Unit 1 chapter 1 final ppt for pilot plant scale up techniques

B. Pharm. Final Year, Sem:- VII,
INDUSTRIAL PHARMACY-II,
Pilot plant scale up techniques,
As per PCI Syllabus

1. PILOT PLANT SCALE- UP TECHNIQUE Represented By, Mr. Audumbar Mali, (Asst. Prof.) Sahyadri College of Pharmacy Methwade .

2. C o n t e n t s Definition Objectives Steps in scale-up General considerations GMP considerations Advantages and Disadvantages Scale up of liquid dosage forms. Scale up of semisolid dosage forms. Contract manufacturing. References 2

3. Plant :- It is a place were the 5 M’s like money, material, man, method and machine are brought together for the manufacturing of the products. Pilot Plant :- It is the part of the pharmaceutical industry where a lab scale formula is transformed into a viable product by development of liable and practical procedure of manufacture. Scale-up :- The art for designing of prototype using the data obtained from the pilot plant model. De f i n i t i o ns 3

4. Objective To try the process on a model of proposed plant before committing large sum of money on a production unit. Examination of the formula to determine it’s ability to withstand Batch-scale and process modification. Evaluation and Validation for process and equipments 4

5. To identify the critical features of the process Guidelines for production and process controls. To provide master manufacturing formula with instructions for manufacturing procedure. To avoid the scale-up problems. Objective 5

6. STEPS IN SCALE UP 6

7. Define product economics based on projected market size and competitive selling and provide guidance for allowable manufacturing costs Conduct laboratory studies and scale-up planning at the same time Define key rate-controlling steps in the proposed process Conduct preliminary larger-than-laboratory studies with equipment to be used in rate-controlling step to aid in plant design 7

8. Design and construct a pilot plant including provisions for process and environmental controls, cleaning and sanitizing systems, packaging and waste handling systems, and meeting regulatory agency requirements Evaluate pilot plant results (product and process) including process Economics to make any corrections and a decision on whether or not to proceed with a full scale plant development 8

9. Why conduct Pilot Plant Studies? A pilot plant allows investigation of a product and process on an intermediate scale before large amounts of money are committed to full-scale production. It is usually not possible to predict the effects of a many-fold increase in scale. It is not possible to design a large scale processing plant from laboratory data alone with any degree of success. 9

10. A pilot plant can be used for  Evaluating the results of laboratory studies and making product and process corrections and improvements.  Producing small quantities of product for sensory, chemical, microbiological evaluations, limited market testing or furnishing samples to potential customers, shelf-life and storage stability studies.  Providing data that can be used in making a decision on whether or not to proceed to a full-scale production process; and in the case of a positive decision, desi g ni n g an d con s t r u c ti n g a f u ll -s i z e pl an t o r modifying an existing plant 10

11. General considerations 1. Reporting Responsibility R & D g r o up w i t h separa te s t a ff i ng The formulator who developed the product can take into the production and can provide support even after transition into production has been completed 11

12. Scientists with experience in pilot plant operations as well as in actual production area are the most preferable. As they have to understand the intent of the formulator as well as understand the perspective of the production personnel. The group should have some personnel with engineering knowledge as well as scale up also involves engineering principles. 2. Personnel Requirement 12

13. 3. Space Requirements Administration and information processing Physical testing area Standard equipment floor space S to r a g e area 13

14.  Administration and information process: Ad e q ua t e o f f ic e a nd d e sk s pa c e sh ou l d be provided for both scientist and technicians. The space should be adjacent to the working area. 14

15.  Physical testing area:- This area should provide permanent bench top space for routinely used physical- testing equipment. 15

16.  Standard pilot-plant equipment floor space:- Discreet pilot plant space, where the equipment needed for manufacturing all types of dosage form is located. Intermediate – sized and full scale production equipment is essential in evaluating the effects of scale-up of research formulations and processes. Equipments used should be made portable where ever possible. So that after use it can be stored in the small store room. Space for cleaning of the equipment should be also provided. 16

