Designing and Successful Exceution of a Compliance Programme

Lene Sinkbæk Bjerregaard
Senior Technology Partner, GMP & Compliance, Global Business Development, NNE Pharmaplan

Prabhakar Shirse
Head - Validation & GMP Compliance, NNE Pharmaplan India Limited
A quality system is a fundamental and necessary component for any pharmaceutical manufacturer seeking regulatory approval anywhere in the world; these regulations are also known as current Good Manufacturing Practices (cGMP). The purpose of a quality system is to achieve compliance of all elements of the pharmaceutical manufacturing process that has potential to affect product quality and patient safety. This article chalks out a compliance model for pharma corporations to emulate so as to ease conformation to the regulatory norms.

Pharmaceuticals and compliance have a long association; however the development of each of these has been on a different stride. At that juncture pharmaceuticals came first with a concern of safety and efficacy. In the mid of twentieth century, incidents resulted in the death of countless patients, led to the formation of GMP. Recently, a “c” has been added in front of GMP, in order to indicate the requirements for GMP that will change and improve with new technologies and methods of working to enhance the quality of pharmaceuticals. A series of improvements in the 21st century has pushed this idea to arise with 21st century initiatives of FDA, ICH Q8, Q9, Q10 & Q11 Guidelines focused on quality risk management (QRM) and Process Analytical Technology – PAT to make sure that consumers get only safe and quality pharmaceuticals. One of the latest practices being implemented is Quality by Design (QbD) approach which is more scientific and engineering based, unlike the previous regulatory practices that are empirical in nature (Quality by testing). Best – in- class compliance is an opportunity for market differentiation.

‘’If you can’t describe what you are doing as a process, you don’t know what you are doing.” - W. Edwards Deming

Traditionally it has been perceived as necessary to validate a process and then lock it and never change it. However, recently the regulatory requirements have started to change; requiring more focus on understanding the science, the process, the risks and on building quality into the manufacturing process.

This has to start already in the research and development phase, and the understanding gained here must be the platform used when designing a facility for commercial manufacturing. Therefore, it is necessary to implement standards and tools built on ASTM E-2500 and Q10 throughout the life cycle of the manufacturing system. The quality system must cover the design, manufacture, packing and labelling, storage and delivery of pharmaceutical manufacturing systems.

Compliance Design
A risk-based and science-based approach shall be applied to the specification, design, and verification of manufacturing systems and equipment that have the potential to affect product quality, patient safety and is the systematic, efficient, and effective way of ensuring that manufacturing systems and equipment are fit for intended use; that risk to product quality and consequently to patient safety are effectively managed to the extent that these are affected by such systems and equipment.

The objectives are to provide manufacturing capability to support well-defined and controlled processes that can consistently produce products meeting defined quality requirements and to support continuous process capability improvements and enable innovation such as the implementation of Process Analytical Technology intended to satisfy both national and international regulatory expectations respectively in ensuring that manufacturing systems and equipment are fit for intended use. It also aims to satisfy requirements for design, installation, operation, and performance applying concepts and principles introduced in the FDA initiative: Pharmaceutical cGMPs for the 21st Century—A Risk-Based Approach as is also consistent with the framework described in ICH Q8 and ICH Q9. Proposed E55 standards to be published by ASTM International.

Key concepts applied in designing the compliance program shall be:
Risk- and science based approach: This approach supports the specification, design, and verification of manufacturing system at each stage based on scientific knowledge. The level of documentation of the quality risk management shall commensurate with the risk to product quality and patient safety. Analyzing the process parameters risk to critical quality attributes (CQAs), and hereby identifying the critical process parameters (CPPs). This will be the basis for a process control strategy. Prior production experience shall be used as the basis for making science based decisions to ensure that the manufacturing systems are designed and verified to be fit for their intended use.

Critical Aspects of Manufacturing Systems: The critical aspects such as features, abilities, and performance or characteristics necessary for the manufacturing process and systems that ensure consistent product quality and patient safety shall be identified and documented based on scientific product and process understanding.

