1.0 PURPOSE

To lay down the procedure of an aseptic process simulation is to:

• Assess the capability of an aseptic process under a given manufacturing environment and process controls.
• Demonstrate that appropriately designed and implemented process changes are acceptable.
• Evaluate the proficiency of aseptic processing personnel.
• Demonstrate compliance with current Good Manufacturing Practice.
• Demonstrate the appropriateness of operating practices used in support of aseptic processing.
• Challenge the aseptic process for microbial contamination susceptibilities.

2.0 SCOPE: 

The SOP describes process for simulation of the entire filling process(s) for aseptically filled vials by substituting the sterile API powder with a sterile placebo powder (like Mannitol, Lactose) and then filling adequate quantity of microbiological growth medium.It does not cover process simulation requirements for any other aseptic manufacturing process.       

5.0 PROCEDURE:

5.1 Prerequisites for media fill validation: The prerequisite checks for media fill shall be executed prior to media fill reviewed by QA. It shall be filled along with media fill BMR.

5.2 General: Process simulations are performed to demonstrate that:

5.2.1 The manufacturing process(s)es used followed in sterile dry powder filling facility have the capability to produce sterile drug products.

5.2.2 The operators involved in aseptic processing are qualified for the intended operations.

5.2.3 The established procedures are followed and the same are in compliance with the cGMP requirements.

5.2.4 Wherever possible a worst-case approach will be adopted, such as using materials and components at the extremes of their holding times and all hold time study should be rotated in media fill at once in two year, extending filling times to increase exposure, incorporating interventions to mimic potential disruptions to the filling procedure.

5.3 Media Batch Numbering and issuance procedure:

5.3.1 For each media fill run production department shall raise the request for issuance of BMR to quality assurance department.

Quality assurance shall issue the media fill BMR as per Preparation, Control, Issuance and revision of Batch Manufacturing and Batch Packing Records and allot the media fill batch number.

5.4 Overview of Aseptic Manufacturing Process Steps at Site:

5.4.1 Manufacturing Process:

5.4.1.1 The Dry Powder Injectable Manufacturing facility is operated in two shifts; the third shift is utilized for cleaning, sanitization and all preparatory work. Hence, the interventions observed and/ or expected in two shifts, including during the shift changeover are being considered in this assessment exercise.

5.4.2 The process of dry power injection manufacturing is divided in following steps:

• Inspection and loading of empty glass vials.
• Washing of the empty glass vials in a closed automatic vial washing machine located in an ISO 7 (Class 10,000) environment.
• Online Depyrogenation/ Sterilization of washed glass vials using a tunnel sterilizer with in-built HEPA filters to maintain ISO 5 (Class 100) environment inside the tunnel.
• Aseptic filling and stoppering of sterile dry powder in glass vials under laminar airflow unit (ISO 5 or Class 100) environment. The powder filling machine is located in ISO 6 (Class 1000) environment.
• Pre and post purging of sterile filtered nitrogen or any other gas according to the process need is purged to flush empty vial and/ or fill the head space.
• Filled and stoppered vials exit into an ISO 7 (Class 10,000) vial sealing room, where the vials are sealed using Aluminium over seals under ISO 5 (Class 100) Laminar Airflow Unit.
• Inspection of filled and sealed vials for cosmetic defects as well as gross contaminants using semi-automatic, online visual inspection machine.

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1.0 PURPOSE

To provide a procedure for Manual Visual Inspection of Vials/Ampoule for Critical, Major and minor or cosmetic/functional defects.

2.0 SCOPE:

This procedure is applicable for Visual Inspection of Parenteral Products manufactured facility.

5.0 PROCEDURE:

5.1 Inspection of Products – General Instructions

5.1.1 Check the cleanliness of the Visual Inspection / Area Booth and take line clearance from QA department before operation.

5.1.2 Update the status board of Visual Inspection, as Product Name, Batch No., Mfg. Date, Exp. Date, Stage, sign, Date.

5.1.3 Unload the parenteral products after Leak Test / Terminal Sterilization and further transfer into plastic trays/carets for visual inspection.

5.1.4 Product shall be inspected by qualified visual inspectors.

5.1.5 Inspection of product shall take place utilizing a lighted non-glare white/matte black inspection booth. The booth will be of suitable design and configuration to meet required light intensity range (2000-3750 lux) at the viewing point.

5.1.6 Standard inspection booth for product inspection, light Intensity shall be verified utilizing a calibrated/traceable lux meter at minimum at the commencement and completion of the inspection lot. The results of this verification will be noted on the Finished Product Inspection Form.

