IPQC: Definition:-

1

• IPQC Definition-
• Checks performed during production in order to
  monitor and, if necessary, to adjust the process
  to ensure that the product conforms to its
  specifications. The control of the environment or
  equipment may also be regarded as a part of
  inprocess control.
• In-process controls are usually performed within
  the production area. The performance of such
  in-process controls should not have any negative
  effect on the quality of the product or another
  product.

2

• IPQC-
• In-process inspection and testing should be
  performed by monitoring the process or by actual
  sample analysis at defined locations and times.
  The results should conform to established process
  parameters or acceptable tolerances.
• Work instructions should delineate the procedure
  to follow and how to use the inspection and test
  data to control the process.

3

• Introduction-
• IPQC is concerned with providing accurate,
  specific, and definite description of procedures
  to be employed from the receipt of raw materials
  to the release of finished dosage forms.
• It is a planned system to identify the materials,
  equipment, process, and operations.
• In general the in process control procedures are
  usually rapid and simple tests or inspections
  that are performed when the manufacturing of a
  product batch is in progress.

4

• It is an imp function of IPQA programme to ensure
  that the finished dosage forms have uniformity,
  purity, and quality within batch and between
  batch.
• Is accomplished by identifying critical steps in
  manufacturing and controlling them within defined
  limits.

5

• IPQC aims to increase the assurance of batch
  uniformity.
• There must be written procedure describing the
  control and test or examination to be conducted.
• In process specification/controls must be
  rational and consistence with the finished
  product specification.
• They derived from previous validated process
  variations.

6
OBJECTIVE

• To minimize the human errors.
• Provides accurate, specific, and definite
  description of the procedure to be employed.
• To detect the errors if and when it does occur.
• Corrective action instituted by people.
• To pin point the responsibility to the personnel
  involved in the operation of the entire process.
• To enforce the flow of manufacturing and packing
  operations according to established routes and
  practice.
• Rigidly followed.
• Should detect any abnormality immediately and at
  the same time indicate the kind of action needed
  to correct the problem.

7
DIFFERENT TYPES OF IN-PROCESS CONTROL

• Environmental control
• Building and equipment control
• Control of records
• Manufacturing control
• Packaging control
• Labeling control
• Warehousing control
• Finished product control

8
IPQC on sterile product, parenteral preparation
and sterile ophthalmic preparations.

• General-
• Sterile products being very critical and
  sensitive in nature, a very high degree of
  precaution, prevention and preparation are
  needed.
• Dampness, dirt, and darkness are to be avoided to
  ensure aseptic condition.
• Environmental Monitoring and Environmental
  control-
• The recommended frequencies of periodic
  monitoring shall be as follows
• Particulate monitoring in air - 6 Monthly

9

• HEPA filter integrity testing(smoke testing)
  -Yearly.
• Air changes rates - 6 Monthly
• Air pressure differentials - Daily.
• Temperature and humidity - Daily.
• Microbiological monitoring by settle plate and/or
  swabs in aseptic areas daily, and at decreased
  frequency in other areas.
• There shall be written environmental monitoring
  programme and microbiological results shall be
  recorded.

10

• Recommended limits for microbiological monitoring
  of clean areas in operation are as given in the
  table below

Grade Air sample Cfu/m3 Settle plates (dia.90 mm) Cfu/2 hrs. Contact plates (dia.55 mm) Cfu/plate Glove points (five fingers) cfu/gloves
A lt1 lt1 lt1 lt1
B 10 5 5 5
C 100 50 25 -
D 500 100 50 -
11

• Appropriate action shall be taken immediately if
  the result of particulate and microbiological
  monitoring indicates that the counts exceeds the
  limits.
• The SOP shall contain corrective action.
• Sanitation-
• There shall be written procedure for the
  sanitation of sterile processing facilities.
• Employees carrying out sanitation of aseptic
  areas shall be trained specially for this
  purpose.
• Different sanitation agents shall be used in
  rotation

12

• Equipment-
• SOP shall be available for each equipment for its
  calibration and operation and cleaning.
• Gauges and other measuring devices attached to
  equipment shall be calibrated at suitable
  interval against a written programme.
• Water and steam systems-
• Potable water - meeting microbiological
  specification of not more than 500 cfu/ml and
  indicating absence of individual pathogenic
  micro-organism.

