MAINTENANCE The EU GMP COMPLIANCE: Internal And External Audit

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MAINTENANCE the EU GMP COMPLIANCE: Internal and External Audit Alessio Ferrari



Regulatory Compliance to Ensure Pharmaceutical product quality is assured by comprehensive development program extensive manufacturing and environmental controls rigorous validation procedures and requirements The high quality thus built into the final product is ensured through in-process controls and verified in a series of confirmatory tests before each manufactured batch is released to the market API GMP COMPLIANCE

Regulatory Agencies FDA: USA MHRA: UK MHW: Japan EMEA: Europe DCGI: India TGA: Australia SAMMDRA : South Africa * IFPMA, ICH, ICMR, PhRMA etc API GMP COMPLIANCE

Applicable Guidelines used in Pharma Good Manufacturing Practice –EU (2003/94/EC ) ICH FDA Guidance -Computerized Systems Used in Clinical Trial FDA CFR 21 GLP Consensus Document -The Applications of the Principles of GLP to Computerized Systems API GMP COMPLIANCE

MANUFACTURER Each manufacturer which has a licence must have: Qualified person Premises and equipment in accordance with GMP requirements All operations in accordance with GMP independent QC unit Contracted activities in accordance with GMP API GMP COMPLIANCE


INTERNAL AUDIT (CE 2001/83 CHAPTER 9) Self inspections should be conducted in order to monitor the implementation and compliance with Good Manufacturing Practice principles and to propose necessary corrective measures. 9.1 Personnel matters, premises, equipment, documentation, production, quality control,distribution of the medicinal products, arrangements for dealing with complaints and recalls, and self inspection, should be examined at intervals following a pre-arranged programme in order to verify their conformity with the principles of Quality Assurance. 9.2 Self inspections should be conducted in an independent and detailed way by designated competent person(s) from the company. Independent audits by external experts may also be useful. 9.3 All self inspections should be recorded. Reports should contain all the observations made during the inspections and, where applicable, proposals for corrective measures. Statements on the actions subsequently taken should also be recorded. API GMP COMPLIANCE

INTERNAL AUDITING An internal audit is a periodic examination of the Quality Management System (QMS) conducted by an internal team or a third party to ensure that an organization’s concepts, principles, and procedures are properly maintained. Generally the internal audit is done by in-house personnel. What, then, is an outsourced internal audit? Outsourcing is often sought when there are shortages of skilled staff, or there is a need to improve upon the processes that an organization is currently using. API GMP COMPLIANCE

INTERNAL AUDITING The primary benefit derived from outsourcing the internal auditing function is that bringing in an outside source not only allows for an exchange of information, but also that the external auditor can focus completely on the task at hand. Many trained professionals within a company deal with multiple job requirements, which often leads to an inability to put their auditing functions first. The primary reason why a company may choose to outsource its internal auditing function is that it will be more cost-effective. A company must weigh the financial aspects of training and maintaining in-house personnel against what the future might hold for the company as well as the changing priorities for the employee, such as retirement, relocation, or the scope of the job. API GMP COMPLIANCE

SUPPLIERS ASSESSMENT: WHY? It is a matter of survival for Companies the need to select Qualified Suppliers at reasonable costs, pursuing an unstable equilibrium between Reliable Quality and Expenses that can be borne. Unlike other industrial sectors, the Pharmaceutical Industry cannot take advantage of techniques as “specifications optimization” or “margin of safety standardization”. The Product Specifications ARE the Product: they cannot be changed, unless the product is substituted. For this reason, Quality Assurance has achieved absolute greatness in Life-Sciences sectors. For the same reason, a combination between the better Quality instruments (Risk Analysis) and means for waste identification (Lean), applied to procurement processes, can help to achieve good results: so, industrial systems of great experience can stand more and more difficult competitions. API GMP COMPLIANCE

SUPPLIERS ASSESSMENT A posteriori method in order to assess Suppliers, starting from historical data, and obtain a Matrix for an efficient Audit Management A priori approach for effectively managing Selection or introduction of new partners API GMP COMPLIANCE

SUPPLIERS ASSESSMENT: SCOPE To seize the opportunity offered by Risk Analysis integrated with a process of Suppliers Assessment / Selection and supported by Lean-Tools. Materials Assessment of use Criticality (product and process) Assessment of use Significance Assessment of Analytical History (Trend Analysis) Suppliers Assessment of Reliabilty and Consistency Assessment of Strategicity and Interchangeabibility Tools Risk Analysis (FMEA, HACCP) Scoring and Performance Indicator Inter-functional Audits Business Continuity Matrix API GMP COMPLIANCE

PRELIMINARY ACTIVITIES To make a study of all the used suppliers, as for active principles, excipients and packaging materials, in order to optimize Qualification Activities: Approved Suppliers List Compliance & Criticality Supplier Quality Scoring Process Capability CAPA Programs API GMP COMPLIANCE

