GMP Training System

Guidance Summary 081 - 090

Guidance 081 Summary - GMP Training System

This document discusses considerations for site GMP Training systems including training on regulations, GMP concepts, GMP tasks and knowledge necessary to perform those tasks.

GMP sites must comply with GMP requirements for training by defining the knowledge, skills and attributes colleagues must have to competently perform GMP tasks and other activities. This may be accomplished through education, training, experience or a combination thereof.

Introduction to the GMP Training System should be part of any colleague’s orientation to the site and should be the structure upon which all the GMP training needs of the colleague are met. This document will cover the various aspects of the system including job function curriculum, training record system, GMP orientation, SOP training, GMP concept training, structured on-the-job training, and training effectiveness assessments.

Procedures and practices for managing and administrating GMP training including, but not limited to, planning, designing, executing, recording, and tracking training.

Components

1. Job Function Curriculum (JFC) – A list of all training (including SOPs, OJT and other topics) that must be completed and kept current for each person in that job function. Each of the items on the JFC are required to be completed as specified, unless there is a documented exemption for an item based on a combination of their previous education, training or experience. The JFC must include achievable targets that, once completed, allow the person to work on a GMP task without direct supervision

2. On-the-Job Training (OJT)– the one-to-one process of providing and mastering knowledge and skills to perform a specific task within a job.

Training should include specific criteria to be met to show that competence has been achieved in the task.

3. Training Record System – process for creating, filing, retrieving, and archiving training records that tracks and reports the status of completed and required trainings. Training records or reports must be readily available to substantiate that all employees performing GMP Related functions have completed the training requirements.

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Guidance 082 Summary - Stability Testing

This document provides guidance for the stability testing for drug products [including: marketed human and animal prescription products and consumer Over-The-Counter (OTC) drug products, consumer non-drug products (e.g., cosmetics), Active Pharmaceutical Ingredients (API), API Intermediates for Sale, and medical devices manufactured at GMP facilities.

Stability Testing for Finished APIs (including API Intermediates for Sale) and Drug Products is required for, but is not limited to, the following situations, unless there is documented rationale approved by the Site Quality Authority for not performing stability testing:

  • Routine required monitoring as per established protocol;
  • Establishment of expiration or reevaluation dates;
  • A change in the reevaluation date of the API or the API Intermediate for Sale; and/or
  • When required by the Regulatory Authority for the specific market, such as:

 

– A change in the qualitative and/or quantitative composition of the primary packaging material;

– A change in packaging that may affect stability (e.g., headspace, surface-to-volume ratio of the container); or

– A change in the manufacturing process of the finished API, API Intermediate for Sale or drug product that may affect stability (e.g., a change in batch or lot size, change in manufacturing Site, process, equipment, raw material (RM) specification, RM supplier, product formulation).

Guidance 083 Summary - Quality Risk Management (QRM) application to identify deviations vs. events

Often times, deviations that occur during the handling, manufacturing, testing or distribution of materials/products have little or no impact on product quality or to its registration filing. The purpose of this guidance is to provide a process for assessing if a deviation does or does not impact the product quality or its filing through the use of a Quality Risk management (QRM) tool.

A deviation with no impact to product quality or to regulatory filings is classified as an event and thus does not require to be investigated while those that impact product quality or regulatory filings are classified as deviations.

Accordingly, the following definitions for Events and Deviations apply:

Deviation – A departure from approved procedures, formulas, specifications, or parameters that has an impact or potential impact to product quality, GMP regulated systems, or regulatory filings. These are typically documented in a Quality Assurance Report (QAR).

Event – A departure from approved procedures, formulas, standards, or parameters that has been determined to have no potential impact to product quality, GMP regulated systems, or regulatory filings. These are typically documented in a Notice of Events (NOE).

This document provides guidance on two approaches to assess the risks associated with identifying deviations vs. events.

Guidance 084 Summary - Implementation of Real Time Release

Real Time Release Testing is defined in ICH Q8 (R1) part II as the ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls.

This document provides practical guidance on how to implement a Real Time Release (RTR) testing approach as part of a manufacturing control strategy to ensure product quality while enabling the rapid release of API, intermediate and/or finished products.

This document provides a framework for RTR projects. It serves to outline the important components that need to be considered in any RTR program. It provides guidance on the development of an underlying control strategy that will enable the adoption of an approach to release that relies on process understanding, monitoring and control rather than on end product testing.

The drivers for moving to RTR testing will be based on business benefits including the reduction in the cost of testing intermediates, API and finished product, enabling a “pull” supply chain, in support of Agile Operations and increasing the overall level of quality assurance through the introduction of real time monitoring and attribute based endpoints.

The scope of RTR testing applications can vary significantly ranging from specific attributes of individual unit operations to RTR for entire processes. Real Time Release testing can replace end product testing, but does not replace the review and quality control steps called for under GMP to release the product

The overview presented in this guide is applicable to all manufacturing operations, batch and continuous, API, drug product, aseptic manufacturing and bioprocessing. The exact approach to RTR will vary from product to product.

