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Pharmaceutical packaging



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Pharmaceutical packaging

  1. 1. Pharmaceutical Packaging Technology Prepared by: Jalal Uddin Lecturer World School of Pharmacy World University of Bangladesh 1March 17
  2. 2. Definition The packaging can be defined as the economical means of providing presentation, protection, identification, information, containment, convenience compliance, integrity and stability for a product during storage, transportation display and until it is consumed or throughout its shelf life. Pharmaceutical packaging is the science, art and technology of enclosing or protecting products for distribution, storage, sale, and use. Packaging also refers to the process of design, evaluation, and production of packages. 2March 17
  3. 3. Ideal packaging requirements 1. They must protect the preparation from environmental conditions. 2. They must not be reactive with the product. 3. They must not impart to the product tastes or odors. 4. They must be nontoxic. 5. They must be FDA approved. 6. They must meet applicable tamper-resistance requirements. 7. They must not be the cause of product degradation. 8. They must be adaptable to commonly employed high speed packaging equipment. 3March 17
  4. 4. Functions of packaging 1. Product Identification: Packaging greatly helps in identification of products. 2. Product Protection: Packaging protects the contents of a product from spoilage, breakage, leakage, etc. 3. Facilitating the use of product: Packaging should be convenience to open, handle and use for the consumers. 4. Product Promotion: Packaging is also used for promotional and attracting the attention of the people while purchasing. 5. Marketing: The packaging and labels can be used by marketers to encourage potential buyers to purchase the product. 4March 17
  5. 5. 6. Convenience: Packages can have features that add convenience in distribution, handling, stacking, display, sale, opening, re-closing, use, dispensing, reuse, recycling, and ease of disposal. 7. Barrier protection: A barrier from oxygen, water vapor, dust, etc., is often required. Permeation is a critical factor in design. Some packages contain desiccants or oxygen absorbency to help extend shelf life. Keeping the contents clean, fresh, sterile and safe for the intended shelf life is a primary function. 8. Security: Packaging can play an important role in reducing the security risks of shipment. Packages can be made with improved tamper resistance to deter tampering and also can have tamper-evident features to help indicate tampering. Packages can be engineered to help reduce the risks of package pilferage. 5March 17
  6. 6. Selection of the Packaging Materials 1. On the facilities available, for example, pressurized dispenser requires special filling equipment. 2. On the ultimate use of product. The product may be used by skilled person in hospital or may need to be suitable for use in the home by a patient. 3. On the physical form of the product. For example, solid, semi-solid, liquids or gaseous dosage form. 4. On the route of administration. For example, oral, parenteral, external, etc. 5. On the stability of the material. For example, moisture, oxygen, carbon dioxide, light, trace metals, temperature or pressure or fluctuation of these may have a deleterious effect on the product. 6March 17
  7. 7. 6. On the contents. The product may react with the package such as the release of alkali from the glass or the corrosion of the metals and in turn the product is affected. 7. On the cost of the product. Expensive products usually justify expensive packaging 7March 17
  8. 8. Hazards encountered by package Hazards encountered by the package can be divided into three main groups. a) Mechanical hazards b) Climatic or environmental hazards c) Biological hazards. The only exception is theft, which can be a serious risk with drugs and may demand special protection in certain cases. 8March 17
  9. 9. a) Mechanical hazards: 1. Shocking or impact damage 2. Compression 3. Vibration 4. Electrical conductance 5. Abrasion b) Climatic or environmental hazards: 1. Moisture 2. Temperature 3. Pressure 4. Atmospheric gases 5. Light 6. Solid airborne contaminants. 9March 17
  10. 10. c) Biological hazards. 1. Microbiological hazards 2. Chemical hazards 10March 17
  11. 11. Types of packaging Primary packaging is the material that first envelops the product and holds it. This usually is the smallest unit of distribution or use and is the package which is in direct contact with the contents. Examples: Ampoules,Vials ,Containers ,Dosing dropper ,Closures (plastic, metal) ,Syringe ,Strip package, Blister packaging. 11March 17
  12. 12. Secondary packaging is defined as the packaging that lies outside the primary packaging. It is perhaps used to group primary packages together. Example: Paper and boards, Cartons ,Corrugated fibers ,Box manufacture) 12March 17
  13. 13. Tertiary packaging is used for bulk handling , warehouse storage and transport shipping. The most common form is a palletized unit load that packs tightly into containers. 13March 17
