--

1. A)
6.4 Processing of Intermediate, Bulk Product and Packaging
Introduction
Pharmaceutical manufacturing operation can be divided into threecategore
(a) Intermediate (b) Bulk products c) Packaging of bulkproduc

2. Manufacturing Operations and Control 287
These categories of product or rather stages of manufacturing operations
can be defined as follows.
c a n
(al Intermediate product: may be defined as all those stage of materials
during manufacturing operations, which the materials undergoes from
dispensed stage of a batch materials tili it gets converted into the
penultimate stage of formulation ready for primary packaging.
b) Bulk product : may be defined as the stage of formulation ready for
primary packing.
c) Packaging of bulk product : is in fact not a stage of materials but a
goods.
process of converting bulk product into the saleable transportable
These are very important stages in the manufacturing operations and
detailed guidelines on GMP about handing these stages of product and process
are available in the regulatory literature. Let us have a look at these now.
REGULATORY TEXTS AND COMMENTS
(a) WHO Guidelines
Processing operations Intermediate and bulk products
Before any processing operation is started, steps should be
taken to ensure that the work area and equipment are clean
and free from any starting materials, product residues, labels,
or documents not required for the current operation. (15.15)
Comments
This refers to what is called "Line Clearance". The normal thinking
is that the line clearance is done for only packaging lines but the
same concepts of packaging should be applied to processing operation
also.
Any necessary in-process controls and environmental controls
should be carried out and recorded. (15.16)
Comments
These records shall be carried out by both production and Q.C.
personnel. Some people keep their own records of these i.e. production
and Q.C. My personal feeling is that it should be in green ink and
production in blue. The biggest advantage of a common document is
that the recorded evidences are seen by both the production

3. and Q.C. personnel and hence any
deviation observed bya.
these can be a
personnel can immediately be discussed and corrective actof
attached t
process
Jons take
Since such documents are part of B.P.C.R. these can be
B.P.C.R. and hence you get complete history of the batch.dChe
Means should be instituted for indicating fait.
o equi
at one place.
ares ot
equipment or of services (e.g. water, gas) to equi
til the
Defective equipment should be withdrawn from use e
defect has been rectified. Production equipment sho
stored
the
cleaned according to detailed written procedures and" be
only under clean and dry conditions. (15.17)
Each piece of equipment shall have 3 SOPs namely SOP for oper.
cleaning and maintenance. These can be part of a single Sopn
The equipment should be cleaned immediately after use and co
Comments
Asing
by a clean equipment cover after drying the equipment. Before q
ked.
The labels should be appropriately fixed on the cleaned equipmens
Containers for filling should be cleaned before filling. Attentio
should be given to avoiding and removing any Contaminante
such as glass fragments and metal particles. (15.18)
the equipment the cleanliness of the equipment should be che
ent.
Comments
This clause particularly refers to cleaning of ampoules, vials, bottles
eye and ear drops etc. Detailed SOPs related to washing machines
should be available and MPCR/BPCR should refer to those relevant
SOPs.
Any significant deviation from the expected yield should be
recorded and investigated. (15.19)
Comments
Every MPCR/BPCR should clearly specify what yield to expect at
each critical stage. If you get the expected yield at every critical
stage identified in MPCR/BPCR then you may be sure that the process
is going on wel. Any significant variation observed should direct you
to investigate the cause and take corrective action, and also take
preventive actions to avoid re occurrence of such incidences.

