VALIDATION METHODS OF EQUIPMENT AND PROCESSING TECHNIQUES FOR MIXING, GRANULATION, DRYING, COMPRESSION,

FILTERATION AND FILLINGPresented ByAQSA FATIMA

M.Pharmacy 1st Year 2nd Semester15451S0602

Under the guidance ofV.M BALARAMM.Pharm, PhD

SULTAN UL ULOOM COLLEGE OF PHARMACY

VALIDATION

Validation is a key process for effective quality assurance.

“Validation is establishing documented evidence which provides a high degree of assurances that a specific process or equipment will consistently produce a product or result meeting its predetermined specifications and quality attributes.”

PROCESS VALIDATION:

Process validation can be defined as means of challenging a process during development to determine which variables can be controlled to ensure the consistency production of a product or intermediate.

It is based on the concept that the processed employed has been optimized, so that the data generated through the testing program may be considered credible and evaluated for consistency as well as relevance.

Types of Process Validation• Prospective validation:  -Conducted prior to market the product. - Documented evidence which provides a high degree of assurances that

a specific process or equipment will consistently produce a product meeting its predetermined specifications and quality attributes.

• Concurrent validation: - Based on information generated during actual implementation of the

process. - Establishing documented evidence that the process is in a state of

control during the actual implementation of the process. This normally performed by conducing in- process testing.

• Retrospective validation: All the processes and subsystems should be validated,

which have been used for the production of batches of numerical data of both process and the end product testing of which are included in retrospective validation

Process equipment used in the development phase is assessed relative to its suitability for large scale manufacture.

This protocol can be divided into • Design qualification• Installation qualification• Operation qualification• Performance qualification• Maintenance (calibration, cleaning, repair)

qualification

Design qualification (DQ): Documented verification of the design of equipment and manufacturing

facilities.

Installation qualification (IQ): Documented verification of the system design and adherence to manufacturer’s

recommendations.

Operational qualification (OQ): Documented verification of equipment or system performance in the target

operating range.

Process performance qualification (PQ): Documented verification that equipment system operates as expected under

routine production conditions. The operation is reproducible, reliable and in a state of control.

EQUIPMENT VALIDATION:A typical Validation Blueprint of Equipment validation:1. Installation qualification Facilities Utilities Equipment 2. Operation qualification Testing Protocols for Utilities and Equipment 3. Validation Testing protocols for products and Cleaning systems 4. Documentation5. Validation of the QA testing laboratory6. SOPs7. Training of personnel8. Organization charts9. Schedule of events.

INDUSTRIAL PROCESS OVERVIEW OF SOLID DOSAGE FORMS

Steps &Process parameter are following- MIXING OR BLENDING: Material have similar physical properties will be easier to form a

uniform mix or blend as compare to difference in properties. Techniques-1.Diffussion(tumble) 2.convection(planetary or high intensity or fluid bed). Mixing and blending depends upon various factors- 1.Mixing speed- Mixing of drug and excipient requires more intense mixing than

adding the lubricant to the final blend.

2.Mixing Time- depends on mixing technique and speed.

3.Drug and excipient uniformity- handling of material is key in obtaining valid content

uniformity results. Sample should be equivalent to the weight of a single tablet.

4.Equipment capacity - the bulk density of material will affect the capacity of

the equipment.

WET GRANULATIONwhat type of wet granulation to be used LOW SHEAR/ HIGH SHEAR/ FLUID BED

wet granulation parameters are • Binder addition: Adding the binder dry avoids the need to determine the optimal binder concentration and a separate manufacture for the binder solution.

• Binder concentration: The optimal binder concentration will need to be determined

for the formulation. If the binder is to be sprayed, the binder solution needs to be dilute enough so that it can be pumped through the spray nozzle.

• Amount of binder solution:The amount of binder solution is related to the binder

concentration.

• Granulation end point:Determined by ammeter and wattmeter equipment.

Drying is a most important step in the formulation and development of pharmaceutical product. It is important to keep the residual moisture low enough to prevent product deterioration and ensure free flowing properties.

Factors-• Inlet/outlet temp- inlet temp is set to high to minize drying with out effecting

physical/chemical parameters.• Airflow- insufficient air flow prolongs drying• Moisture uniformity- moisture content could vary in the granulation• Equipment capacity- high the load high moisture should be removed

DRYING

TABLET COMPRESSION- After the preparation of granules (in case of wet

granulation) or sized slugs (in case of dry granulation) or mixing of ingredients (in case of direct compression), they are compressed to get final product.