  14. 14. Apart from primary and secondary packaging, two types of special packaging are currently in use, as follows: Unit-dose packaging: This packaging guarantees safer medication by reducing medication errors; it is also more practical for the patient. It may be very useful in improving compliance with treatment and may also be useful for less stable products. Device packaging: Packaging with the aid of an administration device is user-friendly and also improves compliance. This type of packaging permits easier administration by means of devices such as pre-filled syringes, droppers, transdermal delivery systems, pumps and aerosol sprays. Such devices ensure that the medicinal product is administered correctly and in the right amount 14March 17
  15. 15. Types of packaging materials I) Glass II) Metals III) Rubbers IV) Plastics V) Fibrous material VI) Films, Foils and laminates 15March 17
  16. 16. Glass  Glass has been widely used as a drug packaging material.  Glass is composed of sand, soda ash, limestone,& cullet.  Si, Al, Na, K, Ca, Mg, Zn & Ba are generally used into preparation of glass Advantages of glass: • They are hygienic and suitable for sterilization • They are relatively non reactive ( depending on the grade chosen) • It can accept a variety of closures • They can be used on high speed packaging lines • They are transparent. • They have good protection power. • They can be easily labeled. 16March 17
  17. 17. • They are available in various shapes and sizes. • They can withstand the variation in temperature and pressure during sterilization. • They are economical and easily available. • They are neutral after proper treatment. • They can be sealed hermetically or by removable closures. • They do not deteriorate with age. • They are impermeable to atmospheric gases and moisture. 17March 17
  18. 18. Disadvantages • It is relatively heavy • Glass is fragile so easily broken. • Release alkali to aqueous preparation • Photosensitive drug can not be protected in the transparent glass container. Amber color glass container is required in this case. • As glass is a chemical substance, some time it reacts with the product contained inside it. 18March 17
  19. 19. Types of glass • Type I ( Neutral or Borosilicate Glass) • Type II ( Treated Soda lime glass) • Type III ( Soda lime glass) • Type NP ( General purpose soda lime glass) • Coloured glass • Neutral glass March 17 19
  20. 20. Type I (Borosilicate Glass) Borosilicate Glass is produced by replacing the sodium oxide by boric oxide(B2O2) and some lime by alumina (Al2O3) in the basic components of glass. Least reactive. High melting point and can withstand high temperature. Resistant to chemical substance. Higher ingredients and processing cost therefore used for more sensitive pharmaceutical products such as parenteral or blood products. Mostly ampoules and vials are made up of Type I glass. March 17 20
  21. 21. Type II ( Treated Soda lime glass) Type II glass is made from commercial soda-lime glass that has been de-alkalized or treated to remove surface alkali. The de-alkalizing process is known as “Sulfur treatment”. Sulfur treatment neutralizes the alkaline oxides on the surface, rendering the glass more chemically resistant.  Higher chemical resistance but not as much as type I.  Cheaper than Type I.  Acceptable for most products accept blood products and aqueous pharmaceutical with a pH less than 7.March 17 21
  22. 22. Type III ( Soda lime glass) It is ordinarily glass prepared from silicon dioxide, soda ash and lime stone and is generally referred to as soda- lime glass. Glass containers are untreated and made of commercial soda-lime glass of average or better than average chemical resistance.  It is cheapest in quality.  This types of glass is not suitable for alkali sensitive products.  has average or slight better than average resistance and is suitable for non- aqueous parenterals and non parenteral products.  Type III glass containers are normally dry sterilized before being filled. March 17 22
  23. 23. Type NP ( General purpose soda lime glass) It is general purpose soda-lime glass used for oral and topical preparation. It has lowest hydraulic resistance and is suitable for solid products, some liquids and semi solids and not for parenteral. March 17 23
  24. 24. Coloured glass Coloured glass is obtained by adding small amounts of metals during fusion of glass. Coloured glass is used for light sensitive products which does not allow the UV rays to pass through it. Coloured glass should not be used for parenteral preparation because it becomes difficult to check clarity in such preparations. March 17 24
  25. 25. Neutral glass It is another commercial variety of glass available in between soda-lime glass and borosilicate glass. 1. It is resistant to alkalies 2. Resistant to weathering 3. Withstand to autoclaving 4. It is used for the manufacture of multidose vials and transfusion bottles etc. March 17 25
