Guidance Summary 061 - 070
Guidance 061 Summary - Application of Quality Risk Management (QRM) to Periodic Review of SOPs
Each GMP site should define the responsibilities and the processes for preparing, approving, maintaining, and archiving GMP-related documents and records. Pursuant to this requirement many sites employ a default frequency for periodic review of SOPs. Since processes and procedures have varying impact on product this practice may unnecessarily consume resources in an attempt to maintain compliance with the stated review policy. This document provides guidance on how to apply quality risk management to periodic review of SOPs utilizing the risk assessment tool known as risk ranking and filtering.
The risk is the likelihood (PROBABILITY) of having non-compliant or deficient procedures which have the potential to impact product quality or regulatory compliance attributed to lack of timely document review and that could remain unchecked or undetected. In addition, the greater potential of an SOP to impact product quality and regulatory compliance directly corresponds to a greater likelihood of that SOP being reviewed during an inspection. The potential undesired consequence (OUTCOME) under such circumstances is a negative impact on product quality and a regulatory citation from having an SOP in a non-compliant status. Considering the number of SOPs that could be subject of periodic review at a site, a more practical approach is to categorize the SOPs on the basis of potential impact to product quality and regulatory compliance.
After agreement is reached on the risk associated with each procedure or type of procedure, a site should then define the level of risk it is willing to accept. This again, will depend on several factors such as the regulatory environment, type of products produced, etc. For the working example, four (4) separate frequencies of review have been proposed for implementation. Formal acceptance of these established risks occurs when the procedure defining the new risk-based approach is approved by the relevant site management.
The use of a risk management approach will allow sites to reach a balance between benefits, risks, and resources as they are now able to set priorities and effectively use available resources to address the review/revision of SOPs. After reaching a well-informed decision, a suitable SOP review period can be assigned for each SOP with a frequency that is reasonable and relevant to the site’s own experiences
Guidance 062 Summary - Statistical Rationale for Raw Material Sampling
Operating characteristic (OC) curves illustrate the probability of accepting a lot over varying percent defective rates (Figure 1). When evaluating sampling plans, two points on the curve are of primary interest: the defective rate when lots will be routinely passed and the defective rate when lots will be routinely failed. It is fairly common to use the 95% probability of accepting a lot as the routinely passing point and the defective rate is called the acceptable quality level or limit (AQL). Lots with a defective rate at or below the AQL would be expected to pass the sampling plan criteria 95% of the time. The 10% probability of accepting a lot is typically used as the failing point and the defective rate is commonly called the unacceptable quality level (UQL) or lot tolerance percent defective (LTPD). Lots with a defective rate at or above the UQL would be expected to pass the sampling plan criteria 10% of the time (fail 90% of the time).
The minimum LTPD of all the plans is 11.62 and the minimum AOQL is around 2.5. Long term outgoing defective rates would be in the 2-7% range if these plans were implemented. When the quality requirements of sampling plans are met by these AQL, LTPD, and AOQL levels, √N+1 plans, as well as the corresponding Military Standard plans, could be used. √N+1 sampling plans offer similar protection as Military Standard plans with specified AQL levels between 1.0 and 1.5 (2.5 for the 16 to 25 lot size) percent for small lot sizes up to 150 units. In these cases the two sampling plan approaches can be used interchangeably with similar risks to lot acceptability decisions and outgoing quality
Guidance 063 Summary - Quality Risk Management Application Critical Instrument Calibration
This document offers a risk assessment approach to document a critical instrument calibration interval change request.
Calibration frequencies for non-critical instruments, if any, can be adjusted by the maintenance team as appropriate based on instrument history and other factors. This practice has no impact to non-critical instrument interval change opportunities.
The impact of an instrument calibration failure from the standpoint of probability, severity, and detectability may be determined through the integration and factoring of multiple parameters associated with each criterion as illustrated in Tables I -III. This section will provide additional narrative description in support of the contents in each table which contain guidance on how these parameters can impact the risk of experiencing an out-of-tolerance (OOT) condition for an instrument.
Due to the dynamic nature of a work environment a ranking cannot be based solely on one factor. Rather, all influences should be considered, for example – a transmitter located in a clean, dry area that does not get washed down but at the same time operates in an unstable environment – while the transmitter may be adequately protected and isolated from dirt and dust or exposure to wash down, the vibration and shock to which it is exposed can physically fatigue components that might cause erroneous reading. In this case, the sub-category of vibration and shock will determine the environmental risk ranking for failure probability.
Human safety – Direct threat to human safety defines the most severe consequence of calibrations OOT. If an instrument reading (or alarm) is the main protection against severe or potentially fatal injury, such as breathing air, oxygen level, or lethal compounds monitor, then severity is potentially high. Depending on whether an instrument is a primary component in a safety system, or part of a redundant system, will determine the severity of this risk.
Guidance 064 Summary - Structured On-the-Job Training System
This document discusses considerations for a site Structured On-the-Job Training system including GMP tasks and knowledge necessary to perform those tasks.
