PROCESS VALIDATION OF AN OINMENT AND LIQUID ORALS

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1. PROCESS VALIDATION OF AN OINMENT AND LIQUID ORALS Prepared by : Neetu Vishwakarma M.Pharm (Pharmaceutical Quality Assurance) Submitted to: Dr. Deepti Jain Associate Professor & Director School Of Pharmaceutical Sciences, RGPV Bhopal

2. Validation is a part of the quality assurance program and is fundamental to an efficient production operation for building quality into the products. Validation of the individual steps of the processes is called the process validation. The goal of validation is to ensure that quality is built into the system at every step, and not just tested for at the end. WHO – Validation is documented act of providing that any procedure, process, equipment, material, activity or system actually leads to the expected results. INTRODUCTION:

3. Process Validation provides the flexibility and constraints in the production process controls in the achievement of desirable qualities in the drug product while preventing undesirable attributes. USFDA – Establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage forms) will consistently produce a product meeting its predetermined specifications and quality characteristics. PROCESS VALIDATION:

4. STAGES OF PROCESS VALIDATION: Stage 1 Process Design Stage 2 Process Qualification (PQ) Stage 3 Continued Process Verification Design of Facilities & Qualification of Equipment and Utilities Process Performance Qualification (PPQ) Distribution Distribution Evaluate/Confirm Changes Changes

5. LIQUID ORALS

6. Oral Liquids are homogeneous liquid preparations that usually consisting of a solution, an emulsion or a suspension of one or more medicaments in a suitable vehicle. WHAT ARE LIQUID ORALS:

7. LIQUID DOSAGE CAN BE PREPARED: By dissolving the active drug substance(s) in an aqueous or non-aqueous (e.g. alcohol, ether, glycerine) solvent. By suspending the drug in appropriate medium. By incorporating the drug substance into an oil or water phase.

8. CLASSIFICATION OF ORAL LIQUIDS: TWO MAIN TYPES MONOPHASIC LIQUIDS BIPHASIC LIQUIDS SOLUTIONS ELIXIRS SYRUP LIQUID DROPS etc. SUSPENSIONS EMULSIONS

9. MANUFACTURING OF MONOPHASIC LIQUIDS: Process Flow Addition of Raw Materials Active Excipients Mixing Filtration Filling Control Variables Mixing time RPM Temperature Final Volume Mesh Size Filter Integrity Filling Machine Speed Measured Responses Clarity Viscosity Assay Clarity Volume

10. MANUFACTURING OF BIPHASIC LIQUIDS: WATER CONTINUOUS PHASE PRESERVATIVES MIXING SURFACTANTS AQUEOUS SOLUTION OTHER HELPING AGENTS

11. MANUFACTURING OF BIPHASIC LIQUIDS contd … DISPERSE PHASE FOR SUSPENSION MILLED DRUG DRUG SOLUTION IN OIL DISSOLVED DRUG IN OIL FOR EMULSION GRINDING OF DRUG & OTHER SOLIDS

12. MANUFACTURING OF BIPHASIC LIQUIDS contd … Fine Dispersed Delivery System Other addictive (flavours and colouring agents Volume Adjustment pH Adjustment Homogenize Continuous Phase Dispersed Phase Pre-mix or Crude Dispersion

13. VALIDATION OF LIQUID ORALS

14. OBJECTIVES OF PROCESS VALIDATION FOR LIQUIDS: For a systematically process to assure the quality of the product. To ensure that the product is meeting with predetermined specifications.

15. VALIDATION OF LIQUID ORALS: Equipment Raw Materials Compounding Microbiological Quality Oral Suspension Uniformity Product Specifications Stability Packaging

16. TEST PARAMETERS FOR EMULSION AND SUSPENSION: Test Parameter Suspension Emulsion Appearance Yes Yes Specific Gravity Yes Yes Viscosity Yes Yes pH Yes Yes Content Uniformity Yes Yes Sedimentation Yes No Resuspendability Yes No Particle Size Yes Yes Release Rate Yes Yes

17. RAW MATERIAL VALIDATION: It includes following important tests Particle size and size distribution. Particle shape or morphology. Microbial count. Rheology of solvent or vehicle. pH of the solvent or vehicle. Raw materials are checked and validated for Particles size and size distribution – Particle size distribution range is 0.2 – 2 microns for suspension. Particle shape (Morphology) – It is also important to consider because it affects the product appearance, solubility, settling rates and drug stability. Microbial content – To prevent microbial growth on the final product.