  26. 26. March 17 26 Package type Type of formulation can be packed Minimum quality of glass that can be used Ampoule Aqueous Injectables of Any pH Type I Aqueous Injectables of pH Less Than 7 Type II Non-Aqueous Injectables Type III Vial Aqueous Injectables of Any pH Type I Aqueous Injectables of pH Less Than 7 Type II Non-Aqueous Injectables Type III Dry Powders For Parenteral Use (Need To Be Reconstituted Before Use) Type IV
  27. 27. March 17 27 Package type Type of formulation can be packed Minimum quality of glass that can be used Bottles and Jars Tablets, Capsules, Oral Solids & Other Solids For Reconstitution Type IV Oral Liquids (Solutions, Suspensions, Emulsions) Type IV Nasal & Ear Drops Type IV Certain Types Of External Semisolids (Rubeficients, Local Irritants) Type IV Blood & Related Products Type I Dropper Auxiliary Packaging Device With Certain Kind Of Products Type IV Aerosol container Aerosol product ( solution, suspension, emulsion or semisolid type) Type I
  28. 28. Test for glass materials U.S.P. and I.P. provides two testes to determine the chemical resistance of glass containers: • Test for surface hydrolytic resistance. • Test for hydrolytic resistance of powdered glass. March 17 28
  29. 29. Plastic Materials According to British standards institutes plastics represents; “ A wide range of solid composite materials which are largely organic, usually based upon synthetic resins or upon modified polymers of natural origin and possessing appreciable mechanical strength. At a suitable stage in their manufacturing, most plastics can be cast, molded or polymerized directly into shape”. March 17 29
  30. 30. Types of plastic materials March 17 30 Plastic Materials Thermoplastic type Thermosetting type Thermoplastic type: On heating, they are soften to viscous fluid which hardens again on cooling. Resistant to breakage and cheap to produce and providing the right plastics are chosen will provide the necessary protection of the product in an attractive containers. E.g. polyethylene, PVC, polystyrene, polypropylene, polyamide, polycarbonate.
  31. 31. March 17 31 Thermosetting type When heated, they may become flexible but they do not become liquid. During heating such materials form permanent crosslinks between the linear chains, resulting in solidification and loss of plastic flow. E.g. Phenol formaldehyde, urea formaldehyde, melamine formaldehyde.
  32. 32. Advantages of plastic materials  Low in cost  Light in weight  Durable  Pleasant to touch  Flexible facilitating product dispensing  Odorless and inert to most chemicals  Unbreakable  Leak proof  Able to retain their shape throughout their use  They have a unique suck-back feature, which prevents product doze.  Ease of transportation  They are poor conductor of heat.  They are resistant to inorganic chemicals.  They have good protection power. March 17 32
  33. 33. Disadvantages of plastic materials  Plastics appear to have certain disadvantages like interaction, adsorption, absorption lightness and hence poor physical stability.  All are permeable to some degree to moisture, oxygen, carbon dioxide etc and most exhibit electrostatic attraction, allow penetration of light rays unless pigmented, black etc. Other negative features include: Stress cracking: A phenomenon related to low density polythene and certain stress cracking agents such as wetting agents, detergents and some volatile oils. March 17 33
  34. 34.  Paneling or cavitation: where by a container inward distortion or partial collapse owing to absorption causing swelling of the plastic dimpling following a steam autoclaving operation.  Crazing: A surface reticulation which can occur particularly with polystyrene and chemical substances (e.g. isopropyl myristate which first causes crazing and ultimately reaches of total embitterment and disintegration).  Poor key of print: Certain plastics such as the poly olefins need pre-treating before ink will key. Additives that migrate to the surface of the plastic may also cause printing problem.  Poor impact resistance: Both polystyrene and PVC have poor resistance. This can be improved by the inclusion of impact modifiers such as rubber in case of polystyrene and methyl methacrylate butadiene styrene for PVC. March 17 34
  35. 35. March 17 35 Polyethylene  This is used as high and low density polyethylene  Low density polyethylene (LDPE) is preferred plastic for squeeze bottles. Properties: Ease of processing , barrier to moisture, strength /toughness, flexibility, ease of sealing.  High density poly ethylene (HDPE) is less permeable to gases and more resistant to oils, chemicals and solvents. Properties: Stiffness, strength / toughness, resistance to chemicals. It is widely used in bottles for solid dosage forms.  Drawback: prone to stress cracking in the presence of surfactants or vegetable or mineral oils. Polypropylene  It has good resistance to cracking when flexed.  Good resistance to heat sterilization.  It is colorless, odorless thermoplastic material with excellent tensile properties even at high temperature.  Excellent resistance to strong acids and alkalis.  Low permeability to water vapour  Permeability to gases is intermediate between polyethylene HD and un-plasticized PVC  Suitable for use in closures , tablet containers and intravenous bottles.
