Introduction to manufacturing operations, Sanitation, Cross-contamination, Packaging, IPQC, time limitation, Expiration,Calculation of Yield, Production record review, process deviation

1. MANUFACTURING
OPERATIONS AND CONTROL
PRESENTED BY:
SHIVANI KAILAS CHAUDHARI
SUBJECT:
QUALITYASSURANCE
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2.  POINTS TO BE COVERED:
 Introduction
 Sanitation Of Manufacturing Premises
 Mix-ups And Cross Contamination
 Processisng Of Intermediate And Bulk Products
 Packaging Operations
 I.P.Q.C. In Manufacturing And Packaging
 Release Of Finished Product
 Process Deviation
 Charge In Of Components
 Time Limitations On Production
 Drug Product Inspection
 Expiration Dating
 Calculation Of Yield
 Production Record Review
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4.  Good manufacturing practices which are currently acceptable should be followed
during carrying out all manufacturing operations and their control. Four key
words should always be kept in mind during this, they are:
(1) Identity.
(2) Strength,
(3) Safety, and
(4) Purity.
 To achieve these things the manufacturing operations must be carried out under
the direct supervision of the qualified technical staff (Industrial pharmacists,
chemists, microbiologists etc), who are approved as "Expert Technical Staff" by
state FDA. Authorities.
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5. A) SANITATION OF MAUFACTURING PREMISES
• For keeping the premises clean and sanitised, one must use validated cleaning
and Sanitising procedures.
• Certain locations in each area should be marked in each processing are for
collection of dust, debris, and waste or trash materials.
• SOP, of facility cleaning should clearly define the detergent and its
concentration to be used, the frequency of cleaning, the method of cleaning and
persons responsible for doing and supervising the job.
 Documents Required
(i) SOP on housekeeping, covering, cleaning and disinfection of the various
areas.
(ii) Reports of cleaning and disinfection activities that have been actually
carried out.
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6. (B) MIX-UPS AND CROSS CONTAMINATION
• Mix-ups can be defined as presence of undesired materials into desired materials,
which can generally be visibly seen e.g. cartons of one product into another.
• Contamination is also presence of some material where it is not desired.
SOURCES OF
CONTAMINATION
AND MIX-UPS
MATERIALS
PEOPLE
AREAS
MACHINES
AND
OPERATION
S
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7. • SOPs and records should be kept for cleaning and sanitation of equipment.
• Manufacturing areas should be classified in various categories of expected cleanliness
 Controlling of Contamination and Mix-ups: Certain procedures should be used to
control contamination and mix-ups e.g.
• Exhaust system with proper air filtration and dust collection should be placed where
heavy dust is generated.
• A SOP and record should be maintained for packaging "line-clearance", before starting
packaging of a new batch or product on the packaging lines.
 Trained people :
In pharma processing the people should be trained in their jobs and also in the principles of
cGMP.
 Technical or Organisational Measures:
Cross contamination should be avoided by appropriate technical or organisational measures.
• Wearing protective clothing in areas where products with special risk of cross
contamination are processed.
• Using cleaning and decontamination procedures.
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8. (C) PROCESSISNG OF INTERMEDIATE AND BULK PRODUCTS
Intermediate Product : A partly processed material that must undergo the further
manufacturing steps before a bulk product.
Bulk Product : Any product that has completed all processing steps up to but not
including final packaging.
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9. Points that
are required
to be kept in
mind so that
the identity,
strength,
safety and
purity of the
product is
maintained.
Before starting any processing, the materials received from
the stores should be checked for the identity and quantity.
Process area and equipment must be clean and no traces of
previous product should be there.
Environmental conditions must meet the processing
requirements.
Yield of materials at all critical stages of operations should be
checked.
All measuring, weighing, recording and controlling
equipment and instruments should be calibrated regularly.
Repairs and maintenance operations should not present any
hazard to the quality of the products.
