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Guidance Summary 071 - 080

Guidance 071 Summary - Weighing and Measuring Practices In Manufacturing Operations

Introduction

This document provides guidance in the weighing and measuring of materials used in the manufacture of drug products, active pharmaceutical ingredients (API), medical devices, and intermediates

Physically Separated, Designated Area(s) should be used for weighing, subdividing, and dispensing materials.

2. When Materials are Exposed During Weighing and Measuring Operations, such operations should be performed in a manner designed to prevent cross-contamination.
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3. Environmental Conditions (e.g., Temperature, Relative Humidity, Lighting) in rooms or areas where materials are exposed during weighing or measuring should meet any specific environmental requirements applicable to the materials being weighed or measured.

4. Prior to Weighing Materials on a Scale or Balance, the operator should verify that the weighing device is clean, within calibration interval, and is working properly.

5. If Liquid Materials are to be charged to a vessel on a weight basis, the volume should be converted to weight using specific gravity. The calculation should be verified as correct by a second person, unless a validated computerized system is used to perform the calculation.

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Guidance 072 Summary - Material Supplier Approval

This document provides guidance in the process for identifying suppliers to be audited and the process for conducting and documenting such audits and approving suppliers.

  1. Approval of a New Supplier, New Materials from an Already Approved Supplier, or a New Supplier Manufacturing Site, actions to be taken, include and are not limited to, the following:
  • Assess the need for a Supplier Audit using risk assessment methodology;
  • Conduct full raw material testing of at least three representative raw material lots;
  • Conduct pilot laboratory use testing;
  • Perform plant trials;
  • Evaluate Packaging Materials; and
  • Evaluate product stability.

 

The number of raw material lots to be used in a pilot study or used in a plant trial should be determined by the Site Quality Principle on a case-by-case basis.

The batches or lots manufactured for plant trials may be used for trade if agreed before hand by the Site Quality Team and produced under conditions that comply with applicable regulatory and site requirements.

  1. Requirement for Supplier Audit prior to purchase can be waived, if necessary, on a case-by-case basis by the Site Quality Team after review with the Quality Principle provided that all other requirements of item 1 and site requirements are satisfied.

Each case should be reviewed with consideration to the following:

  • Supplier history with the site,
  • Local regulatory history,
  • Length of time Supplier has been manufacturing the material in question, and
  • Quality impact the material has on the product.

Guidance 073 Summary - Storage & Distribution of Drug Products and Medical Devices

This document provides guidance the storage and distribution requirements for Drug Products, Medical Devices and related Production Materials from a GMP Site or Logistics Centers, and/or transported between manufacturing and Logistic Sites.

  • Storage Conditions for Drug Products should be based on stability studies.
  • Storage Conditions for Medical Devices and In-Process Materials should be based on stability studies or other experimental evidence approved by the Quality Team.
  • Warehouse Storage should provide for sufficient cleaning/inspection space behind pallets or racks. If warehouse storage area is insufficient for cleaning and inspection, materials should be moved so floors behind stored materials can be cleaned as needed, but at least once every three (3) months.
  • Two (2) or More Lots or Batches should not be stored on the same pallet, unless they are segregated by a physical barrier or they are part of a kit of pre-weighed production materials that has been assigned a unique lot number.
  • When Special Storage Conditions are Required, such as controlled humidity or refrigeration, recording monitoring devices and alarms should be used and maintained to ensure requirements are met.

Guidance 074 Summary - Control of Manufacturing and Packaging Defects Non Sterile

This document provides guidance on the inspection of non-sterile drug products and non-sterile medical devices for manufacturing and packaging defects.

1. Inspection Requirements for each type of product, container/closure configuration, and packaging configuration should be written, approved by the Site Quality Team and include and not be limited, to the following information:

  • Determination of the minimum number of product units that must be sampled and the frequency of inspection; and
  • Identification of physical attributes that are considered defects and their respective Acceptable Quality Limit (AQLs).

 

2. Inspection Personnel should be qualified prior to inspecting products during manufacturing or packaging operations including a test for color blindness and an annual vision test. Requalification should be performed as required. Qualification should include, and not be limited to, the following:

  • Identification and classification of defects for each product, container/closure configuration, and packaging configuration using photos, illustrations, or actual defects as training aids; and
  • Set-up challenge and operation of automated electronic inspection systems and line monitoring devices.

 

3. Manufacturing Defects include, and are not limited to, the following:

  • Broken or chipped tablets;
  • Twinning of tablets;
  • Unusually thick or thin tablets;
  • Uneven film coating of tablets;
  • Unusual appearance (e.g., off color, discolored, cloudy, foreign matter, suspension segregation); • Empty or under-filled capsules; and Missing or partially debossed logo or markings.

