Classification of GMP Deficiencies in Pharmaceuticals Industry

The purpose of regulatory inspections is to ensure that?operations at these establishments are carried out in accordance with approved standards, norms, and?guidelines and are in compliance with the national medical products legislation and regulations. These, in turn, should be consistent with regulatory guidelines and other internationally?recognized guidelines. The scope of the function applies to different Good Practices (GXPs) and is not limited?to Good Manufacturing Practices (GMPs).

This article is intended to provide information about risk based classification of GMP deficiencies from inspections.

Harmonization will help ensure that there is a consistent view across inspectorates of what constitutes a “Critical” deficiency and what constitutes a “Major” deficiency.

Classification of GMP deficiencies will contribution in the following:

1.?Improve inter-agency consistency in reporting and facilitate communication between inspectorates

2.?Harmonise inspectorate response and management of deficiencies classified as “Critical”, “Major” and “Other”;

3.?Provide transparency in how the deficiencies are classified

4.?Simplify international deficiency trend analysis based on harmonised reporting of GMP deficiencies from different inspectorates.

This guidance/article is also intended for following:

• Provide actions to be taken by inspectorates in response to the reporting of critical and major deficiencies.
• Enhance communication, information sharing and scientific exchange to promote increased consistency and probability in regulatory assessments and decisions and the rapid exchange of safety and quality information regarding manufacturers.

Classification of GMP Deficiencies:

1.????Critical Deficiency

A deficiency which has produced or leads to a significant risk of producing a product which is harmful to the human or veterinary patient or a product which could result in a harmful residue in a food producing animal.

A “Critical” deficiency also occurs when it is observed that the manufacturer has engaged in fraud, misrepresentation or falsification of products or data.

A “Critical” deficiency may consist of several related deficiencies, none of which on its own may be “Critical”, but which may together represent a ”Critical” deficiency, or systems’ failure where a risk of harm was identified and should be explained and reported as such.

Examples for Critical Deficiency: [But not limited to]

• Lack of sterilization validation (relevant to all sterile products).
• Lack of adequate control measures resulting in an actual, or significant risk of, cross contamination above the level of the health-based exposure limit in subsequent products.
• Evidence of gross pest infestation.
• Falsification or misrepresentation of analytical results or records.
• Failure to ensure the quality and/or identity of starting materials.
• No master batch documents.
• Absence, falsification or misrepresentation of manufacturing and packaging records.
• Water system for sterile products not validated (sterile products).
• HVAC system for sterile products not validated (sterile products).
• Completely unsuitable premises so that there is a high or likely risk of contamination.
• No evidence that mandated recall processes have been complied.

2.???Major Deficiency

A deficiency that is not a “Critical” deficiency, but which has produced or may produce a product which does not comply with its Marketing Authorisation, Clinical Trial Authorisation, product specification pharmacopoeia requirements or dossier,

Also does not ensure effective implementation of the required GMP control measures,

Major deviation from the terms of the manufacturing authorisation,

Also indicates a failure to carry out satisfactory procedures for release of batches or failure of the authorised person to fulfil his/her duties,

Comprises of several “Other” related deficiencies, none of which on its own may be “Major”, but which may together represent a “Major” deficiency or systems failure and should be explained and reported as such.

Examples for Major Deficiency: [But not limited to]

• Lack of validation of critical processes
• No or grossly inadequate air filtration to minimise airborne contaminants
• Missing or ineffective control measures to provide adequate confidence that cross contamination will be controlled within the health based exposure limit in subsequent products. ?
• Damage (holes, cracks, peeling paint) to walls/ceilings in manufacturing areas where product is exposed in non-sterile areas
• Design of manufacturing area that does not permit effective cleaning
• Insufficient manufacturing space that could lead to mix-ups
• No raw material sampling area for medicine manufacturers
• Sanitary fittings not used on liquid/cream manufacturing equipment
• Stored equipment not protected from contamination
• Individuals in charge of QC/production not qualified by education, competency training and experience
• Inadequate initial and ongoing training and/or no training records
• Cleaning procedures not documented and/or no cleaning records
• Production equipment cleaning procedures not validated
• Reduced QC testing of raw materials without data to certify suppliers
• Incomplete testing of raw materials
• Test methods not validated
• Complex production processes for non-critical products not validated
• Unapproved/undocumented changes to master batch or equivalent documents
• Deviations from instructions not approved
• No or inadequate internal inspection program
• No proper release for supply procedure
• Product reworked without proper approval
• No system/procedures for handling complaints or returned goods
• Inadequate testing of packaging materials
• No ongoing stability program and/or stability data for all products not available
• Insufficient lighting in production or inspection areas
• Containers from which samples have been taken not identified
• The temperature of critical temperature controlled storage areas not monitored and alarmed
• Inadequate change control system
• Inadequate deviation system
• No investigation into alarms and temperature excursions for deviations from storage or transport requirements

3.???Other Deficiency

A deficiency that is not classified as either “Critical” or “Major”, but indicates a departure from Good Manufacturing Practice (GMP).

A deficiency may be judged as “Other” because there is insufficient information to classify it as “Critical” or “Major”

4. Classification Process – Overview?

Reference: PIC/S Guidance on Classification of GMP Deficiencies: PI 040-1

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Author: Dr.Prasadhi Shiva