18. Rheology of solvent – It will determine how well liquid will suspend the insoluble particles. Viscosity of the External phase is generated by one or more of following components. Suspended solids. Blend of oils and waxes. Presence of polyols and polyoxyethylene derivatives. High concentration of dispersed solids in water. Dispersed clays, gums, cellulosic, and/or polymers.

19. pH of the solvent – Solubility of the drug in the solvent or vehicle can be markedly influenced by the pH of the solvent. pH of the solvent is important because large number of chemotherapeutic agents are either weak acids or weak bases so their solubility markedly affected by the pH of the solvent.

20. MONITORING OUTPUTS: There are following outputs to be monitored Appearance pH Viscosity Specific Gravity Microbial Count Content Uniformity Dissolution Testing

21. APPEARANCE: Appearance of the final product is checked and validated because it indicates the signs of instability and degradation. For e.g. settling of solid particles in case of suspension and turbidity in case of emulsion. Time for mixing or agitation and temperature of process can affect the appearance greatly.

22. pH Value: pH of aqueous oral formulations should be taken at a given temperature and only after equilibrium has been reached in order to minimize the pH drift. Electrolytes, such as potassium chloride may be added to the aqueous external phase to stabilize their pH drift.

23. Viscosity: Viscosity is defined as the study of fluid flow. Or it is measurement of the applied stress per unit area to maintain a certain flow rate. The viscometer used for the measurement of viscosity should be properly calibrated at equilibrium at a given temperature to establish system reproducibility. Viscosity of the liquid oral dosage form is important because it affects the settling rate of suspended particles in the suspension and of globules of internal phase in emulsions and also in case of oral solutions it affects the whole appearance of the final product, so it must be measured and validated properly.

24. Proper Gravity: Specific gravity is the weight of the product per unit volume. For most of the liquid oral products it is 1gm/cube centimetre. A decrease in specific gravity of the product like suspensions indicates the presence of air within the structure of the formulation. Hydrometer is used to measure the specific gravity of liquid orals at a given temperature using well mixed uniform solution.

25. Microbial Count: Microbial count for the final product is essential to validate because by performing microbial count we can select the preservative for the final product storage. There are specifications for each liquid oral product for the bio burden content. Preservation system used in the formulation – The use of small amounts of propylene glycol (5-15%) or disodium edetate (about 0.1%) or decrease in the pH of the disperse system have often been use to increase the efficiency of the preservative system. Criteria for selection of preservatives Must be effective against a broad spectrum of microorganisms. Must be chemically, physically and microbiologically stable. Must be nontoxic, non-sensitizing, soluble and compatible with other formulation components.

26. Content Uniformity: In solution, suspensions and emulsions determination of content uniformity affects the dose uniformity in case of multi-dose formulations and also affects the homogeneity of the drug within solvent system. Content uniformity of suspension is affected by settling rate which is governed by following factors- Particle size of the internal phase. Particle density of the internal phase. Density of the external phase. Viscosity and structure of the external phase.

27. Dissolution Testing: There is not any official method for dissolution testing of dispersed system, but the best way to perform dissolution of suspension like system is to place a small amount of formulation inside a secure Durapore ( polyvinylidene fluoride) membrane pouch of suitable viscosity and suspend it in a suitable dissolution medium using a USP method 1 paddle apparatus.

28. NUMBER OF VALIDATION TRIALS: For new product, product transfer or having major changes generally at least three consecutive successful batches are required. One Right = Accident Two Rights = Coincidence Three Rights = Validated SAMPLING FOR VALIDATION For solution, take at least 2 samples at top and bottom of the bulk. For suspension, take at least 2 samples at top, middle and bottom of the bulk. Finished Product Testing (Net content, Microbiology, Content Uniformity)

29. CRITICAL PARAMETERS: Equipment Mixing Speed Homogenizing Speed Mixing Time Heating/Cooling Time Flow Rate Manufacturing Dissolving Step Melting Step Homogenizing Step Processing Mixing Speed Mixing Time Cooling Time Homogenizing Speed Homogenizing Time

30. ACCEPTANCE CRITERIA: Dissolved Active Ingredient Clear Solution Filtration No residue on filter pH Adjustment pH within specification Final Mixing pH, viscometer, appearance, assay content

31. FILLING & PACKAGING OPERATION VALIDATION: There are following steps performed Leakage test for filled bottle. Cape sealing test. Filling volume determination. Water vapour permeability test. Proper control of product temperature. Proper agitation in holding tanks and filling heads. Uniformity and homogeneity of active ingredient. Maintain stability in the primary container closure system.