4. Manufacturing Operations and Control 289
Checks should be carried out to ensure that pipelines an
other pieces of equipment used for the transportation of
products from one area to another are connected in a correct
manner. (15.20)
Pipes used for conveying distilled or deionized water and,
where appropriate, other waterpipes should be
sanitized
according to written procedures that detail the action limits
for microbiological contamination and the measures to be
taken. (15.21)
Comments
Water for injection and purified water carrying lines if not handled
properly are a great source of microbial contamination and this may
result in contaminating product being processed. SOPs should be
available for sanitization and sterilization of pipe lines. These lines
can be sanitized by hot water flushing through them at regular
intervals. The entire line can be closed and filtered. Sterilizing
pressure can be passed and then the pipe line can be sterilized.
Samples on a rotational basis can be taken from all user points for
microbial evaluation. Every user point must get sampled and tested
at least once in a week (this is a practical recommendation). In case
problems are observed, there frequency of sampling and testing can
be increased. Appropriate action and alert limits should be clearly
specified and followed.
Records of sampling, sanitization arnd sterilization of pipes should
be maintained. It is advisable to periodically review the results of
such microbial analysis and to study the trend and take corrective
and preventive actions whenever required.
Measuring, weighing, recording, and control equipment and
instruments should be serviced and calibrated at pre-specified
intervals and records maintained. To ensure satisfactory
functioning, instruments should be checked daily or prior to
use for performing analytical tests. The date of calibration
and servicing and the date when recalibration is due should
be clearly indicated. (15.22)
Comments
All measuring devices must always be in a stage of perfect calibration.

5. 200
cGMP for Pharmaceuticals
m
master
calibration plan for all measuring
devices shouled be
in the form of a matrix giving
instrument deseription instr e
number and wrekly plan for calibration. Generally an yearlysch
is made in consultation with the user department. The exact cd
by the metrology. valicdation or Q.C. departments. It should a
the
user department and the calibrating agency. Recalibration
should also be fixed and written on the certificate.
the week should be finalized preferably in advance to suit botn
ate
A set of calibration SOPs should be available and recorde
calibration carried out (calibration certificate) must be available o
es.
appropriate departments like, validation, metrology, Q.C., engineeri
This certificate can be presented on demand by the authoriti.
Particular attention should be given to the primary standards
rds.
validation and its tracing back to national or international standard
Validity of date of the primary validation instrument must be checko
f the calibration validity of the instrument, against which th.
instrument is being checked, has crossed its expiry date, then th
calibration done with such instrument automatically stands invalid
Repair and maintenance operations should not present an
hazard to the quality of the products. (15.23)
any
Comments
Most of the new pharmaceutical plants are now designed with a
service corridor. This concept avoids direct entry of the maintenanco
personnel in the processing area and naturally risk of contamination
of the processing materials is reduced substantially. It is very much
useful for equipment like fluid bed dryers, big powder blenders etc,
In other cases, before the maintenance is undertaken, the area
must be freed from any processing materials. And after the work is
over the equipment must be thoroughly cleaned and taken back into
operation.
Machine log book should be entered for dates of maintenance,
cleaning and operation. The record must be signed and dated by
appropriately authorized person.
Packaging operations
When the programme for packaging operations is being set
up, particular attention should be given to minimizing the

6. Manulacturing Operations and Control 291
risk of cross-contamination, mix-ups, or substitution.
Different products should not be packaged in close proximiuy
unless there is physical segregation or the use of electronic
surveillance. (15.24)
Comments
At least 1 to 1.2 meter high spatial separation should be done between
two adjacent packaging lines. All materials of previous batches must
be removed.
Before packaging operations are begun, steps should be taken
to ensure that the work area, packaging lines, printinng
machines, and other equipment are clean and free from any
products, materials, or documents previously used and not
required for the current operation. The line clearance should
be performed according to an appropriate checklist and
recorded. (15.25)
Comments
There should be an SOP on "Line Clearance". Following points should
be covered in this SOP:
Removal of all bulk, primary and secondarypackaging materials
of the previous batch on the packagirng line.
Availability of all bulk and primary and secondary packaging
materials of the batch plarnned for packaging.
Specifically areas like tablet/capsule hoppers, vibratory disk,
channels of strip and blistering machine etc. must be checked
thoroughly for complete removal of bulk materials of previous
batch.
Lower part of conveyer belt is many a time a big culprit for the
traces of previous products like a strip or tablets etc. These
areas must be very thoroughly cleaned.
B.P.C.R. should have a record of such line clearances.
The name and batch number of the product being handled should
be displayed at each packaging station or line. (15.26)

