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Laboratory Refrigeration and Freezer Cabinet classification in Accordance with FDA and GMP

In the recent years, the declared aim is to safe-guard the health of the population, and to protect the consumer from dubious products

Although legal requirements have been in existence for some time now, because of continuously growing industry quality requirements, the increasing number of internal audits by the Quality Assurance (QA) and external audits by the end customer, qualifications continue to gain in importance. Increased pressure by the State to inspect by way of mutual audits does not leave any leeway for interpreting normative requirements and references. Industry sectors subject to Good Manufacturing Practice (GMP) like the (classical) pharmaceutical industry, bio technology, the chemical industry, suppliers and active ingredient manufacturers with their manufacturing and operating sectors cannot avoid the rules concerning drugs manufacture (GMP) any longer. Manufacturers of medical technology and plant and appliances absolutely must fulfil the narrowly defined requirements as well. The declared aim is to safe-guard the health of the population, and to protect the consumer from "dubious" products.

QA is part of the GMP/EC GMP-Gudie. It is a binding requirement in the shape of a legal order under para one of the AMG in the Pharmaceutical Operations Order, of which the GMP Guide forms part. Validation / qualification is an essential part of QA. Validation is a systematic evaluation and documentation for systems and facilities so that these fulfil the purpose and so that processes run as expected and in a replicable manner. This measure is to ensure stable processes as well as high and consistent product quality. Under the title of "Licensing Inspections and Validation", the EC-GMP Guide- with its total of 18 annexes - in Annex 15 defines the principles of qualification and validation to be followed for drugs manufacture. It is one requirement of GMP that the manufacturer establishes which validation processes are required to show that the critical aspects of the activities undertaken by him are being monitored. Any major changes to facilities, equipment and processes which could influence product quality are to be validated. In addition, a risk assessment should be undertaken so as to be able to determine the volume and depth of validation. All validation activities should be planned. The key elements of a validation programme should be clearly defined and documented in a Validation Master Plan (VMP) or similar document. The VMP should be a short, precise and clear summary. Validation is a documented demonstration, in accordance with the principles of good manufacturing practice, that processes, methods, equipment, materials, working processes and systems are actually providing for the expected results. In English terminology, no difference is made between validation and qualification.

Qualification of plant and appliances (equipment) means supplying documented proof of the plant's technical suitability when undertaking quality-relevant processes in accordance with valid manufacturing and monitoring regulations. Overall responsbility for qualification in the pharmaceutical industry lies with the manufacturing and monitoring manager, depending on the department using the plant (clearance of personnel resources and costs/ investments). Qualification, establishment of the documentation and monitoring of the implementation is overseen by a qualification team. This team usually consists of representatives from the production, technology and quality assurane departments. Main criteria for clearance of a successful qualification are drawn from the current requirements of GMP legislation in the pharmaceutical industry. Current acceptance as determined by the qualification team, the state of technology and thequality assurance department should be established from the relevant instructions for qualification. Acceptance criteria are limits or ciritical values established for inspections, which the actual condition should meet. In case these limits or critical values are not adhered to, a decision concerning remedial work to the actual condition must be made.

Inspections of refrigeration and freezer units may be undertaken either via qualification in accordance with GMP (DQ, IQ, (KA), OQ, PQ) or via a performance check. A qualification in accordance with GMP offers the user/operator considerable advantages: security concerning audits, everything contained within one documents, it includes performance checks. Disadvantage can be quiet costly in comparison with original purchasing costs. Processing and establishing a prospective qualification (new appliances) and a retrospective qualification (current appliances) is usually similar and only differs in the extent of the inspections undertaken, as new appliances are inspected more thoroughly. For current appliances, it is often possible to undertake a current analysis and inventory (of existing documents, plans etc.) as to their currency and completeness only.

Let us explain the actual process of qualification of a laboratory refrigeration / freezer unit by way of a prospective qualification example:

Establishment of constractual / functional specifications

Contractual Specifications means laying down in writing quality-relevant requirements for the appliance to be newly acquired by the qualification team. Functional Specifications are the written reply to the Contractual Specifications by the manufacturer or supplier (distributor). This is important in case of problems and any compensation claims arising later, by way of written confirmation of the specifications required.

Note by the author: The following basic considerations and problems should be clarified and defined before establishing Contractual Specifications:

• "What" (product / preparation) is to be stored?
• Which regulations / legal requirements are in existence for this preparation / product concerning optimum storage temperatures and max. tolerance in temperature ranges (Ex.:+5 C / 3 K, +4 C / 2K)?
• What are the maximum ambient temperature (Ex.: +32C or +43 C) at the site intended for the refrigeration / freezer unit?
• What is the unit's load state (empty: no insert mass, full: maximum inert mass)
• What is daily handling (door opening cycle) of the appliance like? Is it to be purely a storage unit, or a working unit?
• "Internal compartment free from combustible materials" (as per BGR 120 previously ZH 1/119 Sect. 3.8) required?
• Is it the product temperature or the air temperature inside the cooling unit which is vital for the preparation / product to be stored? Hence, is it necessary to use suitable (volume, dimensions, reference fluids) product-equivalent reference bodies during qualification?
• Can the existing or future freezer unit maintain required temperature ranges even over any defrosting phases?

Design Qualification (DQ)

Documented proof that all quality-relevant requirements contained in the Contractual Specifications for design, including siting, media feed systems and auxiliary facilities, have duly been taken into account. Replies laid down in writing and their justifications constitute the Design Qualification.

