analysis 2

• In-process control


  A standard component of the QA/QC systems throughout the pharmaceutical manufacturing
• Why in-process control is important

  • To check consistency of the product
• Weigh in process product

  Weight of all the products
• In-process control activities


  1. Sampling

  2. Testing

  3. Inspection after every significant stage of the manufacturing process
• Test for deliverable volume


  Prior to filling liquid/product to the bottle
• Finished packages shall be checked throughout the run at regular intervals
• Frequency of in-process checking

  • For high tech and newer machines, check every hour. For manual processes or primitive machines, check every 30 mins.
  • After a power outage, in-process checking should be done
• Written procedures for in-process control

  1. Specs to be checked (consistent with FP specs)

  2. Limits of acceptability of each spec determined by the application of suitable statistical methods
• Test results outside the acceptable limits indicate a process variation problem either in the manufacturing or analytical procedures, which should be investigated and corrected
• Results of in-process tests shall be recorded to become part of the batch record
• Work instructions should define the procedure to follow and on how to utilize the inspection & test data to control the process
• Out-of-specification (OOS) investigations should be conducted
• Sampling for in-process materials

  • Specified sample size
  • Prescribe an increased sampling rate where in-process materials do not appear to be homogeneous
  • Specify the extent of collection of samples for chemical tests - Frequency of sampling
• If there is not a good distribution of active ingredient, there is also not a good distribution of dosage strength
• In-process testing


  1. Product name

  2. Batch/Lot No.

  3. Tests to be conducted: identity, strength, purity and quality as appropriate
• The in-process specs shall be consistent with the FP specs
• Granules testing


  • Moisture content determination using a moisture balance
  • Sieve (screen analysis) to determine particle size distribution
• Tablet compression testing


  • Individual weight determination
  • Average unit weight determination
  • Diameter measurement
  • Disintegration test
• Friability test


  Measures the ability of the tablet to withstand abrasion in packaging, handling, and shipping. Requirement: should not be more than 1.0%
• Hardness test


  Measures the degree of force required to break a tablet. Requirement: usually between 4.0kg/cm2 and 9.0 kg/cm2
• Tablet thickness


  Can vary with no change in weight due to difference in granulation density, pressure applied, and compression speed. A plus or minus 5% may be allowed depending on the tablet size
• Physical defects in tablets

  Contaminations, capping, lamination, picking, sticking, mottling
• In-process testing for syrups/liquid preparations

  Clarity & completeness of solution, color, flavor, pH, specific gravity, viscosity, homogeneity, final batch volume
• In-process testing for capsules

  Average unit weight, individual unit weight, disintegration time
• In-process testing for creams, ointments, semi-solids


  Appearance, homogeneity, color, odour, pH, viscosity, final batch weight
• When determining the frequency of sampling & testing, consideration should be given to the precision of machine, speed of the process, and batch size
• The determination of tolerance limits & in-process material specifications should be derived from the best result obtained from previous acceptable batches and should be consistent with the finished product specifications
• Due considerations should be given to experimental results obtained for the mean and standard deviation in determining the realistic specification limits
• In-process control is important to ensure batch uniformity & integrity of the product
• PICS/GMP requirement for finished product specification

  • Designated name of the product and code reference
  • Formula
  • Description of the pharmaceutical form and package details
  • Directions for sampling and testing
  • Qualitative and quantitative requirements, with the acceptance limits
  • Storage conditions and any special handling precautions
  • Shelf-life
• Finished product specification should include or provide reference to the PICS/GMP requirements
• Monograph


  A written standard that describes an article (e.g. drug substance, drug product, excipient, compounded preparation), which provides the name of substances, its definition, package and storage, labeling requirements, information on tests needed to ensure the substances is of appropriate identity, strength, quality and purity
• There's no toxicology in monographs because the precautions in the monograph indicate that the substance will not be toxic if used as directed
• Release testing


  Tests used for checking quality of the substance or preparations prior to using, distribution or release for consumption
• Stability testing


  Tests used to determine the quality of the substance or preparations during the shelf-life until its expiry date
• Classification of testing based on nature of performance

  • Chemical test
  • Physical test
  • Microbiological test
• Classification of testing based on attribute being tested

  • General quality attributes
  • Product performance
• General test classification


  • Identity test
  • Limit test
  • Potency test
  • Packaging test
  • Dosage form specific test
• Identity test


  Physical method, chemical method, instrumental method
• Limit test


  Gross impurities, chemical impurities, biological impurities