7. 292 cGMP for Pharmaceuticals
Comments
he
The packaging line display board should have following details
minimum:
2
Pkg. line No
Name of the product
Paracetamol Tabs
Strength:
500 mg
TP1234
B. No
10 x10 strips
Pack
01-08-2007
Date
This board should be of suitable size, say 30 cm X 20 cm
prominently placed on the line. It should be ideally placed facid
secondary packaging conveyer belt preferably on the n the
packaging cubicle from where the sealed primary packs are Co
out for secondary packaging purpose.
cm,
ing
Normally filling and sealing should be followed as quickh
possible by labeling. If labeling is delayed, appronria
procedures should be applied to ensure that no mix-ups
mislabeling can occur. ( 15.27)
Comments
The major sources of mix-up is partially-complete packagine
operations. This generally happens for two reasons, e.g. shortage
certain packaging materials and sudden change of packaging schedule
to meet certain urgent requirement of other product, which have to
be taken on the same line. Sometimes shortage of manpower also i
a reason for such partial completion of work.
It is a common scenario in many packaging department tosee
some bulk tablets, uncartoned strips, unshipped carton, labeled
ampoules or vials etc. The main of reason is shortage of packaging|
materials. It must be made a rule that no batch will be taken tor
packing unless all the packaging materials are available in release
state and have been issued to the packaging department.
However, if you cannot avoid this situation then you shouldtar
at most care to segregate the materials stage-wise, batch-wisea"
product-wise to avoid mix-ups.
nd

8. Manufacturing Operations and Control 293
orrect performance of any printing (for example of code
The
nbers or
expiry dates) done
separately or in the course or
ging, should be checked and recorded. Attention
the packagir
thebe paid to
printing by hand, which should be rechecked
course of
shouldbe
at regular intervals. (15.28)
le hecked
Comments
(CO of checking first printed sample by Q.C. or1.P.Q.C. is a
A S Y s t e m
Syctice. The over printed sample, of label, carton or foil must
practice.
g0od
hecked for
hecked for the correctness of details like,
e
. B. No.
Expiry and Mfg date
Price with proper description if any
Mfg lic. (if not already printed).
The checked and approved sample should be kept in the B.P.C.R.
Special care should be taken when cut labels are used and
when overprinting is carried out off-line, and hand-packaging
operations. Roll-feed labels are normally preferable to cut
labels in helping to avoid mix-ups) On line verification of all
labels by automated electronic means can be helpful in
preventing mix-ups, but checks should be made to ensure
that any electronic code reader, label counters, or similar
devices are operating correctly. (15.29)
Printed and embossed information on packaging materials
should be distinct and resistant to fading or erasing. (15.30)
Comments
Laminated carton and label have a problem of erasing the printed
details on them. Appropriate quality of ink should be used for this
Purpose, which is of quick drying type and cannot get erased from
adninated surface. Alternatively a small window without lamination
f the details are embossed the pressure of embossing letters or
Created on the laminated cartons or labels, when you overprint on
s area it will not get erased or get faded.
this
Dn
number must be so adjusted that you get a correct impression without
puncture.

9. If labels or other printed materials is bar-coded or .
tags then the code or RFID readers can verify that
materials is being used. You of course have to see that e
are working properly.
cGMP for Pharmaceuticals
having RT
294
he cort
STte
that the Teade
.Online control of product during packaging should :
least checks on:
ld includ
e aa
(a) the general appearance of the packages
(b) whether the package are complete
materia
(c) whether the correct products and packaging
are used
(d) whether any overprinting is correct
the correct functioning of the monitors.
(e)
Samples taken away form the
packaging line shola
be returned. (15.31) d no
durin
Product that has been involved in an unusual event
special inspection, investigation, and approval by authori
personnel. A detailed record should be kept of this
operati
(15.32)
packaging should be reintroduced into the process
only:alte
this operatior
Comments
All unusual incidents which have a
potential to
adversely affect the
quality of the product must be investigated and recorded.
Any significant or unusual discrepancy observed during
reconciliation of the amount of bulk product and printed
packaging materials and the number of units produced should
be
investigated and
satisfactorily accounted for before release
(15.33)
Comments
There should be an SOP for reconciliation of bulk and packagine
materials and the reconciliation must be done at all critical stag
and at the end of the
packaging operation. This should become
part of the B.P.C.R. Any discrepancies must be identified. investga
recorded and corrective actions taken.
d batch
Upon completion of a
packaging operation, any unusdt
coded
packaging materials should be destroyed a

