Qualification of Water Systems Water is one of the most widely used substances, and raw materials, or an ingredient in the

production, processing, and formulation of pharmaceuticals. Control of the organic and inorganic impurities and microbiological quality of water is important because proliferation of micro-organisms ubiquitous in water may occur during the purification, storage, and distribution of this substance. Although there are various quality grades of water used for pharmaceutical purposes, all kinds of water are usually manufactured from drinking water or comparable grade water as a source water. Grades of water are closely related to the manufacturing methods and distribution systems of water. Major differences among these grades of water consist of the following quality attributes: Microbial counts Endotoxin, which is due to the presence of microbes. Organic and Inorganic impurities. Grades of water specified in the compendia (USP) are classified according to the quality attributes as: Portable water Purified water Water for injection Sterile water for injection Sterile water for inhalation Sterile water for irrigation Sterile bacteriostatic water for injection Selection of Water for Pharmaceutical Purposes The quality attributes of water for a particular application are dictated by the requirement of its usage. Sequential steps that are used for treating water for different pharmaceutical purposes include: Softening Dechlorination Deionization Reverse Osmosis Ultrafiltration Distillation The manufacturing method and distribution system also have a close relationship with the construction design of facilities and equipment. The most important items to consider are: Selection of the most suitable quality grade of water for its intended use. Determination of the water manufacturing system elements, including facility and equipment. Design of water manufacturing system, including the design of system equipment.

After construction of the water system is completed based on its design, the system has to be scrutinized as to whether it has been built to design specification or not. After confirming the installation of facility and equipment, the quality of water produced is examined from various viewpoints according to the predetermined specifications. In the routine production of water, representative quality items of water have to be monitored to confirm the performance of normal operation, and if any undesirable trends or out of specification values are found, corrective action should be taken. The steps of checking design and construction, confirming proper installation and operation, and documenting these processes are collectively called qualification or validation. Major items of quality attributes that should be controlled and specified for pharmaceutical use are: Organic Impurities Inorganic Impurities Particulates Microbes Endotoxins Design Qualification of Water Systems The quality attributes of water for a particular application are dictated by the requirements of its usage. Production of pharmaceutical water employs a combination of sequential unit operations that address specific water quality attributes. The validation plan should be designed to establish the suitability of the system and provide a thorough understanding of the purification mechanism, range of operating conditions, required pre-treatment, and the most likely mode of failure. It is also necessary to demonstrate the effectiveness of the monitoring scheme and to establish the requirements for validation maintenance. The selection of specific unit operations and design characteristics for a water system should take into consideration the quality of the feed water, the technology chosen for subsequent processing steps, the extent and complexity of the water distribution system, and the appropriate requirements. In a system for WFI, the final process must have effective bacterial endotoxin reduction capability and must be validated for each specific bacterial endotoxin reduction capability and must be validated for each specific equipment unit. The final unit operations used to produce WFI have been limited to distillation, reverse osmosis and/or ultrafiltration. Distillation has a long history of reliable performance for the production of WFI. Other technologies, such as reverse osmosis and ultrafiltration, may be suitable in

the production of WFI if they are appropriately validated for each specific set of equipment.

Airlocks The Ventricles of Cleanroom

In Pharmaceutical, Bio-Pharmaceutical and sterile manufacturing, the clean room environment is the major prerequisite for all manufacturing activity: without a proper movement mechanism & background environment, no medicine can be produced for patient consumption. The intentions and purpose are the reality of stable, reliant, and compliant operation within a tightly controlled and monitored environment. Tight User Requirements or Design Philosophies must be written or inked down before building Airlocks in clean rooms. The challenge for any Quality unit is to define URS based on regulatory considerations when the facility exports a product in different regulatory areas. FDA Guidance FDA Guidance for Industry states: Air change rate is another important clean room design parameter. For Class 100,000 ( ISO 8 ) supporting rooms, airflow sufficient to achieve at least 20 air changes per hour is typically acceptable. Design requires hard numbers, so there is temptation for the design team to use this statement as a final Quality positionthat 20 air changes is acceptable in a Grade C area. To design such an air lock one should consider that the quality of product should not get compromised when materials cleaned, Decontaminated, Debagged & when the plant is operated continuously. In such a scenario it is evident that 20 Air changes may not be sufficient to maintain Grade C specifications as multiple particulates are generated by various operations such as debagging, disinfecting etc. FIT FOR PURPOSE Adjacent rooms of different grades should have a pressure differential of 1015 pascals (guidance values) and 12.5 Pa between a classified and nonclassified room. This is the EU requirement. Increase of differential pressures might increase the overall costs for constructing many air locks in the facility. One must not get tempted to look about the basic requirement of 10 Pa. This might give a bigger headache when materials are being packed for sterilization process and other open transfers posing a direct risk. A perfect design must fit for the purpose i.e the differential pressure between adjacent rooms must be

