Documentation in pharaceutical industry

Masters of pharmacy, Pharmaceutical technology (Pharmaceutics)
Subject- Regulatory affairs (MPH-104T)
Lesion no- 1, Documentation in pharmaceutical industry By- Drx JAYESH M.RAJPUT
Points:-
1) Documentation in pharmaceutical industry: -
Golden rule: - if it is not documented it didn’t happened!
What is a document??
A document is a piece of written, printed, or electronic matter that provides information or evidence or that serves
as an official record
What is the need of documentation??
Documents and products are produced in pharmaceuticals but regulatory bodies are interested to
see documents first, different documents can describe the different activity in pharma and its
actual image, due to the importance given to documentation in pharma “good documentation
practices” is required. Good documentation is a systemic procedure of preparation, checking,
verifying, issuing, storing and reviewing of any documents, clearly written documents prevent
errors of various activities in pharma industry and in different related fields.
Purpose of documentation
 Defines specifications and procedures for all materials and methods of manufacture and
control
 Ensures that all personnel knows what to do and when to do it
 Ensure that authorized persons have all information necessary for release of product
 Ensures documented evidence, traceability, provide records and audit trial for investigation
 Ensures availability of data for validation, review and statistical analysis
For good documentation the organization should:-
o Provide enough resources to create and complete documentation
o Ensure that the documents are attributable, legible, recorded, original and accurate
o Conduct a thorough gap analysis of existing documentation for any missing
documentation or revision
o Provide resources for initial and ongoing training to the personnel, involved in
development and manufacturing of the pharmaceutical products, in documents during
lifecycle management of products
o Finally, an oversight of quality assurance is needed to ensure that the personnel are
following the organization SOPs

2) Master formula record (MFR)
Master formula record is “A document or set of documents specifying the starting materials
with their quantities and the packaging materials, together with a description of the
procedures and precautions required to produce a specify quantity of a finished product as
well as the processing instructions, including the in-process controls”
There shall be master formula records relating to all manufacturing procedures for each
product and batch size to be manufactured. These shall be prepared and endorsed by the
competent technical staff i.e. head of production and quality control
MFR introduction:-
 In the 1997 WHO guidance document:”WHO/VSQ/97.01:
A WHO guide to good manufacturing practice (GMP) requirements. Standard
operating procedures and master formulae
 WHO identifies manufacturing instructions as “Master formula” other terms used in
GMP guidelines and regulations are manufacturing formula, master production and
control record
 An approved master document that describes the full process of manufacturing for the
batch of product with at least cross-reference to the support operations for a batch of a
specific product.
WHO-GMP guidelines:- a formally authorized master formula should exist for each
product and batch size to be manufactured
Health Canada GMP guidelines:- “master formula” (formula type) a document or set of
documents specifying the raw materials with their quantities and the packaging materials,
together with a detailed description of the procedures and precautions required to produce
a specified quantity of a finished product as well as the processing instructions, including
the in-process controls.
US-CFR:- to assure uniformity from batch, master production and control records for each
drug product, including each drug product, including each batch size there of, shall be
prepared, dated and signed (full signature, handwritten) by one person and independently
checked, dated, and signed by a second person. The preparation of master production and
control records shall be described in a written procedure and such written procedure shall
be followed.

The master formula record shall include:-
a) The name of the product together with product reference code relating to its
specifications
b) The patient or proprietary name of the product along with the generic name, a
description of the dosage form, strength, composition of the product and batch size
c) A statement of the processing location and the principal equipment to be used
d) Name, quantity and reference number of all the starting materials to be used. Mention
shall be made of any substance that may disappear in the courts of processing
e) A statement of the expected final yield with the acceptable limits, and of relevant
intermediate yields, where applicable.
f) The methods, or reference to the methods, to be used for preparing the critical
equipments including cleaning, assembling, calibrating, sterilizing
g) Detailed stepwise processing instructions and the time taken for each step
h) The instructions for in-process control with their limits
i) The requirements for storage conditions of the products, including the container,
labeling and special storage conditions where applicable
j) Any special precautions to be observed and
k) Packing details and specimen labels
Master formula (production) as per WHO:-
 Name of the product , with a product reference code relating to its specification
 A description of the dosage form, strength of the product and batch size
 A list of all starting materials to be used with the amount of each
 A statement of the expected final yield with the acceptable limits, and of relevant
intermediate yields, where applicable
 A statement of the processing location and the principal equipment to be used

