EQUIPMENT QUALIFICATION ON BLISTER PACKING MACHINE

Transcription

1 WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES P.Ramasubramaniyan et al. Volume 2, Issue 6, Review Article ISSN EQUIPMENT QUALIFICATION ON BLISTER PACKING MACHINE Ramasubramaniyan.P*, Palanichamy.S, Srinag.T,Sharanya.N,Lakshmi.M, Solairaj.P Department of Pharmaceutics, Sankaralingam Bhuvaneswari College of Pharmacy, Sivakasi, Tamil Nadu, India. Article Received on 16 August 2013, Revised on 15 Sept 2013, Accepted on 12 November 2013 *Correspondence for Author: * Dr. P. Ramasubramaniyan, Professor, Department of Pharmaceutics, Sankaralingam Bhuvaneswari College of Pharmacy, Sivakasi, Tamil Nadu, INDIA. ramskit@yahoo.com ABSTRACT This article discusses about the equipment qualification on blister packing machine which covers different types of qualification like design, installation, operational and performance qualification and requalification. It also includes the process involved in the blister packing machine and detail description of equipment parts like unwinding station, forming station, sealing station, heating station, cooling station, feeder, lidding material and labeling through packaging. It also covers the details of packaging importance and its types. Keywords: Equipment, Qualification, Blister Packing Machine, Packaging. INTRODUCTION Equipment The collective analytical measurement instruments, in conjunction with firmware, assembled to perform a mechanical process. In a computerized system, the equipment is controlled by the computer system. The computer collects measurement data from the equipment. A device or collection of components that perform a process to produce the result. ([1]) Qualification 1. Action of proving that any premises, systems and items of equipment work correctly and actually lead to the expected results. The meaning of the word validation is sometimes

2 extended to incorporate the concept of qualification. 2. The action of providing that any equipment or process works correctly & consistently and produces the expected results. Qualification is part of, but not limited to, a validation process. Types of Qualification 1. Design Qualification (D.Q) 2. Installation Qualification (I.Q) 3. Operational Qualification (O.Q) 4. Performance Qualification (P.Q) 5. Re-Qualification. ([2]) History of Validation The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in the mid 1970s in order to improve the quality of pharmaceuticals. ([3]) It was proposed in direct response to several problems in the sterility of large volume parenteral market. The first validation activities were focused on the processes involved in making these products, but quickly spread to associated processes including environmental control, media fill, equipment sanitization and purified water production. The concept of validation was first developed for equipment and processes and derived from the engineering practices used in delivery of large pieces of equipment that would be manufactured, tested, delivered and accepted according to a contract. ([4] The use of validation spread to other areas of industry after several large-scale problems highlighted the potential risks in the design of products. ([5]) Reason for Validation Validation is "Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes. A properly designed system will provide a high degree of assurance that every step, process, and change has been properly evaluated before its implementation. Testing a sample of a final product is not considered sufficient evidence that every product within a batch meets the required specification FDA (1987). ([6]) Design Qualification (DQ) It is the documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose

3 Installation Qualification (IQ) It is the documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer s recommendations and/or user requirements. Operational Qualification (OQ) It is the documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges. Performance Qualification (PQ) It is the documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications. User Requirements Specification The User Requirements Specification should be treated as a contractual document avoiding conflicts with other technical specification documents. The URS should not be considered a mere part of the validation documentation but rather the main and possibly only specification document for the equipment. The URS should as a minimum, cover all mandatory parts including those necessary to guarantee the final product quality and achieve compliance with the rules. Ideally, the requirements should be independent from the supplier s product and express the customer needs without addressing specific design solutions. ([7]) URS Scope User Requirement Specifications (URS) Scope includes but is not limited to; Level-1, full details of end user operability. Level-2, full details of functionality. Level-3, software functionality interface. A full description of the required system performance. Performance criteria, critical parameters and operating range. Cleaning and maintenance requirements. Appropriate regulatory requirements. Documentation requirements