All I.P.Q.C. checks should be carried out at pre-determined
stages and deviations.
Access to production areas should be restricted only to authorised
persons.
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10. (D) PACKAGING OPERATIONS
Similar to manufacturing operations, packaging operations should also have
to follow certain precautions to get a good quality product at the end.
Following are some of the critical points, which should be remembered while
carrying out the packaging Operations.
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11. Avoid risk of cross-contamination and mix-ups.a)
"Line-clearance" SOP should be followed and records maintained.b)
Normally, filling and sealing should be followed as quickly as
possible by labelling and final packing.c)
Over printing on labels, cartons, coated tablet, etc. should be
carefully planned and activities clearly segregated to avoid mix-ups.d)
Empty packet detections system in tab/cap. should be used.e)
Printed and embossed information on packaging materials should be
distinct and and resistant to fading or erasing.f)
Products which are involved in unusual event during packaging
operations, should be fully investigated recorded and packed.g)
Upon completion of a packaging operation, any unused batch coded
packaging materials should be destroyed and the destruction recorded.h)
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FOR
MANUFACTURING
OPERATIONS:
Assay, moisture,
angle of repose at
end of
granulation.
Bulk density
of granulated
material.
Physical parameters
of compression of
tablets.
Fill
weight/volumes
Particle size in
suspentions
pH of solution
before filling.
Sterility testing
in parentral
preparation
Environmental
conditions verification
e.g. Temperature, relative
humidity.
(E) I.P.Q.C. IN MANUFACTURING AND PACKAGING
Standard operating procedures should be available and followed for in-process quality
control activity during manufacturing and packaging activities. Following points should
be kept in mind.

13. FOR
PACKAGING
OPERATIONS
General
appearance
Fill weights,
volumes, unit
quantities etc
Completeness
of package
Correctness of
all materials
used.
Correctness of
over printed
details.
Correct
functioning of all
on line monitors
Environmental
conditions records
e.g. temperature,
humidity etc.
Collection of
samples for testing
and retention
should be recorded
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14. (F) RELEASE OF FINISHED PRODUCT
Releasing of finishing product is the last activity in the manufacturing and packaging
operations at the factory.
Finished products must be placed in quarantine in such a way that these cannot be removed for
use until such time these are released.
Samples of the product taken at intervals during the packaging process must be retained for
examination by the Q.C. laboratory.
Documentation should be re-checked, completed and sent for a complete documentation audit
by Q.A.
When all required parameters are satisfied, including the document audit, Q. C. may
recommend release of the product from its quarantine status.
The finished product should be released for sale by authorised person from Q.A. department.
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15. (G) PROCESS DEVIATION
• Process deviation can be defined as variation, in the production or anyother
prosess from the predefined procedure.
• Such deviations may adversely affect the desired quality of the pharmaceutical
product and hence such deviations should be generally avoided and if
exceptionally required then such deviations must be justified and properly
authoring and recorded.
• The main purpose of written manufacturing procedures is to built the desired
quality into the product.
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16. (H) CHARGE IN OF COMPONENTS
• Each batch is formulated with the intent to provide not less than 100% of the
labelled or established amount of the ingredient.
• Before and after addition of the active ingredient, the product should be weighed
and measured appropraiately.
• Weighing, measuring or subdividing operations for components shall be
adequately supervised.
• Generally, addition is done by an operator or worker and verified by a production
pharmacist.
• It may be advisable that the addition of the active substance is done in the presence
of a I.P.Q.C. person, to enhance the level of confidence in manufacturing .
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17. (I) TIME LIMITATIONS ON PRODUCTION
• A pharmaceutical manufacturing process should be completed in a specified time
period. Normally, starting and finishing of a pharmaceutical process should be
noted and it should be as minimum as possible.
• To avoid problems, all critical stages in the manufacturing process should be
identified for each formulation and time limit of hold at each such stage must be
defined based on the stability data and G.M.P, related issues.