32. LIMITS OF PROCESS VARIABLES FOR FACTORIAL ANALYSIS: Processing Variables Lower Control Limit (LCL) Upper Control Limit (UCL) Moisture Content 5% 15% Processing Temperature 50 Degree Celsius 70 Degree Celsius pH Value 5.0 7.0 Processing Time 2 hrs. 6 hrs. Apparent Viscosity 20,000 cps 200,000 cps Blender Speed 4,000 rpm 20,000 rpm Average Particle Size 20 microns 40 microns

33. VALIDATION REPORT: Validation team must prepare Validation Report. Validation Report must be reviewed and approved by Quality Assurance. Written notification or either successful completion or failure must be informed/issued to top management. In case of failure, an investigation must be completed and documented prior to repeat the validation study.

34. CHANGES AND REVALIDATION: Change of any of the following may need revalidation. Formula Composition Raw Material Source Manufacturing Location All Equipment Batch size CHANGES: MINOR INTERMEDIATE MAJOR

35. OINTMENT

36. INTRODUCTION: Semisolid dosage forms include ointments and creams. Ointments are preparations for external use, intended for application to the skin. Typically, they have an oily or greasy consistency and can appear “stiff” as they are applied to the skin. Ointments contain drug that may act on the skin or be absorbed through the skin for systematic action. Many ointments are made from petroleum jelly. Like many other. Soft, semisolid preparation intended for application to skin and mucus membrane. Appearance: Opaque Type : Oleaginous base, Absorption base, Emulsion base, Water-soluble Base

37. Processes must be validated in pharmaceutical manufacturing are: Cleaning Sanitization Fumigation Depyrogenation Sterilization Sterlilefilling Fermentation Bulk Production Purification Filling, capping, sealing Lyophilisation

38. ORDER OF PRIORITY: A. Sterile: products and their processes (High Risk) LVP SVP Ophthalmic, Other sterile products and medical devices. B. Non-sterile: products and their processes (Low Risk) Low does / high potency / tablets and capsules / TDDS Drugs with stability problems. Other tablets and capsules. Oral liquids, topical ointment and cream. Diagnostic aids

39. SEMISOLIDS MANUFACTURING CONSIDERATION: Combine Water Soluble ingredient in auxiliary kettle. Heat to critical temperature. Combine oil soluble ingredient in main cattle. Heat to critical temperature. Counter sweep agitation Transfer water phase by pump Filling and packaging Homogenize or pass through colloid mill while warm. Cool slowly with counter sweep agitation Transfer finished product by pump into drum or tank 1) Flow Diagram

40. DISPENSING OF MATERIAL 1) Flow Sheet: Q.C. APPROVAL WATER PHASE PURIFIED WATER HEAT ___MINS./SLOW MIXING WITH ADDITON OF ACTIVE INGRIDENT ___MINS./SLOW FILLING, CAPPING & CODING FINAL PACKING OIL PHASE ___MINS./SLOW ADDITION OF EXCIPIENT ADDITION OF ACTIVE INGRIDIENT 1. ADDITIONAL QUANTITY OF WATER ADDED 2. TEMP. 3. SPEED (RPM) 1. MIXING TIME 2. TEMP. 3. SPEED (RPM) 1. MIXING TIME 2. TEMP. 3. SPEED (RPM) 1.WEIGHT 2. CRIPING 3. CODING

41. 2. UNIT OPERATION FOR SEMISOLID SYSTEM: Mixing of semisolid Dispersing Milling and size reduction of solid and semisolid

42. 3. MIXING AND BLENDING OF SEMISOLID: Process Variable Properties affected by variable Monitoring output Type and capacity of unit   Potency Shape of unit and position of mixing elements within unit Homogeneity Content uniformity Product load Specific gravity Viscosity Temperature     Agitation speed Viscosity Density Mixing time    

43. 4. DISPERSING: Process Variable Properties affected by variable Monitoring output Bore opening / power setting   Potency Pressure / rot or speed / power consumption Particle size of solids Particular size distribution Feed rate Viscosity of liquid Viscosity Temperature   Dispersion time Specific gravity Order of mixing    

44. 5. SIZE REDUCTION OF SOLID AND SEMISOLID: Process Variable Properties affected by variable Monitoring output Mill type   Potency Mill size Particle size Particular size analysis Mill speed / air pressure Bulk density Density / surface area Product load Dissolution rate of solid Feed rat e Inert atmosphere  

45. FILLING AND PACKAGING OPERATION: The following critical aspects must be evaluated and controlled during large-scale validation and manufacturing runs. Proper control of product temperature to aid product flow and maintain product consistency before and during filling and packaging operation. Proper agitation holding tank sand filling heads in order to main product uniformity and homogeneity during filling and packaging operation. The use of air pressure and inert atmosphere to achieve product performance and stability in the primary container.