 The methods, or reference to the methods, to be used for preparing and operating
the critical equipment, e.g. cleaning (especially after a change in product),
assembling, calibrating, sterilization
 Detailed step-wise processing instructions (e.g. checks on materials, pretreatments,
sequence for adding materials, mixing times, temperatures)
 The instructions for any in process controls with their limits
 The requirements for storage of the products, including the container, the labeling,
and any special storage conditions
 Any special precautions to be observed
Master formula-Packaging
 The name of the product
 A description of its pharmaceutical form, strength and, where applicable, method
of application
 The pack size expressed in terms of the number, weight or volume
 A complete list of all the packaging materials required for a standard batch size,
including quantities, sizes and types, with the code or reference number relating
to the specifications for each packaging material
 Special precautions to be observed, including a careful examination of the
packaging area and equipment in order to ascertain the line clearance before and
after packaging operations.
 Master formula give the complete production instructions for a specific batch
and batch size of cell banks, virus seed lots, intermediates, final bulks, final
formulated bulks or final container product
 The batch production record (BPR) is the approved copy of the master document
with filled in data entries, signatures, dates, production locations, operators, and
lot number, records of all supporting data (autoclave records, cleaning records,
equipment identification and calibration dates, in-process test results, and QC
results).
Formats of MF:-
Generally MF should be a single documents of that provide step by step production
instruction raw material equipments used location production data, etc.

3) (DMF) Drug master file:-
A drug master file (DMF) is a submission to the food and drug administration (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 drugs.
A drug master file (DMF) is a submission to the food and drug administration (FDA)
that may be used to provide confidential detailed information about facilities, process, or
articles used in the manufacturing, processing, packaging, and storing of one or more
human drugs
The submission of a DMF is not required by law or FDA regulations
The information contained in the DMF may be used to support an investigational new
drug (IND), a new drug application (NDA), an abbreviated new drug application
(ANDA), another DMF, an export application, or amendments and supplements to any
of these.
Submission of DMF:-
o Each DMF submission should contain a transmittal letter, administrative
information about the submission, and the specific information to be included in
the DMF as described in this section
o The DMF must be in the English language. Whenever a submission contains
information in another language, an accurate certified English translation must
also be included

o Each page of each copy of the DMF should be dated and consecutively numbered.
An updated table of contents should be included with each submission.

Format, assembly and delivery of DMF
An original and duplicate are to be submitted for all DMF submissions.
o Drug master file holders and their agents/representatives should retain a complete
reference copy that is identical to, and maintained in the same chronological order
as, their submissions to FDA
The original and duplicate copies must be collate, fully assembled, and individually
jacketed
o Each volume of a DMF should, in general, be no more than 2 inches thick. For
multivolume submissions, number each volume

o For example for a 3 volume submission, the volumes would be numbered 1 of 3, 2
of 3, and 3 of 3
Delivery to FDA:-
Drug master file submissions and correspondence should be addressed as
follows:-
Drug master file staff, food and drug administration, 5901-B ammendale road,
Beltsville, MD 20705-1266
4) Distribution records
 Distribution records shall contain the name and strength of the product and
description of dosage form, name and address of the consignee, date and quantity
shipped, and lot or control number of the drug product
 For compressed medical gas products, distribution records are not required to
contain lot or control numbers
 The primary purpose of this section is to ensure that adequate data are available to
access trade customers should a recall be initiated.
 Distribution records include a wide range of documentation such as invoices, bills
of landing customers receipts and internal warehouse storage and inventory
records
 The information required need not be on every document also customer codes and
product codes may be used as alternatives to customer names and address and
product names

 Records for distribution shall be maintained in a manner such that finished atch of
a drug can be traced to the retain level to facilitate prompt an complete recall of
the batch, if and when necessary.

5) Generic drugs product development
Introduction:-
A generic drug is a pharmaceutical drug that has the same chemical substance as the drug that
was originally developed, patented and innovated. Generic drugs are allowed for sale after
the expiry of the patent of the original drugs. Because the active chemical substance is the
same, the medical profile of generics is believed to be equivalent in performance. The generic
drug has the same active pharmaceutical ingredient (API) as the original, but it may differ in
characteristics such as manufacturing process, formulation, excipients, color, taste, and
packaging.
According to WHO
“A generic drug is a pharmaceutical product, usually intended to be interchangeable with an
innovator product that is manufactured without a license from the innovator company and
marketed after the expiry date of the patent or other exclusive rights”
The English dictionary defines the word GENERIC as:-
“not protected by trademark registration; nonproprietary or any product, as a food, drug, or
cosmetic that can be sold without a brand name”.
Approval for generic drugs:-
The expiry of patent drug for innovator, it can be manufactured and marketed by any
pharmaceutical company.