5.1.7 Inspection shall occur on 100% of product from each manufactured lot.

• Only one product at a time shall be inspected.
• Product shall be appropriately agitated, inverted, and viewed for a minimum of 5 seconds per vial against both black and white backgrounds under the inspection light.
• Visual inspectors shall be qualified half yearly with eye vision checks,        colorblindness checks, and ability to distinguish known product rejects from acceptable product.
• Acceptable Quality Limits (AQL) shall be established for each type of manufactured product. AQLs dictate the maximum number of defective vials beyond which a batch is rejected. These limits are described in the batch record.

5.2 Inspection of Product – Process Instructions

5.2.1 Visual Inspector maintains batch identity by utilizing caution when inspecting and / or placing inspected product on labeled trays by keeping product within the inspection area.

5.2.2 Inspector examines each vial for the defects listed in the Finished Product Inspection Form. Defects shall be categorized into 3 categories:

5.2.2.1 Critical - Defects which may cause serious adverse patient reaction or death if the product is used. This classification includes any non- conformity that compromises the integrity of the container and thereby risks microbiological contamination of the sterile product.

• GB: Broken or cracked glass vial
• SB: Seal on vial broken, missing or jagged
• St: Stopper on vial missing, cock-eyed, or otherwise compromise

5.2.2.2 Major - defects that carry risks of temporary impairment or medically reversible reaction, or involve remote probability of a serious adverse reaction. This classification is also assigned to any defect which causes impairment to the use of the product (which may result in a malfunction that makes the product unusable). Sub-categories of critical defects may be classified as:

• PG: Particle/spot/smudge inside vial, adhered to glass
• PSt: Particle/spot/smudge inside vial, adhered to stopper
• PS: Particle in solution (glass, fiber, stainless steel, etc.). Particles can be black, white, colored, translucent, etc.
• P: Precipitation inside the vial
• C: Cap broken / gone / lifted
• OC: Cap over crimped
• UC: Cap under crimped
• O1 Other: Defect not already included on Finished Product Inspection Form.  Defect are described on the form.

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Title: SOP for Commissioning, Qualification and Periodic Review

1.0 PURPOSE

This Standard Operating Procedure describes the process for carrying out the Commissioning and Qualification of facilities and production systems, including qualification and lifecycle management of related Operational Technology (OT) systems, to demonstrate that they function and perform repeatedly and reproducibly to meet Critical Process Parameters (CPP) and Critical Quality Attributes (CQA) in compliance with the Quality Manual.

It includes current regulatory requirements and expectations. In addition, this SOP describes the process for periodic re-evaluation of qualified systems (direct impact systems) to ensure maintenance of qualified state throughout the systems lifecycle

2.0 SCOPE

2.1 Process Scope

This SOP is mandatory for systems under the regulation of Quality System “Facilities Design and Qualification”. The term “System” in scope of this document covers manufacturing equipment, utilities, facilities, and Process Automation Systems (PAS), e.g., Programmable Logic Controller (PLC), Supervisory Control and Data Acquisition (SCADA), HISTORIAN, Human Machine Interface (HMI)) requiring commissioning and qualification.

3.0 PROCEDURE

3.1 Process Flow

A risk-based approach to Commissioning and Qualification focuses on the identification and assessment of risks to product quality, data integrity and patient safety.

As described below in Figure 1, all new systems within the scope of a GMP relevant project are assessed via a System Impact Assessment to identify those systems, which can have a direct impact on product quality, data integrity or patient safety. All systems are subject to commissioning and are designed, installed and commissioned according to Good Engineering Practices (GEP) and Good Documentation Practices (GDP). Additionally, direct impact systems are subject to qualification.

An integrated workflow of Commissioning and Qualification is provided in Figure 1.

3.2 Process Steps

The defined responsible roles for each process steps defined on chapter 3.2 below are the minimum required approvals but not limited to. Roles can also be combined based on project specifics. In both cases proper justification must be provided on the Qualification Plan (MQP / QP). Actions that do not relate to approval, indicate roles which can take the responsibility individually or shared.

3.2.1 Project Master Qualification Plan

Based on the complexity of the project, a (Project) Master Qualification Plan can be issued to show the overall qualification strategy. That includes the leveraging approach of commissioning activities for direct impact systems and/or system grouping/family approach for identical equipment, if intended to be applied, the documentation, deliverables and the required training for qualification personnel and SOPs.

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