4 Training requirements. All none industry standard testing that may be required. ([8]) Design Qualification (DQ) Design qualification is the documentation of the planning phase, including the decision making for the equipment. Design qualification takes place before the equipment is constructed. With the design qualification, the conformity of the equipment or facility planning with certain requirements is reviewed. To this end, the requirements laid out in the user requirements are compared with the specifications compiled by the supplier (technical specifications) and confirmed in writing. ([9]) Installation Qualification (IQ) The (IQ) execution; verifies that the equipment, and its ancillary systems or sub-systems have been installed in accordance with installation drawings and or specifications. It further details a list of all the GMP requirements that are applicable to this particular installation qualification. These requirements must all be satisfied before the IQ can be completed and the qualification process is allowed to progress to the execution of the Operational Qualification. Installation Qualification Scope (IQ) The scope of the IQ testing/inspections will cover the under listed subjects, but is not restricted to them alone. Verify all components parts. Verify installation is as specified. Insert a brief description of the validated product process. Insert a brief description of the operational function. Verify supplied voltages. Verify whether the electrical installation qualification (IQ) complies. Verify all alarms and visual displays. Confirm the issue level of software. Identify and verify the serial & model numbers. Review all calibration certificates. Verify signal continuity. Verify the ambient conditions. Verify the documentation provided for the maintenance of the system. ([10])

5 Before installation Obtain manufacturer's recommendations for installation site requirements. Check the site for the fulfillment of the manufacturer's recommendations (utilities such as electricity, water and gases plus environmental conditions such as humidity, temperature, vibration level and dust). Allow sufficient shelf space for the equipment itself, related SOP's, operating manuals, logbooks and software. ([11]) The most important aspects to consider during IQ Provide as-built documentation. Check training reports. Check that documentation is complete. Check calibration reports. Identify piping and instrumentation. ([12]) Operational Qualification (OQ) Operational qualification is defined as Documented verification that the system or subsystem performs as intended throughout all anticipated operating ranges. ([13]) OQ demonstrates that an instrument will function according to its operational specification in the selected environment. Operational Qualification (OQ) is the process of demonstrating that a instrument will function according to its operational specification in the selected environment. Before OQ testing is done, one should always consider what the instrument will be used for. Testing may be quite extensive if the instrument is to be used for all types of applications and where some of these place great demands on the performance of the system. ([14]) OQ should include, but not be limited to the following (a) Tests that have been developed from knowledge of processes, systems and equipment; (b) Tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as worst case conditions. The completion of a successful Operational qualification should allow the finalization of calibration, operating and cleaning procedures, operator training and preventative

6 maintenance requirements. It should permit a formal "release" of the facilities, systems and equipment. ([15]) Typical tests in the OQ include the following: Alarm tests Behavior of the system after energy breakdown Accuracy of filling lines Transportation speed in a sterilization tunnel Temperature distribution in an autoclave Performance of a washing machine, accuracy of a weighing system ([16]) Performance Qualification PQ demonstrates that a balance or instrument consistently performs according to a specification appropriate to its routine use. Performance Qualification (PQ) is the process of demonstrating that an instrument consistently performs according to a specification appropriate to its routine use. The test frequency is much higher than for OQ. Another difference is that PQ should always be performed under conditions that are similar to routine sample analysis PQ should be performed on a daily (or at least a weekly) basis, or whenever the instrument is used. The test frequency depends not only on the stability of the equipment but also on everything in the system that may contribute to the analysis results. 1. Define the performance criteria and test procedures. 2. Select critical parameters. 3. Define the test intervals PQ should include, but not be limited to the following: (a) Tests, using production materials, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment; (b) Tests to include a condition or set of conditions encompassing upper and lower operating limits. ([17]) The following technical systems need to be performance-tested and qualified: High purity water systems (monitoring of the quality parameters: ph, Total Organic Carbon, conductivity, Central processor unit, temperature) Heating, ventilation and air conditioning systems (temperature, pressure, humidity)

7 Complex connected systems (e.g., filling line, BPI production line; performance parameters) ([18]) Requalification Requalification is the repetition of the qualification effort or a selected portion of it. ([19]) Packing Packaging is defined as the collection of different components which surround the pharmaceutical product from the time of production until its use. Background Two basic types of pharmaceutical blister packages exist. In one variety the cavity is constructed of clear, thermoformed plastic, and the lid is formed of clear plastic or a combination of plastic, paper, and/or foil. The other type of package contains foil as an essential component of both webs and its cavity is created by cold stretching. ([20]) Types of Packaging 1. Thermoforming 2. Cold forming Importance of Packaging Protects against all adverse external influences that can alter the properties of the product. Protects against biological contamination. Protects against physical damage. Carries the correct information and identification of the product. Tamper evident / Child resistance/ Anti counterfeiting. Functions of Packaging 1. Containment -Not to leak, nor allow diffusion and permeation -Strong enough to hold the contents during handling 2. Protection -Light -Moisture -Oxygen -Biological contamination