PRELIMINARY ACTIVITIES To set up a Risk Analysis oriented to Suppliers classification into criticality classes related to production processes To choose the technique, define and analyze dangers, calculate risks and assess results To issue Risk Assessment Report including Action Plan To define necessary activities for Suppliers Qualification API GMP COMPLIANCE

PRELIMINARY ACTIVITIES After having obtained RPN from RA and set Suppliers in specific criticality classes, qualification activities will be defined through distribution analyses, according to these criteria: Volumes Parameters Procurement Strategy Business Continuity Risk Supplier Performance Index Relationship) Internal Sourcing Evaluation External Sourcing Evaluation situation) (Turnover, # Deliveries) (Local vs. Central) (No-Delivery Probability) (Price, Quality, Delivery, Expertise and (Single vs. Multi) (Stocks and components, Market The result will be the issue of a Risk Assessment for defining a Supplier Audit Matrix, supported by great logic in Audit planning, because it is based on the use of standardized Tools. API GMP COMPLIANCE


EXAMPLE OF CRITICALITY CLASSIFICATION We report as an example a list of criticality classes that could be defined for Suppliers: CLASS A - High Criticality - Annual Audits; statistical test of analytical data for every batch of product received; analytical identification for every unit of product sent; execution of pharmacopoeia monograph and/or specific customized tests every 5 batches; etc. CLASS B - Medium Criticality - Biennial Audits; statistical test of analytical data for every batch of product received; analytical identification for every unit of product sent; execution of pharmacopoeia monograph every 10 batches; etc. CLASS C - Low Criticality - Triennial Audits through sending/receiving a specific check-list; reduced statistical test on future batches; execution of pharmacopoeia trials every 10 batches received; etc. API GMP COMPLIANCE

EXAMPLE OF CRITICALITY CLASSIFICATION If the class distribution point out a too high level of complexity, it would be necessary to use other screening criteria: Volumes parameters (arrivals / shipments) Internal strategies / Market situations Risk Assessment of Business Interruption Index of Global Assessment of Suppliers API GMP COMPLIANCE

ATTAINABLE OBJECTIVES Qualitative: Audits more effective (less for more), efficient (multi-disciplinary Teams) and standardized (integration with database of PQR / APR). Operating: Process of Suppliers selection more rational (common modus operandi for better sharing information) in order to allocate or free resources, and speed up improvement processes for introducing new suppliers / materials / components. Financial: Additional charges optimized, reducing complexity costs and maximizing the Benchmark at a Corporate level. API GMP COMPLIANCE

SUPPLIER AUDITS A supplier audit is a complete investigation and analysis of a factory operation after the customer has provided guidelines on its production methods and specifications. Ideally, a supplier audit is one of the best ways to ensure that the supplier is following the processes and procedures set forth by the company, and will provide objective analysis of a company’s supply chain. A consistent, fact-based approach is used to check that a supplier can match the customer’s guidelines, enabling control of the product. API GMP COMPLIANCE

SUPPLIER AUDITS With many companies outsourcing their manufacturing to other countries, such as India and China, supply chains have become very long, and companies are finding it increasingly important to have onsite supply auditors to ensure quality management. Outsourcing the supplier audit function allows companies to acknowledge cost-effectiveness by maintaining on-site auditors. It also helps to ensure that the factory is abiding by the guidelines of production methods and specifications, monitoring performance, conducting periodic audits, and ensuring that all requirements are being met. API GMP COMPLIANCE

Flow Chart Auditing Activities API GMP COMPLIANCE

CASE STUDY:10 COMMON GMP CHALLENGES FACING MAINTENANCE DEPARTMENTS IN PHARMACEUTICAL PLANTS This white paper lists the GMP compliance problems often seen within the maintenance departments of pharmaceutical operations. These are the problems that will cause you grief when an auditor arrives. It is recommended that you identify, investigate and fix them before the auditor's next visit. API GMP COMPLIANCE

Challenge 1 A risk-based approach to maintenance is not used It’s common to treat every piece of equipment within a pharma plant equally when it comes to maintenance. A better way is to use a risk-based approach that classifies each piece of equipment in terms of its impact on product quality. We recommend a simple four-category system for equipment: Direct Impact (Product Critical Equipment) Indirect Impact (Process / System Critical Equipment) No Impact Equipment Safety/Environmental Impact System API GMP COMPLIANCE

Challenge 2 Computerized Maintenance Management Systems (CMMS) are not utilised, are under utilised or are not validated A CMMS typically performs five GMP-critical tasks: Allocating a Unique Identifying Number (UINs) to each piece of equipment Describing the validated plant configuration Being the repository of maintenance plans Holding records of maintenance activities Scheduling maintenance activities As consultants to the industry, we often see hybrid management systems within maintenance departments. API GMP COMPLIANCE

