GMP FAQ - 1

Q What are the standard calibration methods for a) capacity

balance, which are used for weighing of materials,
including active ingredients, and b) standard weights used
for the calibration of capacity balance ?

A Balances used in the manufacture and testing of

Pharmaceuticals ( including analytical balances ) must be
calibrated at predecided frequencies, using calibrated
standard weights. Standard weights can be had calibrated
and Certificate of Calibration obtained from national
institutes like The National Physical Laboratory.

Guidelines for allowable variance from standard weights are

given in the USP and these may be adopted by the
manufacturer. Calibration details must be retained as
permanent records for each balance. The calibrations status
of every balance must be prominently displayed on the
balance.

A detailed SOP for calibration must be available and SOP

must also state the action to be taken in case the balance
is found to be out of calibration during the routine
calibration exercise. A record should be maintained with
special reference to the batches manufactured or, samples
tested using the out of calibration balance.

Q Is it necessary to sample and analyse each and every

container, irrespective of its numbers, of a non-
pharmacopoeial non-active ingredient of a drug product.
Can’t we use V n + L formula for sampling such
ingredients. What are GMP / FDA guidelines ?

A For inactive raw materials sampling n + 1 formula can be

applied batch wise. However, GMP requirements are that
contents of each container be at least identified, using
suitable identification tests. Rest of the analysis can be
normally done on a mixed sample, exceptions to this being,
supplies from a new source, highly heterogeneous materials,
very hygroscopic materials etc., where the QA Manager
must use his discretion and impose more rigid sampling
and testing.
Q After testing any product on LPC, how many times should
the total path ( including needle, syringe etc ) be cleaned,
to remove / decontaminate ?

A There is no set answer to this question. The analyst should

validate the purging / cleaning / decontamination of the
system based on the type of sample being tested, the
mobile phase in use etc.

Q What is the maximum possible limit for the addition of

recoverable rejects ( RR ) in a fresh batch of tablets. Is
there any provision regarding RR addition in any
pharmacopoeia ?

A There is no maximum limit for recovery mentioned in any

Pharmacopoeia. However, considering batch traceability and
GMP. It is better to keep the recoverable limits to less
than 2%. This figure has once again to be validated.

Q How can one ensure completion of FBD bag cleaning.

A Completion of cleaning of any process is ensured by

cleaning validation. Swabs of the FBD bag are taken and
following the usual procedure, it is examined for any drug
residues.

Q I understand that there are sterilization methods, which,

when used in conjunction, can provide additive effects.
What are the various methods used ?

A Combined methods of sterilization are also referred to as

synergistic sterilization. This method originated in the food
industry and since, has been adapted for use in the
Pharmaceutical industry.

Some of the combinations in use are :

* Aseptic Process + Low - Dose

R Irradiation

* Heat + Amphoteric
Surfactants

* Heat + Microbicidal
Compounds
* Radiation + Bactericides

* Radiation + Salts

* Hydrogen Peroxide ( or Ethylene Oxide ) + Core Water in

Spores

* Hydrogen Peroxide + Low - Temperature Steam

* Hydrogen Peroxide + UV
Irradiation

* Hydrogen Peroxide + Mwetal

Salts

* Hydrogen Peroxide +
Dithiothreitol

These methods may be milder and safer than those

currently used in the industry. But, most of them are not
yet fully validated and hence would require validation
before they could find application.

Q Why are 0.22 u pore size filters used for sterilization of

solutions ? If microorganisms of size less than 0.22 u are
present in the solution, there is a chance of their passage
through the filter. Then, how can we say the solution is
sterile ?

A The industry standard test organism for qualifying

sterilizing grade filters is Brevundimonas diminuta.
[ B diminuta ; formerly Pseudomonas diminuta ] [ Segers etal
1994 ; ATCC 19146 ] AB diminuta meets all the
requirements of a standard test organism.

A microorganism is considered to be a relevant test

organism if it were isolated from a raw material such as
water, a purified intermediate, or final drug formulation
and if it is considered to be at risk for passing through a
sterilizing grade filter ( based on size ).