46. PRODUCT SETTING: Validation testing of bulk and finished product must be based on testing standard release criteria and in process testing criteria. Routine QC release testing should be performed on a routine sample. These samples should be taken separately from the validation samples. Validation sampling and testing typically is 3 to 6 time the usual QC sampling.

47. VALIDATION BATCH: BULK SAMPLING: Take 10 sample from the mixture/tank or during product transfer to the storage/filling vessel. The samples must represent the top, middle and bottom of the vessel. If sampling from the mixture/tank using an specific equipment, samples should be taken immediately. Adjacent to blades, baffles and shaft where product movement during mixing may restricted. The bottom of the tank and any potential dead spots should be sampled and examined for unmixed.

48. SAMPLING PLAN: Samples must be representative of each filing nozzle. For single filling size Take a minimum of 3 fill containers from each of the beginning, middle and end of the filling run. The total number of samples must be not less than 10. All samples must be tested. Multiple filling size Take minimum 3 samples each at the beginning and end of the filling size.

49. OTHER SAMPLING PATTERN: Ten equid is stand point across the filling run must be sampled. The beginning and end of filling must be represented. Samples should be taken in triplicate.

50. MONITORING OUTPUT: 1) Particle size consideration Control of particle morphology and particle size important parameters to attain high quality drug product manufactured and control procedure. Particle size distribution for most dispersed system should in the range of 0.2 – 20 microns. 2) Viscosity The Viscometer-calibrated to measure the apparent viscosity of the disperse system at equilibrium at a given temperature to establish system reproducibility. Consistency type Appropriate viscosity in cps at 25 O C Pharmaceutical example Soft, spreadable 100,000-300,000 W/O, O/W CREAM Plastic flow, spreadable 300,000-1,000,000 Ointment

51. 3) Content Uniformity Most important parameter governing product stability and process control of the disperse system. In ointment/cream formulation are more dependent on particle size, shear rate, and mixing efficiency in order to attain and maintain uniformity of the active drug component (usually the internal phase). The average result to 10 individual results must meet the release limit for assay. The usual sample size for testing ranges between 0.5 and 1.5 per sample assay. Monitoring output Acceptance Criteria (n=10) Sampling Plan Content Uniformity UPL & LPL within 90 – 110 % LA 3 – 4 units from beginning, middle and end of filling cycle; total = 10 units RSD 4.2% Monitoring output Acceptance Criteria (n=10) Sampling Plan Content Uniformity UPL & LPL within 90 – 110 % LA 3 – 4 units from beginning, middle and end of filling cycle; total = 10 units

52. 4) Preservative Effectiveness Incorporating a USP antimicrobial preservative testing procedure or microbial limit test into formal validation of aqueous dispersion. Determination of bio burden for validation and production batches can also be used to establish appropriate validated cleaning procedure for the facilities and equipment used to manufacture of disperse system. 5) Dissolution Testing It is primary used as a quality control procedure to determine product uniformity. Secondary as a means of assessing the in vivo absorption of the drug in terms of a possible in vitro/vivo correlation. For cream/ointments, the Franz in vitro flow through diffusion cell has been modified by using silicon rubber membrane barrier to stimulate percutaneous dissolution unit for testing purpose.