17. It should have two areas divided as approved and unapproved area for active ingredient as well as excipient. Different areas should provided for the storage of the in-process materials, finished bulk products from the pilot- plant & materials from the experimental scale-up batches made in the production. Storage area for the packing material should also be provided.  Storage Area:- 17

18. 4. Review of the formula: A thorough review of the each aspect of formulation is important. The purpose of each ingredient and it’s contribution to the final product manufactured on the small-scale laboratory equipment should be understood. Then the effect of scale-up using equipment that may subject the product to stresses of different types and degrees can more readily be predicted, or recognized. 18

19. 5. Raw materials:- pr oduc t i on can n o t nece s s a r i l y b e the representative for the large scale production One purpose/responsibility of the pilot-plant is the approval & validation of the active ingredient & excipients raw materials. Why? R a w m a t e r i a l s u s e d i n t he s m a l l s ca l e 19

20. 6. Equipment:- The most economical and the simplest & efficient equipment which are capable of producing product within the proposed specifications are used. The size of the equipment should be such that the experimental trials run should be relevant to the production sized batches. If the equipment is too small the process developed will not scale up, Whereas if equipment is too big then the wastage of the expensive active ingredients. 20

21. 7. Production Rates:- The immediate as well as the future market trends/requirements are considered while determining the production rates. 21

22. 8. Process Evaluation:- PARAMETERS Order of mixing of components M i x i n g speed M i x i n g time Rate of addition of granulating agents, solvents, solutions of drug etc. Heating and cooling Rates Filters size (liquids) Screen size (solids) Drying temp. And drying time 22

23.  Why to carry out process evaluation???? The knowledge of the effects of various process parameters as few mentioned above form the basis for process optimization and validation. 23

24. 9. Master Manufacturing Procedures:- The three important aspects Weight sheet P r o c ess i ng directions M a n u f a c tu r ing procedure 24

25.  The weight sheet should clearly identify the chemicals required In a batch. To prevent confusion the names and identifying nos. for the ingredients should be used on batch records.  The process directions should be precise and explicit.  A manufacturing procedure should be written by the actual operator.  Various specifications like addition rates, mixing time, mixing speed, heating, and cooling rates, temperature, storing of the finished product samples should be mentioned in the batch record directions. Master Manufacturing Procedures 25

26. 10. Product stability and uniformity:- The primary objective of the pilot plant is the physical as well as chemical stability of the products. Hence each pilot batch representing the final formulation and manufacturing procedure should be studied for stability. S t a bility s t udi e s sh ou l d b e ca rried ou t in finished packages as well. 26

27. GMP CONSIDERATION Equipment qualification Process validation Regularly schedule preventative maintenance Regularly process review & revalidation Relevant written standard operating procedures The use of competent technically qualified personnel Adequate provision for training of personnel A well-defined technology transfer system Validated cleaning procedures. An orderly arrangement of equipment so as to ease material flow & prevent cross- contamination 27

28. Advantages Members of the production and quality control divisions can readily observe scale up runs. Supplies of excipients & drugs, cleared by the quality control division, can be drawn from the more spacious areas provided to the production division. Access to engineering department personnel is provided for equipment installation, maintenance and repair. 28

29. Disadvantages The frequency of direct interaction of the formulator with the production personnel in the manufacturing area will be reduced. Any problem in manufacturing will be directed towards it’s own pilot-plant personnel's. 29

30. SOLID DOSAGE FORM Material Handling Laboratory Scale Deliver accurate amount to the destination Large Scale Lifting drums More Sophisticated Methods -Vacuum Loading System -Metering Pumps Prevent Cross Contamination by Validation Cleaning Procedures.

31. 2. Dry Blending Powders should be used for encapsulation or to be granulated prior to tabletting must be well blend to ensure good drug distribution. ta b let or Inadequate blending could result in drug content unifor m i t y var i ation, espe c ia l ly when t h e capsule is small & the drug concentration is relatively low. Ingredients should be lumps free, otherwise it could cause flow problems.