10. Manufacturing Operations and Control
e s t
followed if
estrif ncoded printed materials are returned to stock.
uction recorded. A
documented procedure should be
295
( 1 5 . 3 4 )
Comments
co d be an SOP toreturn uncoded, printed or other packaging
T h e r e
s h o u l d
be a
naterials,
erords of such transactions must be made.
back to store. This must be done on a materials return
n o t e . R e c o r d s
Guidelines
A A u s t r a l i a
,Critical
processes
should be validated (5.37)
Comments
cal processes are
Criticeill adversely affect the quality of the product. So for this
those processes which if not carried out
reason you
rocesses arnd
maybe
he like, mixing, sterile filtration, sterilization, compression of
tablet etc.
C o r r e
tly, will adv
vou must identify for each product which are the critical
there process must be fully validated such processes
Any necessary in-process controls and environmental controls
should be carried out and recorded. (5.38)
All products and packaging materials to be used should be
checked on delivery to the packaging instructions. (5.47)
Checks should be made to ensure that any electronic codee
readers, label counters or similar devices are working
correctly. (5.52)
Printed and embossed information on packaging materials
should be distinct and resistant to fading or erasing. (5.53)
Finished products should be held in quarantine until their
final release under condition established by the manufacture.
(5.58)
The evaluation of the finished product and documentation
ch is necessary
before release of product for sale must be
done as described under. Q.C. guide line on release of finished
product. (5.59)
ter release, finished product should be stored as usable
Ck under conditions
established by the
manufacturer.
5.60)

11. 296 cGMP for Pharmaceuticals
1st be cleary
No product, even by accident should go to the market witt.
goods. Both
released by Q.A. Hence, the final finished packs mustt
ould remain
identified as under-quarantine and released finished goode e
Comments
oeny
them can remain in finished goods warehouse but theysho o
to the
wo areas of suitable size can be marketed as goods under a n t
in segregated area and property labeled. For this purpose
ine
and goods released. The goods after packing can com dntin
quarantine area and rest there till tested and released. Afte th
these can be transferred to released goods area.
In case unreleased goods (for sterility test) are sent ou
parametric release, then care should be taken to see that under
not get further distributed without release by Q.C. lab. Theso do
can be sent to company's godown and await release informati50d
u
All the finished goods under quarantine and released ma....
stored as per the storage conditions required. A list of produet be
storage conditions must be made by Q.C. and
communicated to sto
be
(c) USFDA Guidelines
.There shall be written procedure (SOPs) for
production and
process control designed to assure that the drug product have
the identity, strength, quality and purity they purport or
represented to process. Such procedure shall include all
requirement in this subpart (F). These written procedures,
including any changes, shall be drafted, reviewed , and
approved by the appropriate organizational unit and reviewed
and approved by quality control unit. (211.100)
Comments
G.M.P.s first principle under documentation is that if it is not written,
it does not exist. For this reason, every activity performed in
manufacturing must be identified and described in full details, as
how to do it, i.e. you should have SOP for every activity. All these
activities must be validated, i.e. proved or established they work as
desired and people are trained to carry out these on the shop
and
implemented. These SOPs must be reviewed periodically
whether any improvement can be done for betterment of the proation
and, if yes, then these should be changed after sufficient vandalook
data is available. Every one concerned should be motivatea o