  36. 36. March 17 36 Polyvinyl chloride (PVC):  Versatility , ease of blending, strength / toughness, resistance to grease/oil, resistance to chemicals, clarity.  Used as rigid packaging material and main component of intravenous bags.  Drawback: Poor impact resistance which can be improved by adding elastomers to the plastics but it will increase its permeability. Poly vinyledene chloride (PVDC): • Excellent barrier properties against: moisture, water vapour, UV light, aroma, inorganic acids, alkalies, aqueous salt solutions, organic water soluble acids, aliphatic hydrocarbons , esters of long chain fatty acids, detergent base materials, emulsifying agents and wetting agents. • Good thermoform ability. • PVDC is very cost-effective, as coating weight can be customized depending on the requirements of the barrier properties. • Medical grade and non-toxic. • High levels of transparency which improves the aesthetics of the product. Polystyrene  Versatility, insulation, clarity, easily foamed (“Styrofoam”).  It is also used for jars for ointments and creams with low water content.  Drawback: Chemicals like isopropyl myristate produce crazing(a fine network of surface cracks) followed by weakening and eventually collapsible of the container.
  37. 37. March 17 37 Plastic bottles made from PP, HDPE and PS Plastic pouches of HDPE Bottle- PET and spray- PP
  38. 38. Product-Plastic interactions Product-plastic interactions have been divided into five separate categories:  Permeation  Leaching  Sorption  Chemical reaction  Alteration in the physical properties of plastics or products. March 17 38
  39. 39. Constituents of plastic containers The residues, additives, and processing aids that may be used, and therefore possibly extracted from plastic include:  Monomer residues  Catalysts  Accelerators  Solvents  Extenders  Fillers  Slip additives  Anti-slip additives  Antistatic agents  Anti-blocking agents  Release agents. March 17 39
  40. 40. Tests for plastic containers Leak test: The plastic containers (non injectables and injectables): Fill 10 plastic containers with water and fit the closure. Keep them inverted at room temperature for 24 hours. No sign of leakage should be there from any container. Water permeability test: Fill 5 containers with nominal volume of water and sealed. Weigh each container. Allow to stand for 14 days at relative humidity of 60% at 20-25 degree Celsius. reweigh the container. Loss of weight in each container should not be more than 0.2%. March 17 40
  41. 41. Metals March 17 41 Metals Tin LiningsLeadAluminum
  42. 42.  Metal containers are used solely for medicinal products for non-parenteral administration.  Metal is strong, opaque, impermeable to moisture, gases, odors, light, bacteria, and shatterproof, it is the ideal packaging material for pressurized containers.  It is resistant to high and low temperatures  They include tubes, packs made from foil or blisters, cans, and aerosol and gas cylinders.  Aluminium and stainless steel are the metals of choice for both primary and secondary packaging for medicinal products.  Form an excellent tamper evident containers. March 17 42
  43. 43.  ALUMINIUM 1. It is relatively light yet strong 2. Barrier to light and chemicals 3. Impermeable and easy to work into a variety of formats, depending on its thickness. Thickest aluminium is used for rigid containers such as aerosol cans and tubes for effervescent tablets. Intermediate thickness are when mechanical integrity is still important but the pack should be capable of being reformed under a reasonable force. e.g. Collapsible tubes for semi solid preparations or roll on screw caps. Thinnest aluminium is used in flexible foil that are usually a component of laminated packaging material. March 17 43
  44. 44. Disadvantages and their overcome solution • Major disadvantage is its reactivity in raw state, although it rapidly forms a protective film of aluminium oxide it is still liable to corrosion ( when exposed to some liquids and semi solid formulations, particularly at extreme pH or if the product contains electrolytes. Overcome: To overcome this problem, Aluminium is lined with epoxide, vinyl or phenolic resins. • They are work hardening like collapsible tubes are made by impact extrusion which tends to make aluminium less flexible. Overcome: To overcome, flexibility has to restored by an annealing stage. March 17 44
  45. 45. Tin  Tin containers are preferred for food, pharmaceuticals and any product for which purity is considered.  Tin is the most chemically inert of all collapsible metal tubes . March 17 45 Lead: Lead has the lowest cost of all tube metals and is widely used for non food products such as adhesives, inks. paints and lubricants.  Lead should never be used alone for anything taken internally because of the risk lead poison . With internal linings, lead tubes are used for products such as chloride tooth paste.