B diminuta was originally isolated as a contaminant in

penicillinase solution that had been filtered through a 0.45
u filter in a pharmaceutical process ( Bowman and Holdow
Sky 1960 ], that was intended to be aseptic. Hence, it is
considered a relevant test organism.
Aggregation

If a sterilizing grade filter removes organisms via size

exclusion, the most stringent test of this filter should
employ a non aggregated particle ( very small cells that
aggregate may behave as a single large particle ), which is
relatively easy to remove from the fluid stream. When
cultured according to accepted methods, B diminuta exhibits
very little aggregation. Other smaller size bacteria are
found in clusters.

The ideal test organism should be cultured to a very small

size. To date, of all the organisms studied B diminuta
represents the smallest size ( Theodore H. Melizer Mark W.
Jornitz Filtration in the Biopharmaceutical Industry ].

The AICC 19146 indicates the size of B diminuta as 0.68

u long and 0.31 u wide. Another organism which is
considerably smaller is P fluorescens with a tength of 1.02
u and width 0.22 u.

For all the above reasons, 0.22 u pore size is fixed as the
ideal sterlizable grade of filter.

There are smaller organisms like virus which are much

smaller in length and width. But, viruses are not capable
of living on their own. They need a host cell to live on,
which will be above 0.22 u size.

Absolute filter sterilization.

Even if one could claim absolute removal of a given

organism by a given filter, the same filter might not be
effective in removing other smaller organisms. From a
practical point of view, the person using the filter must
know what organism was used in the manufacturers
qualification, and, not expect that filter to be effective
against other, perhaps smaller organisms. Thus today,
sterilizing grade filters with ratings of 0.2 u generally are
not used or recommended as the final filter in applications
that require complete removal of organisms, such as
mycoplasma, that are smaller than 8 diminuta.
 More recently, 0.1 U rated memranes have been advocated
as the filter media, at least for some preparation e.g. high
purity water systems and blow fill seal filling lines.

Q What constitutes a representative numbers of batches that

must be reviewed periodically for quality standards under
the CGMP regulations ?

A The annual review established by 211, 180 (e) is for the

purpose of evaluating the quality drug standards of each
drug product to determine the need for changes is drug
product specification or manufacturing or control procedures.
The selections of records to be reviewed needs to consider
records required by this part which have data therein and
include the records specified in 211, 180 (e0(1) and 211,
180 (e) (2).

The number of batches whose associated records will be

reviewed must achieve the purpose of the review. Any
reasonable approach to achieve the purpose can be
acceptable, the word representative was inserted into this
regulation in January 1995 to simply confirm that every
batch does not necessary have to be included.

Reviewing batches which exhibits varying manufacturing

experiences is a critical element in ensuring that a
representative selection is made. Batches showing different
categories of experiences would include those that.

* Have been approved, rejected and recalled

* have unexplained discrepancies
* were the subject of FARs ( field alert reports ) and
* have any other kind of outcome
that may indicate changes are needed.

Where any of these categories include multiple problems,

the numbers of batches selected for review should fully
represent the different kinds of problems in each category.
Every drug product must have at least one batch included
in the annual review. Different products may not be
grouped by similar processes or any other similar approach,
because the necessary, differences in the process and / or
specifications which make each product unique may result
in different manufacturing outcomes.
Q. What is the systematic approach for deciding the
acceptance criteria for cleaning validation in case of
product charge over.

Is there any fDA pharmacopoeia guidelines for acceptance

criteria of wash water analysis and swab test analysis in
case of product changeover.

A As far as acceptance criteria goes, there should be no

measurable quantities of contaminants in the wash water.

The sensitivity determination of probable contaminants is

very critical. Depending on the capability of the laboratory
to determine the trace contaminants, and their probable
effects on the next product to be manufactured, house
standards have to be established for acceptance. The
acceptance criteria has to be decided by the company.

To the best my knowledge. There are no official guidelines

for acceptance criteria.

Q Is it necessary to sample and analyse each and every

container, irrespective of its numbers, of a
nonpharmacopoed non active ingredient of a drug product.
Can’t we use n + 1 formula for sampling such ingredients.
What are GMP / FDA guidelines ?