• This should be done for each product since the stability related issues of each
product may be different.
• These data should be available with the manufacturing pharmacist or alternatively
such data may be provided in the M.P.C.R. and B.P.C.R. of each product.
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18. (J) DRUG PRODUCT INSPECTION
• Inspection at various stages of manufacturing i.e. production and packaging is
always carried out throughout the process of manufacturing, this job is done by the
I.P.Q.C. or I.P.Q.A. section under the quality management group.
• “Drug Product Inspection” should be done. This concept suggest three things:
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Packaged and labelled products shall be examined during finishing operations to
provide assurance that containers and packages in the lot have correct label.
A representative sample shall be collected at the completion of finishing operation and
shall be visually examined for correct labelling.
Results of these examinations shall be recorded in the B.P.C.R.

19. (K) EXPIRATION DATING
• The responsibility of the pharmaceutical manufacturer is that the drug product
should have the stated potency and therapeutic effectiveness till the end of the
shelf life of the product. This shelf life should be based on the stability studies
data of the product concerned.
• For this purpose a detailed SOP on carrying out drug stability studies is required.
• The expiration dates shall be related to any storage conditions.
• If the drug product is to be reconstituted at the time of dispensing, its labelling
shall bear expiration information for both the reconstituted and unconstituted
drug products e.g. in case of dry syrup preparations.
• Some eye drops are also labelled as how long they can be used after opening the
bottle pack. This is in addition to the expiry product of unopened containers.
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20. Granulati
on.
Compress
ion.
Coating.
Packing.
Mixing.
Filling.
Packing.
Bulk
preparati
on and
filtration
.
Filling.
Packing.
Bulk preparation and
filtration.
Washing of ampoule.
Filling, sealing of ampoules.
Sterilization of ampoules.
Packing.
(L) CALCULATION OF YIELD
According to CFR-211-103
For the common formulations such critical stages are as follows :
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21. (M) PRODUCTION RECORD REVIEW
• The main principle of cG.M.P. is that "The quality of a product is built into it and
cannot be just tested in it".
• Quality control or testing can test only certain testable parameters only in the final
product, but it cannot assure the quality of the product. Testing has certain
limitations.
• Hence, the concept of Q.A. has come into existence. Q.A. not only believes in
testing, but it also tries to assure that the entire process of manufacturing has been
actually followed, the way it should have been followed. This activity is done with
the help of following :
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Carry out in process quality check and record them.
Collect samples throughout the manufacturing process on different times.
Check all the documents related to the batch production, along with quality
control documents

22. In this connection the regulatory literature gives certain important guidelines,
which are very important.
 All drug product production and control records, including those for packaging
and labelling shall be reviewed and approved by the quality control unit.
 Any unexplained discrepancy (including percentage of theoretical yield exceeding
the maximum or minimum percentage established in M.P.C.R.) or the failure of a
batch or any of its components to meet any of its specifications shall be
thoroughly investigated.
 The investigation of such batches shall extend to other batches of the same drug
product and other drug products that may have been associated with the specific
failure or discrepancy.
 A written record of such investigation shall be made and shall include the
conclusion and follow up.
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23. REFERENCES
 Manohar A. Potdar, Pharmaceutical Quality Assurance, fifth edition
August 2016, Nirali Prakashan, page no.6.01-6.13
 Pharmtech,pharmaceutical intermediate and bulk products, published on
Monday, june 17, 2013 available on
http://pharmatechbd.blogspot.in/2013/06/define-pharmaceutical-stating-
materials.html
 U.S. Food And Drug Administraton, current good manufacturing practices,
updated on 10/06/2017 available on
https://www.fda.gov/drugs/developmentapprovalprocess/manufacturing/uc
m169105.htm
 Code Of Federal Regulation, title 21, volume 4, revised as of April 1,
2017, sec. 211.103 Calculation Of Yield. Available on
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?
fr=211.103
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