sufficient to ensure protection of critical process functions from support functions. Regulators will also look for The separate or defined areas or such other control systems for the firms operations as are necessary to prevent contamination or mix-ups during the course ofprocedures. Quality unit and the other Subject Matter Experts (SME/Users) must stand behind the robustness of their design. QUALITY DESIGN Regulations are only a starting point & must be met. A strong scientific and engineering rationale is what makes a Quality design requirement. When these regulations are laid out in a forum of operational needs and technological/ process requirements, very often a simple, robust, and elegant solution for many problems can be found. The new concept is that companies are constructing multi-use manufacturing facilities capable of producing two or more products simultaneously. This refers to a situation where a manufacturer of medicinal products produces two or more products within the same facility either concurrently or on a campaigned basis. This must be designed to facilitate for working with live cells and inactivated products which needs strict containment & Regulatory issues for both personnel safety and cross contamination between areas and products. CROSS CONTAMINATION The following key factors are considered to minimize the chance of cross contamination between different production areas, and consequently the product: The engineering design; Use of functionally closed process systems; Air handling systems segregation; Procedural separation of production activities; Personnel flow, product flow, clean/dirty equipment flow; Gowning regime; Validated cleaning and changeover procedures. AIRLOCK DESIGNS In general, there are three basic airlock designs that can be combined or used individually to protect the clean room and/or prevent cross contamination between two adjacent areas of different process operations served by two different HVAC systems. These three airlock systems are: 1. The cascading pressure airlock 2. The pressure bubble 3. The pressure sink CASCADING PRSSURE AIRLOCK The cascading pressure airlock is used to protect clean areas from adjacent areas with lower required cleanliness. Normally, in this type of airlock, the

movement or transfer from the cleaner area to the lower classified area or Hallway which does not pose any issue with cross contamination. PRESSURE BUBBLE The pressure bubble airlock is used to create a barrier between the clean room where the process resides and the adjacent area or area with lower air classification. As the name implies, this type of airlock is a pressurized space that pushes the air out and into both the areas it protects. This type of airlock creates a barrier between the two spaces it serves, thus preventing cross contamination. PRESSURE SINK The pressure sink airlock is used to create a barrier between the clean room where the process resides and the adjacent area or less classified area. This type of airlock is a negatively pressurized space that pulls the air in from both the process area and the adjacent space thus creating a barrier between the two spaces it serves. A combination of sink and bubble air lock design is also used for creating a barrier between Potent compound or bio-contained clean areas and the adjacent space. GOOD AIRLOCK DESIGN Identifying Requirements: The basic airlock requirement is where people and materials movement must be properly spaced to accommodate that daily capacities and also for special purposes for movement of equipments during emergency break downs. Some needs such as Col-chain management, special gowning needs, Containment of Bacteria , Live virus , CHO cells, Potent compounds & Beta Lactums. In the basic stages the users must make clear that along with process the supporting infrastructure must run as desired. Quantify Requirements: A quantification of the above must be done in this phase. The SMEs must work on backward calculation starting from Peak consumption of all working materials and also defining a steady state and worst case schedules for the men and material movements into the controlled areas. These includes how many bags, Vessels, men, Utensils, Disposable and Reusable filters, Sterilized tubing, storage of liquids, toxoids and solutions and different sizes of adjuvant blend material moments along with the frequency of movement based on hours or Half day schedules. If large items are potentially in scope, the working height and width of those items are exceedingly important. Doorways must be sufficiently designed to prevent any breaking down of walls or doors after construction is done. The whole process needs proper knowledge of Tools & equipments used in the production and process operations. Personnel movement will be just as complex as the movement of materials as it varies from type of operation and product that is manufactured in the facility such as Vaccines & Potent compounds. Vaccine production process may run days or weeks. In such an event the peak movement load and shift

change loads must be properly noted. During such events proper lighting, size of airlocks, air change rate and air flow direction in a personnel airlock are the key issues to be focused. Additional Needs: Now that the variety and amounts of material are known to move thru the airlocks. Large attention must be paid on such activities, Cleaning and disinfection activities, how such activities are handled and how the materials are tracked with lot numbers. Attention must be paid to the actual activity taking place in the airlock. How material enters and leaves the air locks into controlled areas must be clearly stated and usage of any kits for such activities must be stated. Depending on the process, there may be some temperature sensitive material, requires a temperature-controlled environment, so a hand-off controlled temperature unit (CTU) may need to fit in the airlock. CONCLUSION Pharmaceutical and Biopharmaceutical industries are meant to treat diseases and also give immunity for patients from dangerous diseases. A proper design must ensure that clean and sterile products are produced preventing any re introduction of bacteria or allergens or any disease causing materials into the systems, materials and process. A proper URS and Subject matter expertise is the need of the hour to design, Qualify and operate such Clean room facilities with good airlocks, In one say we would call Air Locks are ventricles of heart. If they fail the whole system collapses.