13

• Purified water prepared by demineralization
  shall meet the microbiological specification of
  not more than 100 cfu/ml and indicates absence of
  pathogenic micro-organism in 100 ml.
• Water for injection shall be prepared from
  potable water or purified water meeting the above
  specification by distillation.
• WFI shall meet microbiological specification of
  not more than 10 cfu/100 ml.
• Bulk solution of liquid parenteral shall be made
  in WFI.
• It also meets IP specification for WFI.

14

• Water for non injectable sterile products
• Like eye drops shall meet IP specification for
  purified water.
• In addition microbiological specification of not
  more than 10 cfu/100ml and absence of pseudomonas
  aeruginosa and e. coli in 100 ml shall also meet.
• Steam coming in contact with the product, primary
  containers and other products.
• Contact surface shall be sterile and Pyrogen
  free.
• The steam condensate shall meet microbiological
  specification of not more than 10 cfu/100ml.

15

• Manufacturing process-
• Bulk raw material shall be monitored for
  bio-burden periodically.
• Bio-burden of bulk solution prior to membrane
  filtration shall be monitored and a limit of not
  more than 100 cfu/ml is recommended.
• Gases coming in contact with the sterile product
  shall be filtered through two 0.22 µ filters
  connected in series.
• These filter shall be tested for integrity.

16

• Sterilization (autoclaving)-
• Sterilization process shall be validated
  appropriately.
• The validity of the process shall be verified at
  regular interval, but at least annually.
• Whenever significant modification have been made
  to the equipment and product, records shall be
  maintained thereof.
• The use of biological indicator shall be
  considered as an additional method for monitoring
  the sterilization.

17

• Sterilization ( By Dry Heat )-
• Each heat sterilization cycle shall be recorded
  on a time/temperature chart of a suitable size by
  appropriate equipment of the required accuracy
  and precision.
• The position of temperature probes used for
  controlling and/or recording shall be determined
  during the validation.
• Sterilization ( By Moist Heat )-
• Both the temp and pressure shall be used to
  monitoring the process.

18

• Control instrumentation shall normally be
  independent of monitoring instrumentation and
  recording charts.
• System and cycle fault shall be registered by the
  system and observed by the operator.
• Frequent leak test done on the chamber during the
  vacuum phase of the cycle.
• Product container and closures-
• All container and closures intended for use shall
  comply with the pharmacopoeia and other specified
  requirement.

19

• Suitable sample sizes, specification, test
  methods, cleaning procedures, sterilization
  procedures, shall be used to assure that
  container and closures other components part of
  drug packages are suitable are not reactive,
  additive, absorptive, or leachable.
• Finished product control-
• Checking the bulk solution before filling, pH,
  color and completeness of solution.
• Checking the filled volume of liquid or filled
  weight of sterile powder for injection in the
  final container at the predetermined interval
  during filling operation.

20

• Testing for the leakage of flame sealed ampoules.
• Subjecting the product to physical examination,
  for appearance, clarity, particulate
  contamination.
• Sterility testing procedure- determines
• Physical condition of testing room.
• Laboratory procedure for handling sterile
  samples.
• Use of UV lights.
• No. of units tested per batch.
• Procedure for identifying test media with
  specific batches.

21

• Pyrogen testing procedure.
• Determine if animal involved in positive Pyrogen
  test are withdrawn from use for the required
  period.
• Indicators
• Determine type of indicator used to assure
  sterility, such as lag thermometer, peak control,
  test cultures, biological indicators.
• If biological indicators are used, review the
  current USP on sterilization and biological
  indicators.
• In some cases testing biological indicators may
  become all or part of the sterility testing.

