutical Ingredients (APIs) and Drug Products (DPs).