Good and Bad Responses to 483s for Life Science Companies Preparing a response to a Form FDA 483 can be a time-consuming and stressful process. It diverts resources from other activities and, if not managed properly, the process can be overwhelming. If a 483 response is well written, factually correct and complete, it will establish that the firm has taken or is in the process of taking appropriate corrective and preventive action. This can allay FDA concerns about the firm's compliance, and reflect positively on the organization. If the response is poorly written, contains errors or omits critical information, it can trigger additional inspections or a Warning Letter. If the firm submits inadequate responses to a Warning Letter, the firm is at risk for seizures, suspension of product approvals, injunctive action or possibly criminal prosecution. While thisarticle is focused on 483 responses, the recommendations apply equally to Warning Letters. Firms that adopt a "check the box" or "fill in the blank" approach to 483 responses do so at their own peril. Some firms use template responses, directing staff to use boilerplate language to respond to certain types of observations. This is a mistake. Firms that adopt a "check the box" or "fill in the blank" approach to 483 responses do so at their own peril. Crafting an acceptable response requires thoughtful analysis and precision. Following the three rules below will make this exercise more efficient and productive. Rule 1. Have a plan. The response is an opportunity to communicate to the agency that you understand your compliance obligations. It is also an opportunity to demonstrate that you have corrected, or will correct, any deficiencies identified in the response and ensure that the problems do not recur. Most importantly, the response needs to demonstrate that your firm is operating in a state of control. Understand each observation. Section 5.2.3 of FDA's Investigations Operations Manual (IOM) requires that investigators make "every reasonable effort" to discuss observations as they occur or on a daily basis "to minimize surprises, errors and misunderstandings when the 483 is issued." The IOM also informs investigators that firm management may ask questions about observations, request clarification and inform the investigators about corrections that have been made or will be made during the inspection. During the inspection exit interview, you should take the opportunity to ask additional questions if an observation is not clear. If you believe that there are factual mistakes or that an observation is based on a misunderstanding, you should bring this to the inspection team's attention. You should not squander this opportunity by arguing about the observation. In medical device inspections, the firm has the opportunity to annotate the

FDA-483 during the exit interview, to document corrections have already been made, are underway, or will be made. The firm is also allowed to annotate the FDA-483 to document the firm's disagreement with an observation. Form a team. Once you have read and understood the basis for each observation, you should form the response team. Depending on the number of observations and the types of deficiencies identified, the team could consist of 1-2 individuals or a much larger group. You should designate team members for the following roles. Subject matter experts. Subject matter experts (SMEs) provide technical expertise and should be knowledgeable about the particular issue identified in the observation. Subject matter experts typically are involved in development of corrective and preventive actions (CAPAs), or at least have the ability to explain and evaluate CAPAs. Subject matter experts can provide background and context regarding an observation, and should be involved throughout the drafting process to ensure that the response remains consistent with the facts. The writer. Don't assume that your Vice President of Regulatory Affairs or your Chief Scientist is necessarily the best writer in the organization. The writer should be someone who can communicate clearly and effectively. Subject matter experts should provide information to the writer, who will be responsible for the final written product. The clerk. Someone should be responsible for obtaining documents for review and possible submission as part of the response. (During the inspection, FDA requests copies of documents for its inspection file. The firm's inspection management SOP should require the inspection management team to make a second copy for the firm's inspection file. Subject matter experts should review the inspection file in preparing the response. They should not be allowed to remove documents from the inspection file.) Rule 2. Address FDA's concerns. Determine the scope of the problem. Does the observation identify a problem that is isolated or systemic? Is the problem limited to a certain lot? Does the problem extend to other lots of the same product or to other products? Is the problem contained within a particular department or does it extend to other departments? Is the problem contained within a particular facility or does it extend to other facilities?