Guidance 075 Summary - Pest Control

This document provides guidance in the implementation and maintenance of pest control program for buildings and facilities at a GMP Site and Logistics Centers that are used for production, testing, or storage of the following:

  • Raw Materials,
  • Starting Materials,
  • In-Process Materials,
  • Intermediates,
  • Active Pharmaceutical Ingredients (API),
  • Drug Products,
  • Over-The-Counter (OTC) Products,
  • Cosmetic products,
  • Biologics, or
  • Medical Devices.

 

  1. Each Site Pest Control Program should be supervised by a qualified Site Pest Control Coordinator who should ensure that the program is coordinated among departments, the Site Quality Team and any contracted pest control service employees allowed on Site.
  2. Chemical Application should be restricted to areas not used for production, testing, and/or storage of items listed above without prior written approval of the Site Quality Team.
  3. Contractor Employees Applying Pesticides should be accompanied by a Site employee escort when pesticides are applied in areas of potential product exposure or in production areas.
  4. All Pest Control Treatments and Inspections should be recorded and the records maintained in a manner approved by the Site Pest Control Coordinator. Records should display the location, date, and time of treatment or inspection, the chemicals applied, traps and equipment inspected, the name of the individual making the application or inspection, and, when an escort is required, the name of the Site employee who served as escort.

Guidance 076 Summary - Raw Materials and Packaging Materials Receipt

This document provides guidance for receipt and storage of raw materials (RM), components, and packaging materials used in the manufacture and packaging of active pharmaceutical ingredients (API), drug products, and medical devices.

1. Prior to Unloading a Shipment, examinations and inspections should be conducted to verify that:

  • The shipment matches quantities and materials ordered (by comparison of the purchase order with the packing slip or delivery note);
  • Observable onboard materials appear properly labeled and free from apparent damage or contamination;
  • For bulk raw materials received in bulk carriers, verification that tamper-evident seals are in place and intact on all openings or locations as defined in a Site Standard Operating Procedure (SOP) and on capped discharge lines. Tamper-evident seals are not required on pressurized bulk carriers. Where shipping documents include the identification numbers of the tamper-evident seals, the numbers should be verified against those on the seals; and
  • If the bulk carrier may also be used for transport of other bulk raw materials (i.e., non-dedicated carrier), evidence of cleaning (e.g., certificate of cleaning) from the prior load should be provided.

 

2. Actual Shipment Quantities should be verified against those recorded on the packing slip or delivery note either during or immediately after unloading.

Guidance 077 Summary - Sampling of Production Materials and Finished Goods

This document provides guidance for a sampling program for:

  • Raw Materials (RM),
  • Starting Materials,
  • Packaging Materials,
  • Labeling,
  • In-Process Materials,
  • Intermediates,
  • Active Pharmaceutical Ingredients (API),
  • Drug Products,
  • Biologics,
  • Medical Devices,
  • Medical Device Components, and
  • Materials with Direct or Potential Product Contact.

1. Sampling SOPs should include, and are not limited to, the following information:

  • Sampling method;
  • Sampler apparel;
  • Sampling tools, utensils, and equipment to be used;
  • Amount of the sample to be taken;
  • Instructions for any required sub-division or compositing of the sample;
  • Type and condition (e.g., sterile or endotoxin-free) of the sample container to be used;
  • Identification of containers sampled;
  • Sample identification;
  • Any special precautions to be observed, especially with regard to the sampling of sterile or noxious materials;
  • Special storage conditions; and
  • Instructions for the cleaning and storage of sampling equipment, if disposable sampling equipment is not used.

 

Guidance 078 Summary - Water Purification, Storage and Distribution For Pharmaceutical Production

This document provides guidance for the purification, storage and distribution of water used for Production including water used for cleaning of product contact equipment, containers, and closures.

1. Selection of Water Quality Requirements for APIs, Drug Products, and Medical Device Manufacturing should be based on the stage of production, intended use of the water, and the end product requirements. Water should meet the minimum quality requirements defined in Table 1.

For Veterinary Pre-mixes and Soluble Powders that are used in the field and mixed with potable water or animal feed, potable water may be used for equipment cleaning and manufacturing.

2. Potable Water may be used in the final steps in the manufacture of APIs for use in nonsterile drug products, if the Site Quality Team has approved a documented rationale justifying the continued use of potable water. Such documented rationale should include, but not be limited to, information which demonstrates that:

  • Potable water is compatible, throughout seasonal variations, with the API process steps in which it is used;
  • Use of potable water is consistent with registration commitments for the API;
  • There is an effective change control system for the potable water distribution piping that is defined as a direct impact system; and
  • A monitoring system is in place to ensure the ongoing review of potable water quality. Sources of information to support the rationale include, but are not limited to:
  • Review of API quality data;
  • Review of API validation data;
  • Review of potable water chemical and microbiological quality;
  • Review of the customer complaint history for problems traceable to potable water; and
  • Review of API registration requirements.