Sites must comply with GMP training requirements for training by defining the knowledge, skills and attributes colleagues require to competently perform GMP tasks. On-the-Job training should be part of those colleagues’ job function curriculum (JFC) who have a direct impact on product quality to ensure that colleagues can competently perform all job skills prior to working unsupervised.
Select a qualified trainer, who has expertise, training or a combination of these in the specific area/topic. This may be an individual who performs training as their job function or an SME who performs training secondary to their primary job function.
Then create training materials around these smaller tasks which can be clearly defined. This also allows trainee’s to begin working on certain tasks in the process prior to completing training on the entire process which can help with scheduling and resources. For example, once the trainee has completed trainings for labelling the can work unsupervised on that section of the packaging process while continuing training on the other areas of the packaging process.
Some procedures define default re-qualification requirements. Review all material related to the task and ensure that your re-qualification plan matches what is stated in the area SOP and other documentation. When re-qualification is not defined in local procedures, the site should take a risk based approach to determining if and when re-qualification may be necessary. For example when a colleague has not worked in the function for an extended period of time, if there are major changes to the skills required to perform a job, when a new piece or equipment has been installed or when a batch record has been revised.
Guidance 065 Summary - Training system for Aseptic and Preparation for Aseptic Operators and Support Staff
Aseptic processing takes place in a controlled, but non sterile environment where sterilized components are brought together and aseptically assembled. There are four major components of an aseptic processing environment; product, components, facilities and equipment, and operators. Operators, including those that prepare equipment and components for and also those that work in an aseptic processing area, are the greatest potential source of contamination. The operator qualification program, which consists of initial and ongoing training, is crucial to ensure that colleagues are prepared to fulfill their roles.
Training is more effective when the trainee can do and see as opposed to simply hearing the information. For example, simulations of unidirectional airflow using smoke generators or smoke sticks can provide a clear picture the difference quick vs. slow and deliberate movements can have on unidirectional airflow. It also demonstrates how placement of objects and equipment on and around the filling line affects the airflow patterns. Another example is videotaping operator gowning practice which can enhance gowning training as it provides a tool to the operator and trainer to be able to examine the gowning process and point out areas of improvement or determine contamination sources.
If an APA operator has not worked in the APA nor done sterile gowning for a significant length of time, the site must assess when demonstration of competence of critical job skills or a refresher course on certain classroom topics is required.
Guidance 068 Summary - Material Status Indication
- Be clearly defined by signs;
- Be bounded by colored lines or chains (e.g., supported by wall hooks or portable stanchions), or by colored netting or tarpaulins that cover the material;
- Exclude material of any status other than that designated; and
- Be separated from other status-designated areas by at least one pallet width; or
- If space limitations prohibit the pallet-width separation, barriers must be used that physically prevent movement of any containers into or out of the dedicated area.
Guidance 069 Summary - Annual Product Records Review
Data from Production Batches/Lots of all APIs and Marketed Drug Products, including Quarantined-HOLD and Rejected batches/lots, should be summarized on, at least, an annual basis. The criteria used to identify the first and last batch in the review period should be defined in Site procedures [e.g., Manufacture Date, Quality Control (QC) testing date, final disposition].
Each Production and Quality Department Head should be responsible for:- Providing Annual Product Records Review Supporting Data generated in their departments to the Site Quality Team for inclusion in the Annual Product Records Review;
- Ensuring that the data is trended, if applicable; and
- Ensuring that any departmental-level conclusions based upon the data are accurate.
Guidance 038 Summary - Process Validation Sampling for Non-Sterile Solid Dose Drug Products
This guidance provides Process Validation Sampling guidelines for non-sterile solid dose drug product dosage forms.
There are many concerns regarding blend uniformity sampling, for example:
- Inappropriate sample thief technology;
- Powder segregation of samples may occur after sampling;
- Difficulty in proving that the blender sample plan will be representative of worst-case locations;
- Segregation of blend that can occur during discharge, storage, and transport prior to final processing.
Solid dosage forms typically provide many opportunities for applying appropriate and scientifically sound sampling approaches.
A approach to demonstrating blend uniformity by combining blend testing with in-process dosage unit compendial testing. This approach postulates that the analysis of finished tablets/capsules can support or provide statistical evidence that a failing blend result was due to poor sampling or handling technique.
Guidance 070 Summary - Receipt, Approval and Use of Labels and Labeling
Labels and Labelling should be identified by a code that is part of the printed text, and shall be either an optical bar code or an alphanumeric revision-specific label code, which can be read optically. In addition, cut labels and labelling may include a bleed line on the edge to assist a visual check for foreign labels or labelling.
If Labels and Labelling are needed for Packaging Equipment Set Up, then the labels and labelling materials that are specified on the Packaging Batch Order for the current lot or batch to be packaged in the packaging area should be used. The same issuance and verification, and receipt and verification controls should be applied to all labels and labelling materials used for packaging equipment set up as used for the remainder of the lot or batch.