Conduct a thorough investigation and take appropriate corrective action. Far too often, firms respond to 483s by simply defending their actions or relating the history of a problem. You should thoroughly investigate FDA's concerns and describe your investigation, investigation results and corrective actions in your response. Submit a well-written and precise response. Do not submit a response that is impossible to understand or omits pertinent information. Responses should be factual, complete and easy to read. They should include reasonable timelines, address issues item-by-item and demonstrate an understanding of regulatory requirements. A sloppy or defensive response will not be well received. In addition, you should provide supporting documentation as part of the response. Note also, that you should not make blanket admissions. There is a difference between acknowledging a mistake and agreeing with a 483 observation. Such an admission could be used against the firm in an FDA enforcement action, or a product liability or securities lawsuit brought by a private plaintiff. Rule 3. Keep your promises. A common mistake is a firm's promise during the inspection's exit interview to submit a response as quickly as possible. While it is appropriate to respond in an efficient and timely manner, a lengthy 483 or one involving complicated issues could require more investigation than anticipated. In such cases, rushing to meet an arbitrary deadline could result in submission of a substandard response. If it becomes apparent that it will not be possible to meet your deadline, you should contact the agency and request permission to submit an interim response. You should assure the agency that submission of the final response remains a high priority, and submit the final document as soon as it is practicable to do so. A firm should set timetables for CAPAs that demonstrate an appropriate sense of urgency. Commitments should be realistic, and firms must meet their commitments. Failure to keep your 483 promises will result in repeat observations (often the basis for a Warning Letter or other enforcement action). Failure to meet commitments in a Warning Letter response without keeping FDA apprised of the reasons for delay will most likely result in enforcement action. Conclusion Responding to a 483 can be a stressful process. Proper management of the response, thoughtful analysis and precision will make the process far less stressful. A bad 483 response is one that is incomplete, factually incorrect, poorly written and defensive. A bad response will ensure additional

regulatory scrutiny. A good 483 response communicates an understanding of regulatory requirements and that the firm is operating in a state of control.

Entry Procedures: An Evolution of Concept in Pharma Industry Technological advances in processes and equipments are the major areas to improve the therapeutic efficacy of the dosage form and are therefore constantly under evolution. Environmental conditions prevailing in the manufacturing premises, water used in the processes are the exogenous factors which influence product quality. cGMP requirements define these factors critically and are also subject of continuous review. It has therefore become necessary to define the environmental conditions at design stage. Environmental conditions are influenced by entry procedures. Entry procedures to pharmaceutical manufacturing premises are therefore looked upon in different perspective apart from security and confidentiality. Purpose The present article attempts to review personnel entry procedures to pharmaceutical manufacturing facilities in steps like Need, Evolution, Design and Compliance. The ever changing Need sows the seeds of Evolution of Technology over a period of time. Evolution of Design/ Technology is a continuous improvement in Concepts mainly driven by cGMP requirements. The Compliance of the design to cGMP requirement reflects the Effectiveness. The matrix explains this flow (Table 1). 1. Need: The exclusion or reduction of contamination is the prime objective in designing any manufacturing process. The contamination can be viable or non-viable and if not controlled at process stage, forms an integral part of the finished dosage form resulting in serious quality failures. Such failures may be of repetitive nature. 1.1 Origin - Impurities / contamination can originate from: Materials used in the process Surfaces of contact Products themselves (intermediates, raw materials, actives) The environment Utilities Persons intervening the process, 1.2 Types of Contamination: The above mentioned sources of contamination can give rise to: Cross-contamination - when different products are manufactured in the premises. The particulate contamination - when product or personnel carry such particulate matter due to uncontrolled entry procedures and handling procedures. Biological / microbiological contamination - when microbial controls and monitoring is poor due to improper sanitation and unhygenic conditions. Microbial contamination is difficult to eradicate at latter stage.

1.3 Control of contamination: The factors providing proper controls include: Process: The process design and transfers involved during processing stages. Air purity: Properly validated AHU Systems. Material: Material purity and flow Personnel: Awareness, training on hygiene and routine medical examination Entry procedures: Well-defined entry procedures. Evolution Entry procedures to pharmaceutical manufacturing facilities have undergone fundamental changes over the years either due to obsolescence or improvisation. Entry procedures form a part of quality system audit evaluation. Failures or deviations from the written and authorised procedure canresult in noncompliance. Entry procedures have evolved over a period of time due to Dosage form categorisation Cleanliness Zone concepts API characteristics cGMP requirements Upgradation of purity standards Dosage form Categorisation: Dosage forms have been classified by regulatory agencies depending upon microbial limits. Microbial limits are defined for bacterial count, yeast and moulds and pathogens for oral dosage forms, topical preparations including Transdermal Therapeutic Systems (TTS) and Inhalation systems. Dosage form and API related microbial and cleanliness zones requirements are summarised in Table 2. Cleanliness Zone Concept: Cleanliness zone is a dedicated space in which the concentration of airborne particles is controlled as per required norms to carry out particular activity. Zone concept is achieved by enclosing the space and providing it with proper HVAC system. Restricted entry procedures, gowning requirements and material handling procedures in the given zone determine the adherence to required norms. API Characteristics: Hormones, Steroids, Oncology products and various other categories require specialised handling. In such cases, the entry procedures have further evolved to address specific relevant issues like negative pressure in rooms as compared to corridors or vise versa. This is also important from HSE (Health Safety and Environment) point. In such cases, restrictions on male andfemale entry are desirable so as to avoid adverse effects on biological systems. cGMP requirements: Adherence to entry procedures reflects not only on good compliance but also on effectiveness of training imparted to personnel.