Before marketing the drug, generic manufacturers need to obtain permission from relevant
drug regulatory authorities
1. Any drug manufactured should follow good manufacturing practices guidelines, the
enforcement of which is the responsibility of drug regulators.
2. There is a requirement for in-vitro dissolution and in-vivo bio-availability and bio-
equivalence (BA-BE) testing of new brand (i.e. generic manufacturer) which compares the
release of active pharmaceutical ingredient (API) on certain dissolution and liberation
characteristics and pharmacokinetic parameters (Cmax, Tmax, and area under the curve) with
those from reference standard.

6) Hatch-Waxman act and amendments:-
The “drug price competition and patent term restoration act of 1984”, also known as the
hatch-Waxman amendments, established the approval pathway for generic drug products,
under which applicants can submit an abbreviated new drug application (ANDA) under
section 505(j) of the federal food, drug, and cosmetic act (FD&C act) is a 1984 united states
federal law which encourages the manufacture of generic drugs by the pharmaceutical
industry and established the modern system of government generic drug regulation in the
united states.
In order to overcome the above problem an act was needed to promote generic drug and
innovators. In 1984, two American politicians’ Orrin grant hatch& Henry Arnold Waxman
sponsored the official act “the drug price competition and patent term restoration “ since then
this act was informally known as Hatch-Waxman act
AIM: - to make available more low cost generic drugs.
Objectives of the act:-
 Reducing the cost associated with the approval of a generic drug
 Allowing early-experimental use
 Compensating the branded drugs manufacturers for the time lost from the patent term
because of the regulatory approval formality
 Motivating the generic drug manufacturers
Provision of the act:-
o Creation of section 505(j)
o This section outlines the process of pharmaceutical manufacturers to file a
abbreviated new drug application (ANDA) for approval of generic drug
manufacturer
o NDA must include any patent that claims the “drug” or a “method of using the
drug” for which a claim of patent infringement could reasonably be asserted
o On approval of NDA, FDA publishes patent information for drug in orange book
Four types of patent certifications:-
o When an applicant submits an ANDA to the FDA, the applicant must certify one
of four things under section 505(j)(2)(A)(7):
o that the required patent information relating to such patent has not been filed
(para1)
o that such patent has expired (Para 2)
o that the patent will expire on a particular date (para 3)

o that such patent is invalid or will not be infringed by the drug, for which approval
is being sought (Para 4-patent challenge)
Drug approval:-
The FDA requires every new drug, including generic drugs, to be safe and effective.
Before the adoption of the Hatch-Waxman act, the FDA required branded and
generic drug companies alike to demonstrate the safety and efficacy of their products
in the same manner through a new drug application (NDA).
ORANGE BOOK
The orange book is a resource which identifies drug products approved on the basis of safety
and effectiveness by the FDA and related patent and exclusivity information. This orange
book is available on the internet and is updated monthly.
The hatch Waxman act provides an expedited USFDA program for speedy generic entry and
market exclusivity. The hatch Waxman act allows for a patent term extension of a maximum
of 5 years for the branded drug manufacturer to compensate for the time lost during the NDA
approval by the USFDA
7) CFR (code of federal regulation):-
The code of federal regulations (CFR) is the codification of the general and permanent rules
and regulations (sometimes called administrative law) published in the federal register by the
executive departments and agencies of the federal government of the United States. The CFR
is divided into 50 titles that represent broad areas subject to federal regulation

History of the code of federal regulations
o Franklin d.roosevelt-32nd
president of the US
o 1935- instrumental in passing the federal register act-empowered the national archives
of the US to form an administrative committee publish the federal register
o The federal register act- amended in 1937 to provide a “codification” of all regulations
every five years known as code of federal regulations.
o The first edition of the CFR was published in 1938 and included all finalized
regulations that were published in the federal register from march 14, 1936 to june
1,1938
o Beginning in 1963 for some titles and for all titles in 1967, the office of the federal
register began publishing yearly revisions
o Beginning in 1972- published revisions were conducted in staggered quarters