A It is nor necessary to sample and analyse each and every

container of an ingredient. Whether it is active or nonactive
A statistically derived formula like n+1 may be employed
for sampling. There are no fixed norms prescribed in any
of the GMP guides for this purpose Both the CFR and EU
guidelines for sampling of materials, direct the cost of
satistical criteria for variability, confidence in the supplier.
Degree of precision required, past quality records of the
supplier etc. For arriving at the number of containers to
be sampled. However EU GMP guidelines direct that each
and every container should be suitably identified prior to
use. The manufacture must define the sampling norms in an
SOP and follow the same. Any change from this must be
justified and documented.

Q What is the rationale to weight 20 tablets for uniformity

of weight ( weight variation ) as per ( P / BP ?
A It is general practice to use 20 tablets for determining the
average weight of tablets. The same 20 tablets are used
for the determination of weight variation. However, during
validation of the compression process of a compression
machine. It is essential to establish that tablets from each
station are checked for weight variation and consistency of
weight established. Once this is established. The generally
accepted norm of checking 20 tablets for weight variation
may be adopted.

These questions have been answered Raghunandan, GM

Corporation Quality Glaxo India.

Q What should be done with raw material which conforms to

all the standards laid down in the respective monographs of
the IP/BP/USP, but tests positive for other types of
inpurities not mentioned in the monograph ?

A This question has already been taken care of in the

General Notices of the Indian Pharmacopoeia (P) which
says The requirements given in the monographs are not
framed to provide against all possible impurities
contaminants or adulterants ; they provide appropriate
limitation of potential impurities only. Material found to
contain an impurity. Contaminant or adulterant not detectable
by means of the prescribed tests is not of pharmacopoeial
quality if the nature or amount of such substances found is
objectionable under conditions in which the article is
customarily employed or is incompatible with good
pharmaceutical practice Much the same kind of comments
are also to be found in the other pharmacopoeias. It is
upto the user to decide for himself how much of the
impurities found in a material is acceptable, without in any
way rendering the final product unsafe or ineffective.
Microbial limit tests. Is repetition allowed ?

A The failure of the raw material to pass the microbial limit

test could also be atributed to

* Test analysis error in QC lab

* Lab equipment malfunctioning or off calibration

* Operator error
 The out of specification procedure requires
* Conduct investigation before proceeding with additional
tests.

* Retain original sample and dilution in controlled conditions

until the investigation is completed. Any other standard
sample or reagent used in the original analysis must also
be retained.

* Write the investigation report and arrange for retest.

* If there is no error in lab or instrument, request for

resample

* Retest twice with a larger number of sample

* Pass lot when resamples pass.

* Reject the lot when it fails in retest ( out of specification

result confirmed ).

The following are answers to a question asked in the

interactive column.’

Q In the shapfloor, where more than a few machine are

operative, how can all the SOPs be displayed as they
would occupy entire sections of wall, making cleaning
difficult ?

A The sheets of all the required SOPs of the machinary and

cleaning procedures of that area can be laminated. These
bunch of sheets can be kept in a clip pad and be
displayed at one place. This ensure effective utilization and
cleaning of the place.

Or

The laminated SOP’s can be hung to that part of machine

which does out affect the production and this allows for
easy reference and cleaning.

Or

The workers have to be trained to fllow the working

procedure mentioned in SOP’s. The CGMP has mentioned
that the SOP’s be displayed in the working area. But has
not mentioned that they should be displayed on the walls.
It can be placed on one table and the persons working in
that area should be aware of the accessibility of the SOPs
for ready reference.

To save the space in the operating area for SOPs we can

have colour differentiation of folders, for eg. Cleaning
SOPs can have one colour, PVC self sticking folder. All
the pages for one machinery can be put in one folder and
hung near the machine, with a small plastic hok on the
wall. In the same way, operating SOPs can be a different
colour folder. General SOPs pertaining to the department,
can be in a clear transparent PVC folder. But it is
essential that the same colour be maintained throughout in
the factory.