12. Manufacturing Operations and Control 297
for imprOved process but they should not be allowed to effect u
change. uniess it IS fully studied, validated, approved and authOrisEu
for implementation. When a revised method is implemented previous
SOPs related to that must be withdrawn and revised SOP issued
Remember that no single process should have two SOPs in place at
any point of time. There should be SOP on withdrawal of superseded
SOPs in place. All superseded SOPs must come back to the departmern
for change control and SOP management (including SOP withdrawal
process and records there of.
.Written production and product control procedure shall De
followed in the execution of various production and process
control function and shall be documented at the time or
performance. Any deviation from the written procedure shal
be recorded and justified. (211.101)
Comments
Another principle of GMP is: - "Do as you have written (i.e. follow SOPs)
and write what you have done (i.e. records)". These records must be
completed when the manufacturing activity is being carried out.
B.P.C.R. must move along with the product. Incomplete B.P.C.R. is
the biggest flaw in the manufacturing system. In 1991 when I was
working as a "Plant Manager" in one of the biggest Indian pharmaa
company in Dewas, I found one of the plants had about 150 in-
complete BPCR. We took a decision to stop the production activity for
3 days (two weekly offs and one working day) and put all the
supervisory and managerial staff to complete these incomplete
B.P.C.R. and then made it mandatory to see that Q.A. release the
product only when they receive completed B.P.C.R. The responsibility
of completion of B.P.C.R. was given jointly to the IPQC and production.
shop floor people.
Procedure shall be utilized to reconcile the quantities of
labeling issued, used and returned, and shall require
evaluation of discrepancies found between the quantity of
drug product finished, and the quantity of labeling issued
when such discrepancies are outside narrow preset limits
based on historical operating data. Such discrepancies shall
be investigated in accordance with 211.192. Labeling
reconciliation is waived for cut or roll labeling if a 100%
examination for correct labeling is performed in accordance
with 211.122 (g) (2) ( 211.125 (c) ).

13. 298 cGMP for Pharmaceuticals
Comments
Reconciliation of bulk and packaging materials must be done a
critical stage and not only at the end of the packaging processery
gives us a confidence that the process Is going on as desired, A.is
at
any discrepancy arises then it is easy to investigate and corrif
the earliest stage in the process when this discrepancy is f
Trect
packaging materials. But it is advisable to do the same for alld
critical activities. It is a misconception that reconciliation of rne
packing materials like label and cartons must be correct till the
digit, but that is not true. USFDA allows to set a narrow limits ha
F.D.A. insists that this must be done specifically for the nund
nted
othe
printed
ditors
he
and should also be acceptable to all other auditors also,
on the historical operational data. It is acCceptable to USFDA audito
to
manufacturing pharmacist must know this guiding clause to refer
the auditors in case of need.
Identification and handling of filled drug product container
that are set aside and held in unlabeled condition for futura
labeling operation to preclude mislabeling of individual
containers lot, or portions of lots. Identification to determina
name, strength, quantity content lot and control number of
each container. (211.130(b))
Inspection of the packaging and labeling facilities immediately
before use to assure that all drug products have been removes
from previous operation. Inspection shall also be made to
assure that packaging and labeling materials not suitable for
subsequent operation have been removed. Result of inspection
shall be documented in the batch production records.
(211.130(e))
(d) MCC South Africa Guidelines
Every effort should be made to ensure that packaging takes
place in an
orderly manner that will ensure there are no mix
ups between one
product and another. (6.5.1)
Products that are similar in appearance should notDe
packaged in close proximity to one another at the same tn
(6.5.2)
Packaging lines should be well separated and, if possibe
physical barriers that will prevent the migration of matera
from one line to another should be in place. (6.5.3)

14. Manufacturing Operations and Control 299
Special precautions should be taken to prevent the inadvertent
transfer of
components by personnel moving between
packaging lines, e.g. inspection and maintenance stat.(6.3.
Process Deviations
6 . 5
Proces deviations can be defined as variation in the production or arny
other process from the predefined procedure. Regulatory guidelines
discuss this issue and provide guidance as fottów.
TEXTS AND COMMENTS
EGULATORY
(a) TGA Australia Guidelines
Any deviation from instruction or procedures should be
avoided as far as possible. If a deviation occurs it should be
aPproved in writing by a competent person, withthe
involvement of the quality control department. When
appropriate. (5.15)
(b) USFDA Guidelines
.Written production of process control procedure shall be
followed in the execution of the various production and
process control functions and shall be documented at the
time of performance. Any deviation from the written
procedure shall be recorded and justified. (211.100(6))
Comments
There should be an SOP to control deviations. This is called
"SOP on deviation control". This SOP not only deals with process
deviations in releasing a materials (raw/packaging) or any
process like change in times of mixing. speed of a machine
beyond the validated speed. We must remember here that
deviations is a one-time change, which is controlled by deviations
control system. If the changeis of permanent nature thenit
should be controlled by the change control system.
.The purpose of controlling and recording deviation is to have a
control or rather prevent unauthorized change in the process.
.Change control can be initiated by any body through a proper
channel as defined in the SOP and followed strictly. Deviation
can be taken only after proper approval and authorization by Q.A.