8 -Mechanical damage -Counterfeiting General properties of blister packaging material: - Tensile strength - Tear strength - Impact resistance - Stiffness - Temperature resistance - Moisture resistance Factors Affecting Blister Thickness A. Material: The nature of material e.g. softening temperature, hardening time, elasticity etc. B. Process: Pressure and plug system usually produce forming produces thicker top section while in vacuum forming, it is thicker near the base and thinner at the top. C. Essential machine operation: 1. Heating and thermoforming. 2. Cold forming. 3. Feeding and filling. 4. Heat sealing of the bidding material. 5. Punching out or guillotining the tray from the web. 6. Printing of the lidding web. 7. Batch marking. Advantages of Blister Packaging 1. Blisters are very inexpensive to produce. 2. Can be used for promoting products. 3. Protects and holds the product securely. 4. Many sizes available, from small unit-dose. 5. Allows products to be seen, but not touched. 6. Product is very visible. Disadvantages of Blister Packaging 1. Blisters require some type of a card to seal the blister. 2. Requires heat sealing the blister to the card

9 Blister Packaging Components The four basic components of pharmaceutical blister packages are the forming film, the lidding material, the heat-seal coating, and the printing ink. Forming films account for approximately 80 85% of the blister package, and lidding materials make up 15 20% of the total weight of the package. Since the forming film and the lidding material form an integrated package, they must match precisely. Forming film The forming film is the packaging component that receives the product in deep drawn pockets. One key to package success is selecting the right plastic film for the blisters in terms of its property type, grade, and thickness. Consideration must be given to the height and weight of the product, sharp or pointed edges of the final package, and the impact resistance, aging, migration, and cost of the film. The plastic also must be compatible with the product. Factors influencing package production and speed of assembly must be taken into account, including heat sealing properties and the ease of cutting and trimming formed blisters. Lidding materials The lidding material provides the base or main structural component upon which the final blister package is built. It must be selected according to the size, shape, and weight of the product as well as the style of the package to be produced. Lidding materials range in caliper or thickness from 0.36 to 0.76 mm, but mm is the most popular range. The surface of the lidding material must be compatible with heat-seal coating process. Clay coatings are added to the lidding material to enhance printing. Heat-sealing and printability are both important considerations in blister packaging, and the lidding material must offer the best workable compromise. Printing inks Printing inks provide graphics and aesthetic appeal. They can be applied to the lidding material by letterpress, gravure, offset, flexographic, or silk-screen printing processes. Printing inks must resist heat sealing temperatures as high as 300 ºC without showing any discoloration or tackiness (blocking). In addition, they must sufficiently resist abrasion, bending, and fading and must be safe for use with the intended product. Printing inks should not contain excessive amounts of hydrocarbon lubricants, greases, oils, or release agents

10 Qualification tests should always precede production runs. Finally, printing inks must comply with FDA recommendations. Cold-formed foil/foil Best known to Americans is the blister package made of a foil, film, paper, or multimaterial backing that is adhered to a sheet of thermoformed plastic blisters. However, a less common type of blister is the foil/foil lamination used for products that are particularly susceptible to moisture and/or light. Unlike all-plastic blisters, these are not thermoformed but instead are cold-pressed into shape. Products that require the highest degree of protection are packed in an all-foil package. Cold-formable foil is finding favor because it is the only material that provides a 100% barrier to moisture, oxygen, and light. Machinery and assembly Blister packaging machinery Modern thermoform fill seal machines can operate at speeds <800 packages/min. Today, much of the emphasis in improving production is placed on applying microprocessor controls that electronically connect the filling and forming equipment with other downstream machinery for cartooning and wrapping. These controls also feed tablets or liquids into the unit-dose blisters, ensuring that an exact volume is put into each. Modern machinery also uses integrated vision systems to help ensure the accuracy of the fill and the integrity of the product in the blister. These machines have become quite versatile and can readily accommodate several types of lid stocks and base stocks, allowing the manufacturer to obtain better compatibility between the medicine and its packaging material as well as better patient compliance. Detailed assembly Blister packaging machines typically operate with intermittent motion. The seal is made during the dwell time required for thermoforming. The essential parts and functions of an intermittently operating packaging machine include the following: The unwinding station The unwinding station supplies the forming films and the lidding material at a rate corresponding to the speed of the packaging machine