8) Drug product performance:-
Defined as the release of the drug substance from the drug product leading to
bioavailability of the drug substance. The assessment of drug product performance is
important since bioavailability is related both to the pharmacodynamics response and
to adverse events. Thus, performing tests relate the quality of a drug product to clinical
safety and efficacy. Bioavailability studies are drug product performance studies used
to define the effect of changes in the physicochemical properties of the drug substance.
The formulation of the drug and the manufacture process of the drug product.
Bioequivalence studies in new drug development (NDA):-
a. Early and late clinical trial formulations
b. Formulations used in clinical trials and stability studies, if different
c. Clinical trial formulations and to-be marketed drug products, if different
d. Product strength equivalence, as appropriate
Bioequivalence study designs support new formulations of previously approved
products. Such as a new fixed-do se combination version of two products
approved for co-administration, or modified-release version of immediate
release products

Analytical methods:-
 In vivo bioavailability, bioequivalence or pharmacodynamic studies must
be validated for accuracy and sufficient sensitivity
 The analytical method for measurement of the drug must be validated for
accuracy, precision, sensitivity, specificity and robustness
 The use of more than one analytical method during a bioequivalence study
may not be valid, because different methods may yield different values
 Measurement of the active metabolite is important for very high-hepatic
clearance (first pass metabolism) drugs when the parent drug
concentrations are too low to be reliable.

Study designs:-
The FDA provides the guidance for the performance of: in-vitro dissolution and in-vivo
bioequivalence studies which include (solid oral dosage form)
1. Fasting study
 This study is required for all immediate release and modified release oral
dosage forms
 Both male and female subjects are included
 Overnight fasting is required (at least 10 hours)
 After administration of drug fasting is continued up to 4 more hours
 Blood sampling is performed before dose and at different intervals after
dose
 Plasma drug concentration time profile is obtained
 No other medication given at least 1 week prior to study
2. Food intervention study
 It uses single dose, randomized, 2 treatment, 2 period crossover study
 Conducted using meal conditions that have greatest effect on GI physiology
 Meal containing high calories (50% of total caloric content) and fat (800-
1000 cal) is taken
 After a overnight fast of 10 hrs, meal is given 30 min prior to dosing
 The meal is consumed over 30 min with administration of the dug (with 240
ml of water) immediately after meal
 No food is allowed 4 hrs after dosing
 Study on drugs like ibuprofen and naproxen which is affected by food
2. Sprinkle BE (bioequivalence) study (extended release capsules having beads).

9) ANDA regulatory approval process
Abbreviated new drug application (ANDA)
 These are submitted to the FDA’s CDER (center for drug evaluation and research)
 The office of the generic drugs (OGD) is located within the CDER under the
office of pharmaceutical science, to obtain approval to market a generic drug
product
 The OGD ensures the safety and efficacy of generic drugs by employing a review
process that is similar to the NDA process
 Once approved the applicant may manufacture and market the generic product to
provide a safe, effective and low cost alternative
 These are termed “abbreviated” because they generally need not include
preclinical and clinical data to establish safety and effectiveness
 They must scientifically demonstrate that their product is bioequivalence to the
innovator drug.
 Using bioequivalence as the basis for approving generic copies was established by
the “drug price competition and patent term restoration act of 1984” (Hatch-
Waxman act)
 The HWA to the federal food, drug and cosmetics act (FD&C) gave statutory
authority to submit ANDA for all approved innovator drugs
 Generic drug application (FDA 356h) reviewers focus on bioequivalence data,
chemistry and microbiology data. Request for plant inspection and drug labeling
information.
 The primary difference between the generic drug review process and NDA
process is the study requirements
 For ex. An ANDA generally requires a BE study between the generic drug
product and reference list of drugs (RLD) product
 The safety and efficacy of the RLD product were established previously through
animal, clinical, BA studies. So, no need to repeat for ANDA
STEPS:-
 Filling review
 The process begins when an applicant submits an ANDA to the OGD
 The document room staff assigns it an ANDA number and stamps a
received date on the cover letter of ANDA
 It is sent to a consumer safety technician who reviews the preliminary
sections of ANDA checklist
 Within first 60 days – submission, filling review is completed.
Regulatory support branch (RSB) is responsible for this process.