Up-gradation of purity standards: With risk based GMP approach, the impurity levels permitted in the dosage form or API have been constantly under revision. This can be achieved by automation supported by a proper environmental infrastructure. Design In the primary stages of designing of manufacturing facility, capacity and processes are considered. In addition, compliance to cleanliness zone concept with proper air-locks and change rooms are necessary as cGMP norms. Entry to sterile manufacture is well-defined but cGMP now requires proper entry procedures to oral dosage forms too, particularly in critical manufacturing areas. Strategy considerations at design stage should cover following objectives: Segregation and Control of personnel type (e.g. operator, engineer, staff, visitors etc.) This involves security standpoint to begin with and further designed to prevent product contamination, cross-contamination and also protecting people from hazards and toxicity. Gowning and Degowning: Gowning provides barrier between personnel and the product. Use of hand-gloves, nose-masks form part of gowning. Particle shedding from the fibre itself should be eliminated. Degowning procedures often necessitate separate areas so as to effectively prevent crosscontamination and personnel safety. Breathing apparatus, water showers, air showers are included in the design based on specific considerations. Entry procedures thus include two important aspects. Airlocks and Change Rooms Gowning and Degowning Procedures. Ideal entry procedures can be described as given in Flow Sheet. Air locks/changing rooms Air locks are enclosed spaces or rooms required for every transfer of personnel or material into a room with controlled environment. Air locks should be effectively flushed. The final stage of changing room should be, at rest, be the same grade as the area into which it leads. Interlocking system permits opening of one door at a time there by reducing the chances of contamination. Step-over benches provides physical barrier between the area with proper segregation of footwear and garments. Mirror is to be provided at this point so as to enable self viewing of the uniform and ensure that body parts, hair are properly covered. The lockers provided in the change rooms at primary entry to manufacturing area should store only gowning clothes. Historically, lockers were looked upon as personal storage places. The design of the lockers should also provide for efficient air flushing to avoid any microbial proliferation due to dampness in small, closed spaces. Hand washing facilities with disinfectant at the entry point is necessary.

In case of entry into core areas of sterile manufacturing, three air-locks are recommended for transition from Class 100000 to Class 10000 or aseptic filling area. During transition through these air-locks into core area, outside factory uniform and shoes are removed and sterile suit, sterile booties and protective hood with nose mask is worn. For exit it is recommended to have separate air lock. Protective clothing and gowning: The gowning with nose masks, beard covers, hand-gloves is adapted to the level of protection desired with respect to the product and to the operator in contact or proximity with the product. Often there is tendency to expose certain body parts like face and neck areas due to the feeling of discomfort. Protective clothing after usage needs careful handling and hence exit procedures can be isolated as shown in Flow sheet. Ideal guidelines for various components of protective clothing for various cleanliness zones are summarised in Table 3. The gowning philosophy reflected from the table indicates stringent precautions as personnel reach closer to the areas where product is approaching final stages of manufacturing and still is in exposed condition. In Class 100000, it is necessary to take proper precautions by additional use of face masks and gloves, if the personnel are in close proximity with the product. This area is accessed from ancillary areas through an air- lock where it is advisable to undergo a secondary change or wear an overall to cover the clothes of outer areas. It is also recommended to change the shoes and enter over a cross-over bench. In case of Class 100 areas, the overall, boots and the gloves must be sterile. Whereas in case of Class 10000, the gowning components need not be sterilised for dispensing and compounding areas for aseptically filled preparations. However when class 10000 is the background area for parenteral filling and sealing, the gowning component should be sterile. The sterilised gloves in class 100 areas must be unpowdered rubber or plastic gloves. Gowning Materials: Gowning is made of cotton or cotton mixed with synthetics for class 100000 areas, general areas and factory garments. In case of clean rooms it is necessary that material used for protective clothing should shed as few fibers or particles as possible. It should also retain any particles released from the body. Polyesters with anti static properties are also materials of choice. Control and change of Gowning: The contamination levels from the garments increase after every usage and therefore it is necessary to decide the frequency of change depending upon experience and requirements. Irrespective of the decided frequencies, if clothes are visibly soiled, they have to be changed. In case of sterilised clothing, it is necessary to check the gownings for microbial contamination by taking counts on sterile garments at defined frequencies.