32. 3 . Granulations Reasons :- * To improve the flow properties. * To increase the apparent density of the powder. * To change the particle size distribution so that the binding properties on compaction can be improved.

33. Types :- Wet Granulation Dry Granulation Direct Compression Method A small amount potent active ingredient can be dispersed most effectively in a carrier granulation, when the drug is dissolved in granulating solution and added during the granulating process.

34. Wet granulation has been carried out by using, - Sigma Blades - Heavy-duty planetary mixture -Tumble Blenders -High Speed Chopper Blades used in mixing of light powders . Multifunctional Processors, dry blending, wet granulation, drying, sizing & lubricating . Effect of Binding Agent.

35. 4 . D ry i n g Hot Air Oven * air temperature * rate of air flow * depth of granulation on the trays Fluidized Bed Dryer * optimum loads * rate of airflow * inlet air temperature * humidity Data used for small scale batches(1-5 kg) cannot be extrapolate processing conditions for intermediated scale (100 kg) or large batches.

36. TABLET COATING Equipments :- * conventional coating pan * perforated pans of fluidized-bed coating column Types :- 1. Sugar coating 2. Film coating Tablet must be sufficiently hard to withstand the the tumbling to which they are subjected while coating. Operation conditions to be established for pan or column operation are optimum tablet load, operating tablet, bed temperature, drying air flow rate, temperature, solution application rate.

37. CAPSULES To produce capsules on high-speed equipment, the powder blend must have, * uniform particle size distribution * bulk density * formation of compact of the right size and of sufficient cohesiveness to be filled into capsule shells. Equipments :- 1. Zanasi or Mertalli – Dosator(hollow tube) 2. Hoflinger – Karg – Tamping pins Weight variation problem can be encountered with these two methods. Overly lubricated granules – delaying disintegration.

38. Humidity affect moisture content of – * granulation * on the empty gelatin capsules Empty gelatin capsules have a recommended storage condition of 15-25 ºC temperature & humidity 35-65 % RH. At high humidity – capsule swells make separation of the capsule parts difficult to interfere with the transport of the capsule through the process. At low humidity – capsule brittle increased static charge interfere with the encapsulation operation.

39. Scale up of liquid orals

40. Liquid orals The physical form of a drug product that is pourable displays Newtonian or pseudo plastic flow behavior and conforms to it’s container at room temperature. Liquid dosage forms may be dispersed systems or solutions. In dispersed systems there are two or more phases, where one phase is distributed in another. A s o lution r e f e r s t w o o r m o r e su b s t anc e s m ixed h o m ogeneo u s l y . 40

41. Steps of liquid manufacturing process Planning of material requirements: Liquid preparation: Filling and Packing: Quality assurance: 41

42. Critical aspects of liquid manufacturing  Physical Plant: Heating, ventilation and air controlling system: The effect of long processing times at suboptimal temperatures should be considered in terms of consequences on the physical or chemical stability of ingredients as well as product. 42

43. Formulation aspects of oral liquids Suspensions: Purpose Facilitating the connection between API and vehicle Protecting the API Maintaining the suspension appearance Masking the unpleasant taste/smell Agent -wetting agents Salt formation ingredients - Buffering-systems, polymers, antioxidants Colorings, suspending agent, flocculating agent. Sweeteners, flavorings 43

44. Particle Size Protecting the API Maintaining the appearance Taste/smell masking Solid particles, Droplet particles Buffering-systems, antioxidants, polymers Colorings, Emulsifying agents, Penetration enhancers, gelling agents Sweetners, flavorings Formulation aspects of oral liquids Emulsions: P urpos e A g ent 44