 This group, organized under the division of labeling and program
support (DLPS), consists of project managers and a support staff
including technical information assistants, legal instruments examiners
and consumer safety technicians
 The branch chief who reports to the division director of DLPS
supervises the branch
 To determine whether an application is acceptable for filling, an RSB
project manager (RPM) compares the contents of each section against a
list of regulatory requirements
 An applicant may “refuse to receive” letter when an inactive ingredient
level exceeds the level previously used in an approved drug product via
the same route of administration
 Other reasons:-
o Incomplete bioequivalence studies
o Incomplete stability studies
o Incomplete packaging
o Incorrect basis for submission
o RSB verifies that all applications contain a patent certification and
exclusively statement
 The patent certification and exclusivity statement must address all
existing patents and exclusivities for the RLD (reference list of
drugs) published in the “approved drug products with therapeutic
equivalence evaluations” commonly known as ORANGE BOOK
 If an RLD has expired patents an applicant may certify that no
relevant patents remain
 The review of patents and exclusivities is an ongoing process
throughout the review cycle, as new patents and exclusivities may
become listed in the orange book
 Once the RSB completes the filling review of the ANDA and verifies
that the application contain all the necessary regulatory requirements
an “acknowledgement” letter is issued to the applicant indicating its
acceptance for filling and the official filling date
 The application is then assigned to technical reviewers
 If the ANDA does not met the criteria for filling a “refuse-to-receive”
letter is issued with a list of deficiencies.
 Upon filing an ANDA, the RPM forwards an establishment
evaluation request (EER) to the office of compliance
 Office of compliance are operating in compliance with current good
manufacturing practice (cGMP) regulations
 Currently, ANDA can be submitted entirely electronically

 All applicants who plan to submit ANDA electronically should
consult CDER’s website for electronically submissions at
www.fda.gov/cder/regulatory/rsr/default.htm.
 Coordination of generic drug review process
 Now application enters the review queue, this means that the application
is assigned to a bioequivalence reviewer, a chemist and a labeling
reviewer
 Each chemistry team consists of a team leader, a project manager and
several reviewers. The chemistry project manager serves as the
“applicant project manager (APM)”, they plan, organize and coordinate
all of the review activities for the applications that they manage.
 APMs serves as co-leaders for the chemistry review teams
 They manage, coordinate the work in a timely manner and identify,
resolve potential problems such as inequality of individual workload and
regulatory issues
 The APMs play a key role in coordinating the various disciplines to
review the applications within 180 days from the submission date.
 APM enter the key information about their applications into a project
management database
 They are designated as the primary contacts for all issues relating of the
application
 It attempts and address all applicant inquiries within 2 working days of
receiving request
 APM request applicants to submit a proposed agenda prior to the
telephone conference or meeting
 Bioequivalence review process
 The BE section assign to the division of bioequivalence to review
 Bioequivalence project manager (BPM) access list of pending ANDA
assign to individual reviewers according to “first in, first reviewed”
policy
 The DBEs responsibilities include BE section of ANDA, bio-INDs,
protocols and controlled correspondence
 The DBE is organized into three branches of which each branch consists
of six reviewers supervised by team leader (secondary review). A BPM
is assigned to each branch (processing and managing) and statistician for
statistical issues
 This process establishes BE between a proposed generic drug and the
RLD

 BE is established when the ratio of T/R of the PK parameters for rate
(Cmax), AUC of log transformed data meet the 90% confidence
intervals of 80-125%
 It resolve the regulatory and scientific issues regarding the BE of drug
products submitted for marketing approval.
 The BPMs request and track inspections of the clinical and analytical
sited through the division of scientific investigations (DSI)
 If BE reviewers requires information to complete the review, first
consult the team leader and then the BPM to obtain information from
applicant
 If issue is resolved within 10 working days, teleconference is initiated by
BPM. The applicant response to the teleconference is labeled
“bioequivalence telephone amendment”
 If any deficiencies are determined then a bioequivalence deficiency
letter is issued to the applicant
 Once the BE review is completed, all BE requirements are addressed,
DBE forwards an acceptable letter and then forwarded to APM.
FDA requires an ANDA applicant to provide information to establish
bioequivalence. It includes:-
o A formulation comparison for products whose bioavailability is self
evident. Eg. Oral solutions, injectables, ophthalmic solutions where
the formulations are identical
o Comparative dissolution testing where there is a known correlation
between in vitro and in vivo effects
o In vivo bioequivalence testing comparing the rate and extent of
absorption of the generic to the reference product
o For non classically absorbed products, a head to head evaluation of
comparative effectiveness based upon clinical end points.
 Chemistry review process
 The chemistry, manufacturing and controls (CMC) section of the
application is assigned to the app chemistry division and team based on
therapeutic category of the drug product
 The team leader assigns the application to a reviewer on his/her team
according to the “first in, first reviewed policy”
 The chemistry division reviews CMC section of ANDA, drug master
files, annual reports and controlled correspondence
 They are organized in to review teams consisting of six reviewers and a
team leader
 Team leaders perform secondary review