  46. 46. Linings If the product is not compatible with bare metal, the interior can be flushed with wax-type formulation or with resin solutions, although the resins or lacquers are usually sprayed on. A tube with an epoxy lining costs about 25% more than the same tube uncoated. Wax linings are most often used with water-based products in tin tubes, and phenolic, epoxides, and vinyls are used with aluminium tubes, giving better protection than wax, but at a higher cost. March 17 46
  47. 47. Rubbers (Elastomers): March 17 47 • Excellent material for forming seals, used to form closures such as bungs for vials or in similar applications such as gaskets in aerosol cans.  Categories of Rubbers: 1) Natural rubbers: Suitable for multiple use closures for injectable products as rubber reseals after multiple insertion of needle. • Disadvantages are; i. It doesn't well tolerate multiple autoclaving becoming brittle and leads to relative degree of extractable material in presence of additives. ii. Risk of product absorbing on or in to a rubber. iii.It has certain degree of moisture & gas permeation.
  48. 48. 2) Synthetic rubber: • Have fewer additives and thus fewer extractable and tends to experience less sorption of product ingredients. • Are less suitable for repeated insertions of needle because they tend to fragment or core pushing small particles of the rubber in to the product. e.g. Silicone, butyl, bromobutyl, chlorobutyl etc. • Silicone is least reactive but it does experience permeability to moisture and gas. Softer rubbers experience less coring and reseal better, harder rubbers are easier to process on high speed packaging lines. March 17 48
  49. 49. Fibrous materials  The fibrous materials are the important part of pharmaceutical packaging.  Fibrous materials include: Papers, Labels, Cartons, Bags, Outers etc.  The Applications as well as Advantages of Cartons include:  Increases display area  Provides better stacking for display of stock items  Assembles leaflets  Provides physical protection especially to items like metal collapsible tubes.  Fiberboard outers either as solid or corrugated board also find substantial application for bulk shipments.  Regenerated cellulose film, trade names Cellophane & Rayophane, is used for either individual cartons or to assemble a no. of cartons. March 17 49
  50. 50. Films, foils & laminates  Characteristics: ◦ Applicable to tablets, capsules, pills, etc. ◦ It's a good substitute for PVC sheet. ◦ No cracking, delamination or pinholes ◦ It has the quite good blocking properties effectively protecting drugs from water vapor, oxygen and ultraviolet. ◦ It can extend the storage period of drugs. ◦ It is particularly suitable for packing moisture-sensitive drugs or those sold in the hot and humid areas. ◦ Taking out a part of the drugs from the drug boards without any impact on other well-packaged drugs. ◦ It is used by cold-moulding packaging machines. ◦ It is shaped easily by changing the mold. ◦ Nice appearance can upgrade drug's image March 17 50
  51. 51. Blister pack Blister packaging is a type of pre-formed plastic packaging commonly used as unit dose packaging for pharmaceuticals such as tablets, capsules or lozenges. Blister packs consist of two principal components : 1) The cavity made from either plastic or aluminium. 2) the lidding, made from paper board, paper, plastic or aluminium. The cavity contains the product and the lidding seals the product in the package. There are two types of forming the cavity into a base web sheet: thermoforming and cold forming March 17 51
  52. 52. Thermoforming  In the case of thermoforming, a plastic film or sheet is unwound from the reel and guided though a pre-heating station on the blister line  The temperature of the pre-heating plates (upper and lower plates) is such that the plastic will soften and become moldable. March 17 52 Cold forming • In the case of cold forming, an aluminum-based laminate film is simply pressed into a mold by means of a stamp. • The aluminum will be elongated and maintain the formed shape. • Advantage of cold form foil blisters is that the use of aluminum is offering a near complete barrier for water and oxygen, allowing an extended product expiry date. • The disadvantages of cold form foil blisters are the slower speed of production compared to thermoforming and the lack of transparency of the package and the larger size of the blister card
  53. 53. Materials used in blister packaging PVC(Polyvenyl Chloride) PCTFE (Polychlorotrifluroethylene) COC (Cyclic olefin copolymers ) PVDC(Polyvenyledene chloride) PP(polypropylene) PE (polyethylene), PETg (glycol-modified polyethylene terephthalate) March 17 53
  54. 54. Advantages 1. Product integrity 2. Product protection 3. Tamper evidence 4. Reduce possibility of accidental misuse 5. Patient compliance March 17 54
  55. 55. Strip packaging Strip packaging is an alternative form of pack for a unit dosage. It is a method of enclosing the product concerned between the two web of material so that each is contained between separate compartment. Two web of material may not be necessary to be identical. March 17 55
  56. 56.  It is commonly used for the packaging of tablets and capsules. A strip package is formed by feeding two webs of a heat sealable flexible film through a heated crimping roller .The product is dropped into the pocket formed before forming the final set of seals. A continuous strip of packets is formed which is cut to the desired number of packets in length.  The materials used for strip package are cellophane, polyester, polyethylene, polypropylene, polyvinylchloride. March 17 56