45. Maintaining the appearance Buffers, antioxidants, preservatives Colorings, stabilizers, co- solvents, antimicrobial preservatives Taste/smell masking Sweeteners, flavorings. Formulation aspects of oral liquids S o luti o ns: Protecting the API 45

46. Layout of the pilot plant 46

47. Equipments Mixer Homogenizer Filteration assembly Bottling assembly 47

48. Filtration assembly 48

49. General flow chart Raw Materials Measured and weighed M i x i n g F i l l i n g P a ck i n g Distilled water Finished products storage Quality Assurance 49

50. Quality assurance Dissolution of drugs in solution Potency of drugs in suspension Temperature uniformity in emulsions Microbiological control Product uniformity Final volume Stability 50

51. Scale-up of semisolid dosage forms

52. Semisolid dosage forms In general, semisolid dosage forms are complex formulations having complex structural elements. Often they are composed of two phases (oil and water), one of which is a continuous (external) phase, and the other of which is a dispersed (internal) phase. The active ingredient is often dissolved in one phase, although occasionally the drug is not fully soluble in the system and is dispersed in one or both phases, thus creating a three-phase system. 52

53. The physical properties of the dosage form depend upon various factors, including the size of the dispersed particles, the interfacial tension between the t h e a c ti v e t h e p r od u c t p h a ses , the p a r titi o n c o e f f i c i e n t o f ingredient between the phases, and rheology. These factors combine to determine t h e r e l ease a s o ther c h a r a c t e r i s ti c s of t h e d r u g, a s we ll characteristics, such as viscosity. Semisolid dosage forms 53

54. Critical manufacturing parameters For a true solution, the order in which solutes are added to the solvent is usually unimportant. The same cannot be said for dispersed formulations, however, because dispersed matter can distribute differently depending on to which phase a particulate substance is added. In a typical manufacturing process, the critical points are generally the initial separation of a one-phase system into two phases and the point at which the active ingredient is added. 54

55. Because the solubility of each added ingredient is important for determining whether a mixture is visually a single homogeneous phase, such data, possibly supported by optical microscopy, should usually be available for review. This is particularly important for solutes added to the formulation at a concentration near or exceeding that of their solubility at any temperature to which the product may be exposed. Critical manufacturing parameters 55

56. Variations in the manufacturing procedure that occur after either of these events are likely to be critical to the characteristics of the finished product. This is especially true of any process intended to increase the degree of dispersion through reducing droplet or particle size (e.g., homogenization). Aging of the finished bulk formulation prior to packaging is critical and should be specifically addressed in process validation studies. Critical manufacturing parameters 56

57. General stability consideration The effect that SUPAC changes may have on the stability of the drug product should be evaluated. For general guidance on conducting stability studies, see the FDA Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics. 57

58. For SUPAC submissions, the following points should also be considered: sca l e - u p , w ill b e 1. In most cases, except those involving stability data from pilot scale batches acceptable to support the proposed change. 2. Where stability data show a trend towards potency lo s s o r deg r a d an t i n c r e as e u nder a c c e l e r a t ed h i s t o r i c a l conditions, it is recommended that accelerated stability data from a representative prechange batch be submitted for comparison. General stability consideration 58

59. It is also recommended that under these circumstances, all available long-term data on test batches from ongoing studies be provided in the supplement. Submission of historical accelerated and available long-term data would facilitate review and approval of the supplement. General stability consideration 59

60. 3. A commitment should be included to conduct long-term stability studies through the expiration dating period, according to the approved protocol, on either the first or first three (see section III-VI for details) production batches, and to report the results in subsequent annual reports. General stability consideration 60

61. The Role of In Vitro Release Testing The key parameter for any drug product is its efficacy as demonstrated in controlled clinical trials. The time and expense associated with such trials make them unsuitable as routine quality control methods. Therefore, in vitro surrogate tests are often used to assure that product quality and performance are maintained over time and in the presence of change. 61