 Tertiary review is by deputy director rather than by division director in
BE review
 The goal of the chemistry review process is to assure that the generic
drug will be manufactured in a reproducible manner under controlled
substances
 Areas such as raw material specifications and controls, sterilization
process, container and closure systems, stability data, manufacturing
procedures
 After the issues resolved, APM responsibility is to communicate the
status of the application to applicant. Chemistry deficiencies (major,
minor) and faxes them to applicant
 Application (final approval), approval package is processed through
immediate office, applicant is contacted.
 Labeling review process
 Labeling section of the application is assigned to the app labeling
reviewer based on the therapeutic category of the drug product
 The labeling review branch is part of DLPS
 A team leader oversees the work of 4-6 reviewers
 The basis for the labeling review is to ensure that the generic drug
labeling is the “same as” the RLD labeling
There are expectations to the same as regulations those expectations are
allowed for:-
o Unexpired patients
o Differences due to changes in the manufacturer or distributor
o Other characteristics inherent to the generic drug product such as
tablet size, shape or colour
The labeling reviewer identifies and resolves concerns about medication errors.
Ex sound alike or legibility of drug names on the container label, to ensure that the
proposed labeling in an ANDA is the same “same as” the RLD
a. The reviewer must first identify the RLD
b. Next step is to find the most recently approved labeling for the RLD
c. If it is not the recently approves, it is considered as discontinued labeling (so not
acceptable for labeling review)
d. The applicant may submit four copies of draft labeling or 12 copies of final
printed labeling as proposed labeling. They are submitted for tentative approval
e. The labeling branch supports the submission of electronic labeling which is
preferred and strongly encouraged

f. As the container label is reviewed, the labeling reviewer decides of the labeling is
easy to read and positioned in accordance with the regulations
g. After completion the review of the proposed label is reviewed, the labeling
reviewer drafts a review that either identifies labeling deficiencies approval
h. A tentative approval may be issued for an application with outstanding patent and
exclusivity issues
i. The team leader completes a secondary review
j. If the proposed labeling is deficient, the APM or labeling reviewer communicates
the deficiencies to the applicant
 Putting it all together
 After the final office level administrative review and individual disciplines
have resolved their deficiencies, the application will either receive a full
approval or a tentative letter
 When the review of an ANDA is completed, the APMs draft the app
approval letter and circulate it with the reviews and application for
concurrence
 The APMs communicate with the OGD management on a weekly basis to
update them on the progress of reviews.
 A full approval letter details the conditions of approval and allows the
applicant to market the generic drug product
 A tentative approval letter is issued if there are unexpired patents or
exclusivities accorded to the RLD, and delays the marketing of the product
 Once the office director has signed the final approval letter, APM calls and
faxes a copy of the approval letter to the applicant
 The document room staff then mails the final approval letter to the
applicant.

10) NDA (New drug application) approval process
The submission of new drug application to the food and drug administration (FDA) is an
official request by pharmaceutical company (applicant) to sell and market a drug.
When complete, an NDA contain thousands of pages non-clinical, clinical and drug
chemistry information that supports the proposed labeling of the product
New drug application (NDA) is the submission to the US-FDA (united states food and
drug administration) or concerned regulatory authority of the country containing clinical
and non-clinical test data/ analysis report along with drug chemistry information
NDA is submitted by innovator company to the FDA for purpose of review of various
activity carried out during the various phases clinical studies before final marketing
authorization to the new pharmaceutical product
The information contained in NDA should the satisfy FDA review team to reach the
following key decisions
 The new drug safe and effective in its proposed use (s), and whether the benefits
of the drug out past the risks
 The new drugs proposed labeling and package insert is appropriate
 The method used in manufacturing of new drug and controls used to maintain the
quality are adequate to preserve the drugs identity, strength, quality and purity
 The NDA document should explain detailed information of:-
o Clinical trials
o The data generated result of animal studies
o Ingredient of new drug
o Manufacturing process
o Labeling
o Packaging
o How the drug behaves in the body