53. IDENTIFICATION OF CRITICAL PROCESS VARIABLES/PARAMETER: PROBABLE CAUSES THAT MAY EFFECT THE FINAL PRODUCT DISPERSING OF MATERIAL OIL PHASE SOLUTION DISPERSION TUBE FILLING WATER PHASE SOLUTION DISPERSION MANUFACTURING SPEED TEMPERATURE LOAD SIZE ACTIVE EXCIPIENT SPEED WEIGHT / TUBE LOAD SIZE COOLING TEMPERATURE pH BOILING TEMPERATURE TEMPERATURE SPEED SPEED LOAD SIZE

54. CRITICAL PROCESS PARAMETERS: # CRITICAL PROCESS VARIABLE RESPONSE PARAMETER REMARKS 1 Water Phase Solution Preparation Water Phase Uniformity   Sequence of excipient addition Fixed order of addition Water Boiling Temperature Fixed Boiling Temperature Range Time Variation of time for boiling Cooling Temperature Fixed Heating Temperature Range Time Variation of time for cooling pH Fixed limit of pH Mixing Time Variation of mixing time (RPM) 2 Oil Phase Solution Preparation Oil Phase Uniformity   Sequence of excipient addition Fixed order of addition Heating Temperature Fixed Heating Temperature Range Time Variation of time for heating Cooling Temperature Fixed cooling temperature range Time Variation of time for cooling Mixing Time Variation of mixing time (RPM) 3 Manufacturing Active Ingredient Uniformity   Sequence of active addition Fixed order of addition Mixing Time Variation of mixing time Cooling Temperature Fixed temperature range 4 Filling     Filling, Cirmping & Cooling 1. Weight of tube 2. Crimping Fixed machine speed, no variation Filling Speed Fixed machine speed, no variation

55. CRITICAL PROCESS VARIABLE: # PROCESS/VARIABLE MACHINE SETTING (CONTROL VARIABLES) REMARKS 1 Water Phase Solution Preparation Quantity of water Setting and conditions as mentioned in the batch manufacturing record to be followed. 2 Oil Phase Solution Preparation Quantity of Paraffin & Wax & Other Oil 3 Manufacturing Mixing Time Cooling Time 4 Filling Speed, Weight/Tube

56. SAMPLING, TEST PARAMETERS, ACCEPTANCE CRITERIA: SAMPLING LOCATION: MFG. TANK BOTTOM VALVE 1. TOP-SAMPLE A1 2. MIDDLE-SAMPLE A2 3. MIDDLE-SAMPLE A3

57. STAGE/TEST PARAMETER EQUIPMENT (SIZE/LOCATION/TIME) ACCEPTANCE CRITERIA Water phase solution preparation Determination on each sample, for temperature, sample weight 10g. 80 5 O C Oil phase solution preparation Determination on each sample, for temperature, sample weight 10g. 80 5 O C Manufacturing ASSAY pH Sampling thief Assay 90% to 110% Rel. std : FILLING Appearance Weight of Tubes Weight of variation Identification test Visual inspection Analytical balance Analytical balance H.P.L.C. As specified in the BMR ___gm (__gm - ___gm) ___% of average weight. Test should complies to its specifications. 90% to 110% Assay STAGE/TEST PARAMETER EQUIPMENT (SIZE/LOCATION/TIME) ACCEPTANCE CRITERIA Water phase solution preparation Determination on each sample, for temperature, sample weight 10g. Oil phase solution preparation Determination on each sample, for temperature, sample weight 10g. Manufacturing ASSAY pH Sampling thief Assay 90% to 110% Rel . std : FILLING Appearance Weight of Tubes Weight of variation Identification test Visual inspection Analytical balance Analytical balance H.P.L.C. As specified in the BMR ___gm (__gm - ___gm) ___% of average weight. Test should complies to its specifications. 90% to 110% Assay

58. VALIDATION REPORT: STANDARD FORMAT Executive summary Discussion Conclusion & Recommendation List of attachment Topic should be presented in the order in which they appear in the protocol. Protocol deviation are fully explained & justified. The report is signed & dated by designated representatives of each unit involved in water system validation.

59. REFERENCES: P.P. SHARMA, “Validation in Pharmaceutical Industry Concepts Apparatus & Guidelines”, 1 st Edition; 2007, Vandana Publication House. Pavel Anthony, Grilti Anthony, De Santis Phil and Agalloco James, “Handbook of Validation in Pharmaceutical Process”, 4 th Edition; 2022 by CRC Press. Agalloco James and Frederick J. Carleton, “Validation of Pharmaceutical Process” 3 rd Edition; 2008 by Informa Healthcare USA. Robert A. Nash and Alfred H. Wachter , “Pharmaceutical Process Validation” 3 rd Edition; 2003 by Marcel Dekker. Process Validation of Pharmaceutical Dosage form; A review article by Goyal Anju and Priyambada Pandey; Published in Biomedical Journal of scientific & technical research; October 25, 2017.