QM: 8.2.4 Monitoring and measurement of product

Introduction

In phrama/biopharma, product realization process is established through rigorous scientific experimentation, optimization, development, validation followed by regulatory review and approval, making them the only consumer product to follow this life cycle. Approved processes are used for production and any change to this state is controlled by change control procedure. Change which may potentially affects the quality, safety and efficacy of the product need to be approved by national regulatory authority before implementation.

Measuring and monitoring of product characteristics is an integral part of pharmaceutical/biopharmaceutical manufacturing process. The quality is not tested into product (by testing final product) but is built in a product through process control, control of starting material, intermediates and finished product. When all the stages of the production process/product meet the predefined requirements (specifications) the final product is accepted as a quality product and released by an authorized person. The production process is performed and controlled as per Standard Operating Procedures and inspection plans. Materials used in production are inspected, sampled and tested as per sampling and testing plan. Records of product realization are maintained in Batch Manufacturing Record and Analytical Reports.

8.2.4

Product Monitoring & Measurement

8.2.4 Monitoring and measurement of product

The company monitors and measures the characteristics of the product to verify that product requirements are fulfilled. This is carried out at appropriates stages of the product realization processes. The process of product realization is charted out in Drug Master File/Master Formulae Record these documents also defined the sampling and inspection points in a process. In-process testing is conducted at defined stages and finished product is tested to ensure it conforms to specification. When appropriate, statistically relevant inspection and sampling plan is utilized. 

Product testing can be divided into three stages:

    a.    Receiving inspections and Testing: All purchased products are subjected to a visual inspection by the receiving staff. Materials used in processing or as part of the product or packaging (RM/PM) is released for use after the samples have been successfully inspected against predefined specifications. Release of materials prior to verification is neither allowed nor practiced. No material is released prior to being verified per requirements and specifications.

    b.   In-process inspection and Testing: In process inspection and testing for manufactured products are in accordance with the prescribed Standard Operating Procedure, inspection and testing plan, Master Formulae Record and specifications. These procedures specify the acceptance criteria, and action to be taken if non-conformity occurs. Where subjective criteria are referenced, the final decision is made by Quality Department. In process inspections and monitoring can also be performed using automated equipments and instruments or statistical process control wherever applicable. Where such methods are used acceptance criteria shall be defined and approved. This stage focus on defect prevention rather than detection.

    c.    Final Inspection and testing: Finished product is subjected to final Quality inspection. Final inspection and testing is performed in accordance to sampling plan and test specifications following approved procedures. These procedures specify the acceptance criteria (which shall include the criteria for validity of test and acceptance limit) and action to be taken if the product fails. Where subjective criteria are referenced, the final decision is made by Quality Department.

Tests are performed by trained and qualified personnel and product is released (for next operation or for market) by authorized person after review of all the requirements.

    d.   Inspection and test records: Records that demonstrate inspection and test results are maintained in accordance with the appropriate procedures. Test results are recorded, reviewed and filed in Analytical Record File by batch number. Wherever applicable the certificate of analysis is prepared (COA). Records are maintained as evidence of conformity with the acceptance criteria. The records include the person(s) performing the inspections and tests and person(s) authorizing the release of the product.

The products are not released until all the required inspections and test have verified that it meets specification and the appropriate records have been generated. Non-conforming products are stored separately from other products.

Shipping of the product does not proceed until planned arrangements have been satisfactorily completed. The organization ensures that documents required by the contract or order to accompany the product are present at delivery and product is protected against loss and deterioration.

QM: 8.2.3 Monitoring and Measurement of processes

Introduction

The ISO standard states that, ‘The organization shall apply suitable methods for monitoring and, wherever applicable, measurement of quality management system processes’.

This can be achieved by setting quality objectives for a process which are consistent with the company’s Quality Policy and Quality Objectives. These objectives shall be “SMART” i.e. Specific for that process, Measureable, Achievable, Realistic and Time Bound.

ISO 9004:2009 highlights a Key Performance Indicator (KPI) approach. It states that, ‘Factors that are within the control of the organization and critical to its sustained success should be subject to performance measurement and identified as key performance indicators (KPI). The KPIs should be quantifiable and should enable the organization to set measurable objectives, identify, monitor and predict trends and take corrective, preventive and improvement actions when necessary.’

8.2.3

Process Monitoring & Measurement

8.2.3 Monitoring and measurement of processes

Monitoring and measurement of the processes is carried out with respect to Quality Objectives/ Key Performance Indicators at regular intervals using methods and criteria defined therein.

The processes are also monitored through:

Conducting audits of the quality system

Monitoring trends in corrective and preventive action requests

Analyzing product conformity and other quality performance data and trends,

Measuring and monitoring customer satisfaction.