The compression is done either by single punch machine (stamping press) or by multi station machine (rotary press).

Factors-• compression speed- range of compression speed to determine the operating range

of the compressor.• compression or ejection force- determined optimal compression force to obtain the desired

tablet hardness.

The following in-process tests should be examined during the compression stage-

• Appearance• Hardness• Tablet weight• Friability-0.5-1%• Disintegration• Weight uniformity

FILTERATIONReproducibility of filtersIntegrity testOperating conditionsSheddingFilter inertnessToxicityConsistency and Reliability

FILLINGPerform installation qualificationProduct contact surfaces must be compatible with

the productRate of filling should be readily controllablePhysical characteristics of the powderPowder hopper agitation speed Vibration rate Vacuum setting Machine filling speed The need for lubricant fluids should be minimized by

use of limited friction bearing surfaces

EQUIPMENT EVALUATION

• Selection of equipments is based on;1. Formulation.2. Safety requirements.3. Handling / production efficiency.4. Commercial demands.

• Equipment should be qualified.• Cleaning procedure should be available.

MIXER / GRANULATOR:

1. What is the method of mixing?2. Capable to provide high / low shear?3. Can mixing be varied?4. Availability of monitoring system OR capability

to accommodate one?5. Working load range and capacity?6. How is material charged and discharged from

the unit?7. Are there options to introduce granulating

fluid?

BLENDER:1. Type of blender?2. Positioning of the axis of rotation?3. Working load range and capacity of the

equipment?4. Features for the ease of handling of powders?5. Can samples be easily taken from the unit? Can

samples be taken from more than one location?6. Are there dead spots?7. Can the equipment be easily cleaned?8. Can the equipment heat the powder if needed?

What is the heating source?

DRYER:1. What is the operating principle?2. Will the wet material be static or fluid?3. Working load range and capacity?4. Heating range and airflow capabilities?5. What is the heat distribution of the unit? Are

there any hot &/or cold spots?6. Can the unit pull a vacuum? What is the

vacuum range of the unit?7. Can the equipment handle different types of

filter bags?8. Filter bag shaking mechanisms with options?

MILLS:1. Type of mill?2. What is the configuration of the impact mill or screen

mill?3. What type or size of hammers or pin / disc can be used

on the unit?4. Can the impeller be positioned in different ways?5. What size screens or plates can be used on the unit?6. Is the speed on the impeller/screen variable? What is the

rpm range?7. What type of feed system is required? What feed rate

can unit handle?8. Can the unit handle wet &/or dry mill material?9. Does the unit generate a significant amount of heat,

possibly affecting the product?10.Is the unit portable?

TABLET COMPRESSION:1. How many compressing stations does the compressor

have?2. What is the operating & output range of the unit?3. Will the unit meet the future demand?4. What kind of powder feeding capabilities does the

equipment have? Can this capability be altered/controlled?5. What is the compression force range of the equipment?6. Is the equipment capable of monitoring compression and

ejection force?7. Does the unit have pre-compression capabilities?8. How long can the equipment operate without routine

maintenance?9. Does the equipment require special tooling or tools from

other equipment can fit?10.Protection to operator?

CONCLUSION• Solid dosage form validation should be part of

comprehensive validation program within an industry.

• The multidisciplinary validation team must identify the product and process characteristics that must be studied and incorporate specific validation tests to ensure that product will meet all quality, manufacturing and regulatory requirements.

• Continuous awareness of validation will produce reproducibility.

REFERENCES Pharmaceutical process validation, page no.: 170 – 184, 1 – 12; an

international 3rd edition, revised & expanded, edited by: Robert A. Nash, Alfred H. wachter, MARCEL DEKKER INC.

  Pharmaceutical dosage forms: tablets, volume 3, 2nd edition, revised and

expanded, edited by: Herbert A. Liebermann, Leon lachman, Joseph B. Schwartz, MARCEL DEKKER INC.

   Agalloco James, Carleton J. Fredric “Validation of Pharmaceutical Processes”  FDA. "Guidelines on General Principles of Process Validation".  Validation of Analysis Procedures. International Conference on

Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use