Quality by Design: This concept should be applied to ensure that critical aspects are designed into systems during the specification and design process. Assurance that manufacturing systems are fit for intended use shall be achieved by a planned and structured verification approach applied throughout the system life cycle and the critical aspects of the design and related acceptance criteria shall be documented.

Good Engineering Practice: This practice is the established engineering method and standards such as specification, design, installation and verification activities including GxP, safety, health, environmental, ergonomic, operational, maintenance, recognized industry standards and related statutory requirements that are applied throughout the life cycle to deliver appropriate and effective solutions to produce documentation covering planning, specification, design, verification, installation, acceptance and maintenance.

Provisions related to quality shall be included in specification, design, procurement, and other contractual documents with desired degree of oversight and control achieved by suitable verification of execution, construction and installation activities.

Use of Vendor Documentation: Vendor documentation including test documents shall be used as part of the verification documentation provided the regulated company has assessed the vendor, and has evidence of an acceptable vendor quality system, vendor technical capability and vendor application of GEP such that information obtained from the vendor will be accurate and suitable to meet the purpose of verification.

The decision and justification to use vendor documentation to support the verification of critical aspects of the manufacturing element shall be based on the intended use of the manufacturing system and shall be documented and approved by the quality unit.

Continuous Improvement: In this section opportunities for improvements shall be sought based on periodic review and evaluation, operational and performance data and root-cause analysis of failures, where change management shall be used for implementation of technical improvements.

Execution of Compliance
The process of compliance in manufacturing system specifi cation, design, and verifi cation shall be commenced by describing the requirements, acceptance and release criteria supported by quality risk management & design review as appropriate and change management applied during the process throughout the life-cycle along with quality system and essential documentation, contamination control, in-process controls, cleaning and disinfection, facility design and operation, containers & closures, environmental monitoring, quality assurance, laboratory and IT systems, employee health and safety.

Definition of Requirements: At this stage specifi c requirements shall be identifi ed to provide on the basis of specifi cation, design, and verifi cation of the manufacturing system relative to quality and safety shall be based upon product - process knowledge including sources of variability in the product and process, the identifi cation of critical quality attributes and information of process control strategy based on scientifi c data gathered during experimental and development stage and related Regulatory requirements.

Specification and Design: At this stage, appropriate mechanisms to communicate required inputs, including product quality to those liable for design shall be developed to ensure that the manufacturing system has been designed is appropriate to product and process requirements.

Verification: At this stage a defi ned systematic approach shall be followed to verify that manufacturing systems are fi t for intended use, have been properly installed and are operating correctly with generation of detailed documentation based on risk, associated with quality and safety. The verifi cation plan developed for systems containing critical aspects shall be approved by the quality unit. The completion of verifi cation activity shall be documented and all documents shall be reviewed by independent qualifi ed person and all the observed deviations shall be addressed and resolved.

Acceptance Criteria: At this stage the acceptance criteria of critical aspects shall be defi ned that a manufacturing system must satisfy in order to be fi t for intended use and to be accepted by a user and approved by the quality unit.

Release Criteria: At this stage the qualifi ed person shall confi rm that the manufacturing system is fi t for intended use and this confi rmation shall be documented. Such documents shall be prepared and approved by the quality unit. Following these approvals the manufacturing system shall be released for operational use. Such documents shall include a review of the results and a review of any non-conformance with stated acceptance criteria of critical aspects covering a clear statement as to whether or not the manufacturing system is fi t for intended use based on the review. The persons involved in making this determination shall be identifi ed and documented.

Quality Risk Management: At appropriate stages of manufacturing, the risk assessment, control, communication and review of identifi ed risks to the quality of the drug and safety of the patient should be completed. Based on risk assessments, appropriate controls and verifi cation techniques shall be selected to manage risk to an acceptable level, centered on critical aspects of the manufacturing system. The level of control shall be appropriate with the level of risk to quality and safety.

Design Review: This stage shall include planning and reviewing of specifi cations, design development and continuous improvement changes, evaluation of deliverables against standards and requirements, identifi cation of problems, and proposing required corrective actions performed as appropriate throughout the life-cycle of the manufacturing system.