When the quality system process does not confirm with requirements the Quality Department will:

         Take appropriate action to correct the nonconformance process,

         Evaluate whether the process nonconformity has resulted in product nonconformity,

Determine if the process non conformity is limited to a specific case or whether it could affect other processes or products,

Identify and control nonconforming product in accordance with set procedure,

Ensure implementation of corrective and preventive action.

QM: 8.2.2 Internal Audit

8.2.2

Internal Audit

8.2.2 Internal Audit

Internal audits are conducted at planned intervals to determine conformance to planned arrangements, to the requirements to ISO 9001:2008 standard, applicable regulatory requirements (Drug and Cosmetic Act and Rules, WHO, FDA, EU etc), GMP and company’s established Quality Management System. In addition, internal audits are conducted to ascertain whether the QMS is effectively implemented and maintained and to identify opportunities for continual improvements.

An audit program is defined and implemented, and identifies an audit schedule based on the importance of the areas to be audited, as well as the results of previous audit. The audit criteria, scope, frequency, methods, responsibilities and requirements for planning and conducting audits, and for reporting and maintaining results, are defined and documented in the internal audit procedure. 

The audit program includes:

Audits will be carried out against documented procedures and regulatory requirements on a yearly schedule

The schedule will be set based on importance of area to be audited (every activity and area is subject to an internal quality audit at least once a year)

Scope of the audit should be defined

Trained auditors will be selected independent of the area to be audited

Follow-up corrective actions and results of these audits will be documented and reported

Corrective and preventive actions are reviewed by the Quality department and follow-up audits are conducted, as appropriate

Records will be maintained of the audit and reviewed during the next audit scheduled for effectiveness

Managers and/or supervisors of the department being audited ensure that required actions (investigation and CAPA) from audit results are completed without undue delay. These actions should eliminate the nonconformities and their causes.

Results of the internal audits are evaluated and reviewed to verify the effectiveness and are used as inputs to the Management Review to ensure suitability of the Quality System.

QM: 8.2.1 Customer Satisfaction

8.2	MONITORING & MEASUREMENT
8.2.1	Customer Satisfaction

8.2 Monitoring and Measurement

8.2.1 Customer Satisfaction

The company monitors and measures information related to customer’s (doctors, distribution companies, and patients) perception at defined intervals as to whether the organization has met customer’s needs and expectations according to customer communication procedure. Customer feedback provides an early warning of quality problems, which will be managed through corrective and preventive action system. 

Methods of obtaining and using customer satisfaction and/or dissatisfaction information may include the following:

         Customer complaints

Customer returns and claims

Questionnaires and surveys

Direct customer communication

Recognition and awards from customers, associations, and consumer

Customer visit

Repeat Customer, Referrals and Market Share

1^st article responses

Previous audit

Corrective action   

The departments associated in gathering customer information are Quality Assurance, Dispatch and Distribution, Marketing and Sales.

A documented procedure has been established and is maintained for customer feedback.

The results of analysis of customer satisfaction data collected from various sources are discussed in management review.

QM: 8 Measurement, Analysis and Improvement (8.1 General)

Introduction:

To achieve sustained success in an ever-changing and uncertain environment, it is necessary for the organization to regularly monitor, measure, analyse and review its performance (ISO 9004:2009). The organization shall continually improve the effectiveness of the quality management system (ISO 9001:2008).

Measurement, Analysis and Improvement emphasizes on the control and continual improvement of product quality and quality management system. ISO 9004:2009 explains the requirement of measurement and analysis as, ‘Top management should assess progress in achieving planned results against the mission, vision, policies, strategies and objectives, at all levels and in all relevant processes and functions in the organization. A measurement and analysis process should be used to monitor this progress, to gather and provide the information necessary for performance evaluation and effective decision making. The selection of appropriate key performance indicators (KPI) and monitoring methodology is critical for success of measurement and analysis process’.

Measurement and analysis of a process and product will result in data which when analyzed forms an input for continual improvement of QMS and product quality. The organization shall identify the key performance indicators (of process and product quality) and device a methods for collecting information regarding key performance indicators. Typical examples of these methods given in ISO 9004:2009 are:

         Risk assessment and risk control,

Interviews, questionnaires and survey on customer and other interested parties’ satisfaction,

         Benchmarking

         Performance reviews, including suppliers and partners, and

         Monitoring and recording of process variables and product characteristics.

8	MEASUREMENT, ANALYSIS & IMPROVEMENT
8.1	GENERAL

8.0 Measurement, analysis and improvement

8.1 General

The organization has defined, planned, and implemented the monitoring, measurement, analysis and improvement processes needed to assure product and QMS conformity and achieve continual improvement of quality management system.

