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Validation of dry mixing and tablet production processing

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1. What is validation and why is it necessary?

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.This article focuses on the process of dry mixing of powders, as one of the steps in producing tablets.Validation can therefore be applied to the dry mixing process itself, as well as the overall manufacture of tablets.

2.What are the benefits of validation?

A successful validation of process and equipment provides a high degree of assurance that a consistent level of quality is maintained in each unit of the finished product from one batch to another batch.

Successful validation of a process can result in a reduction of sampling and testing procedures and hence fewer product rejections and the need for retesting. The lower rejection rate leads to cost-saving benefits.For compliance to current good manufacturing practices, validation is essential.

3.How important is validation of dry mixing in the tablet production process?

Dry mixing is usually the first step in tablet production and it is therefore of paramount importance that the quality of mix is of the highest standard if high quality tablets are to be produced. All of the steps in tablet production are of course important, and the manufacturing company should not lose sight of all of the process steps, and that to validate each one will lead to the best outcome.The process steps and suggested validation protocols for each step are outlined in the table below.

No.

Step description

Control variable to be monitored

Measured response to be tested

1

Dry mixing or pre-blending

Blending time, RPM, load size, order of addition of components

Blend uniformity

2

Granulation

Mixing speed, feed rate,granulation time, load

API distribution, water or solvent content, particle size distribution

3

Drying

Initial temperature, drying temperature, final temperature

Particle size distribution, density, loss on drying, assay (for heat sensitive materials)

4

Milling

Screen size, milling speed, feed rate

Particle size, distribution/shape,

5

Lubrication

Blend time, blender speed, load

Particle size, distribution/shape, flow properties

6

Tableting

Compression rate, granule feed rate, pre-compression force, compression force

Appearance, weight variation, hardness, friability, thickness, moisture content, dissolution/disintegration,assay dose uniformity

7

Coating

Pan load, inlet/exhaust temperatures, inlet/exhaust humidity, pan speed, atomising pressure, spray rate

Weight gain, thickness of coating, dissolution assay, degradation level, residual solvent.

4.How is dry mixing validated?

The mixing of API and excipients is perhaps the most critical step in the solid dosage form preparations that affect the content uniformity of the finished product.Mixing can be carried out using :

  • V cone blenders
  • Double cone blenders
  • Drum mixer
  • Ribbon blenders
  • Conical screw mixer
  • Tumble blender
  • Convection (planetary mill or high high intensity mixer or fluidized bed mixer)

Each type of blender is usually validated or qualified at different stages, for example:

  • During design or development
    • Documented verification of the design of equipment and manufacturing facilities.
  • Installation Qualification
    • Documented verification of the system design and adherence to manufacturer’s recommendations.
  • Operational Qualification
    • Documented verification of equipment or system performance in the target operating range.
  • Process Performance Qualification
    • Process validation can be defined as means of challenging a process during devlopment 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 processesemployed has been optimized, so that the data generated through the testing program may be considered credible and evaluated for consistency as well as relevance.
  • Change Control
    • Equipment must be re-validated if significant changes are made to the equipment or the way that it is used.

Each type of blender presents different issues in terms of validation. The most important parameters to be monitored are:

1.Particle sizes and uniformity of the original materials (API and excipents).Handling of material is key to obtaining valid content uniformity results.Sample size taken should be equivalent to the weight of a single tablet.

2.Mixing speed- mixing of drug and excipient requires more intense mixing than adding the lubricant to the final blend.

3. Mixing Time – this depends on mixing technique and speed.

4. Equipment – note that the bulk density of material will affect the capacity of the equipment.In validating mixing equipment, attention should be given to the following:

  • Operating criteria must be adequate
  • Spares should be available
  • Equipment should be easily maintained
  • Equipment should not disseminate dust
  • Capital and running costs should be as low as practical
  • Equipment must have non reactive surfaces
  • Mixing speeds must be adequate.

5. Uniformity of blended material.

This parameter is perhaps the most important to measure.It is not easy, however, to define as it is both a physical (size, shape), and chemical (composition) property.Blend and can therefore be problematic in quantifying.Many papers and conferences have indeed been devoted to the subject of powder blend uniformity and a paper reviewing the subject was published in February 2017*.A protocol for measuring blend uniformity should be agreed with the Quality control department and analytical methods adapted according to the type of drug being produced. At the end of a mixing batch, samples should be taken and passed to a QA department to check uniformity of chemical composition, e.g., measure the concentration of API in each sample,measure bulk density and particle size analysis (sieve analysis).

Some techniques have been developed to measure uniformity during the mixing process itself. Most notable of these are near infra-red spectroscopy, Raman spectroscopy, and Microscopic FTIR mapping.

5.What are the basic validation requirements?

In evaluating a mixing process it is important to consider the worst case in all measurable parameters.These include maximum and minimum mixer load, maximum and minimum speed (rpm), maximum and minimum mixing time.In each case samples should be taken of the mixture that represent the whole of the mixed material within the equipment. A sampling protocol should be agreed by all parties. For example, samples should be taken from the top, middle and bottom of the mixed bed of material as illustrated below. Duplicates should be taken and analysed to avoid sampling bias.

For initial qualification or validation of equipment the following are the minimum requirements:

  • Equipment name, make and model No. shall be recorded.
  • Location for the installed equipment should be checked.
  • A record should be made of all the required utilities (e.g., electricity, compressed air, gases, water).
  • Any deviation observed while following the installation procedure should be recorded in case corrective action is required.
  • After checking all the specifications as mentioned in the selection criteria, service engineer shall commission the equipment.
  • Authorized validation team shall carry out installation checks.

For operational qualification of the mixer the following are required:

  • After completions of successful installation qualification initiate the actual operation of to ensure that machine is operating within specification.
  • Check the operation qualification parameters against the manufacturers specifications.
  • Document any deviation from specifications.
  • The Quality head and the department head should decide whether deviation is acceptable or not.

To validate mixer performance:

  • Load the materials to be mixed in the mixer
  • Start the mixer and rotate it for the time as mentioned in the BMR.
  • After completion of mixing switch OFF the mixer and separate out the drum.
  • Collect the sample as per sampling procedure.
  • Send the samples to Quality control dept. for blend uniformity, bulk density and sieve analysis.

* Pramote Cholayudth, 2017, Establishing Blend Uniformity Acceptance Criteria for Oral Solid-Dosage Forms,Pharmaceutical Technology, Volume 41, Issue 2, pp. 42-52.