The critical aspects of manufacturing systems must be addressed and risks to product quality and patient safety identified. Unacceptable risks can be mitigated and performed and documented by qualified persons with statements that the item in question is acceptable, provided the proposed corrective actions are completed.

Change Management: This process shall be established and be applied before acceptance throughout the life-cycle and it shall be managed and approved by qualifi ed persons. Changes affecting critical aspects of manufacturing systems shall be communicated to the quality unit. Operational change management shall be applied after acceptance and prior to manufacturing for commercial use. Under this, all changes related to specifi c requirements relative to product quality and patient safety will require prior approval by the quality unit.

Quality System and Essential Documentation: In terms of quality system, the site master file and quality manuals shall be mandatory for compliance. Good documentation system constitutes an essential part of the compliance. Documents shall be clearly written & easily understandable beside accurate, complete, legible and timely records. Data shall be consistent with the source document.

Acquisition and control of materials: Handing suppliers, their quality systems, storage and test of incoming materials is one of the key elements in ensuring good quality.

Contamination Control: Control of contamination specifies warrant recourse to specialist publication. Nevertheless the causes of contamination within pharmaceutical manufacturing are of great importance. The primary causes of contamination were identified as people, environment, records, equipment, procedures, ingredients, product itself.

In-Process Controls: In terms of compliance, sampling shall be undertaken to a pre-approved sampling plan and all test methods shall be validated and the data is regularly reviewed as part of batch review. An in-process test to determine the completion of a reaction or processing step that does not meet the target value is considered as OOS or deviation. The process is continued until the target is reached.

Cleaning and Disinfection: Cleaning and disinfection is an important part of contamination control. It is important to build cleanable surfaces for easy to clean and disinfect. A disinfectant used shall have wide spectrum of activity.

Facility Design and Operation: The design of facility shall be such that contamination is minimized

Containers and Closures: Aside form the pharmaceutical use of product stability the choice of the means of primary containment is a function of factors such as protection of physical composition and microbial contamination.

Environmental Monitoring: The monitoring program is designed to describe the routine particulate and microbiological monitoring of processing and manufacturing areas including a corrective action plan when levels are exceeded. A comprehensive set of monitoring locations shall be developed on the basis of experience of where contamination has actually been found in the past, likely to occur and non-viable particulate counts obtained in validation.

Quality Management and Personnel: Active participation by senior management in establishing and maintaining an effective quality system is essential. Management is to establish the quality policy and quality objectives. A quality manual is a living document prepared by management that articulates the quality principles of the corporation. A regional regulatory requirement necessitates an overall structure that has a quality unit independent from production units and reports to the highest level of the organization.

Laboratory Controls and Stability Studies: Quality control is a function of the independent quality unit and is responsible for all laboratories testing of raw materials, stability studies and complaint samples. There shall be approved procedures for sampling, testing, instrument operation, maintenance and calibration, acceptance and rejection of materials and recoding and storage of collected data. The stability characteristics shall be monitored as per ICH guidelines.

Storage and Distribution: Ensuring adequate storage control and segregation of incoming materials, intermediates, quarantined products, controlled substances, products for release and released products for distribution is required. Also it is important to ensure that the product is stored and transported as per label claim. Some products may require specifi c conditions like cold chain control or protection from light.

Training: Training employees on site is probably the most important way to ensure a successful execution of a Quality System. A good and comprehensive training in the required procedures is imperative to make sure that you implement a quality mindset with all employees.

The foremost issue in designing and implementing a pharma compliant system is the provision of solid, meaningful documentation that is respectful of the user requirements and resulting design specifications. The documentation must be supportive of the commissioning and qualification testing that is performed on the system following implementation. The documentation must be highly structured and well-organized. A high degree of linkage must exist between the various design documents and engineering deliverables. Good engineering practices must be followed with regards to design reviews, management of change, and overall traceability of the design so as to produce process designs and system software that meet specification that are thoroughly documented and are fully capable of being validated.

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