22

• Particulate matter testing-
• Particulate matter consist of extraneous, mobile,
  undissolved substance, other than gas bubbles,
  unintentionally present in parenteral solution.
• Cleanliness specification or levels of non-viable
  particulate contamination must be established.
• The levels of particulate contamination in
  sterile powder are generally greater than in LVP.
• LVP solution are filtered during the filling
  operation.

23
IPQC ON ORAL LIQuIDS

• Building and equipment-
• Manufacturing area shall have entry through
  double door air lock facility.
• It shall be made by fly proof by use of fly
  catcher and/or air curtain.
• Tank, container, pipe work and pumps shall be
  designed and installed so that they can be easily
  cleaned and sanitized.
• Purified water-
• The chemical and microbiological quality of
  purified water used shall be specified and
  monitored routinely.

24

• The microbiological evaluation include testing
  for absence of pathogens and shall not exceeds
  100 cfu/ml.
• There shall be written procedure for operation
  and maintenance of the purified water system.
• Care shall be taken to avoid the risk of
  microbial proliferation with appropriate methods
  like recirculation, use of UV treatment,
  treatment with heat and sanitizing agent.

25

• Manufacturing-
• Care shall be taken to maintain the homogeneity
  of emulsion by use of of appropriate stirrer
  during filling.
• Mixing and filling processes shall be specified
  and monitored.
• The primary packaging area shall have an air
  supply, which is filtered through 5 micron
  filters.
• The temp of the area shall not exceed 30 .C

26

• Finished product protocol-
• Checking the bulk solution before filling, pH,
  color, sedimentation volume, viscosity
  completeness of solution.
• Use of water for cleaning shall be restricted
  controlled.
• Routinely used disinfectants are suitable for
  sanitizing the different areas.
• Equipments-
• Suitable check weights, spray testing machines,
  labeling machines shall be provided in the
  equipment.

27

• All the equipment shall be suitably calibrated
  and their performance validated on receipt and
  thereafter periodically.
• Manufacture-
• There shall be an approved master formula records
  for the manufacture of metered dose inhalers.
• All propellants, liquids gases shall be
  filtered through 2 µ filters to remove particle.

28
IPQC ON ACTIVE PHARMACEUTICAL INGREDIENTS.

• In process controls for chemical reaction may
  includes the following
• Reaction time or reaction completion
• Reaction mass appearance, clarity, completeness
  or pH solution.
• Reaction temperature.
• Concentration of the Reactant.
• Assay or purity of the product.
• Process completion check by TLC/any other means.

29

• In process controls for physical operation may
  includes the following
• Appearance and color.
• Uniformity of the blend.
• Temperature of a process.
• Concentration of a solution.
• Processing rate or time.
• Particle size analysis.
• bulk / tap density.
• pH determination.
• Moisture content.

30
IPQC ON METERED DOSE INHALERS.

• General-
• Manufacture shall be done under condition which
  shall ensure minimum microbial and particulate
  contamination.
• Assurance of the quality of components and the
  bulk products is very important, where medicament
  are in suspended state, uniformity of suspension
  shall be established.
• Building and civil work-
• The manufacturing area shall be segregated into
  change rooms for personnel, container preparation
  area, bulk preparation filling area, quarantine
  area, and spray testing packing area.

31

• Environmental condition-
• The requirements of temperature and humidity in
  the manufacturing area shall be decided depending
  on the type of product and propellant handled in
  the facility.
• There shall be difference in room pressure
  between the manufacturing area and the supported
  areas that is not less than 15 Pascal.
• Written scheduled for monitoring temp, humidity.
• Sanitation-
• Written procedures for the sanitation of the MDI
  manufacturing facility.
• Care taken to handle residues and rinses of
  propellants.