62. A variety of physical and chemical tests commonly performed on semisolid products and their components (e.g., solubility, particle size and crystalline form of the active component, viscosity, and homogeneity of the product) have historically provided reasonable evidence of consistent performance. More recently, in vitro release testing has shown promise as a means to comprehensively assure consistent delivery of the active component(s) from semisolid products. The Role of In Vitro Release Testing 62

63. combined effect of several physical A n i n v i t ro r e l ea s e r a t e c a n r e f l ec t t he an d chemical parameters, including solubility and particle size of the active ingredient and rheological properties of the dosage form. In most cases, in vitro release rate is a useful test to assess product sameness between prechange and postchange products. The Role of In Vitro Release Testing 63

64. However, there may be instances where it is not suitable for this purpose. In such cases, other physical and chemical tests to be used as measures of sameness should be proposed and discussed with the Agency. With any test, the metrics and statistical approaches to documentation of “sameness” in quality attributes should be considered The Role of In Vitro Release Testing 64

65. The evidence available at this time for the in vitro-in vivo correlation of release tests for semisolid dosage forms is not as convincing as that for in vitro dissolution as a surrogate for in vivo bioavailability of solid oral dosage forms. Therefore, the Center’s current position concerning in vitro release testing is as follows: The Role of In Vitro Release Testing 65

66. In vitro release testing is a useful test to assess product “sameness” under certain scale-up and postapproval changes for semisolid products. The development and validation of an in vitro release test are not required for approval of an NDA, ANDA or AADA nor is the in vitro release test required as a routine batch-to-batch quality control test. The Role of In Vitro Release Testing 66

67. In vitro release testing, alone, is not a surrogate test for in vivo bioavailability or bioequivalence. The in vitro release rate should not be used for comparing different formulations across manufacturers . The Role of In Vitro Release Testing 67

68. Scale-Up and Post-Approval Changes (SUPAC ) Guidelines:- Level 1 is defined as a: Change in batch size, up to and including a factor of 10 times the size of the pilot/ biobatch , where: The equipment used to produce the test batch( es ) is of the same design and operating principles The batch( es ) is (are) manufactured in full compliance with cGMPs The same standard operating procedures and controls, as well as the same formulation and manufacturing procedures, are used on the test batch( es ) and on the full-scale production batch( es ) Level 2 discusses Changes in batch size beyond a factor of 10 times the size of the pilot/ biobatch . Otherwise, requirements of level 2 are similar to level 1 requirements.

69. Level 1 requires:  Chemistry documentation application/compendia release requirements Notification of change and submission of updated batch records in annual report One batch on long-term stability reported in annual report No dissolution or  in vivo  testing Filing documentation: annual report (long-term stability commitment)

70. Level 2 additionally requires: Stability testing: one batch with three months accelerated stability data and one batch on long-term stability Dissolution documentation: case B testing Filing documentation: prior approval supplement; annual report

71. Changes in process or formulation that go beyond straightforward scaling may require costly clinical and  bioclinical studies to prove safety and efficacy and a prior approval statement from the FDA, which notifies you that the agency has accepted your changes. Although this may take six months or more, it may be possible to delay process validation while waiting on the results of a stability program and use the time pending FDA approval for developing validation and commercial launch or supply plans. Next Time: Part 3 — Scale-Up Checklist

72. Introduction to Platform Technology:- Platform technologies  are considered a valuable tool to improve efficiency and quality in drug product development. The basic idea is that a  platform , in combination with a risk-based approach, is the most systematic method to leverage prior knowledge for a given new molecule.

73. Ref e rence T h e t h e ory & p r a cti c e o f in d u s t ri a l pha r m a cy b y L eo n L ac h m a n, H e r b er t A . L i e b e r m an , 3 rd J o s ep h L. ke ni g , ed i t i o n , pub l i s he d b y Varghese Publishing house. an d pr ac t i c e o f L ach m a n L. The T he ory industrial pharmacy. 3 rd E d itio n. Va r ghe se publication house. www.google.com 73

74. 74 .