15. routinely. Belotu
Such change can be taken exceptionally and not routinel
the conse
300 cGMP for Pharmaceuticals
taking such a change and authorizing it, all the consef
ever
mee
must be evaluated. The finished product must hoWev
the same specification as un-deviated product.
Such changes are required to be taken during manufas
process, when we face a situation of borderline cac.n
not
Contro
es, e
materials has specification of moisture content as ne
then 1.5% and the testing reveals that it has a moisture e more
of 1.7%. If Q.C. production and F and D department feelsi
nay b
materials can be dried to 1.5% and used, it will not
affect
he
quality of the finished product. In such case deviation me
in
y
taken following the deviation control procedure. Similarlv
tablet compression sometimes we find that if I run the mi
slightly lower speed than validated range then the product meeh
the specification. Then in such cases we may go for deviatinn
nlc
meets
However, a tendency to deviate too often must be discouramn4
by the management. Records of such change must be maintained
for further review and corrective and preventive action purpose
6.6 Charge in of Components
The concept of "charge in of components" is advocated by U.S.F.D.A.
This concept came into existence with a view to assure that the
pharmaceutical products have the desired strength and quality of the
product. There should be a SOP to provide guide lines on this.
REGULATORY TEXTS AND COMMENTs
(a) USFDA Guidelines
Written production and control procedures shall includethe
following which are
designed to assure that the drug products
produced have the identity, strength, quality and purity the
purport or are
represented to possess.
The batch shall be formulated with the intent to provia
not less than 100 percent of the labeled or establisheu
amount of active
ingredients. (211.101(a))
(a)

16. Manufacturing Operations and Control 301
Lomments
addition ofthe active ingredients to the calculated
ers to ad
d also to adjust the assay or potency of the active substance
s n o u n t .
A n d
o 1 0 0p e r c e r
indalso i
Pont. This means if a tablet is claimed to be containing
T h i s
r e f e r
he active substance and if we have the released ac
ctive
s r e l e a s e d a r
eleaf adding 500 mg the substance we must add 506.07 mg or
substance o f 9 8 . 8 %
stanat 98.8 % it should be actually adjusted to 100% means
ng of the
n m f 98.8% assay or potency then eventhough the material
instead
tive substand
steaesubstance. This calculation must be recorded in B.P.C.R.
t h e .
Components of drug product manufacturing shall be
(b)
weighed, measured, or subdivided as appropriate. If a
component is removed form the original containers to
another, the new container shall be identified with the
following information.
1. Component name or item code
2. Receving or control numbers
3. Weight or measure in new container
4. Batch for which the component was dispensed,
including the product name, strength, and lot number.
(211.101b))
Comments
This activity relates to dispensing of the active materials. Hence we
must add that the weighing details must also give the details about
net, tare and gross weight in the containers so that the
manufacturing pharmacist can check all these 3 by weighing before
addition of the materials for mixing with other ingredients. Since
verification by weighing is easier and more accurate, even liquidis
mUst be dispensed by weight rather than volume.
(c) Weighing, measuring. or subdividing operation for
components shall be adequately supervised. Each
Container of component dispensed to manufacturinng
shall be examined by second person to assure that,
1. The component was released by the quality control
unit.
. The weight or measure is correct as stated in the
batch production record.
. The containers are properly identified. (211.101(c)