Product: Measurement and monitoring activities to ensure and verify product conformity are defined in specifications, sampling and testing plan & procedures, work orders, drawing and layouts and process control procedures.

Sampling: Sampling plan for inspection, testing and other product acceptance activities are documented. Sampling plans are reviewed and approved by quality department to ensure that they are based on valid statistical rational and are defined appropriately. These plans are reviewed when nonconformities are identified and such reevaluation is carried out within the framework of the pertinent corrective action.

Quality management System: The conformity and effectiveness of the quality system are monitored by internal audits, non-conformance reporting, and Corrective and Preventive actions and by measuring quality performance and customer satisfaction. The results of these activities are discussed in management review meetings and are used to identify opportunities for improvement. Activities related to internal audits and to measuring customer feedback and quality performance are defined (Section/Clause 8.2).

Statistical Techniques: Instructions and procedures for implementing and controlling the application of statistical techniques including control charts, analysis using histograms, Pareto, cause and effect diagrams and other statistical tools are available.

Statistical techniques are used for establishing, controlling, and verifying process capability and product characteristic. They may be used for:

Setup of process equipment/Design (performance/capability measurement, reliability, maintainability, safety)

Design of experiments (DOE)

Validation and/or testing of process/method

Control of process stability and performance (SPC)

Establishment of sampling plans for inspection and testing,

Evaluation of measurement system; and

Analysis of quality performance and other company-level data.

QM: 7.6 Control of monitoring and measuring equipment (Calibration)

NIST-F1 Cesium Fountain Atomic Clock (http://www.nist.gov/)

Introduction

Measuring and monitoring devices includes measuring and test equipments, comparative reference hardware (such as gauges and templates), and test software used for:

Setup and monitoring of production processes,

Monitoring of environmental conditions,

Verification of product conformity, and

Operations where defined accuracy of a measurement is required to assure product conformity.

7.6	Control of monitoring and measuring equipment (Calibration)

7.6 Control of monitoring and measuring equipment

The company has a defined process for the control of measuring and monitoring devices needed to provide evidence of conformity of the product to specified requirements. This includes details of equipment type, unique identification, location, and frequency of checks, check method, acceptance criteria and the action to be taken when results are unsatisfactory.

Quality assurance is responsible for calibration and maintaining measuring and monitoring devices. All active devices are inventoried in a controlled list, indicating their calibration status and location. Instruments that are used for reference only (not verification) are not included in the calibration system and are labeled with ‘DO NOT USE, FOR VERIFICATION ONLY’ stickers warning that is not in calibration plan.

Calibration is either performed by external calibration laboratory or internally. When external services are utilized, they are incorporated into the approved vendor list after successful vendor qualification program and rated accordingly. All internal calibration is performed in accordance with the written instructions.

The company determines the measurement to be made and the accuracy required to assure conformity of the product to specified requirements. Equipment is selected that is capable of functioning with the required accuracy and precision. Software used for measuring and monitoring of specified requirements shall be checked periodically and validated prior to use.

Measurement and monitoring devices are used in a manner that ensures that measurement capability is consistent with the measurement requirements (accuracy and precision). This includes ensuring that the environmental conditions are suitable for the calibration, inspection, measurements and tests being carried out. The company control all measuring and monitoring devices that can have an effect on product quality.

Periodic Calibration: The Company has identified the measuring and monitoring devices that can affect product quality and calibrate and adjust them at prescribed intervals. Calibration is performed against certified standard traceable to international or national standards.

Where no such standard exist, the basis used for calibration is documented.

If any adjustments or readjustments are required the same are performed and reported in calibration report. Recalibration is performed after adjustments.

Identification of Calibration: Measuring and monitoring devices are identified with unique identification numbers. Calibration status of measuring and monitoring devices is shown on the calibration sticker on the equipment and/or by the information in the calibration database.

Safeguard from Adjustment: The Company ensures that measuring and monitoring devices are safeguarded from adjustments that would invalidate the calibration.

Protection from damage: The Company ensures that handling, maintenance and storage of measuring and monitoring devices is such that accuracy and fitness for use are maintained.

Validity re-assessment: If it is confirmed that the equipment is out of calibration, validity of the measurements for which the equipment was previously used is investigated and assessment of the acceptance status of all the affected products is made. If applicable, all nonconforming products are identified and appropriate action taken to address the situation.

Calibration records: The Company maintains appropriate calibration records for measuring and monitoring devices. Each instrument is traceable to its own calibration history record which contains it identification number, storage location, make or type, frequency of calibration, reference standards used, actual calibration findings including date, and actions to be taken in case of unsatisfactory results.