Use of colour codes can effectively support gowning compliance with respect to usage and movement and thus prevent contamination. A well documented cleaning programme, control over laundry if contracted out are supporting pillars of gowning requirements. Recently materials of gowning with resistance to bacterial growth have been introduced. One time use garments are also recommended. Compliance Constant evolution of concepts of cleanliness zones and risk based GMP approach necessitate frequent revisions in the Entry Procedures. Compliance issues arise due to low training, unclear SOPs and lack of willingness to enforce the procedures which are sometimes felt stringent. Personnel training programmes therefore should include entry procedures as one of the key topics. Displaying the SOP and the photograph depicting the entry procedure effectively ensures compliance. It is possible to map the manufacturing and other facilities for zone compliance through transition analysis. It is necessary to routinely monitor entry cubicles for microbial load. In case of findings which are OOE (Out Of Expectation), it is necessary to quickly identify the cause and rectify it. Contracted out garment cleaning, should be evaluated for effectiveness by regular checks. Summary Entry procedures reflect management philosophy in handling HSE (Health, Safety and Environment) issues. It is necessary to define entry procedure at the VMP stage. Well defined Entry Procedures to pharmaceutical manufacturing facilities reflect first impression on cGMP compliance of the facility. Contamination issues can be minimised with effectively implemented entry procedures. The deviations are principally because of improper implementation and lack of training. Entry procedure should supplement compliance to cleanliness zone concepts having different product category and manufacturing activities. Well defined gowning procedures form an integral part of the entry procedures. Failures in HVAC systems and improper airlocks can affect entry procedures.

Types of Validation Plans

The following documents are the most common types of validation plan documents: 1. 2. 3. 4. SVMP Site Validation Master Plan VMP Validation Master Plan VP Validation Plan VPP Validation Project Plan

So whats the difference between these 4 documents, why are they sometimes (apparently) used interchangeably? I will try to explain this in an Easy to Understand format. The question is whether this should be a top-down or bottom-up approach. Im going to start with the VMP, the Validation Master Plan is a document that is usually owned by a department or functional area, for example there might be an Engineering VMP, Utilities VMP or Automation VMP. The purpose of the VMP is identify all areas under validation and to specify the overall validation approach for that department or functional area as well as giving a high-level approach to the validation activities/deliverables that occur underneath the VMP. Taking a Scaled Approach In this context, a VMP will reference its subordinate Validation Plans it wouldnt make logical sense to group an entire departments validation efforts under the umbrella of one plan so it is the norm to reference individual validation scopes within a logical group (such as a department) from the VMP. For example, Automation may fall under either IT or Engineering, or it might be a department in its own right (depending on the extent of the scope of systems and processes that are subject to formal validation).

This means that the IT or Engineering VMP would include a high-level description of the Automation component and then reference the Automation VMP, the Automation VMP would then contain all information pertinent to only automation items, similarly to the way in which the VMP as mentioned above will include departments, the Automation VMP would contain specific systems and processes and their respective subordinate VPs would be referenced. Each of the systems under the Automation VMP would be listed and described (at a high-level) in the Automation VMP and the VMP would reference the actual Validation Plans for each system that belongs to the Automation department, for example there may be a Building Management System (BMS) VP and a Manufacturing Control System (MCS) VP. The Nitty Gritty The actual VP for each system or process would include all of the relevant scope and detail necessary to validate that particular system. The VP would go down to a level of granularity such that the validation methodology would be defined and explained this would include all aspects from detailed design though testing and reporting; periodic review and retirement of the system. The VPP is a Validation Project Plan; basically this is identical to the VP but utilised for projects. On completion of a project the on-going validation activities would be referenced in the VMP and controlled by the VP for that particular system or process; the VPP is effectively converted to a VP. Under the Site Umbrella The SVMP is a VMP for the entire site or facility, a high-level document that can be used to determine where the validation of a certain system or process lies, this will reference the relevant VMP which will lead to the VP itself that holds the detail. Due to the extent and scope of Validation and Validation Planning, this hierarchal structure has become the norm in most companies. Whilst it is completely possible and viable to scale these documents to suit

business needs, a company with hundreds of validated systems and processes would find that their SVMP is working as a massive document index and furthermore, it would be in revision so frequently as part of multiple lifecycles that a deadlock could occur holding up work whilst waiting to update the SVMP. By having a structured set of Validation Plans, a facility is able to allow multiple operations and projects to continue concurrently whilst only minimally impacting external groups or departments. At the same time, different methodologies are applicable to different systems and process based on a variety of factors including complexity, risk, safety, ease of implementation, etc. Summary In summary, the SVMP, VMP, VP and VPP are all scalable validation planning documents; they are broken down from the site level to the departmental level, they exist on a per system or process basis and projects are driven by their own individual VPP; this is to allow ease of use whilst minimising impact on different departments. At the same time these documents are generated with backward and forward traceability such that being able to find a specific component and an explanation of the validation approach should never be too difficult in a well-documented environment. An auditor should be able to find the validation documentation for a specific system by identifying a given VMP from the SVMP and then the VP or VPP from the VMP.