 

The rationale should conclude that no quality or regulatory risk is identified for the API and for the drug product in which it is used.

Guidance 079 Summary - Use of a Risk-Based Approach To Establish External Quality Assurance Audit Frequency

The purpose of this document is to provide guidance for GMP Quality Audits stakeholder’s responsibility to utilize a risk-based approach for determining External Quality Assurance Audit (EQAA) prioritization and frequencies.

The Site Quality Team shall be responsible for the following audit related activities:

  • Review and issue Supplier Audit prioritization and schedules
  • Conduct Supplier Audit.

 

Process

1. Collect and organize relevant information.

The following epresents suggested data to gather prior to performing the assessment:

  • Listing of material suppliers, materials sourced and where used
  • Prior audit records
  • Performance data related to material (lots rejected/finished product issues related to material
  • Correspondences with supplier related to changes in operation or process Regulatory inspection records for material supplier, if available.

 

2. Identify the Risk Question

The Quality Risk Management (QRM) process is guided by the establishment of a risk question that identifies the scope, sought outcome and areas of focus (risk factors) for the assessment. If applicable the question can also capture constraints such as limited personnel to participate in the audit program. In the case of the EQAAs, the following are examples of a potential risk question related to development of a risk based supplier audit schedule:

  • “How should supplier audits be prioritized and scheduled as a function of their risks to product safety, quality and, market share (business)?
  • “What are the patients, product quality, and business risks associated with materials/components/services used in the production of medicinal products in relation to their supplier’s audits, and how could these audits be prioritized and scheduled to minimize such risks?”

 

3. Assess Method to be Used

There are several simple to intermediate QRM tools that could be applied to this assessment; for this example we are using Risk Ranking and Filtering (RRF). In using this simple tool we will limit the assessment to a review of the severity and probability associated with each hazard.

4. Determine the Potential Risk Factors and related Hazards

In order to determine the potential risk factors and related hazards, one might need to answer:

1. What are the risk factors (e.g. patient safety, regulatory compliance, and business) from which each scenario must be viewed to ensure that all potential or related hazards are identified?

  • What are the sources of potential harm related to each risk factor?
  • Could the material sourced have a potential impact on patient safety?
  • Could the material sourced have a potential impact on product quality and conformance to registered specifications?
  • Could the supply of the material have an adverse impact on the business?

 

2. What are the related hazards?

For the purpose of prioritizing the EQAA schedule, each material supplier represents a potential risk to the finished product(s) in which the material(s) sourced are used, therefore, all material suppliers can be viewed as hazards for the purpose of this assessment.

3. Define the Risk Assessment Scales for Probability and Severity

In order to perform an assessment of the risk posed by each hazard (material supplier) the probability and severity characteristic of each hazard must be defined.

Severity and probability scales must first be defined by determining the range of possibilities and differentiation for each as indicated below: 

Severity: Severity is the measure of the consequence (impact) that a defect or failure borne of the material supplier (hazard) may have on your operation/products.

Assessing the severity requires an understanding of how the material supplier might impact the risk factor. For example, when looking at material suppliers and their potential impact on finished product quality, an API supplier may be assigned a higher severity scale than a tertiary packaging supplier since the API may impact potency or dissolution of the finished product, whereas a shipper has no impact on product performance.

Guidance 080 Summary - Reduced Testing Program

This guidance document defines a science and risk-based approach for the evaluation and

implementation of a reduced testing program for the release of starting materials, intermediates, APIs, excipients and packaging components at a GMP user site upon receipt from vendors (manufacturer/supplier). The guidance also provides an example of the application of Quality Risk Management principles in the implementation of a reduced testing program.

There is limited value in testing starting materials, intermediates, APIs, excipients and packaging components previously released from vendors or other sites whose operations are in a state of compliance with cGMPs and where the materials have reliably supported the production/supply of goods that meet the site’s in-house specifications.

The chief benefits of reduction of in-house testing of starting materials, intermediates, APIs, excipients and packaging components upon receipt are reduced lead times for production and significant reduction in resource utilization (test reagents, equipment, analysts, reviewers, etc.). Therefore, each site should assess opportunities to eliminate in-house release testing of raw materials and packaging components on a case by case basis. A review of organizational directives (constraints), in regards to sourcing of materials, should be reviewed prior to initiation of any assessment.

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