 It takes 12-15 years and hundred dollars to get a new drug from the pharmacy
cell
 Then application is made to the US food and drug administration (FDA) to
begin testing the drug in human
 Only 1 in 1000 the compound that enters makes it to human testing

11) BE and drug product assessment.
Bioavailability and bioequivalence studies provide important information in overall set
of data that ensure availability of safe and effective medicines. The concept of
bioavailability and bioequivalence has gained during the last three decades. Now it is
very important for approval of brand name and generic drug worldwide.
Objectives:-
The most important objective is to measure and compare the formulation performance
between two or more pharmaceutically equivalent drug product.

Need of in-vivo studies:-
Oral immediate release prouct with systemic action, narrow therapeutic margin
Modified release product with systemic action
Non oral immediate release product
Statistical evaluation of bioequivalence data:-
o Statistical evaluation based studies is based on analysis of drug blood or plasma
concentration
o Area under the plasma concentration v/s time curve (AUC) is used as an index of
extent of drug absorption
o In the early 1970s, approval was based on mean data. Mean AUC and Cmax
values for the generic product had to be within 20% of that brand-name product.

12) Scale up process approval changes
SUPAC scale up- and post approval changes
In the process of developing the new product, the batch size used in earliest human
studies are small, the sizes of the batch is gradually increased (scale up). The scale up
and the changes made after approval in the composition manufacturing process,
manufacturing equipment and change of site have become known as scale up and post
approval changes (SUPAC)
 The FDA has issued various guidance for SUPAC changes designed as
 SUPAC-IR (immediate release solid oral dosage form)
 SUPAC-MR (for modified release solid oral dosage form)
 SUPAC-SS (for non-sterile semisolid dosage form including creams,
ointments, gels and lotions)
Level of changes
Likelihood of impact on formulation quality and performance
o LEVEL 1:- those changes that are unlikely to have any detectable impact on
formulation quality and performance. Example changes in the colour, flavors
changes in the excipients express as the percentage (w/w) of total formulation,
less than or equal to the following range
o LEVEL 2:- changes are those that could have significant impact on the
formulation quality and performance example changes in the technical grade of
excipients (avicel PH 102 vs. avicel PH200) changes expressed as percent (w/w of
total formulation) level 2 change
o LEVEL 3:- changes are those that are likely to have significant impact on quality
and performance. Example any qualitative or quantitative excipients changes to a
narrow therapeutic drug beyond the range for level 1 all other drug not meeting
the dissolution criteria as level 2.

SUPAC-IR
These guidelines provide recommendation for post approval changes in
o In component or composition
o The site of manufacture
o The scale up of manufacture, and
o The manufacturing (process and equipment)
Components and composition changes
1) Focus on the changes in amount of excipients in the drug product
2) Not focus on changes in the amount of the drug substance
LEVEL 1 changes
 Test documentation
 Chemistry documentation
 Application/compendia release requirements stability testing (one batch long
term)
 Dissolution documentation
 None beyond the compendial requirements
 In vivo bioequivalence documentation none filling documentation
 Annual report
LEVEL 2 changes
 Level 1+1 batch with 3 month accelerated stability study
 Dissolution documentation
 Case A- high permeability, high solubility
 Case B- low permeability, high solubility
 Case C- high permeability, low solubility drugs in vivo
 Bioequivalence documentation- none
 Filing documentation- as level 1+ accelerated stability study
LEVEL 3 changes
 Chemistry documentation- level 1+1 month accelerated stability of 1 batch
(SBOIA) or 3 batches (SBOINA)
 Dissolution documentation- case b
 In vivo bioequivalence- full bioequivalence study. Except IVIVC verified

 Filing documentation- prior approval supplement, annual report
Site changes:-
It includes the changes in location of the site of manufacturing facilities for both
company owned and contact manufacturer. It do not include scale up
LEVEL 1:-
 Site change within a single facility where same equipment, sop, environment
condition and common personnel
 Test document, chemistry, dissolution are according to compendial and in vivo
BE not required
 Filing the annual report
LEVEL 2:-
 Site change within a contiguous campus, or between facilities in adjacent city
blocks
 Test documentation level 1+ one batch long term stability in chemistry
documentation
 Filing documentation-annual report
LEVEL 3:-
 Site change to a different campus
 One batch for accelerated stability (3 months)+ one batch for long term stability
for SBOIA or 3 batches for accelerated and long term stability (SBOINA)
 Dissolution testing- case B
 No BE required
 Filing documentation- annual reports
Change in batch size:-
 Post approval changes in the size of a batch from the pivotal/pilot scale biobatch
material to larger or smaller production
 Scale down below 1,00,000 dosage units is not covered by this guideline
 Scale up changes should be properly validated and if needed, inspected by
appropriate agency personnel.