17. 302
cGMP for Pharmaceuticals
Comments
In checkingthe second person should preferable be a O.C
person. He should check for following things during the dtme
operation:
he dispensi
dispensin
(i) Environmental conditions like temp. and humidity in dic.
room
(ii) Calibration status of the weighing balance
(iii) Cleanliness of the materials and area
(iv) Differential pressure of the R.L.A.F. unit
v Proper observance of the dress-code and protective
liances
(vi) Release of the materials by Q.C. by verifying the A.R.
of raw materials, container and dispensing sheet number
(vii) Correct quality of right materials
(vii) Any calculation and materials to adjust the assay or potenn.
(ix) Proper sealing of containers and labels on them.
ncy
d) Each component shall be added to the batch bv
are
person and verified by a second person.(211.101.(d)
Comments
Normally the process operator adds the materials and production
pharmacist supervises the addition and records in the B.P.C.R
However, the addition of active substance should also be checked by
two persons namely one the production pharmacist and other I.P.QC
supervisor and both these people must sign in the B.P.C.R.
67 Calculation of Yield
To assure that the process at every stage is going on as desired,citica
stages in the process must be identified and limits of expected yield a
each of these stage must be defined. B.P.C.R. should record these a
any deviations must be justified, investigated and recorded.
nd
REGULATORY TEXTS AND COMMENTs
(a) USFDA Guidelines
Actual yields and percentage of theoretical yieldse
yield shallbe
determined at the conclusion of each appropriate Pa
2seof

18. Manufacturing Operations and Control
303
product.
onanufacturing,
Such
processing, packaging and holding of the
perso
drug
aroduct. Such calculation shall be performed by
and independently verif ail be performed by one person
ad independently verified by a second person
person
son. (211.10
C o m m e n t s
appropriate phases in
manufacturing process must be defined
T h e a p p r o p r i a r
he MPCR/BPCR- on each product and formulation e.8
in he
1.
Tablets (a) End of lubrication stage,
(b) End of compression,
(c) End of coating.
(d) End of primary packaging.
(e) Finished goods packs.
On the similar lines appropriate phases can be decided. This
exercise gives us the confidence that the process is going on well
and without any problem. Such data should be recorded in B.P.C.R.
& Time
Limitation on Production
Time limitation on production is a techno-commercial issue. Technically
it refers to the stability of the product, ifa started product remains ata
partially finished stage for unreasonably long period. And commercially
it refer to blocked inventory and that means blocked money of the
Company
without getting the financial returns as expected.
REGULATORY TEXTS AND COMMENTS
(a) USFDA Guidelines
When appropriate, time limits for the completion of each
phase of production shall be established to assure the quality
of the drug product. Deviation from established time limits
may be acceptable if such deviation does not compromise
the quality of the drug product. Such deviation shall be
justified and documented. (211.111)
Comments
Ihe product development document should have established data on
Stability and quality of the product to say how long a product can
Temain without further processing and without affecting the quality
he materials at that stage and so also the quality of the finished

19. 304 cGMP for Pharmaceuticals
product processed with that material. Such data should be provi
to both production and Q.C. department for informationed
implementation. and
M.P.C.R. and B.P.C.R. should have these limits of time sDecit
ified
andy.
so that the manufacturing pharmacist have these intormation hand.
this
B.P.C.R. should have records of any deviations observed in
regard.
6.9 Reprocessing
at
Reprocessing is an activity which is carried out on a manufactured batch
any stage of processing, when it fails to meet the required specificatio
ed
ion.
This activity is carried out to bring the batch to meet the reguira
specification after reprocessing.
Following are the available guide line on this topic in the ld
regulatory literature.
REGULATORY TEXTS AND COMMENTS
(a) Schedule M of Dand C act and Rules India Guidelines
Where reprocessing is necessary, written procedures shall
be established and approved by Q.A. department, that shall
specify the conditions and limitations of repeating chemical
reactions such reprocessing be validated. (24.1)
Comments
This guideline seems to be for active pharmaceutical ingredients,
where certain chemical reactions must be repeated. Primarily
in formulation such situation does not arise, hence I do not
comment on thisS.
If the product batch has to be reprocessed, the procedure
shall be authorised and recorded. An investigation shall be
carried out into the causes
necessitating re-processing ana
appropriate corrective measures shall be taken for prevention
of recurrence. Re-processed batch shall be subjected to
stability evaluation. (24.2)

