IN-PROCESS QUALITY CONTROL

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 in-process 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.

IN-PROCESS QUALITY CONTROL:

- 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 (indicate precisely) the procedure to follow and how to use
the inspection and test data to control the process.

OBJECTIVES

1. To minimize the human errors.

2. Provides accurate, specific, and definite description of the procedure to be employed.
3. To detect the errors if and when it does occur.
4. Corrective action instituted by people.
5. Should detect any abnormality immediately and at the same time indicate the kind of action
needed to correct the problem.

DIFFERENT TYPES OF IN-PROCESS CONTROL

1. Environmental control
2. Building and equipment control
3. Control of records
4. Manufacturing control
5. Packaging control
6. Labeling control
7. Warehousing control
8. Finished product control

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:

1. Particulate monitoring in air - 6 Monthly
2. HEPA filter integrity testing (smoke testing) -Yearly.
3. Air changes rates - 6 Monthly
4. Air pressure differentials - Daily
5. Temperature and humidity – Daily
6. Microbiological monitoring by settle plate and/or swabs in aseptic areas – daily, and at
decreased frequency in other areas.
7. There shall be written environmental monitoring program and microbiological results
shall be recorded.
- Appropriate action shall be taken immediately if the result of particulate and microbiological
monitoring indicates that the counts exceed 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

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 programmed.

Water and steam systems:

1. Potable water
- meeting microbiological specification of not more than 500 cfu/ml and indicating
absence of individual pathogenic micro-organism.
2. 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.
3. 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.
4. 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.
 5. 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.

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 filters shall be tested for integrity.

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 has 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.

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.
- 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.
- 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.
 Testing for the leakage of flame sealed ampoules.
 Subjecting the product to physical examination, for appearance, clarity, & particulate
contamination.

Sterility testing procedure:

- Determines
1. Physical condition of testing room.
2. Laboratory procedure for handling sterile samples.
3. Use of UV lights.
4. No. of units tested per batch.
5. Procedure for identifying test media with specific batches.
6. Pyrogen testing procedure.
7. 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.

Particulate matter testing:

- Particulate matter consists 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.

IN-PROCESS QUALITY CONTROL 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.

IN-PROCESS QUALITY CONTROL ON ORAL LIQUIDS

Purified water:
 - The chemical and microbiological quality of purified water used shall be specified and monitored
routinely.
- 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.

Manufacturing:

- Care shall be taken to maintain the homogeneity of emulsion by use 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 ⁰.C

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.

Equipment’s:

- Suitable check weights, spray testing machines, & labeling machines shall be provided in the
equipment.
- 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.

IN-PROCESS QUALITY CONTROL ON ACTIVE PHARMACEUTICAL INGREDIENTS

In process controls for chemical reaction may include 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.

In process controls for physical operation may include 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.

IN-PROCESS QUALITY CONTROL 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 is 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.

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.
 Physical / Chemical Stability Tests

These describes approaches to predicting how well cosmetics will resist common stresses such
as temperature extremes and light. Typically, manufacturers determine whether to perform such
specialized testing based on the vulnerabilities of the particular cosmetic product and its anticipated
shipping, storage display and use conditions. Common test procedures include:

Temperature Variations:

- High temperature testing is now commonly used as a predictor of long-term stability. Most
companies conduct their high temperature testing at 37oC (98F) and 45oC (113F). If a product is
stored at 45oC for three months (and exhibits acceptable stability) then it should be stable at
room temperature for two years. Of course, the product must be stored at 25oC (77F) for a
period of one year. A good control temperature is 4oC (39F) where most products will exhibit
excellent stability. The product should also be subjected to -10oC (14F) for three months.

Cycle Testing:

- The product should pass three cycles of temperature testing from -10oC (14F) to 25oC (77F).
Place the product at -10oC for 24 hours and place it at room temperature (25oC) for 24 hours.
This completes one cycle. If the product passes three cycles, then you can have a good degree of
confidence in the stability of the product. An even more rigorous test is a -10oC to 45oC five-
cycle test. This puts emulsions under a tremendous stress and, if it passes the test, indicates that
you have a really stable product.

Centrifuge Testing:

- The dispersed phase (of an oil-in-water emulsion) has a tendency to separate and rise to the top
of the emulsion forming a layer of oil droplets. This phenomenon is called creaming. Creaming is
one of the first signs of impending emulsion instability and should be taken seriously. A good
test method to predict creaming is centrifugation. Heat the emulsion to 50oC (122F) and
centrifuge it for thirty minutes at 3000 rpm. Then inspect the resultant product for signs of
creaming. This test is an absolute necessity for those products that contain powders of any kind
such as liquid/cream make-up.

