VALIDATION OF PROCESSING TECHNIQUES

By Ch.Sandhya

Steps for validation and acceptance criteria in wet granulation process

1. Mixing or Blending ensures production of uniform mixture of active pharmaceutical ingredients and excipients that do not segregate post blending. So this step is carefully scrutinized and validated.

• Parameters to consider: Mixing or blending technique Mixing or blending speed Mixing or blending time: Drug uniformity Excipient uniformity Equipment capacity/load .

1. Mixing or Blending - Material have similar physical properties will be easier to form a uniform mix or blend as compare to difference in properties.

2. Techniques- 1- diffusion(tumble) 2- convection(planetary or high intensity or fluid bed. Mixing or blending depending on various factor- (a)Mixing speed - mixing the drug & excipient will require more intense mixing than adding the lubricant to the final blend. (b)Mixing time - mixing time will be dependent on the mixing technique & speed.

• If over mixed occured at the result demixing or segregation of the material. (c)Drug uniformity - handling of the material is key in obtaining valid content uniformity results . • Segregation of the sample can occur by handling resulting inaccurate results. • Sample should be equivalent to the weight of a single tablet. (d)Excipient uniformity - excipient need to be uniform in the granulation. Two keys excipient are- (A)-LUBRICANT- lubricant needs to be distributed uniformly in the mixture/granulation for high speed compression operation

Uneven distribution of the lubricant can result in picking & sticking problem during compresion. (B)Color-evenly distributed in the mixture so the tablets have a uniform appreance (color,hue & intensity) • Uniform dispersed in the blend prior to compression to avoid shading(molting). (e)Equipment capacity/load-the bulk density of material will affect the capacity of the equipment . • Undercharging or overcharging a blender can result in poor drug or tablet lubricant distribution.

2. Wet Granulation : Wet granulation parameters to be considered during development and validation are: Binder addition Binder concentration Amount of binder solution/granulating solvent Binder solution/granulating solvent addition Mixing time Granulation end point

Wet granulation parameters to be considered during development and validation are:Binder concentration and addition: 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 diluted enough so that it can be pumped through the nozzle. It should also be sufficiently concentrated to form granules without overwetting the materials.Amount of binder solution: how much binder or solvent solution is required to granulate the materials?. Too much binder or solvent solution will over wet the materials and prolong the drying time.

Binder solution addition rate: Define the rate at which the binder solution can be added to the material. Mixing time: How long the material should be mixed to ensure proper formation of granules. Over mixing the granulation can lead to harder granules and a lower dissolution rate. Granulation end point: How is the granulation end point determined? Is it controlled by specifying critical processing parameters?. •EQUIPMENT VALIDATION:•MIXER/GRANULATOR: • a. What is the method of mixing (e.g., planetary, pneumatic)?

• b. Is the equipment capable of providing low and/or high shear to the material? •c. Can the mixing be varied (e.g., changing the rpm of the impeller)? • d. Does the mixer/granulator have a monitoring system (e.g., end point detection) or can it accommodate one? e. What is the working load range and capacity of the equipment? f. How is material charged and discharged from the unit? Is it manual, semi-automated, or automated? g. Are there options to introduce the granulating fluid (e.g., dump, meter, or spray)?

3. Drying The type of drying technique (e.g., tray, fluid bed, and microwave) required for the formulation needs to be determined and justified. The type of technique may be dependent on such factors as drug or formulation properties and equipment availability. Changing dryer techniques could affect such tablet properties as hardness, disintegration, dissolution, and stability. The optimal moisture content of the dried granulation needs to be determined. High moisture content can result in tablet picking or sticking to tablet punch surfaces and poor chemical stability as a result of hydrolysis.

An over dried granulation could result in poor hardness and friability. Moisture content analysis can he performed using the conventional loss-on-drying techniques or such state-of-the-art techniques as near infrared (NIR) spectroscopy. Factors to be considered are: 1. Inlet/outlet temperature 2. Airflow 3. Moisture uniformity 4. Equipment capability/capacity

(A) Inlet/outlet temp.• Inlet temp.should be set high enough to maximinise drying without affecting the physical/chemical stability. • The outlet temp. is an indicator of the granulation temp. & insufficient air flow could prolong drying will increase toward the inlet temp.as the moisture content of the granulation decreases (evaporization rate). (B) Air flow & moisture content could vary within the granulation • Drying also affect the moisture in the granulation.

•EQUIPMENT EVALUATION • DRYER • a. What is the operating principle of the dryer (e.g., direct heating—fluid bed, indirect conduction—tray, or indirect radiant—microwave)? • b. Will the wet material be static (e.g., tray) or fluid (e.g., fluid bed)? • c. What is the working load range and capacity of the equipment? • d. What is the heating range and airflow capabilities of the equipment? •

•e. What is the heat distribution of the unit? Are there any hot and/ or cold spots?• f. Can the unit pull a vacuum? What is the vacuum range of the unit? • g. Can the equipment handle different types of filter bags? For example, can a filter bag be dedicated to a particular product?

4. Tablet Compression Compression is a critical step in the production of a tablet dosage form. The materials being compressed will need to have adequate flow and compression properties. The material should readily flow from the hopper onto the feed frame and into the dies. Inadequate flow can result in “rat holing” in the hopper and/or segregation of the blend in the hopper/feed frame. This can cause tablet weight and content uniformity problems. Factors to consider during compression are as follows: Tooling Compression speed Compression/ejection force

• Tooling: The shape, size and concavity of the tooling should be examined. • Compression speed and force: compression speed of the tablet press is adjusted based on the flow rate of the granulation, tablet weight required and tablet hardness required.• TABLET COMPRESSION MACHINE • a.How many compression stations does the

compressor have? • b. What is the operating range (rpm) of the unit? • c. What is the output range of the compressor (e.g.,

tablets per min)? Will the unit meet the demands (sales forecast) for the product?

•d. What kind of powder feeding capabilities does the equipment have (e.g., gravity, power-assisted, or centrifugal)? Can this capability be altered or controlled (e.g., open feed frame, forced below feeder)? • e. What is the compression force range of the equipment? f. Is the equipment capable of monitoring compression and ejection force? g. Does the unit have precompression capabilities? h. How long can the equipment operate without routine maintenance?