Presentation Transcript

1. ASEMINARON PROCESS VALIDATION OF OINTMENT/CREAM FORMULATION

2. Why need of process validation for ointment/cream? • Product bio burden high? • Multiple
component? • More adequate preservative system? • All have Newtonian flow behavior? •
History: Zinc oxide rash cream that was heated to a relatively high temperature solely by the
action of rotating mixing plate.
3. Ointment Cream Viscous emulsion of semisolid consistency intended for application to skin
and mucus membrane. Appearance: Translucent Type: oil-in-water(o/w) water-in-oil(w/o) •
Soft, semisolid preparation intended for application to skin and mucus membrane.
Appearance: Opaque Type: Oleaginous bases Absorption bases Emulsion bases Water
soluble bases
4. ● Processes must be validated in pharmaceutical manufacturing are: • Cleaning •
Sanitization • Fumigation • Depyrogenation • Sterilization • Sterile filling • Fermentation • Bulk
production • Purification • Filling, capping, sealing • Lyophilization
5. Process Validation • Documentedevidence, a high degree of assurance that a specific
process will consistently produce a product that meets its predeterminedspecification and
quality characteristics.
6. Process Validation Program
7. cont..
8. Process validation • WHY ENFORCE IT? • WHEN IS IT PERFORMED? • WHO
PERFORMS IT?
9. Why? • Makes good engineering sense. • Results in fewer product recalls and troubleshooting
assignments in manufacturing operations. • Results in more technically and economically
sound products and their manufacturing processes.
10. When?
11. Who? • Formulation development • Process development • Pharmaceutical manufacturing •
Engineering • QA • QC • API operations • Regulatory affairs • IT operations
12. ORDER OF PRIORITY • Sterileproducts and their processes(High Risk) 1) LVP 2) SVP 3)
Ophthalmic, other sterile products and medical devices B. Non- sterileproducts and their
processes(Low Risk) 1) Low dose/high potency tablets and capsules/ TDDS 2) Drugs with
stability problems 3) Other tablets and capsules 4) Oral liquids , topical ointment and cream 5)
Diagnostic aids
13. Validation Protocol • Written plan describing the process to be validated, including
production equipment. • How validation will be conducted • Objective test parameter • Product
characteristics • Predetermine specification • Factors affecting acceptable result
14. Protocol for validation of manufacturing process • Purpose and prerequisite for validation
• Presentation of the whole process and sub processes including flow diagram and critical
step analysis • Validation protocol approvals • Installation and Operation qualification •
Qualification reports including method, procedure, release criteria, calibration of test
equipment, test data, summary of result.
15. Cont.. • Product qualification test data from prevalidation batches • Test data from formal
validation batches • Sampling plan - where, when and how the samples to be taken •
Evaluation of test data, conclusion • Any need for requalification and revalidation •
Certification and approval • Summary report of finding with conclusion • Copies of product
stability
16. Components Included in cGMP Process Validation All should be validated. • Facility •
Environment • People • Analytical laboratory • Raw materials • Equipment • Procedures •
Process
17. Process Validation Option • Prospective Process Validation- performed before the process
is put into commercial use • Retrospective Validation- done for established products whose
manufacturing processes are considered stable • Concurrent validation- in process monitoring
of critical processing steps and end product testing of current production
18. Revalidation - change in critical component(raw material) - change or replacement in a
critical piece of equipment. - change in a facility and/or plant - significant increase or decrease
in batch size - sequential batches that fail to meet product and process specifications
19. Semisolids manufacturing consideration 1) Flow diagram Combine water soluble
ingredient in auxiliary kettle. Heat to critical temperature Transfer water phase by pump
Combine oil soluble ingredient in main kettle. Heat to critical temperature. Counter sweep
agitation Homogenize or pass thru colloid mill while warm. Cool slowly with counter sweep
agitator Filling and packaging operation Transfer finished product by pump into drum or tank
21. 2) Unit Operation for semisolid System • Five unit operation • Mixing of liquid • Mixing of
solid • Mixing of semisolid • Dispersing • Milling and size reduction of solid and semisolid
22. 1. Mixing of Liquids Equipment: Kettle and tank fitted with agitator
23. 2. Mixing and Blending of Solid Equipment: Blade mixture and tumbler
24. 3. Mixing and Blending of semisolid Equipment: Blade mixture and knider
25. 4. Dispersing Equipment: Homogenizers, Colloid mill, or ultrasonic device
26. 5. Size Reduction of Solid and Semisolid Equipment: end-runner mill, hammer mill, ball
mill, colloid mill, micronizer
27. 3)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 operations 2. Proper agitation in holding tanks and filling heads in order to main
product uniformity and homogeneity during filling and packaging operation • The use of air
pressure and inertatmosphere to achieve product performance and stability in the primary
container.
28. Product testing • 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.
29. 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 shafts where product movement during
mixing may restricted. • The bottom of the tank and any potential dead spots should be
sampled and examined for unmixed material, if possible.
30. Sampling Plan Samples must be representative of each filling 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
31. OTHER SAMPLING PATTERN • Ten equidistant points across the filling run must be
sampled. • The beginning and end of filling must be represented. • Samples should be taken
in triplicate.
32. Monitoring Output • Particle size Consideration Control of particle morphology and particle
size are important parameters to attain high quality drug product manufacture and control
procedure. Particle size distribution for most disperse system should be in the range of 0.2-20
microns.
33. 2) Viscosity The Viscometer- Calibrated to measure the apparent viscosity of the disperse
system at equilibrium at a given temperature to establish system reproducibility.
34. 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).
36. 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 in manufacture of disperse
system.
37. 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.
38. Validation Report • STANDARD FORMAT • Executive summary • Discussion • Conclusions
& 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.
39. References • Lieberman H. A. , Rieger M. M. and Banker G. S. “Pharmaceutical Dosage
Forms: Disperse System” ,vol.3; Second Edition,473-511 • R. A. Nash and A. H. Wachter
“Pharmaceutical process validation”; Third edition • Agalloco James, Carleton J. Fredric
“Validation of Pharmaceutical Processes”; Third edition,417-428