Guidance 085 Summary - Preventive Maintenance

This document provides guidance in for Preventive Maintenance (PM) of direct impact systems and associated critical components used in production, storage, and testing that may affect the safety, identity, strength, quality, or purity of active pharmaceutical ingredients (API), drug products, drug product raw materials (RM), API starting materials, critical in-process materials, critical intermediates, biologics, or medical devices.

Definitions

Like-for-Like Changes – replacement of a part with a part that meets the original specification in terms of:

  • Functionality,
  • Input Range,
  • Output Range,
  • Accuracy Specifications,
  • Operational Specifications, and
  • Material of Construction.
  • Non-Intrusive Condition Based Monitoring – inspection which does not require the equipment to be taken out of service, physically removed from the system or taken apart to access condition (e.g. visual or audible).
  • Predictive Maintenance Activity – an activity in which equipment inspections or monitoring is conducted using devices that access equipment condition during normal operation (e.g., vibration analysis, oil analysis, thermography).

 

  1. The PM Program should include or reference the following:
  • List of all systems and associated components that require PM;
  • Definition of responsibilities for PM requirements and activities, including on-Site contractors and vendors;
  • Management of off-Site contractors and vendors performing PM activities (e.g., Quality Agreements, vendor audits, and vendor assessments);
  • Method for establishing and managing PM frequency;
  • Method for establishing and documenting acceptance criteria;
  • Establishment and management of inspection-based PM;
  • Definition and acquisition of materials and parts to be used [e.g., lubricants (food grade versus non-food grade)];
  • PM activities, requirements, and checklists
  • Evaluation and documentation for addressing deviations;
  • Sources of technical data and drawings [e.g., floor plans, Piping and Instrument Drawing/Diagrams];
  • Change control for PM (e.g., definition of Like-for-Like);
  • Removal from and return to service for PM activities;

Guidance 086 Summary - Calibration

This document provides guidance for the calibration of equipment, instruments, and standards used in production, storage, and testing that may affect the identity, strength, quality, or purity of Pharmaceutical drug products, active pharmaceutical ingredients (API) and medical devices.

1. Instrument Specifications include, and are not limited to, the following:

  • Definition of required accuracy and precision;
  • Expected Process Parameter values, including unit of measure;
  • Expected Normal Operating Range (NOR) of the process parameter values;
  • Acceptable tolerance;
  • Instrument stability requirements; and
  • Safety and environmental considerations.

 

2. An Instrument History File should be maintained for each instrument that includes, and is not limited to, the following information:

  • Instrument identification;
  • Instrument manufacturer, model, and serial number, if available;
  • Instrument type (e.g., thermometer, pressure gauge);
  • Instrument classification (e.g., critical, non-critical, major, minor);
  • Reference to calibration procedure(s) for the instrument;
  • Instrument location;
  • Type and accuracy requirements of standard(s) to be used;
  • Calibration frequency;
  • Limits for accuracy and precision;
  • Calibration range;
  • Calibration test points;
  • Specific environmental conditions for calibration, if applicable;
  • Calibration records; and
  • Repairs and service records.

The Instrument History File should be retained in accordance with the Site record retention procedure.

Guidance 087 Summary - Evaluation Process Supporting Elimination of Defined Shipment Temperature Range

Some GMP sites may be practicing to ship some oral dosage form products from manufacturing facilities to Distribution Centers under controlled (defined temperature range) temperature conditions. Given the characteristics and stability performance of many solid oral dosage form products, shipment under a defined temperature range is not necessary. This document provides the scientific and risk management assessment process to support the evaluation and, where appropriate, discontinuation of solid oral dosage form shipment under defined temperature range conditions, dependent upon the results of individual product analyses.

Assumptions

1. During summer months and in tropical climates, pharmaceutical products being shipped under ambient conditions have the potential to be exposed to elevated temperatures reaching an approximate maximum temperature of 50ºC (122ºF).

2. Review of central America to United States Distribution Centres shipment time indicates that the typical shipment time for these pharmaceutical products from manufacturing facilities to distribution centers is less than two weeks.

The presented rationale may be applied to discontinue defined temperature range shipments for other shipping routes if the shipment time is known and falls within the assumptions of this model.

3. Since the maximum exposure to elevated temperatures occurs during day time hours (approximately 12 hours per day), for a two week shipment time the actual exposure to elevated temperatures is estimated to be a maximum of one week as a worst case scenario.

Guidance 088 Summary - Determining Testing Patterns and Acceptance Criteria for Analytical Method Transfers

This document provides guidance for setting experimental testing patterns and acceptance criteria for Analytical Method Transfer Exercises (ATME).

This document provides guidance to GLP sites in identifying lots and number of samples for testing, setting appropriate acceptance criteria for conducting transfers.

The extent of AMTE testing should be commensurate with the method capability and its intended use. The specification levels, validation data and historical performance for each method should be reviewed (where available) to determine the appropriate transfer criteria/limits. Based on the intended use of the method, appropriate acceptance criteria may include evaluation of inter laboratory differences, system suitability, reproducibility, selectivity, sensitivity, recovery and/or comparison to the appropriate specification or method requirements (e.g. spectroscopic or chromatographic identification).