Challenge 3 Maintenance plans are not updated as part of new equipment introduction Buying a new piece of hi-tech machinery is very exciting. All the engineers scramble to be the first one to stroke its gleaming steel. Amongst all that excitement, the fact that this newbie has to be maintained is often neglected. Updating the maintenance plan should be included as an activity in the procedure covering new equipment installation. Buying a new piece of hi-tech machinery is very exciting. All the engineers scramble to be the first one to stroke its gleaming steel. API GMP COMPLIANCE

Challenge 4 Maintenance staff and contractors are not trained properly Do your maintenance workers and contractors know the impact of changing a setting on a piece of production equipment? Do they understand the concept of a validatedstate? Do they know when to involve QA? Let’s face it – maintenance staff would rather watch 15 hours of snail racing on TV than complete paperwork. It’s hard enough to get them to complete maintenance records, let alone Change Control forms. Yet simple maintenance activities such as changing filters or adding lubricant can dramatically impact product quality. The GMP regulations require all contractors to be trained appropriately before they enter GMP areas. Developing tight, long term relationships with your contracting suppliers is critical. Their HR systems should trigger GMP training for every new hire. You could request that small contracting companies use a simple checklist when a new hire commences work. "GMP training" could be on that checklist. API GMP COMPLIANCE

Challenge 5 The GMP impact of lubricants is not considered When we ask the question, “What affect do your lubricants have on product quality?”, we frequently get a puzzled look and a shrug. Lubricants are often ignored in terms of their GMP impact. Yet they can have direct contact with the product and, as such, are considered GMP-critical. Make sure that lubricants are on your criticality assessment list. The assessment and impact of lubricants on product quality should be documented. The introduction of new lubricants should be assessed and documented. Bottom-mounted or indirect drive systems used in plant design are strongly recommended. API GMP COMPLIANCE

Challenge 6 Maintenance of utilities and supplies falls between departmental cracks The not-so-glamorous end of the maintenance activity list includes: chemicals power supplies fire protection systems security systems HVAC water and gas supplies. Make sure it’s clear who manages all this non-production equipment. Too often these items fall into the cracks between departments. The finger pointing starts when things go wrong and the cracks are revealed. We recommend that "who is responsible for what" be documented in the quality system. API GMP COMPLIANCE

Challenge 7 Maintenance activities are undocumented Policies, procedures and work instructions should exist for all maintenance activities. These documents form an essential training resource for maintenance staff and contractors. This documentation will also be requested by auditors, who know that maintenance is a GMP-risk. They will ask to see documentation that describes the what, when and how of maintenance. Make sure that you have it and that it’s followed. It’s worthwhile to get a professional technical writer to produce this documentation; this will ensure that the documents are useful and understandable. Auditors have a practiced eye to detect impractical systems and drill down. You don’t want to be at the bottom of the drilling. API GMP COMPLIANCE

Challenge 8 Modern maintenance management techniques are not used It’s easy to keep doing things the way you’ve always done them – particularly with dailypressures to manage. With a few exceptions, we’ve seen little adoption bypharmaceutical plants in Australia and New Zealand of maintenance best-practice techniques. Total Preventative Maintenance (TPM) is one we recommend, as well as Condition Based Monitoring (CBM) and Lean Maintenance. With both GMP and your company’s expectation that you are continuously improving your processes, we recommend that you get some training in these techniques or call in a consultant to help. API GMP COMPLIANCE

Challenge 9 Equipment documentation is not readily accessible The ideal here is that all the documentation for a piece of equipment should be in the hands of the maintenance technician before he starts work. Extra marks if he’s read it! This documentation includes: The manufacturer’s operation manual The manufacturer’s installation manual The manufacturer’s service manual Details of the validated state of the equipment, e.g., settings used Any maintenance records Any work instructions or procedures covering the use of the equipment Engineering drawings API COMPLIANCE GMP Process and instrument diagrams

Challenge 10 Maintenance is not considered during equipment purchases The maintenance department is often at the bottom of the heap when it comes to selecting new equipment. The production engineers and product development scientists base their selection on criteria such as through-put and ease of cleaning. Let’s say you have a choice between two products for a clean room. They are pretty well equal on most selection criteria, but one is installed completely inside the clean room. The other has its maintainable "bits" outside the clean room, and only its product-contact components are inside the controlled area. Which one are you going to buy? The second one, because any maintenance tasks performed on it are unlikely to threaten the validated state of the clean room. The tasks will also be much quicker and easier to complete than if they had to be performed inside the clean room, making the cost of owning that equipment less than the other choice. API GMP COMPLIANCE



changing filters or adding lubricant can dramatically impact product quality. The GMP regulations require all contractors to be trained appropriately before they enter GMP areas. Developing tight, long term relationships with your contracting suppliers is critical. Their HR systems should trigger GMP training for every new hire.

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