Installation Qualification (IQ)

Documented proof that appliances have been supplied and installed in accordance with the requirements stated in the Design Qaulification and legal safety regulations. These inspections are usually undertaken by the technology department responsible, or a partner company qualified to do so (external service provider). The IQ serves to inspect completeness and correct installation of appliances and documents correct implementation of the requirements previously defined in the DQ. For every appliance to be qualified, a document (Inspection Schedule) concerning inspections to be undertaken in connection with the IQ is drawn up. The IQ contains details concerning identification of the complete scope of supply, and confirmation that the components supplied agree with the required specifications. The Inspection Schedule contains the inventory of components supplied and of the inspection compared to order documents, inspection of user documentation as to conformity, inspection of installation based on RI schedules and other plans, drawing up a list of feed and disposal lines (energy, electricity, communications, media). establishment of an MSR list, quality-relevant measuring point declarations and codings, calibration, inspection of calibration facility measuring points (extendable, accessible), inspection of product contact surfaces (surface roughness, material specifications) visually and/or certificates/ declarations, listings of lubricants used, cleaning documentation (materials, procedures), training documents (training intervals). Any differences coming to light during execution, and all measures taken to remedy these, must be documented. After remedying any differences, these must be re-inspected, a re-documented and re-assessed in a new report. After completing the IQ, results are summarised, assessed and inserted into a report. The IQ is cleared by way of the responsible qualification team persons' signatures on the report.

Operational Qualification (OQ)

To inspect correct functionality of an appliance, an Operational Qualification (OQ) is undertaken. For technical clearnace, it is necessary to successfully undertake an OQ. The OQ can only be undertaken once the IC has been undertaken and successfully concluded. The inspection shedule contains identification and inspection of quality-relevant alarm, switching and regulatory functions, safety-relevant functions (personal, machinery and product protection), and test runs. The OQ is an inspection process to assess an appliance. All items stated in the Inspection Schedule are worked through the documented in writing to ensure that the system is working in line with specifications. These inspections can sometimes only be undertaken with the product. Once the OQ is concluded, results are summarised, assessed and inserted into a report. Any differences and measures taken to remedy these are to b documented. After remedying these differences, these must be re-inspected, re-documented and re-assessed in a new report. The OQ is cleared by way of the responsible qualification team persons' signatures on the report.

Maintenance / Upkeep

Maintenance is becoming an increasingly important part of product, machine and quality assurance. It is vital to ensure high availability of appliances. As for qualification, intense study of the contents of the manufacturer's documentation is required, it makes sense to draw up a Maintenance Schedule at the same time.

Performance Checks

During the preparation period, measuring devices required for distribution measurements are selected. For instance, the following can be used for recording purposes - logging systems (Testo, Ebro, elpro, Fluke) where all temperature sensors should be connected in once place, if possible. Ideally, thermal elements should be used as temperature sensors (rapid reaction times).

Measuring devices need calibrating before and after use (reset). If a reset calibration of the appliance measuring unit has been undertaken previously, an inspection at normal operating temperature will suffice (more advantageous as to time required). Otherwise, a performance check is to be undertaken at three different temperature levels.

Processing is done with shelf inserts (drawers, grids, glass trays) in place and the internal compartment empty. Steady condition should be reached before you start. Measuring time should be at least one hour. In case of drawn-out processes and appliances, this inspection should be undertaken over a period of 72 hours. If required, distribution can be undertaken with contents in place to start with (Worst Case, referring to PQ). Analysis is undertaken in list form (exact details as to temperature progression) and in diagram form (clear progress of the process).

Further essential parts of the analysis consist of temperature distribution in time, temperature distribution in space, maximum and minimum temperatures, coldest and warmest spots in the inspection space, and average temperature throughout the period. During documentation and in the concluding report, reference to the tested item must be ensured, and the analysis documentation must be integrated. In conclusion, an assessment with reference to the specifications is done. This report is passed to the person responsible for the appliance.

In its structure, layout and content, the qualification documentation is vastly different from one company to the next. The qualification team establishes how the document should look. Only specific regulatory rules are to be taken into account. Qualification schedules should be drawn up, processed and assessed in accordance with operational instructions. Such operational instructions should exist for all qualification sectors. With pharmaceutical companies, there should exist a supervisory Master Validation Schedule (MVP) to co-ordinate and describe all qualification processes within an operational sector or the whole company. This MVP defines responsibilities and competencies for specific sectors or products. It shows appliances / systems and time schedules for future projects. The MPV is a document providing clear overviews to inspectors during an audit. Each page of the qualification schedules or protocols must be clearly identifiable. Inspection protocols must be marked as such (type of inspection, space for individual notes). Each page having notes or assessments inserted by hand must include a signature block for the person undertaking the inspection and the one monitoring it.

Additional hand-written notes or amendments must be initialled with signature and date. Details as to the type of qualification and of the description of the appliance by type and identification number (e.g. serial and/or inventory number) must be included. This is also applicable to the company name and clear document coding. The creation date and insertion of page numbers is not a "must", but a sensible addition. The following supervisory information. The following supervisory information must also be included: clearance blocks for the persons responsible, names of persons responsible (qualification team), distribution key ("who gets what"), amendment history, purpose of inspection, system description (possibly includinga digital picture).

Medical Systems Business
Sector 17, Opp Der Hei
9809 Hosingen, Luxembourg
Tel.: +49 234 923 1994
Fax: +49 234 923 1995 / 1996
Carsten.neuwald@domestic.lu
www.domestic.lu

Shrinivas Arkasali
Country Manager
Dometic AB , Sweden- India Liaison Office, #512-513, Nav Nirman Kendra, Famous Studio Lane, Off Dr.E.Moses Road, Mahalaxmi,
Mumbai 400011, India
Tel: 022 66545430/31
Fax: 022 66545432
Email: shrinivas.arkasali@dometic.in
Mob: 9819214626

The writer is from Dometic sarl