11 The heating station The heating station raises the temperature of the plastic forming films to a level suitable for deep drawing. Forming films containing the polyvinyl chloride (PVC) support material are heated to C. Polypropylene (PP) forming films are heated to C. Forming films containing aluminum are not heated before the forming process. The forming station The forming station forms the plastic blister cavities via compressed air or die plates. Films containing aluminum are formed with mechanical forming tools only. The cooling station The cooling station cools PP films after the forming process. Laminates containing PVC or aluminum do not need to be cooled. The feeding machine The loading area fills the blister cavities with product. The feeding machine can be linked, or the product to be packaged can simply be swept into the blisters. The sealing station The sealing station heat seals the lidding material to the forming film that contains the product. All heat-sealing methods mate the blister and lid under constant pressure for a specified time, during which heat is supplied. The mating surfaces fuse and bond, setting almost instantaneously when heat input stops. Depending on the type of machine, the sealing temperature typically ranges between 140 and 340ºC. The cooling station The cooling station is necessary with all forming films. PP forming films must be cooled longer than other types of film. Labeling through packaging Packages are labeled, notched, and then marked with a batch number at the coding station. The perforating device makes a cross-shaped perforation along the sealing seams. At the punching station, the packages are then separated into sheets that typically contain from 10 to 20 individual blisters. The vision system checks the filled packages for defects. Finally, a multipacking machine packs the individual packages into bigger cartons. ([21])

12 METHODOLOGY The execution of equipment qualifications involved the following: Development of IQ, OQ and PQ protocols. Approval of IQ, OQ and PQ protocols. Executing the IQ, OQ and PQ. Workout of IQ, OQ and PQ report. Approval of IQ, OQ and PQ report. Design Qualification (DQ) The Blister packing machine was to be checked whether the user requirements are fulfilled. Installation Qualification (IQ) Instrument specifications during installation: Table No. 1: Equipment details 1 Equipment to be installed as per drawing(s)/ manufacturer s recommendation. 2. Equipment identification nameplate is to be visible. 3. Major components are to be securely assembled. 4. Any physical damage is to be checked. 5. Required electric connections are to be tight and grounded. Earthing connection is to be done properly. 6. Sufficient space is to be provided around the equipment/ system for servicing. 7. All moving parts are to be covered with suitable guard. 8. All utilities related to equipment are to be connected. 9. Parts are to be accessible for easy cleaning. While installing the machine, the following parameters were observed and confirmed Identification of Execution Team members. Purchase order verification

13 Verification of Manual, Drawing and Related documents. Installation Verification. Verification of Material of construction. Verification of Utilities. Major component verification. Operational Qualification The machine was run as per the operating instructions for 30minutes with empty load and observed the operation and recorded. While machine was in operation, switch off the mains power supply. After few minutes, the machine was restarted and the operation performance was observed and the result was recorded. During the operation of equipment, the temperature was controlled or adjusted to c to c to form the blister cavities and then adjusted to c to c for sealing the lidding material. Then the operation was observed. The result of operational qualification was noted. While operating the machine, the following tests are to be carried out: Safety features; Alarm tests; Behavior of the system after energy breakdown; Accuracy of filling lines; Continuity of Operation; Power Failure Recovery Study; Functionality of Push buttons/switches provided on Electrical /Control panel; Temperature Controller performance verification; Operational Performance of ACG Pampac Blister Packing Machine and Performance Verification of ACG Inspection system Performance Qualification During PQ, the temperature was adjusted from C to C for optimal forming temperature study and finally the temperature was fixed