  57. 57. Closures  Closures are the devices by means of which containers can be opened and closed. Proper closing of the container is necessary because ◦ It prevents loss of material by spilling or volatilization. ◦ It avoids contamination of the product from dirt, microorganisms or insects. ◦ It prevents deterioration of the product from the effect of the environment such as moisture , oxygen or carbon dioxide.  Material used for closures are; The closures for containers meant for storage of pharmaceutical products are generally made from the following basic materials. *Cork *Glass *Plastic *Metal *Rubber March 17 57
  58. 58. Symbols used on packages and labels March 17 58 Fragile This way up Keep away from sunlight Keep away from water Recycle
  59. 59. March 17 59 Quality Assurance Aspects of Packaging  To ensure that patients and consumers receive high-quality drugs, the quality management system must take the following considerations into account if the required quality of packaging is to be obtained: ◦ — the requirements of the national authorities and the relevant legislation ◦ — the product ◦ — the production process ◦ — the manufacturers’ internal policies (safety, marketing, etc.).  Bad packaging which is the result of deficiencies in the quality assurance system for packaging can have serious consequences, and packaging defects can create problems that may result in drug recalls. Such defects may include breakage, and problems relating to printing or inks, or errors on labels and package inserts (patient information leaflets). The use of GMP and quality control will prevent the release of a defective medicinal product.  Packaging processes and equipment need validation/qualification in the same way as any other part of processing within a pharmaceutical facility.
  60. 60. March 17 60 Sampling and testing of packaging materials  Sampling Sampling is used;  To check the correctness of the label, packaging material or container reference, as well as in the acceptance of consignments,  Detecting adulteration of the medicinal product, obtaining a sample for retention, etc.  The sampling procedure must take into account the homogeneity and uniformity of the material so as to ensure that the sample is representative of the entire batch.  The sampling procedure should be described in a written protocol.  Testing programme Quality control tests are intended to check the identity of the material concerned. Complete pharmacopoeial or analogous testing may also be carried out, as may special tests, where necessary. All written specifications for packaging materials and containers should include the nature, extent and frequency of routine tests. Routine tests vary according to the type of material and its immediate packaging, the use of the product, and the route of administration. Nevertheless, such tests usually include the following: ◦ — visual inspection (cleanliness, defects) ◦ — tests to identify the material ◦ — dimensional tests ◦ — physical tests ◦ — chemical tests ◦ — microbiological tests
  61. 61. March 17 61 Package validation Package validation involves two separate validations: 1) The design validation of the package as a component of the device. Design validation uses evidence to establish what design specifications will conform with the user needs and the intended use and 2) The process validation of the packaging process. Process validation establishes by objective evidence that a process consistently produces a result or product that meets predetermined specifications. The regulation, of course, refers to establishing evidence that the manufacturing steps involved in packaging the device will consistently produce packaging which meets specifications. For example, the process capability of packaging and sealing equipment should be determined during process validation and documented. Validation of the package design shall be performed under actual or simulated use conditions that show the package conforms to its stated intended uses. Risk analysis shall also be included where appropriate.
  62. 62. March 17 62 Design validation results shall include: the design identification, name of the individual(s) performing the validation, method(s) used, and the date. All of this information should be recorded in the design history file. If any significant change is made in the packaging or packaging operation after validation, the new process will need to be revalidated. One of the most difficult aspects of package validation is determining how many samples to test. The goal is not to over test because of cost considerations while still running sufficient tests to provide statistically valid sampling. Statistical methods of analysis are important in process validation. The following decision tree from Medical Device and Diagnostic Industry, "Streamlining Package-Seal Validation," October 1992, provides various methods of statistical analysis. The manufacturer is challenged with determining which statistical method is most applicable to their individual needs. The resulting validation plan should identify, measure, and evaluate the key processes and variables that will require assessment to complete a validation or revalidation of the packaging and the packaging process.
  63. 63. March 17 63