Appendices I and II provide decision trees for conducting assay and impurity method transfers.

Identification of Lots to be used for Transfer

When an API or a single strength of a drug product is being transferred, a minimum of one lot may be used for the AMTE. If a single lot is to be used, it is recommended that the testing pattern include multiple analysts, multiple days and /or multiple instruments to assess the Receiving Laboratory’s (RL) ability to generate consistent, reproducible results. Where multiple lots or batches are used for the transfer, the

Transferring Laboratory (TL) should evaluate the necessity for including multiple analysts, multiple days and /or multiple instruments in the transfer testing pattern.

If multiple drug product strengths are manufactured from a common or similar blend, only the highest and lowest bracketing strengths need to be included in the AMTE.

Guidance 089 Summary - Risk Basis for Establishment of Weighing Device Testing Intervals

The quality risk management approach as applied to the evaluation of reduction of performance verification frequency illustrated in this guidance not only identifies the different risk factors to consider when performing the evaluation but also demonstrates a simple tool (depicted in tabular format) for determining how to group potential risks into low, medium, and high categories. For the purpose of this evaluation, two risk factors, probability and severity, will be examined for each perceived risk associated with the defined risk scenario. From this evaluation of individual perceived risks the cumulative risk profile associated with a potential change in frequency will be devised. Through application of a simple tool coupled with requisite background knowledge it is expected that this assessment will serve as a model to GMP sites to standardize the evaluation of changes to the frequency of weighing device performance verification testing.

The potential risks associated with decreasing the frequency of weighing device performance verification testing were derived through completion of a brainstorming exercise. The risks identified should be relevant to most weighing devices and operations.

The probability of the weighing device encountering drift during the proposed period should be based on the operating history of the device. This review should include the frequency of unscheduled maintenance over the previous two year period and the device’s performance history from, minimally, the last five calibrations. If the idealized running history, respective of maintenance and calibration, is not available for a specific weighing device, the history of a like model instrument deployed under similar conditions may be used for reference.

Guidance 090 Summary - Analytical Laboratory Management

The primary roles of a GLP analytical and microbiology laboratory at a GMP site include testing of pharmaceutical raw materials, in-process and finished products, which are intended to be distributed into a marketplace. Broadly speaking, the test specimens rang from raw materials, regulatory starting materials, intermediates, active pharmaceutical ingredients (API), in-process materials, drug products, biologics and medical devices.

As a good management practice the analytical and microbiology laboratories should be built separately into designated areas with limited access and should be maintained in a clean and organized state. Practices should be established at each GMP site to assure laboratory housekeeping is maintained. Work surfaces in the microbiology laboratory (e.g., benches, bio-safety cabinets, unidirectional airflow units) should be cleaned, organized and disinfected prior to and after use. Those disinfectants should be chosen which are effective in cleaning the expected types of organisms.

Laboratory equipment should be maintained in a clean state and should be stored in a manner that prevents contamination. Incubators, refrigerators, ovens & water baths, used in the microbiology laboratory, should be cleaned and maintained according to an approved schedule.

Laboratory instruments should be calibrated upon installation and thereafter, according to an approved schedule and be used within the calibration period or calibrated upon use.

Laboratory facilities and equipment should be qualified. Automated laboratory equipment and computer-related laboratory systems should include validation of the computerized System.

Laboratory processes (e.g., sterilization and depyrogenation) should be validated. Equipment and utilities (e.g., vacuum, compressed air, gases) used should be properly designed, commissioned and/or qualified.

Laboratory water systems should also be qualified for their intended use. The water system should be maintained, monitored on a routine basis and must be suitable for use for the specified test method or test material preparation. In addition, the water system in the microbiology laboratory must, at a minimum, meet the quality attributes for purified water.

Biological, toxic, and hazardous waste materials should be handled according to local, regional, and/or national guidelines as well as environmental health and safety (EHS) guidelines.

A sample handling system should be in place and include provisions for sample receipt, proper sample labeling and sample log-in; prevention of sample loss, sample mix-ups and contamination;  verification that information on the sample label matches the accompanying document submission; identification of potent, toxic or hazardous compounds requiring special precautionary measures; sample storage at room temperature unless otherwise indicated; tests performed within a defined time period after sample receipt; investigation of sample mix-ups or contamination; sample retention until all tests are completed and there is a determination as to whether a result is valid or invalid; and sample destruction or disposal.

Controls for preventing cross contamination should be available and implemented.

Reference standards used for testing production materials, actives, drug products and medical devices should be obtained or established, used, controlled, maintained and approved according to written procedures approved by the site quality assurance. 

Laboratory materials for testing, such as reagents, buffers, reference standards, microbial cultures, microbiological indicators and culture media should not be used beyond their Expiration Dates. Expired materials should be discarded promptly. An investigation should be conducted if expired materials are used in error.

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