14 Later the temperature was adjusted to C C to study the optimal sealing temperature study and finally the temperature was fixed. During performance of the machine, the following parameters were observed: Defective tablets; Missed tablets; Black spots; Machine speed; Optimal forming temperature; Optimal sealing temperature. RESULTS AND DISCUSSION The equipment qualification of Blister packing machine was conducted by four types namely, Design qualification, Installation qualification, Operation qualification and Performance qualification. Design Qualification For qualifying the Blister packing machine, the vendor manufactured and supplied the machine as per the requirements of the user. The design qualification was satisfied. Installation Qualification i. Instrument specifications: 1. Equipment was installed as per drawing(s)/ manufacturer s recommendation. 2. Equipment identification nameplate was visible. 3. Major components are securely assembled. 4. There was no physical damage. 5. Required electric connections and earthing connections are tightly grounded and done properly. 6. Sufficient space was provided around the equipment/ system for servicing. 7. All moving parts were covered with suitable guard. 8. All utilities related to equipment are connected. 9. Parts were accessible for easy cleaning

15 The following parameters are within the limits and it was observed that the installation of the equipment was in proper manner. Identified the Execution Team members. Verified the Purchase order. Verified the Manual, Drawing and Related documents. Installation was verified. Material of construction was verified. Utilities were verified. Verified the Lubricants. Procedures were identified. Installation checks specific to equipment were identified and carried out as per individual test procedures. Verified the Major component. The details of each component were recorded and the supplied component was checked and installed as per the User Requirement Specification / Manufacturer s recommendations. All are found correct. (Table No. 10). Table No. 2: Basic Unit Description Specified Supplied Make ACG Pampac ACG Pampac Model B45 R B45 R Sr. No. BR BR Inspection System Shall be provided Provided Temperature control and Indication Servo drivers Machine Dimension Forming Area Shall be provided on MMI Shall be provided for various access operations of Pulling & perforation stations with other 4400(L) x 2170(W) x 2350 (H) mm. Maximum 240 mm (Width) x 210mm (Advance) provided on MMI provided for various access operations of Pulling & perforation stations with other 4400(L) x 2170(W) x 2350 (H) mm. Maximum 240 mm (Width) x 210 mm (Advance) Forming Depth Upto 12mm Up to 12mm

16 Forming cycles Forming Speed Upto 45 cycles per minute for PVC Upto 35 cycles per minute For ALUMINIUM Upto 9.5 meters per minute Up to 45 cycles per minute for PVC Up to 35 cycles per minute For ALUMINIUM Up to 9.5 meters per minute Operational Qualification Operational qualification was carried out by the vendor under the supervision of machine operator, validation person and the engineering person. The following parameters are within the limits: Alarm tests were good. System after energy breakdown works properly. Accuracy of filling lines was good. Continuity of Operation was good. Power Failure Recovery Study was good. Functionality of Push buttons/switches provided on Electrical /Control panel works properly. Temperature Controller performance verification was within the limit. The safety feature testing was carried out by operating the equipment. The exercise was repeated for 2 more times. All the safety features were tested and found in compliance with the URS. Table No. 3: Safety Features Sr. No Description of safety features Base Foil end sensor Lidding end Foil Method of Testing Foil Consumed / take out the base foil manually during machine is in operation Lidding Foil Consumed / take out the Lidding foil manually during machine is in operation Acceptance Criteria Machine Stops at Zero Position Machine Stops at Zero Position Buzzer will made ON Sensor for If the foil roll level reaches to indicate the operator 3. base foil Low low after completion of set level time machine will stop 4. Loop sensor Manually Operate the sensor Base foil unwinding

17 for base foil unwinding motor shall be ON 5. Sensor for Base foil Joint When sensor detects the joint in the base foil The joint blister will get rejected at Sensor Lidding Joint for foil When sensor detects the joint in the Lidding foil The joint blister will get rejected at 45 0 Critical Parameters Some important critical parameters such as Continuity of Operation, Power Failure Recovery Study, Functionality of Push buttons/switches provided on Electrical/Control panel, Temperature Controller performance verification, Operational Performance of ACG Pampac Blister Packing Machine Model: B45 R and Performance Verification of ACG Inspection System were performed and the results are presented. Continuity of Operation Machine ran for 30 minutes and found no abnormal noise or vibrations. Motor ran continuously without tripping, motor/machine parts were not excessively heated up. Hence continuity of operation with empty load for 30 minutes was found within the limits. Power Failure Recovery Study Power failure alarm was in good condition. When power supply was stopped, machine also got stopped at zero position. When power resumes, machine started with the existing set parameters. Performance Qualification The following parameters are within the limits Machine speed was verified. Optimal forming temperature was good. Optimal sealing temperature was good. Black spots were identified and rejected. Missed tablets were identified and rejected. Defective tablets were identified and rejected. Machine Speed Verification: The machine speed was maintained at three different ranges such as minimum (10 cycles / min), optimum (25 cycles / min) and maximum (43 cycles / min) in order to evaluate the