Light Exposure Testing:

- Both formulas and packaging can be sensitive to the UV radiation. All products should be placed,
in glass and the actual package, in the window and if its available a light box that has a broad-
spectrum output. Place another glass jar completely covered with aluminum foil in the window
to serve as a control. All too often we will see significant discoloration of the product and
sometimes of the package also. This discoloration may be due to the fragrance or some other
sensitive ingredient. Usually all that is needed is the addition of a UV absorber (e.g. 0.1% of
benzophenone).
Mechanical Shock Testing:

- In order to determine whether or not shipping movements may damage the cosmetic and its
packaging mechanical shock testing is often conducted. Vibration testing (e.g. on a pallet shaker)
can help to determine whether de-mixing (separation) of powders or granular products is likely
to occur.

Monitoring:

- For all the above-mentioned tests you should monitor the color, odor / fragrance, viscosity, pH
value, and, if available, particle size uniformity and/or particle agglomeration under the
microscope.

Microbiological Stability Tests

Microbial contaminants usually come from two different origins: during production and filling,
and during the use of the cosmetic by the consumer. From the moment the cosmetic unit is opened by
the consumer, a permanent microbial contamination of the cosmetic is introduced caused by contact
with the consumers hands and body.

Microbial preservation of cosmetics is important to ensure the microbial safety of cosmetics for
the consumer, maintain the quality of the product, and confirm hygienic and high-quality handling.
Although only a small number of cases of microbial infections of the consumer has been reported,
microbial contamination of cosmetic products may spoil them or seriously reduce the intended quality.

Therefore, it is necessary to carry out routine microbiological analysis of each batch of the
finished product coming on the market. Pseudomonas aeruginosa, Staphylococcus Aureus and Candida
Albicans are considered the main potential pathogens in cosmetic products. These specific potential
pathogens must not be detectable in 0.1 g or 0.1 ml of a cosmetic product. The parameters examined,
the criteria and methods used, and the results obtained per batch should be documented.

Screening Tests:

- There are various easy testing kits available on the market (e.g. dip-slides or plate counts) which
provide quick and semi-quantitative results whether a cosmetic product is significantly
contaminated or not. Sampling and evaluation of the results is simple and can be performed
also by personnel without any microbiological training.

Quantitative Tests:

- Quantitative tests determine the actual count level of bacteria, mold and yeast in a cosmetic
product. These tests are very sophisticated and laborious and can be performed only by
professional microbiological testing laboratories. Typically, methods for isolation of
microorganisms from cosmetic products include direct colony counts and enrichment culturing.
 Packaging Stability Tests

Packaging can directly affect finished product stability because of interactions which can occur
between the product, the package, and the external environment. For example, product constituents
may be absorbed into the container or may chemically react with the container. In addition, the
container may not fully protect the product from the adverse effects of atmospheric oxygen and/or
water vapor, or volatile product constituents (e.g., fragrances) may evaporate through the container.

Glass Tests: Glass is the most inert material and does not react with a cosmetic product in any
way. For this reason, all testing should be done in glass and the actual packaging. In this way you can
determine if the cause of product failure is the formula or the package.

Weight Loss Tests:

- To determine evaporation (water loss through the container wall or closure gaps) weight loss
evaluation is one of the most important tests that must be conducted. This testing (performed
in the actual package with the cap torqued to 100% of target torque) is done at room
temperature and at 45oC (113F) for a period of three months. The weight loss should not
exceed 1% per month for the package to be considered acceptable.

Leaking Tests:

- It may be advisable to test the packaged product in various orientations (upright, inverted, on its
side, etc.) to determine whether the packaging may leak (especially during transport).

COSMETICS AND COSMECEUTICALS

DEFINITION:

1. COSMETICS
- is an External Application intended for cleansing, beautifying, promoting attractiveness
or altering appearance of any part of body or whole body
2. COSMECEUTICALS
- a term that has found application and recognition to designate the products at the
borderline between cosmetics and pharmaceuticals.

CLASSIFICATION:

1. COSMETICS
- SOLIDS
 POWDERS
 SOAPS, etc.
- SEMISOLIDS
 CREAMS
 OINTMENTS
 SAMPOOS
  TOOTH PASTE, etc.
 LIQUIDS
 LIQUIDS SAMPOO
 ROSE WATER, etc.
- GASEOUS
 AEROSOLS
2. COSMECEUTICALS
- Photoaging Agents
- Peeling agents – Hydroxy acids
- Sebum regulators
- Hair Growth Enhancers
- Moisturizers
- Botanical Extracts
- Topical Retinoids
- Depigmentation Agents

DIFFERENCE BETWEEN COSMETICS AND COSMECEUTICALS:

1. COSMETICS
- are for the purpose of beauty or style, such products merely cover the skin. It can keep
the skin moisture and clean but not much more than that.
2. COSMECEUTICALS
- are used to improve and enhance the skin’s appearance by using biologically active
ingredients. This group of products work on cellular and molecular level in order to be
potently effective and safe.

MATERIALS AND FUNCTION USE IN COSMETICS:

DIFF PRODUCTS UNDER COSMETICS AND COSMECEUTICALS, HAIR CARE BODY CARE: