guide.pdf

1
Q. How you develop the product?
A Firstly we do carry out the literature search.
Q. Where you search literature from?
A
Sr.No. WEB SITES PURPOSE
1 vidal.fr Composition of innovators
2 luhs.com Image and information of innovator
3 tsrlinc.com/search3.cfm BCS classification
4 drugs.com Information of drug
5 rxlist.com Innovator and its information
6 Drugbank---homepage
7 Dissolution.com(By-law) Send mail for disso problems
8 Drugsearcher.com
9 Answers.com Answer
10 Google.com
11 Orange book
12 Fda.gov/cder/ogd/
13 Cder---freedom of information---
index---cder---search
14 Sengpielaudio.com/convForce.htm Conversion of units
15 Emc.medicines.org.uk/ Europe Innovator Information
16 DailyMed US Innovator Information
PATENT SITES
1 USPTO-Homepage-Patent search
1)Issued patent---QS
2)Published patent---Q.S
US Patents
2 Europian Patent homepage
espacenet Homepage
EU Patents
OTHER PATENT SITES
1 Pat2pdf Full Patent Pdf
2 Patentlens
3 Patentstorm
4 WIPO
BOOK REFERENCES
1 Merck Index
2 Martindale
3 PDR (Physician Desk reference)
4 Medicine Compendium
5 Therapeutic Drugs
6 Handbook Of Excipients
7 Florey
PHARMACOPOEIAS
1 USP, EP, BP, IP,JP,
Q. What you get from Orange Book?
A Innovator‟s Leaflet, Patent Number, Patent Code & Exclusivity, RLD status.

2
Q.What appears on clicking orange book First page?
A Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations
Publications
FAQ
 Search by Active
Ingredient
 Search by Applicant Holder
 Search by Proprietary
Name
 Search by Application
Number
 Search by Patent
Q.What will you get after clicking on Search by active ingredient?
A Active Ingredient Search Results from "OB_Rx" table for query on
Example: Levonorgestrel.
Appl
No
TE
Code
RLD Active
Ingredient
Dosage
Form;
Route
Strength Proprietary
Name
Applicant
N021998 Yes LEVONORGESTREL TABLET;
ORAL
1.5MG PLAN B ONE-
STEP
DURAMED
Q.What is TE Code?
A Therapeutic equivalent Codes are as follows.
1 There are no known or suspected bioequivalence
problems. These are designated
AA, AN, AO, AP, or AT,
depending on the dosage form
2 Actual or potential bioequivalence problems
have been resolved with adequate in vivo and/or
in vitro evidence supporting bioequivalence.
These are designated AB.
3 Drug products for which actual or potential
bioequivalence problems have not been resolved
by adequate evidence of bioequivalence. Often
the problem is with specific dosage forms rather
than with the active ingredients
These are designated BC, BD, BE,
BN, BP, BR, BS, BT, BX, or B*.

3
Q.What is NDC Code (National Drug Code)?
A Each listed drug product listed is assigned a unique 10-digit, 3-segment number. This
number, known as the NDC, identifies the labeler, product, and trade package size.
The first segment, the labeler code, is assigned by the FDA. A labeler is any firm that
manufactures (including repackers or relabelers), or distributes (under its own name) the
drug.
The second segment, the product code, identifies a specific strength, dosage form, and
formulation for a particular firm.
The third segment, the package code, identifies package sizes and types. Both the
product and package codes are assigned by the firm.
The NDC Code will be in one of the following configurations: 4-4-2, 5-3-2, or 5-4-1.
Q. What is SBOA (Summary Basis of Approval_& what you get from SBOA
Data/FOI.?
A The 1996 amendments to the Freedom of Information Act, FOIA, mandate publicly
accessible „„electronic reading rooms‟‟ with FDA FOIA response materials and other
information routinely available to the public with electronic search and indexing features.
Before submitting an FOIA request, the sponsor should check to see if the information is
already available on FDA‟s website. (http://www.fda.gov/foi/foia2.htm)
Sr No. Parameters
1) Clinical Pharmacology & Biopharmaceutics Review clinical Parameters:
Cmax, Tmax, AUC, t1/2)
2) Bio Recommendations
3) Formula, manufacturing process
4) API characteristics
5) Dissolution Media
6) Compression Parameters.
7) Detailed Labelling Recommendations,
8) Stability
Q. What is DMF & different types of Drug Master File?
A The Drug Master File (DMF) is a submission to the FDA that may be used to provide
confidential detailed information about facilities, processes, or articles used in the
manufacturing, processing, packaging, and storing of one or more human drug
substances. The submission of a DMF is not required by law or FDA regulation. Further
information regarding DMFs is available in the CDER Guidance Document on Drug
Master Files or 21CFR 314.420.
There are following types of DMF
Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel
Type II Drug Substance, Drug Substance Intermediate, and Material Used in
Their Preparation, or Drug Product
Type III Packaging Material
Type IV Excipients, Colorant, Flavor, Essence, or Material Used in their Preparation

4
Type V FDA Accepted Reference Information
Q. What is Exclusivity and are the different types of Exclusivity?
A The generic applicant must notify the patent holder of the submission of the ANDA.
Since the patent holder can immediately sue the first generic sponsor company who
submits an ANDA with a Paragraph IV statement, a 180-day period of market exclusivity
is provided to that generic applicant. This special dispensation is considered as a reward
to the generic manufacturer who took a risk in challenging the patent. If the patent holder
files an infringement suit against the generic applicant within 45 days of the ANDA
notification, FDA approval to market the generic drug is automatically postponed for 30
months, unless, before that time, the patent expires or is judged to be invalid or not
infringed. This 30-month postponement gives the patent holder time to assert its patent
rights in court before a generic competitor is permitted to enter the market. Only
an application containing a Paragraph IV certification may be eligible for exclusivity, and
to earn the period of exclusivity, the ANDA applicant must be sued by the patent holder
and successfully defend the suit.
Under certain circumstances, the patent holder may obtain exclusivity for a branded drug
product that essentially extends the time on the market without competition from the
generic drug product. Exclusivity work similar to patents and is granted by the FDA if
statutory provisions are met.
Types of exclusivity are listed in following Table.

5
There are following types of Exclusivity
Exclusivity Time for exclusivity Exclusivity criteria
Orphan drug exclusivity
(ODE)
7 years Upon approval of designated orphan drug –
Office of Orphan Products issues letter when
exclusivity granted separate from other types of
exclusivity
New chemical entity
(NCE)
5 years Upon first time approval of new chemical entity
“Other” exclusivity
3 years for a
“significant
change’” if criteria
are met
For certain ‘‘significant changes’’ approved on an NDA
or supplement if new clinical studies essential for
approval, conducted or sponsored by applicant, have
been done ‘‘Changes’’ may include
(but are not limited to): newester = salt, new dosage
form, new route, new indication, new strength, new
dosing schedule
Pediatric exclusivity
(PED)
6 months added
to existing
patents or
exclusivity
A period of 6 months ’exclusivity is added to any
existing exclusivity or patents on all applications held
by the sponsor for that active moiety
Pediatric exclusivity does not stand alone
Q. What are different types of Patents listed in Orange Book?
A
 Patents that are listed in the Orange Book include:
 Patents that claim the active ingredients or ingredients.
 Drug product patents which include formulation-composition patents.
 Use patents for a particular approved indication or method of using the product.
The Bolar amendment to the Drug Price Competition and Patent Term Restoration Act
allows a pharmaceutical manufacturer (sponsor) to seek approval from FDA to market a
generic drug before the expiration of a patent relating to the brand name drug upon which
the generic is based.
As part of the ANDA, the sponsor must consider the pertinent patents and provide the
results to the FDA. The Act requires patent information to be ¢led with all newly
submitted Section 505 drug applications and that no NDA may be approved after
September 24, 1984, without the submission of pertinent patent information to the FDA.
The ANDA sponsor must provide a certification that, in the opinion of the sponsor and to
the best of the sponsor‟s knowledge with respect to each patent that claims the listed
drug, some or all of the following certification may be submitted:
Paragraph I: that such patent information has not been filed;
Paragraph II: that such patent has expired;
Paragraph III: of the date on which such patent will expire, or
Paragraph IV: that such patent is invalid or will not be infringed by the manufacture, use, or sale of
the new drug for which the application is submitted.

6
A certification under Paragraph I or II permits the ANDA to be approved
immediately, if it is otherwise eligible.
A certification under Paragraph III indicates that the ANDA may be approved on
the patent expiration date.
If the Orange Book lists one or more unexpired patents, the sponsor of The
ANDA who seeks effective approval prior to the patent‟s expiration must either:
 Challenge the listing of the patent (e.g., file a Paragraph IV Certification that the
patent is invalid or will not be infringed by the manufacture, use, or sale of the
drug product).
 File a statement that the application for use is not claimed in the listed patent.
Then we purchase the API (Sourcing of API).
Q. What are criteria for API Procurement (Sourcing of API)?
A We actually request samples for from at least two suppliers fully.
(International Suppliers US, European, Asian, e.g. (ACIC-Canada) (All Chem-UK)
(Lek-Czech), (Esteves; Moehs; Uquifa-Spain) ;( Biopharma, S.I.M, Midy-Italy)
(Chemcaps, Reddy; Tricon-India) ;( Federa-Brussels) - Review suppliers catalogues &
data critically.)
The Criterias are as following.
We evaluate at least two to three potential active suppliers
• It should compliance with USP/EP monograph
• Rate of the API (We go for lowest cost material)
• Impurity profile and stability
• Potential Polymorphic forms
• Particle size
• Commitment for physical specifications
• DMF availability
• Statement of non-patent infringement
In Details as following
Purchasing an API raw material can be quite demanding and is not as straight forward as
one might perceive. Databases are consulted as to which manufacturers have the required
material available and once the potential vendors are identified, each is requested to
furnish the following information:
1. The detailed synthetic pathway whereby the API is produced, including all solvents, catalysts,
materials, etc. utilized at every step.
2. A statement indicating that the process pathway does not infringe any patents that may be in force
and must be verified by the generic company’s patent lawyers.
3. A statement indicating the possible polymorphic nature of the active drug in question, where
relevant.
4. The batch sizes of API which have been manufactured to-date.
5. Any validation data which may be available to provide some degree of assurance that the synthetic
process has been evaluated/controlled.
6. Fifty to one hundred gram samples from three discrete batches of material manufactured according

7
to the synthetic pathway provided. In each case, the batch-size should be made available.
7. A complete list of synthetic impurities and potential degradation products which may be used to
fingerprint the API, together with full chemical characterization of each as well as 50 - 100mg
samples of each synthetic impurity/degradation product alluded to Appropriate methodologies
such as mass spectroscopy, high performance liquid chromatography (HPLC), X-ray diffraction
(where polymorphs may be present),nuclear magnetic resonance (NMR), electron spin
resonance(ESR), amongst others are generally used for the characterization.
In some instances, one of the recognized international compendia such as the United States
Pharmacopoeia (USP) and/or Pharmacopoeial Forum , the British Pharmacopoeia (BP) and the
European Pharmacopoeia (EP)may list potential impurities and=or degradation products for the API
in question. Depending on the route of synthesis followed, there may be no possibility for a listed
impurity to be present in the API. Should such a situation present itself, the onus is on the API
manufacturer to provide a statement as to why there is no possibility for the stated impurity to be
present.
Note: Such a statement would have to be supported by actually demonstrating the absence of said
impurity by HPLC analysis, and in order that this be done, it is essential that the impurity be synthesized
(and chemically characterized), either by the API manufacturer or by a contract laboratory.
8. A complete list of solvents used in the synthetic process (which should relate to those claimed in
the detailed synthetic pathway) together with those which should be monitored in the API. Where
appropriate, a statement must be made by the API manufacturer claiming that none of the organic
volatile impurities (OVIs) listed in the US Pare present.
9. Specifications pertinent to raw material particle size, which may become better defined as the
drug-product manufacturer closes in on a final formulation.
10. A Technical Package, which embraces the information requested, plus stability data to confirm
suitability of the raw material in question and validated analytical methods pertinent to assay,
related substances/degradation products and residual solvents.
11. A commitment by the API manufacturer to undertake the necessary validation of the synthetic
process, and the batch-size envisaged for future commercial production. Manufacturer of API
should continue to manufacture of API & the impurity of same API for further 9 – 10 years.
Once the exhibit-batches of API (whose documentation is part of the submission dossier) have been
produced, the API manufacturer will be in a position to file a relevant DMF with the appropriate
government agency. A DMF may be used to provide con¢dential detailed information about facilities,
processes, or articles used in the manufacturing, processing, packaging, and storing of the API (40). The
information contained in the DMF may be used to support an Abbreviated New Drug Application (ANDA).
Any updates/amendments to the DMF must only be made after consultation with the drug-product
manufacturer since such changes may jeopardize approval of the finished product. Frequently, API
manufacturers will supply drug-product manufacturers with the “open part” of a DMF, since the
information therein may be necessary and useful in formulating a drug-product.
An “open part” of the DMF would typically include the following:
A. Drug Substance
1. Description of API,
2. Manufacture of drug substance (synthetic pathway only) which includes:
Flow chart, impurity profile, demonstration of chemical structure, and physical characteristics of the
product (spectroscopic analysis),
3. Purity of the reference material, and
4. Packaging and labeling,
B. Laboratory Controls
1. Specifications and test methods used for the API,
2. Scheme of the stability evaluation protocol, and
3. Batch size,
C. Complaints File and

8
D. Environmental Impact Analysis.
Then we carry out Preformulation Study.
Q.What ratio you take and in what condition you will put samples in
Preformulation/Compatibility I.e. Force Degradation Study (Stress Testing)?
A There is no specific guideline for compatibility study. What we do is we put samples
on accelerated condition 40º C /75% RH for 4 weeks, on 60º C for 2or 3weeks, and
Control samples (25º C /60% RH) for 4 weeks.
Tests for Excipient- drug interactions are usually conducted on bends of Drug and
Excipient in ratios similar to those in the final dosage form. Samples can be exposed in
open pans or sealed bottles or vials.
Stress Factors are as follows.
Sr. No. Stress Factors
1 Heat
2 Humidity
3 Acid
4 Base
5 Oxidation
6 Solution stability
7 Photolysis(Optional)
8 Metal ions (Optional)
9 Control sample (2 – 8 ºC)
Preferably Ratio we prefer as following.
Excipients API : Excipient Ratio
Low Dose
(< 20 % of the formulation)
High Dose
(> 20 % of the formulation)
Diluent 1 : 10 1 : 1
Binder 1 : 1 1 : 1
Disintegrant 1 : 5 1 : 0.5
Lubricant 1 : 5 1 : 0.5
Colour 1 : 0.25 1 : 0.25
Flavour 1 : 0.25 1 : 0.25
Sweetner 1 : 0.25 1 : 0.25
We evaluate the following.
A) Visual inspection of changes in colour and texture.
B) DSC (Check – Melting Point)
C) Related substances by HPLC.

9
After completing following points
1. Relevant patents have been accessed and investigated,
2. The appropriate literature search has been undertaken,
3. Regulatory and formulation strategies have been established, and
4. The desired API(s) have been ordered and received.
We carry out Formulation Development trials.
Q. How you select the excipients?
A While Formulation Development, First of all we carry out Innovator Characterization
Innovator Testing Evaluate physical parameters:-
Tablet shape, tablet color, code for punch embossing, pack sizes Containers
materials, closure types; cotton and desiccants.
Innovator Physical
Testing
Physical testing
Weight, Thickness, Hardness, LOD; Friability, Disintegration:
Evaluation of tablet punch; size; score; embossing and shape
Evaluation of
Innovator formula
ingredients
Summary Formula in PDR; International PDRs (Italian, French, and Swiss) and
Innovators product’s insert (obtain latest FOI –FDA)
Perform actual analytical testing on innovator’s product.
Microscopic
observation
Particle/crystal information on
Particle size Crystal shape, habit,
Differentiation on the presence of specific excipients can be verified from
microscopic observation. E.g., Cross-linked cellulose’s Starch and Avicel have a
specific shapes and morphology and maybe easily detected.
Reverse Engineering Soluble/insoluble fraction
Then mostly on the basis of Innovators excipients we carry out formulation Trials.
(We have to purchase at least 3 different lots in smallest and largest pack size for
each product strength)
Selection of appropriate quantities of key excipients such as binders, glidants,
Disintegrants/dissolution enhancers, compressibility aids, lubricants, anti-adherents, and
surface-active agents is an important consideration for the formulation scientist. In this
regard, a valuable reference that should be consulted is
The Handbook of Pharmaceutical Excipients
All compression trials are undertaken with trade dress requirements in mind, using the
same punches and dies envisaged for future commercial production. This approach
circumvents future compression problems such as sticking, picking, and poor friability
upon subsequent exhibit-batch/commercial-batch production. In addition, it may be
difficult to predict hardness/compression force settings if tooling of different
dimension(s) and shape were used at development level, which in turn may affect
dissolution profiles to a considerable degree.

10
During the initial formulation process, it is extremely important to Validate/characterize
each key process, such as:
1 Screen-sizes and milling rates (pre-granulation)
2 Dry blend mixing times (pre-granulation)
3 The quantity and rate of addition of the granulating vehicle
4 The specific granulating times
5 The temperature and air flows employed during the drying process
6 Loss on drying of the granules
7 screen-sizes and milling rates (post-granulation), as well as granulometry assessment (pre-blending)
8 Times and speeds used during all blending operations where the active granule is blended with the
inter-granular/extra-granular phases
9 All coating parameters and conditions.
It is not recommended the use of different types of equipment between the different
phases of development.
As far as possible, the type of tablet compression equipment and tooling
should be identical in principle to those used for manufacture of Initial formulation
trials & scale-up Batch to that of manufacture of the exhibit batches/commercial
batches resulting in technology transfer from pilot scale to production batch.
The type of blender used can also affect the compressibility and, to a lesser extent, the
encapsulation characteristics of a granule/powder blend. Blenders which offer too
intimate a mix between granule and inter-granular excipients (as in the case of wet
granulation formulations) can result in granules for compression which provide tablet
cores demonstrating:
 Prolonged disintegration times (due to excessive hydrophobic layer build-up
because of “over blending” with hydrophobic lubricants such as magnesium
Stearate), and
 Low hardness, which again is a symptom of too intimate a contact between
granule, lubricant(s), and some inter-granular disintegrants.
The selection of blender and blending times can also impact the final granule with respect
to active/Excipient homogeneity and compressibility.
In the case of direct-compression formulations,
 Over-blending can result in de-mixing of active, in addition to prolonged
disintegration times and soft tablets.
 Under-blending can give rise to homogeneity and Compressibility/encapsulation
problems

11
Q. How you select the Batch Size as per capacity of Equipment?
A We can not take 100 % Occupancy, because processes like blending, drying, mixing
will not occur properly. That is the reason generally we take 30 – 70% occupancy of
Equipment
General Formula is as below
Batch size = {Capacity of Equipment * x % of Occupancy * Bulk density (gm/ml) of API
/Excipient whichever is more in the formula compared to other Excipients}
For Example In Case of Low Dose Products, Excipient which is more generally Lactose
And the Easiest formula is as follows.
Suppose For Example
B.D. of API /Excipient is X gm/ml.
Capacity of equipment is 5 L = 5000 ml
Now we have to calculate how much Batch size we can take?
According to BD i.e. = X gm/ml
Therefore 1 ml = X gm
And hence 5000 ml = X * 5000 = 5000X gm = 5X Kg
So, 5 L = 5X Kg = 100 % Occupancy. (We can not take 100 %, we generally take
30 – 70% occupancy)
So for Example 70 % of 5X Kg = 5X * 70/100 = 350 X/100 = 3.5 X = Final Answer.
Q. How you overcome the problem of BLEND UNIFORMITY?
A By optimizing sifting and geometric dilution (mixing) and by optimizing Blending
Time & speed (rpm)
Then we finalize/assess the Final formula after checking following factors.
A) In vitro dissolution
B) Stability of Product.
C) “Ruggedness of Product & Process
The most promising formulation, selected on the basis of consistent/satisfactory in vitro
drug release over a broad hardness range, is then scaled-up from an initial development
batch-size of 5000 units to about 20,000 units. Samples of the drug product
(which may be in the form of uncoated/coated tablets or capsules) are then packaged in
all possible configurations intended for future commercialization, and placed on
“stability” (investigative stability assessment) together with the appropriate packaging(s)
of innovator product, both of which have been analyzed for
potency, degradation products, and dissolution profile. By doing so, it is possible to
evaluate the comparative stability of the generic product against the product of original
research.
It is also vitally important to ensure that all desirable characteristics observed during the
manufacture of the final formula at development-level are maintained as closely as

12
possible when the formulation is scaled-up. The dissolution and disintegration profiles at
the pre-determined hardness levels (where applicable) should be consistent.
Attention must be focused on the following once the generic drug product has shown a
minimum of two months satisfactory stability.
1) Development of specifications for both raw material (API) and the dosage form.
2) Ordering of the API and excipients for exhibit-batch manufacture.
3) Ordering of all relevant tooling, change parts.
It is essential that the raw material specifications are set in conjunction with the API
manufacturer, in order to avoid setting specifications which may be considered too
restrictive by the latter. The debate invariably involves limits with respect to related
substances/impurities/degradation products, residual solvents and particle size.
In certain instances, microbial limits, especially where the active raw materials is
produced by fermentation at some stage during the synthetic pathway. Only once both
parties are in full agreement, should the requisite specifications be confirmed and signed
by the responsible persons.
Q. How you do Formula Optimization & Process Optimization? / In other words
how do you check the ruggedness of Process & Formulation?
A
 “Ruggedness”of process *investigating such effects as “under” and “over”
granulation; ‘‘over’’ and ‘‘under’’ blending; the impact of varying the screen-
size(s) and milling rates during the comminuting processes, etc. and
 ‘‘ruggedness’’ of formulation (by varying the percentages of all ‘‘key’’ ingredients
as permitted by the SUPAC ‘‘level1’’ change) and a comparison of all ‘‘trial’’
formulations to a ‘‘control’’ (the derived ‘‘final formulation’’) with all batch-sizes
identical to those produced at the formulation development stage.
Instead of varying excipient ranges at the level advocated by SUPAC ‘‘level 1’’
change, many formulation scientists prefer to investigate the effects of raising and
lowering the percentages of all key excipients by 20% of their level in the final
formulation since this is thought to provide more meaningful data reflecting the
robustness of the formulation.
SUPAC – IR Excipients Levels
Level Excipients % Change (w/w) Allowed
I Guidant : Talc,other ± 1.0%, ± 0.1 %
Disintegrant : Starch, other ± 3.0%, ± 1.0 %
Binder ± 0.5%
Lubricant : Ca/Mg Stearate, other ± 0.25% ,± 1.0 %
Filler ± 5.0%
Film Coat ± 1.0%
II Guidant : Talc,other ± 2.0%, ± 0.2 %
Disintegrant : Starch, other ± 6.0%, ± 2.0 %
Binder ± 1.0%
Lubricant : Ca/Mg Stearate, other ± 0.5%, ± 2.0 %
Filler ± 10.0%
Film Coat ± 2.0%

13
III Higher than SUPAC – IR Level II Excipient changes ----------
In Formula Optimization, we do carry out effect of functional excipients on
physicochemical parameters. (Binder, Disintegrant & lubricant)
In case of binder, we select 10 % binder concentration in final formula, and then we see
effect of 7.5 % & 12.5 % of binder concentration on physicochemical parameters.
Likewise for the disintegrants and for lubricant also.
In Process Optimization, we optimize following parameters w.r.t. different process.
GRANULATION
OPTIMIZATION
Effect of granulation parameters
 Granulation time
 Speed of choppers (I & II) or mixer blades
 Solvent addition rate and overall amount
 Ratio of intra-granulate Disintegrant and binders agents
 Screen size for milling (e.g. 0.6 or 0.8mm)
 Adjusting mill screen size up or down to fine tune hardness
 Evaluation of optimized granulate and tablet attributes
DRYING  FB Drying temperature versus target LOD and range limits and the
effect on granulate and tablet properties (flow, capping, sticking).
BLENDING  Blending times
 Lubricant Split into two parts (pre-blending and final blending)
 The effect on Content Uniformity, Granule lubrication and Dissolution
profile.
 Evaluation of unit dose sampling vs. Content Uniformity
COMPRESSION  Effect of hardness on tablet properties (aging, dissolution, friability)
 Evaluation of Hardness Range Limits
 Evaluation of stability results of optimized mfg. process
Q. How much the f2 & f1 should be?
A F2 (similarity factor) should be between 50 – 100.
F1 (Dissimilarity factor) should be between 0 – 15.
(Note: But If BE study is passing but f2 is not between 50 – 100 Still that product is
Bioequivalent.)
Q. What is f2 & criteria for f2 calculation?
A Logarithmic transformation of the sum of squares of the difference between test and
Reference profiles.
f2 = 50 log {[1 + I/N Ε Wt (Rt – Tt)
2
]
-0.5
100} {Ε I (Rt – Tt I]}
f1 = -------------------
[Ε Rt +
Where f = fit factor;
Rt = reference assay at time t (percent dissolved);
Tt = test assay at time t (percent dissolved);
N = number of sample points;
Wt = weighting at time t (optional);

14
Ε = summation from t = 1 to t = n.
 A minimum of three time points (zero excluded)
 The time points should be the same for the two formulations
 Twelve individual values for every time point for each formulation
 Not more than one mean value of > 85% dissolved for any of the formulations
 The relative standard deviation or coefficient of variation of any product should
be less than 20% for the first point and less than 10% from second to last time
point.
An f2 value between 50 and 100 suggests that the two dissolution profiles are similar.
Cases where more than 85% of the drug is dissolved within 15 minutes, dissolution
profiles may be accepted as similar without further mathematical evaluation, except in
the case of gastro-resistant formulations where the dissolution takes place in the intestine
and the 15 minutes for gastric-emptying lacks of physiological meaning.
For immediate release dosage form comparison a sample at 15 min is essential to know if
complete dissolution is reached before gastric emptying, i.e. a mathematical calculation is
not necessary. In case more than 85% is not dissolved at 15 minutes but within 30 min, at
least three time points are required: the first time point before 15 minutes, the second one
at 15 minutes and the third time point when the release is close to 85%. For gastro-
resistant formulations frequent sampling (e.g. every 5 minutes) is required during the
rapid dissolution phase.
In general five to eight sampling times within a 0-60 minutes interval are recommended
to achieve meaningful dissolution profiles.
Q. If API/Product is not official in any Pharmacopoeia then how will you
select/develop the Release media for Dissolution?
A First we have to check API solubility in different pH Medias and using surfactants.
And select that media in which solubility is more.
After selection of media we have to test for sink condition.
(3 to 10 times of BCS Class Volume) then decide the volume of media.
Q. If Solubility is same in all Medias then which media you will select?
A Mostly we take 0.1 N HCL media.
Q. What is sink condition and how is it performed on tablets and pooled samples?
What is the importance of the sink condition in the development of dissolution tests?
A Sink conditions describe a dissolution system that is sufficiently dilute so that the
dissolution process is not impeded by approach to saturation of the compound of interest.
Sink conditions affect the production of the sample but not the condition of the solution
upon sampling. Thus, any concerns regarding the subsequent pooling of samples are
unnecessary. The only physical measurement required is that of solubility at the test
temperature. Once the solubility is known, the volume of medium or the acceptability of
a particular medium can be determined. Typically, sink conditions are considered to exist
if, at the dissolution of 100% of the highest strength of the product to be tested, a
concentration of not more than 1
/3 of saturation will be achieved.

15
Q. During development of a dissolution test for a tablet containing a poorly soluble
drug, very high percentages, well above 100%, of the drug release are being
obtained. What could be the possible reasons for these results?
A There are some possible reasons for having dissolution results well above 100% of the
label claim. The interference of excipients or components of the dissolution medium on
the quantitative step of the dissolution test must be evaluated. This evaluation is done by
carrying out the dissolution test with the placebo and running the quantitative method to
verify that the components of your formulation do not interfere with the quantitation of
the drug dissolved. Also, you need to verify that the filter selected is the appropriate type.
The filter needs to have a porosity that will retain all the suspended particulates in the
medium to prevent attenuation of the signal leading to an overestimation of drug
concentration. Most of the filters used in dissolution testing are in the range of 0.45 μm
up to 70 μm, but because of the characteristics of the formulation, it may be necessary to
use filters with smaller porosity.
Q. Differences in the dissolution results were observed when using glass and plastic
dissolution vessels. What should be the recommended procedure in a case like that?
A As part of the development of a dissolution test, you may want to verify what type of
dissolution vessel is the most appropriate for your formulation. Depending on the
characteristics of your formulation and the drug present in it, adsorption on the walls of
the plastic vessel may occur. As a consequence, lower and very variable dissolution
results can be obtained. If this kind of interference is observed, your dissolution method
should specify what type of dissolution vessel should be used to run this particular test.
You need to do the same kind of evaluation when using automated sampling, because
most of the components of these systems are made of polymeric materials, and when
doing manual sampling with plastic syringes. In addition, the filter needs to be evaluated
with respect to adsorption of the drug and leachables. Finally, bear in mind that while
plastic materials can often adsorb drug compounds, glass has also been shown to be
active.
Q. It was observed that the quality of the surfactant used in the dissolution medium
affects the results in the dissolution test. What should be done?
A The presence of related compounds and a low content of the surfactant can affect the
amount of drug dissolved in the dissolution medium and can interfere with the
quantitative step of the test. One of the surfactants that is well known for this kind of
problem is sodium lauryl sulfate, mainly when the amount of drug released is measured
by HPLC.The use of surfactants with high purity and high content can eliminate this
problem.
Q. Is there any guidelines for Dissolution of Ointments, Gel and Creams? The
Active Ingredient in my Topical preparations which I‟m studying is not soluble in
any aqueous media. It is freely soluble in THF or can be extracted from the matrix

16
at higher temperature. Can THF be used as Dissolution medium? If YES, then what
are the limitations?
And secondly, can the temperature of the dissolution bath be raised higher than say
60°C for those topical formulations which leave the Active Ingredient on heating?
A For semisolids, the receiving medium composition can have up to significant amount
of organic solvent but pure THF is probably a stretch. Buffers or solubilizing agent in
aqueous phase with some proportion of organic solvent may be a better choice. Also, for
semisolids, you don‟t have to release more than 30% (less than 30% is OK too) of the
active ingredient in the medium as long as the assay method is sensitive enough to detect
the active ingredient. The temperature should have some biological relevance– 32 °C or
37 °C is commonly used.
Then we carried out the multimedia dissolution.
(In 0.1 N HCL, pH 4.5 Acetate Buffer & pH 6.8 Phosphate buffer)
Q. What is Discriminatory media and how you develop it?
A. Discrimination, in the dissolution world, is having a dissolution test which will show
a difference between one formulation and another. Basically, that you will be able to
discriminate between a drug that passes and one that fails.
Discriminatory dissolution Media is which are sufficiently sensitive to highlight
differences between innovator and test products.
Failure of dissolution can be due to a lot of factors (stability issues, poor formulation). A
discriminatory test ideally should be able to show which samples are not working
properly, so that they are not released to the public and may cause health concerns.
A discriminatory media is one part of a discriminatory dissolution test. The media
should be able to meet sink condition (dissolve 3+ times the amount of drug), be a
biologically relevant pH, contain as little surfactants or other solubilizers as needed. To
determine a good media, typically it is best to study several different pH media,
determine a couple which best dissolve your drug. If you haven't met sink, test the good
media from your first experiment and try each with varying concentrations of surfactant
until you get the lowest amount of surfactant needed to reach sink.
You can verify the media by trying various formulations of the drug in the media if you
wish, and see if it is able to discriminate the difference between multiple formulations
(such as different coating levels, compression, etc.).
We can use the following modifications in the
development of discriminatory dissolution testing:
1. Low rpm of the apparatus. (e.g. 25 rpm for paddle or 50 rpm for basket)
2. Decreased volume of the dissolution media (500 ml)
3. Modified pH (0.01 N in place of 0.1N HCL)
4. Use of other Medias (e.g. dissolution in the mixture of IPA - water & use of Surfactants)

17
Q. What are the different Dissolution Apparatus as per USP?
A As per Following
Apparatus 1 Basket Solid dosage form
Apparatus 2 Paddle Solid dosage form
Apparatus 3 Reciprocating
Cylinder
Modified release solid dosage form
Apparatus 4 Flow Through Cell Modified release solid dosage form with limited solubility
Apparatus 5 Paddle Over Disc Transdermal Patches
Apparatus 6 Rotating Cylinder Transdermal Patches
Apparatus 7 Reciprocating
Holder
Non-disintegrating oral modified release oral dosage form and
Transdermal Patches.

Q. How you carried out stability study?
A We carried out stability study as per ICH guidelines. (Q1A) in blister in carton/Alu.
Pouch (with /without desiccant)
Market Conditions
Accelerated Intermediate Long Term Long Term Photo stability study
US
(1 batch to
be kept)
40º C /75%
RH
(1,2,3 M)
30º C /65%
RH
(3,6,9 & 12
M)
25º C /60%
RH
(1,6, 12 ,18 &
24 M)
EU
(3 batches
to be kept)
40º C /75%
RH
(1,2,3 & 6 M
)
30º C /65%
RH
(3,6,9 & 12
M)
25º C /60%
RH
(1,6, 12 ,18 &
24 M)
CANADA
(3 batches
to be kept)
40º C /75%
RH
(1,2,3 & 6
M)
30º C /65%
RH
(3,6,9 & 12
M)
25º C /60%
RH
(1,6, 12 ,18 &
24 M)
Photo stability study
Overall illumination of
not less than 1.2 million
lux hours and an
integrated near
ultraviolet energy of not
less than 200 watt
hours/square meter.
BRAZIL (3
batches to
be kept)
40º C /75%
RH
(1,2,3 & 6
M)
25º C /60%
RH
(1,6, 12 ,18 &
24 M)
30º C /75%
RH
Photo stability study
Overall illumination of
not less than 1.2 million
lux hours and an
integrated near
ultraviolet energy of not
less than 200 watt
hours/square meter.
Note If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate
condition.
For Other Conditions.
In
refrigerator
Long term 5 ºC ± 3 ºC 0, 3, 6, 9 & 12 months
Accelerated 25 ºC ±2 ºC /60 ± 5%RH 0, 3 & 6 months
In freezer Long term -20 ºC ± 5 ºC 0, 3, 6, 9 & 12 months

18
Stability Commitment
When available long term stability data on primary batches do not cover the proposed re-
test period granted at the time of approval, a commitment should be made to continue the
stability studies post approval in order to firmly establish the re-test period.
Where the submission includes long term stability data on three production batches
covering the proposed re-test period, a post approval commitment is considered
unnecessary. Otherwise, one of the following commitments should be made:
1. If the submission includes data from stability studies on at least three production
batches, a commitment should be made to continue these studies through the proposed re-
test period.
2. If the submission includes data from stability studies on fewer than three production
batches, a commitment should be made to continue these studies through the proposed re-
test period and to place additional production batches, to a total of at least three, on long
term stability studies through the proposed re-test period.
3. If the submission does not include stability data on production batches, a commitment
should be made to place the first three production batches on long term stability studies
through the proposed re-test period.
The stability protocol used for long term studies for the stability commitment should be
the same as that for the primary batches, unless otherwise scientifically justified.
If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant
change” occurs at any time during 6 months‟ testing at the accelerated storage condition,
additional testing at the intermediate storage condition should be conducted and
evaluated against significant change criteria. Testing at the intermediate storage condition
should include all tests, unless otherwise justified. The initial application should include a
minimum of 6 months‟ data from a 12-month study at the intermediate storage condition.
“Significant change” for a drug substance is defined as failure to meet its specification.
In general, “significant change” for a drug product is defined as:
1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria
for potency when using biological or immunological procedures;
2. Any degradation product‟s exceeding its acceptance criterion;
3. Failure to meet the acceptance criteria for appearance, physical attributes, and
functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose
delivery per actuation); however, some changes in physical attributes (e.g., softening of
suppositories, melting of creams) may be expected under accelerated conditions; and, as
appropriate for the dosage form:
4. Failure to meet the acceptance criterion for pH; or
5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.

19
Q. How you select the pack of your product for stability?
A Generally we select pack as per innovator/RLD. (0.025 mm PVC)
But for our confidence and to save the time of stability study we select various packs for
study (This is to be done because if in one pack product fails, then we have to select
different pack and study will start from that day. In this case, we lost our time. To avoid
this we have to select different packs.)
Packs are as following in our Company.
1 PVC/PVDC(60GSM) 9 PVC/PVDC(120 GSM) + TLP (Tri Laminated Pouch)
2 PVC/PVDC(90 GSM) 10 PVC/PVDC(120GSM) + IN TLP
3 PVC/PVDC(120 GSM) 11 PVC/PVDC(60GSM) + IN CARTON
4 PVC IN TLP 12 PVC/PVDC(90GSM) + IN CARTON
5 PVC IN TLP + SILICA BAG 13 PVC/PVDC(120GSM) + IN CARTON
6 PVC IN TLP + SILICA BAG 14 PVC/PVDC(60GSM )+ SILICA BAG+IN CARTON
7 PVC/PVDC(120 GSM) +TLP 15 PVC/PVDC(60GSM) + SILICA BAG +TLP
8 PVC 250+CARTON 16 PVC/PVDC(60 GSM) + SILICA BAG +TLP
Q. How you establish Shelf Life - For Drug Products & Re-Test Date - For Drug
Substances after evaluation of Stability data?
A Answer as following.
Sr.
No.
X Y
1 Accelerated (6months) Long Term (9 months OK) y = 2x
Shelf life / re-test date is 18 months
2 Accelerated (6months) Long Term (12 months OK) y = 2x
3 Accelerated (6months) Long Term (18 months OK) y = x + 12
4 Accelerated (6months) Long Term (24 months OK) y = x + 12
5 Accelerated (6months) Long Term (36 months OK) y = x
No extrapolation beyond 36 months
Q. How you establish Shelf Life - For Drug Products & Re-Test Date - For Drug
Substances after evaluation of Stability data If accelerated stability data for 6 months
is NOT OK?
A
Sr.
No.
X Y
1 Accelerated (6months) Intermediate 12 months OK y = 1.5x
2 Accelerated (6months) Intermediate 9 months OK y = 1.5x
Shelf life / re-test date is 13.5 months
3 Accelerated (6months) Intermediate
(9 months NOT OK & if long
term 9 months OK)
y = x + 3

20
Q. How you develop the method for R. S. Of API which is not official in any
Pharmacopoeia & How we decide limit for R.S.?
A Firstly we take the method which has given in the DMF supplied by supplier as a base
Then we develop method for R.S.on the basis of method given in DMF supplied by
Supplier by referring the ICH Guideline
(IMPURITIES IN NEW DRUG SUBSTANCES Q3A(R) &
Firstly we check the Limit for R.S. given in COA supplied by supplier & then we do
carry out stress stability study for Tablets of formulation containing that API for force
degradation & then check whether it complies with Limit given COA & then we select
the limit as per ICH Guideline
IMPURITIES IN NEW DRUG SUBSTANCES Q3A(R) & IMPURITIES IN NEW
DRUG PRODUCTS Q3B(R)
IMPURITIES IN NEW DRUG PRODUCTS Q3B(R)

21
After finalizing formula and checking stability data (1 – 3 months) we take the
Scale - up Batch / Optimization batch. We take batch Size of Scale up is same as that
of Exhibit Batch.(i.e.100,000 units or 1/10 of Commercial Market Batch)
(100000 units should be packed finally) and we optimize the parameters w.r.t.
processes same described below for Scale - up size Batch and prepare of a Scale-up
Report.
While taking Scale – up Batch, we optimize the process.
The Process Qualification Protocols must monitor and control all key processes in the
manufacturing pathway such as:
 Volume and rate of addition of granulating vehicle,
 Exact drying conditions,
 Milling rates, screen-sizes, etc.,
 Blender rotation speeds and mixing times,
 Blend uniformity after blending,
 Blend uniformity after discharge of the granule into „„holding bins‟‟ (to evaluate
if active segregation has resulted on discharge),and
 Granulometry assessments, bulk and tapped density determinations and loss on
drying measurements before and after granule discharge from the blender.
Prior to compressing the batch of granules into tablets at the optimum hardness and
speed, the following parameters need to be established:
 „Low‟ and „High‟ hardness levels at which the tablets can be compressed
meeting all pre-determined acceptance criteria, with specific reference to
dissolution profiles,
 The highest speed at which the particular press can be operated to provide tablets
meeting pre-determined acceptance criteria, with specific reference to content
uniformity, and
 Humidity and temperature (these are controlled in plant operations by SOPs
whereas specific conditions are imposed byproduct-specific demands during
formulation development).
Then we prepare TTD (Technology Transfer Document / Master Manufacturing
Document) & Sampling Guideline. After it reviewed by all departments we send it to
Plant & they send us BMR. (Batch Manufacturing Record) We review it. Then if
corrections are there we corrected & then we go ahead with Exhibit Batch. (Pivotal
Batch)
(A copy of the signed Master Manufacturing Document is then provided to the Process
Validation Department for generation of the Process and Cleaning Qualification
protocols. In general, the validation process requires at least three batches of each
strength of drug product to be assessed whereas the qualification process relates to a
single batch of each strength of drug product only)

22
Market Number of Exhibit
Batches
Stability Data
required
Multimedia
Dissolution Data
Bio -
Recommendations
US 1 3 M data Required Not Necessary Yes
(Fasting + Fed,
if they recommend
)
SOUTH AFRICA 1 6 M data Required Not Necessary
EUROPE 2 and 1 Small scale
size (Small scale size
not mentioned in
any Guideline)
6 M data Required Compulsary with
justification
No (Fasting)
AUSTRALIA 2 6 M data Required
BRAZIL 3 6 M data Required Compulsary with
justification
No (Fasting)
CANADA 3 6 M data Required Compulsary with
justification
No (Fasting)
JAPAN 3 6 M data Required
Manufacture of the exhibit batch is the responsibility of the formulation
scientist/technicians associated with the development of the final formulation together
with the scale-up or „technical transfer‟ team.
Exhibit-batch manufacture is required to be carried out under cGMP conditions
Points should be taken into consideration while Production of Pivotal (Exhibit) Batch
1) Pivotal batch must be compressed in a production tabletting machine (or
production type with same principle and operation)
2) Preparation of FINAL Master Formula and Processing Instructions
3) Review of FINAL formula, manufacturing process and control parameters with production
personnel and QA Staff. Pivotal authorization signatures (RD; QA-QC; RA; and Production) attached.
4) Operation of production and control personnel during Pivotal manufacture, aided by Formulation
development team.
5) Critical manufacturing steps designated and sampling and testing parameters specified.
6) The preparation of a Pivotal Report. This pivotal report forms part of the overall Development
Report.
After completing E- batch & prior to packaging of the batch,
the necessary Packaging Documentation needs to be prepared. This describes the actual
packaging disposition of each batch.
The packaging operation must be carried out under c- GMP conditions, using large-
plant equipment
Once the product has been packaged, samples of each pack size are incorporated into
formal stability programmes (usually 40ºC/75% RH; 30ºC/65% RH and 25ºC/60% RH)
according to a Stability Protocol, which outlines the pack sizes and types to be evaluated,
the manufacturers of the packaging components and actual composition there of, the pre-
determined times at which samples must be drawn, the necessary testing that needs to be
undertaken and the pre-determined acceptance criteria that are required to be met.

23
Drug product(s) containing APIs sensitive to light should be tested in appropriate
photo stability chambers according to an approved protocol.
After studying the all results (Physicochemical Parameters) of Exhibit/Pivotal Batch
comes OK.
Then we send the Samples of Pivotal Batch to BIOEQUIVALENT STUDY
Following points should be taken into Considerations while B.E. Study.
1) Perform Fasted / Food Effect Biostudy on Pivotal Lot Samples.
2) Perform Food Effect Biostudy on Pivotal Lot Samples
(See food effect guidelines, where appropriate)
3) Biostudy generally performed on highest strength of product
4) WAIVER CONDITIONS : For multiple strength products In- vitro dissolution testing conducted in
three different pH media on lower dosage forms
(0.1 N HCL,pH 4.5 acetate Buffer,pH 6.8 Phosphate Buffer)
5) Perform Similarity Test [F2 Test] on dissolution results.
6) We check three parameters mainly.
1) Cmax
2) Tmax
3) AUC(0- t)
7) All the parameters must pass criteria for Confidence Interval (C.I.) – 90%
8) All the parameters must be within 80 – 125
Q. Why in between 80 – 125?
A We can take both ratios =T/R & = R/T Ratio Reference(R), Test (T)
Standard Case Reverse case
Applicable for
Parameters
For General Drugs
We have to take ± 20 % Deviation of Innovator/RLD.
Innovator (R) 100 80 Cmax
tmax
AUC
For All markets
Test (T) 80 100
Deviation - 20 % + 20 %
Conclusion = T/R = 80/100*100 = 80 % = T/R = 100/80*100 = 125 %
For Highly Variable Drugs
We have to take ± 25 % Deviation of Innovator/RLD.
Innovator (R) 100 75 For Cmax only.
& for Europe Market
Test (T) 75 100
Deviation - 25 % + 25 %
Conclusion = T/R = 75 /100*100 = 75 % = T/R = 100/75*100 = 133 %
For Highly Potent Drugs
Innovator (R) 100 90 Cmax
tmax
AUC
For All markets
Test (T) 90 100
Deviation - 10 % + 10 %
Conclusion = T/R = 90 /100*100 = 90 % = T/R = 100/90*100 = 111 %

24
Then we prepare Product Development Report (PDR) & send to DRA.
(As Per Guideline Q8 R1)
A Product Development Report is a summary of the complete development process and
will be the subject of keen regulatory agency scrutiny during a Pre-approval Inspection
(PAI) (FDA) or any other similar audit. This report must make detailed reference to the
following:
1 An overview of the actions and uses of the particular active, as well as any information
pertinent to the relevant pharmacokinetics.
2 A brief description of the innovator product and the pack-sizes commercially available and
appropriate to all markets where the product is destined to be sold.
3 A detailed summary of the innovator product’s physical characteristics (such as appearance,
size, shape, and weight).The inclusion of a photograph, as visual confirmation, is desirable.
4 A comprehensive account of the APIs used during the formulation development process
including sources of supply. All information pertinent to the polymorphic form used in
development as compared to that used by the innovator (which is usually easier to
determine in drug products containing more than 25%of active) as well as particle sizes of
the APIs, bulk=tapped densities information and the mechanism whereby the appropriate
specifications were established. Generally three lots of API from an approved supplier should
be analyzed and on the basis of the resultant data, specifications need to be set. Compendial
monograph(s) may be too lenient as far as impurity limits are concerned and often data
relating to residual solvent presence, particle size, polymorph, and polymorph ratio are
either absent or scant.
5 A section dealing with the development of a discriminatory dissolution method including
profiles of the generic and RLD product(s) using this method and conditions. The dissolution
methodology outlined in the USP, BP, or EP may not be sufficiently discriminatory to serve
formulation development needs. Because the particular compendial method serves as a
“batch release” specification for the commercial product, it is essential that both the
innovator and generic drug products meet applicable compendial specifications.
6 A detailed account of all experimentation undertaken to arrive at the ‘‘final formulation’’.
Reference should be made (ideally in the form of an ‘‘Appendix’’) to each formula employed,
details of granulometries, bulk and tapped densities, loss on drying and ranges of tablet core
hardness together with associated disintegration times and dissolution profiles.
7 A detailed account of all experimentation undertaken to prove:
 ‘‘Ruggedness’’ of process *investigating such effects as ‘‘under’’ and “over”
granulation; ‘‘over’’ and ‘‘under’’ blending; the impact of varying the screen-size(s)
and milling rates during the comminuting processes, etc.], and
 ‘‘Ruggedness’’ of formulation (by varying the percentages of all ‘‘key’’ ingredients as
permitted by the SUPAC “level1” change) and a comparison of all ‘‘trial’’
formulations to a ‘‘control’’ (the derived ‘‘final formulation’’) with all batch-sizes
identical to those produced at the formulation development stage.
8 For each trial formulation, only the pertinent physicochemical attributes need be assessed,
such as content uniformity and dissolution profile, the latter employing a discriminatory
dissolution method
9 An account of the formulations to be progressed to exhibit batch level, as well as outline of
the desired manufacturing pathway.

25
Then Before submission of ANDA, AUDIT has been carried out.
For AUDIT following points should be taken into consideration
Development Report Audit all raw data supporting Development Report
ANDA Regulatory File Audit Plant and Laboratory Documentation as per ANDA
SOPs Review SOP System and Update level
cGMP Review cGMP of Manufacturing Processes
Biostudy Report Evaluate and develop a IVIV correlation (Level A where possible.)
Validation Protocol Product Process Validation Protocol complete and signed
Then we submit ANDA (i.e.DRA part is started)
1) DRA submits ANDA in e - CTD Format.
2) By manually as following:
Submit ANDA structured as Part Two of this Handbook
(9 Copies -as per Color system) and (1 Field Copy)
Generic drug sponsors do not have to duplicate the non clinical animal toxicity studies or
expensive clinical efficacy and safety studies that are included in the new drug
application, NDA, which is submitted to the FDA for market approval of the brand name
drug product. The ANDA contains data, which, when submitted to FDA‟s Center for
Drug Evaluation and Research, Office of Generic Drugs, provide for the review and
ultimate approval for marketing a generic drug product.
FDA approved generic drugs must meet the same rigid standards as the innovator drug.
To obtain FDA approval,
A generic drug product must contain:
1 The same active ingredients as an approved reference listed drug product
(generally, the innovator drug /the inactive ingredients may vary)
2 Be identical in strength, dosage form, and route of administration;
3 Have the same use indications;
4 Be bioequivalent;
5 Meet the same batch requirements for identity, strength, purity, and quality;
6 Be manufactured under the same strict standards of FDA’s good manufacturing
practice regulations as required for innovator products.

26
Generic Drug (ANDA) Review Process.

27
After approval of ANDA, we carried out Commercial batches.
Following points should taken in consideration while validation of 3 commercial batches.
1) Prepare Process Validation Protocol for 3 consecutive marketing lots.
2) Execute Process Validation of 3 consecutive marketing lots.
3) Prepare Process Validation Report.
4) Show intra-batch similarity.
5) Show inter-batch similarity between Bio-batch (Exhibit/Pivotal) and the Commercial Validation Lots.
Suppose if there is some major change in commercial batches then we have to
perform RE - VALIDATION on the COMMERCIAL batches
1) If there is Formula
Change/Equipment
Change
We have to Revalidate procedure with new formula process
or equipment with
2) If there is Process
Change
we have to revalidate with different operating principle
3) If there is Minor
change
Follow SUPAC Rules Level I II or III

guide.pdf

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to guide.pdf

Similar to guide.pdf (20)

Recently uploaded

Recently uploaded (20)

guide.pdf