Audit
The word "audit," in the broadest sense, refers to a variety of activities. It may refer to an accounting firm examining the financial statements of a public corporation, or a consultant checking the process of lid sealant dispensing in a semiconductor package assembly line. It may even refer to a mystery shopper testing the patience of sales clerks in an upscale department store. In these examples, there's a systematic attempt to take a closer look at something - whether financial statements or a factory process or customer service - for the purpose of evaluation and, ultimately, decision making. The fact that the audit process casts auditors on one side and the people being audited on the opposite side has created a general impression that auditing is adversarial. While there may, indeed, exist a point-and-blame atmosphere in some cases, more and more organizations recognize that an audit does not have to be a negative experience or a dreaded event. When implemented properly, it can be one of the most effective means for improvement. From financial institutions to manufacturers to hospitals, audit is being utilized as an important management, compliance, and quality tool. In the FDA and ISO environments, audit - both compliance and performance - is critical. Considering the type of products that the FDA regulates and the diversity of the industries where ISO quality standards are applicable, auditing for the purpose of maintaining high quality standards directly impacts public health and safety. In these environments, the audit process is closely associated with quality and directly related to regulatory compliance.

Regulations & Standards

The International Organization for Standardization (ISO), the world's leading developer of international standards, is instrumental in boosting interest in quality audits among manufacturers and other types of businesses when it published the ISO 9000 standards in 1987. Today, popular standards such as ISO 9001: 2000, ISO 14001:2004, and ISO 13485 all require internal audits of the quality system (or the environmental management system in the case of ISO 14001: 2004). Under these standards, audit serves as a mechanism for evaluating and improving quality. The same principle is reflected in a number of regulations enforced by the Food and Drug Administration. Under the Quality System Regulation (21 CFR Part 820), medical device manufacturers are required to conduct audits to ensure that the quality system is compliant (Sec. 820.22). The Current Good Manufacturing Practice (CGMP) regulations for pharmaceuticals (21 CFR Parts 210-211) and for blood and blood components (21 CFR Part 606) include general requirements for regular evaluation of quality standards. Guidances for the pharmaceutical industry and blood establishments also emphasize the importance of audits. For example, the "Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations" recommends internal audits and supplier audits.

The "Guidelines for Quality Assurance in Blood Establishments" call for comprehensive audit of the quality assurance program.

Nature of Audit
In general, there must be a basis (specific requirements) for an audit and a systematic method for gathering facts or evidence. An auditor compares the evidence with the requirements and comes up with observations, which can be either positive or negative. Up to this point, the process is similar to inspection. But an audit entails much more. The auditor analyzes his or her observations for patterns - also called findings - in order to draw conclusions. The auditor then presents the observations, findings, and conclusions in a report to all parties involved. The focus of an audit can be a product/service, a process, or a system. Going back to the example of the mystery shopper, the focus was customer service in just one store. A product audit of a vacuum cleaner may entail randomly pulling out a box from the assembly line and taking the vacuum cleaner apart to examine it from a consumer's perspective. In both cases, the audit has a narrow focus. A process audit focuses on a single activity. For example, a process audit at an ISOcertified car manufacturing plant might examine the process of welding body panels together, or of installing doors and windows. The audit is likely to be short but intense. It must be conducted several times in order to analyze patterns. This kind of audit is useful in troubleshooting and in solving specific issues. A system consists of related processes with a common goal. Using the example of the car manufacturer, an audit of the quality system will cover not just the process of welding body panels, but all other processes, from design to assembly to safety tests, etc. This type of audit is longer and broader, covering not only different processes but also their controls.