18 forming and sealing of the blister as specified in protocols. The forming and sealing of the blister was found satisfactory. Optimal Forming Temperature Study This study was carried out using the dummy product with PVC as forming foil at different machine speeds (10, 15, 20, 25, 30, 35, 40, 43 cycles / min) under various temperatures such as 110ºC, 120ºC, 130ºC and 140ºC. The parameters like pocket shape, deformations, pin holes, cracks and dents were evaluated at top and bottom of the heating plate. The results showed that all the parameters were found within the limits. Optimal Sealing Temperature This study was carried out using the dummy product foiled with PVC as forming foil and aluminium as lidding foil at different machine speeds (10, 15, 20, 25, 30, 35, 40, 43 cycles / min) under various temperatures such as 180ºC, 195ºC, 220ºC, 235ºC and 250ºC. The parameters like knurling quality, pin holes, cracks, dents and leak test were evaluated. The results proved that all the parameters were found within the limits. Performance of ACG inspection system This study was performed at 10, 20 and 30 cycles / min to evaluate or identify the defects such as missed tablets, black spots and defective tablets. From the results it was found that the evaluated parameters were within the limits. After completion of performance qualification we observed that the obtained results were within the limits and found satisfactory. SUMMARY The design, installation, operational and performance qualification of ACG-PAMPAC BLISTER PACKING MACHINE, Model: B45 R was performed as per the approved qualification protocol. During installation qualification, the material of construction of all product contact parts were verified and certified as SS316L and its equivalent and the non contact parts were certified for SS304 and its equivalent. All the utilities are connected and found to be adequate. All the major components i.e. Basic Unit, Base foil unwinding station, Heating station, Forming station, Linear indexing station, Feeding station, Lidding foil unwinding station, Sealing station, Cooling station,

19 Punching & Perforation station, Rotary pickup station, Web support assembly, Electrical controls and other were identified, installed, checked and mounted properly during installation qualification. During operation qualification, all the accessories provided to the equipments were calibrated and the results were found satisfactory. Control panel components and function of each key/component of the panel against its specified function was checked as per the operational instructions and the results were found satisfactory. Safety feature testing has been tested as per the procedure mentioned in the protocol and all the results are within the limits. The critical operating parameters such as Verification of continuity of operation, Power failure recovery study, Verification temperature controllers, Operation performance of Blister packing machine and Verification of security, Recipe management functionalities were verified and found correct. All the observations during operational qualification were found satisfactory and were within the limits. As part of performance qualification, the machine was run with dummy tablets at 10 cycles/min, 20 cycles / min and 30 cycles / min and the quality of blisters were found satisfactory. CONCLUSION All the results observed for individual qualification steps are found within the limits as per the proposed protocols and the equipment was successfully qualified in compliance with the URS, cgmp and FDA requirements. The installation, operational and performance qualification of ACG-PAMPAC BLISTER PACKING MACHINE, Model: B45 R was performed as per the approved protocol No.GITPRIOP307 and GITPRPQP307 respectively. Hence the ACG-PAMPAC BLISTER PACKING MACHINE, Model: B45 R can be released for routine use

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21 2003, volume 129, Marcel Dekker, Inc, pp Robert A. Nash, Alfred H. Wachter., Pharmaceutical Process Validation. 3rd Ed., 2003, volume 129, Marcel Dekker, Inc, pp J.Agalloco, Master Planning of Validation, PDA Training and Research Institute, 1998, pp R. Pilchik, Pharmaceutical Blister Packaging, Part I: Rationale and Materials, Pharm. Technol. 2000, 24 (11), pp R. Pilchik, Pharmaceutical Blister Packaging, Part I: Rationale and Materials, Pharm. Technol. 2000, 24 (11), pp