Software: Test software (developed or purchased) that is used for inspection and testing and/or monitoring of process performance is validated before it is used for verification of products. Standard software purchased from commercial sources is ordered with validation certificates. Software that is developed in-house are validated and approved in accordance with its documentation, which contains instructions for validation of proper functioning. Software is re-validated at prescribed intervals of whenever a change from the original release in introduced. 

Calibration Labels

                                                           Traceability 

QM: 7.5.5 Preservation of product

7.5.5

Preservation of Product

7.5.5 Preservation of product

The company preserves the conformity of the product during internal processing and delivery to the customer. The systems are designed to address the identification, handling, packaging, storage, preservation and delivery requirements of our in-process and final product.

Identification: The products at different stages of processing are identified as per point 7.5.3.

Handling and preservation: Production is responsible for product handling and preservation; and in particular for ensuring that containers holding products are suitable and are in good condition (this includes containers closure systems, pallets, platforms etc.), that the equipments used for internal transportation of products is well maintained and is properly operated (this includes transport trolleys, fork lifters, lift trucks, loaders and other vehicles), and that products are adequately protected during production and storage. Methods and precautions for handling hazardous materials (biological, chemical etc.) are part of Standard Operating Procedure. Warehouse is responsible for storage of materials such as raw materials and finished product under the specified conditions. Personnel are trained for handling procedures.

Packaging: Procedures are in place for packaging of the materials (intermediate and finished product) where such requirements are necessary for storage and transportation. Wherever the packaging is performed the process of packaging is qualified and validated before selecting the method/material of packaging. The records of such validations are maintained. The process of packaging is then defined in a standard operating procedure/work/packaging instruction. Packaging is done as primary packaging, secondary packaging, tertiary packaging or special packaging so as to prevent damage from vibration, shock, abrasion, corrosion, humidity, temperature, or any other conditions occurring during handling, storage and shipping as per requirements. Packaging and labeling are production processes and are controlled and defined. Final packaging for shipping of release product is a warehouse function and is controlled and defined.

Storage: Defined storage areas (stock rooms and storage, staging, and holding areas) are designed for product to prevent damage or deterioration of the product and meet the storage specifications. These areas are maintained and controlled by the department which is responsible for the particular processing stage. Limited shelf life materials are issued on a “first in, first out basis”. Records of appropriate storage conditions are maintained. Procedures and/or work instructions are established for control of all the products.

In general raw materials are stored in their shipping container in warehouse stores with designated stock location (segregated and identified) under appropriate environmental conditions. Intermediates and finished product prior to release are stored in production store rooms with designated stock location under appropriate environmental conditions. Released finished product ready for shipping is stored in warehouse with designated stock location (segregated and identified) under appropriate environmental conditions.

Delivery: The Company utilizes company owned as well as sub-contracted transportation firm for product transportation and delivery. Sub-contractors are approved and reevaluated periodically as per the supplier qualification procedure and list of approved sub-contractors is maintained. Product being prepared for shipping shall pass the final release criteria. Before materials are dispatched, person authorized verifies that the shipment contains the same products and quantities as specified in the shipping/purchase order and the packaging and labeling confirms to in-house requirements, customer and/or carrier requirements. Products are delivered to the customers in a manner that prevents damage and conforms to legal and customer requirements. Distribution records are maintained identifying the consignee name and address, date shipped, product quantity and control numbers (batch/lot numbers) along with mode of transportation in order to maintain traceability and facilitate and corrective action post marketing.

QM: 7.5.4 Customer Property

Introduction

The organization can come across customer property which can be:

Information: Confidential document, proprietary information, plans & layouts, drawings, confidential information such as supplier details, market strategies, business plans etc.

Material: Starting material, intermediate, drug product, drug substance or any other materials which belong to customer but are within the company premises or control such as in-transit, intermediate warehouse or stores.

The standard states that, ‘The organization shall identify, verify, protect and safeguard customer property provided for use or incorporation into the product’.

Requirements of the clause become more important in contract manufacturing or job work scenario.

7.5.4

Customer Property

7.5.4 Customer Property

Customer materials are received and inspected following the same procedure that applies to the purchased products. In the event the supplied product fails receiving inspection, or is not suitable for any other reason, the customer is contacted.

Labeling, storage, handling and preservation of customer supplied product follow the same procedures that apply to purchase products.

Customer software, documents, and other intellectual property are protected to same extent as would internal documents of similar content, unless there are contractual requirements for specific measures to protect customer’s intellectual property.

Wherever specified special handling instructions for customers take precedent over the company’s standard procedures.

Customers are immediately informed in the events of loss, damage, deterioration or, or unsuitability of their products. Records of such events are maintained.