20. Manufacturing Operatlons and Control 305
C o m m e n t s
There should be an SOP to spell out the administrative procedure of
re
reprocessing of a product, The technical procedure of actually carrying
department in consultation with quality and production departments.
The SOP on administrative prOcedure should have at least following
out reprocessing shall be provided by formulation development
points.
() Who has recommended the reprocessing and when?
(ii) Deficiency observed in testing, which lead to the decision of
reprocessing.
(ii) Who has taken the decision of reprocessing the batch?
(iv) Are stability studies needed? If so how long and by what
method?
(vWho defines the method of reprocessing?
(vi) Copy of the method of reprocessing should be appended to the
B.P.C.R.
(vii) Batch number may be modified to indicate that the batch is
reprocessed.
(viii) This batch must be taken in the annual product review, to see
if any specific issues observed.
Recovery of a product residue may be carried out, if
permitted, in the master production and control records by
incorporating it in subsequent batches of the product. (24.3)
Comments
Normally following guidelines can be considered for such residue
addition
(a) 5% to 10% recovery can be added in a fresh batch.
(b) The recovery added should not be more than 3 months old,
from the date of manufacturing.
(c) Recovery mixture (if from more than one batch ) should be
analyzed and if found within specification then only it should
be added to the fresh batch.
(d) In above condition the date of manutacturing may not be changed
for the fresh batch.
(e) This batch must undergo in routine stability studies.
(0 All information related to such recovery addition should become
part of the B.P.C.R.

21. 306 cGMP for Pharmaceuticals
(b) WHO Guidelines
(Ref Section 4.6 in Materials Management chapter)
(c) USFDA Guidelines
wed
Written procedure shall be established and follow
prescribing a system for reprocessing batches that do n
conform to standard or
specification and
the steps to be taken
to issue that the reprocessed batches will contirm with all
established standard specifications and
characteristics
en
(211.115 (b))
Reprocessing shall not be performed without the review and
approval of the quality control unit. (211.115(b))
(d) MCC South Africa Guidelines
Materials may be reworked or recovered by an
appropriate
and authorised method, provided that the materials is suitable
for such reprocessing, that the resultant product meets its
specification, that there is no
significant changes in the
product quality and that the quality control authorization is
obtained. Documentation should accurately record the
reworking process carried out. The reprocessing of rejected
products should be exceptional. (5.7.1)
Residues and re-worked or recovered materials which might
adversely affect product quality, efficacy or
safety should
not be used in subsequent batches. (5.7.2)
The treatment of product residues and reworked or recovered
materials and the means of their inclusion in a
subsequent
batch should be specifically authorised and documented.
(5.7.3)
Limits approved by Q.C. should be established for the amount
of any such materials which may be added to a
subsequent
batch. (5.7.4)
Batches incorporating residues should not be released unti
the batch which the resides originated have been tested and
found suitable for use. (5.7.5)
Methods of reprocessing should be specifically authorised an
fully documented, once any potential risks have De
evaluated and found negligible. (5.7.6)

22. 307
Manufacturing Operations and Control
The need for additional testing including sterility of
auy
finished product which has been reprocessed (or to whlcn
residue have been added) should be considered. (5.7.)
Comments
MCC South Africa has given detailed treatment to the issue ol
reprocesSing of the product and also addition of recoveries to fresh
batches. I personally find the guidelines are very much practical,
e.g following 3 points are very practical and seems to have been
written after considering the actual situation in the manufacturing.
Let us see what these are.
(i) It accepts that there may be some non-significant changes in
the product quality, which may be acceptable. (5.7.1)
(ii) There can be a negligible potential risk. (5.7.6)
(iii) The stability of such reprocessed product may be considered.
One important point however the guideline takes seriously is
that the recovery added must be only from released batches
and not otherwise. (5.7.5)
As usual it talks about complete documentation arnd approval
and authorization of the entire process of reprocessing.
6.10 Drug Product Inspection
U.S.F.D.A. guideline talks very clearly about inspection of the packaged and
label product. This primarily refers to visual examination (not laboratory
testing) of the finishing product on packaging line.
REGULATORY TEXTAND COMMENTS
(a) USFDA Guidelines
Drug Product Inspection
(a) Packaged and labeled products shall be examined during
finishing operations to provide assurance that containers
and packaging in the lot have the correct label.
(b) A representative sample of units shall be collected at the
completion of finishing operations and shall be visually
examined for correct labeling.
(c) Results of these examinations shall be recorded in the
B.P.C.R. (211.134)