Compliance & Performance Audits

Audits can be categorized by purpose. The following two categories are particularly relevant to FDA-regulated and ISO- certified companies.
Compliance

Audit: This type of audit is about conformance to rules and regulations. The goal is to see if activities, processes, and systems meet requirements. The result is usually black or white - a product or process or system being audited either passes or fails. When the FDA conducts a CGMP (postapproval) inspection at a pharmaceutical company, it is essentially conducting a compliance audit. A conformance assessment for the purpose of ISO certification is another example. In both cases, the outcome is directly tied to compliance or certification. The companies being audited are primarily concerned about passing the audit with flying colors.
Performance

Audit: In the third edition of Quality Audits for Improved Performance, Dennis Arter writes that a performance audit looks at three things: compliance to the rules, effectiveness of those rules for use, and suitability of

those rules for achieving an organization's goals. Going back to the example of the car manufacturer, a performance audit may be conducted not only to make sure that the plant's quality system will pass an ISO conformance assessment, but perhaps to see how the system's efficiency can be improved in order to boost production and profitability. A performance audit is usually conducted internally to look at a company's business results, or it can be applied to a supplier to help a company decide whether to sign or renew a contract with the supplier.

Auditors & Auditees

Audits may be categorized according to the parties auditing and being audited, such as:
First-Party

Audit: In this type of audit - also known as internal audit or self-audit - those auditing and those being audited all belong to the same organization. Taking the case of the car manufacturer, the headquarters in Detroit may be concerned about productivity of a plant in Ohio and may send an internal audit team to help find ways for improvement. An ISO-certified supplier may also conduct a first-party assessment to make a self-declaration of its conformity with specific ISO standards.
Second-Party

Audit: A second-party audit refers to a customer conducting an audit on a supplier or contractor. For example, a medical device company that contracted a laboratory to do sterility testing may conduct a second-party audit to make sure that the lab meets QSR requirements and to be able to demonstrate to FDA investigators that the contractor is compliant. The same company may audit a parts supplier to make sure that it conforms to ISO 9001 or ISO 13485 standards. It may also evaluate a potential raw materials supplier through an audit, although some auditors might argue that such a process is more of a supplier survey than an audit.
Third-Party

Audit: Neither customer nor supplier conducts this type of audit. A regulatory agency or an independent body performs a third-party audit for the purpose of compliance or certification or registration. An example would be an FDA investigator conducting a CGMP inspection at a pharmaceutical company. Another example is a College of American Pathologists (CAP) team inspecting a blood bank for the purpose of accreditation. ISO conformity assessments are not carried out by ISO itself, but by private-sector third parties or regulatory bodies in countries where ISO standards have been incorporated into law.

Challenges
For audit to be an effective improvement and compliance tool, it must be conducted on an on-going basis. And this can be daunting for companies that rely on a paper-based or a partially electronic system. The following are some of the biggest challenges faced by such companies.
Poor

Communication and Scheduling: Starting with planning and scheduling, a paper-based or hybrid process would entail face-to-face meetings and conference calls to bring together the auditors, auditees, corporate management, and others involved. Follow-up work would entail uncoordinated phone calls, e-

mail, and personal reminders. Scheduling of audit-related tasks would depend on someone remembering to send assignments at certain dates. The situation may be manageable if there's only one audit being conducted at a time and if the parties involved are 100 percent attentive. It can be downright problematic if there are multiple customer audits happening at the same time that either an ISO audit or an FDA inspection is taking place, especially if the same teams are involved in all audits. And if the scenario happens several times a year, it is likely that tasks will fall through the cracks, and the company might fail some audits.
Inefficiency:

Most internal auditors are out in the field inspecting facilities. They might use paper forms and either paper or electronic spreadsheet to collect data. Then they enter all data in the computer as soon as they return to the office. The process is pretty straightforward if there's only one auditor conducting one audit once a year. However, if there are several auditors working as a team, using large checklists, generating voluminous paperwork, and conducting multiple audits under tight deadlines, then the inefficiency of the process becomes a serious problem.
Poor

Tracking: Even when a company performs only a small number of audits annually, each audit typically results in numerous findings and related corrective/preventive actions (CAPAs) that all need to be addressed and managed. Under a manual or hybrid system, tracking these findings and related documents, evaluating risks, verifying findings, and ensuring proper closure could mean combing through voluminous paperwork and a lot of legwork, both of which could result in delayed CAPA completion.
Lack

of Oversight: It's difficult to generate accurate and timely reports and trends using disparate tools (electronic spreadsheets, flowcharting software, paper documents). Without an effective reporting tool, managers are unable to see the big picture that audit findings may reveal. When audit is not connected to other quality processes (change control, CAPA, training control, etc.), such as in a paper-based system, it is almost impossible to monitor the entire quality system.

Conclusion
Gone are the days when auditors and auditees treat each other like adversaries. More and more companies now see audit as an occasion for auditors and auditees to work together in achieving a common goal - improved performance. Forward-looking organizations recognize that the audit process is one of the best tools for continuous improvement of the quality system and for making sure that the system is always compliant.