LEVEL 1 change:-
 Changes in the batch size up to and including factor of 10 times the size of the
pilot/ biobatch where
 The equipment is of same design and principle
 Both manufacturer, according to the CGMP compliance
 Same SOP’s followed
 Test and filing documents are same as of the level 2 of the site changes
requirement
LEVEL 2 changes:-
 Changes in the batch size beyond the factor of 10
 Test documentation
 As per level 1 + one batch with three months accelerated stability + case B
dissolution testing
Manufacturing changes:-
A. Equipment,
(Level 1 change)
This consists of:-
 Change from non-automated to automated or vice versa to move ingredients
 Change to alternative equipment of same design and the operating principle of the
same or different capacity
 Test and filling documentation- as per level 1 of batch size change 22 SUPAC
(Level 2 change)
 Change in equipment to a different design
 Test and filing documentation
 As per level 3 of the site change except case c dissolution instead of case b
B. Process changes
(Level 1 change)
 This changes includes process changes like mixing times and operating speed
within application/ validation range
 Test and filing document as per level 1 of site change

(Level 2 changes)
This changes includes process changes like mixing ties and operating speed outside the
application/ validation range, test and filing documentation- as per the level 2 changes in
site changes
(Level 3 changes)
Change in the type of the process used in the manufacture of the product, such as a
change in from the wet granulation to the direct compression of dry powder.
Documentation as per the level 3 changes of components and composition changes.
SUPAC-MR
 Components and composition- non release controlling excipients
 Focuses on changes to non release controlling excipients
 Changes in components or composition that have the effect of adding a new
excipients or deleting an excipients are defined at level 3
Level 1 changes
 Test documentation
 Chemistry documentation
 Application/ compendial product release requirement
 Stability: first production batch-long term stability data dissolution
documentation: none
 Bioequivalence documentation: none
 Filing documentation
 Annual report- all information including long term stability data
Level 2 changes
a) Chemistry documentation
Application/ compendial product release requirements and updated
executed batch records. Stability : one batch with three month accelerated
stability data reporting in prior approval supplement and long term stability
data of t production batch reported in annual report
b) Dissolution documentation
 Extended release
 Multipoint dissolution profile in 0.1N HCL and USP buffer media at
PH 4.5 and 6.8 for the changed drug product and the bio batch or
marketed batch (unchanged drug product)
 Bioequivalence documentation: none

 Filing documentation
 Prior approval supplement (accelerated stability data) annual report
(long term stability)
Level 3 changes
o Chemistry documentation: application/ compendial product release
requirements and updated executed batch records.
o Stability
o Significant body of information available:- one batch with three months
accelerated stability data reported in prior approval supplement and long
term stability data of first three production batches reported in annual
report.
 Bioequivalence documentation
 A single dose bioequivalence study. The bioequivalence study may be
waived in presence of an established In vitro/ in vivo correlation
Site changes:-
 It consist of changes in location of the site of manufacture, packaging operations,
and/or analytical testing laboratory for both company owned and contract
manufacturing facilities
 They do not include any scale up changes, changes in manufacturing (including
process and or/equipment), or changes in components or composition
 New manufacturing locations should have had a satisfactory CGMP inspection
 A stand alone packaging operations site change and laboratory changes, may be
submitted as a changes being effected supplement.
Manufacturing equipment changes:-
 Manufacturing changes may involve the equipment used in the manufacturing
process (critical manufacturing variable)
 If manufacturer wishes to use manufacturing equipment that is not identical in
every respect to the original manufacturing equipment used in the approved
application, appropriate validation studies should be conducted to demonstrate
that the new equipment is similar to the original equipment

Level 1 changes
 It consists of
1) Change from non-automated or non-mechanical equipment to move ingredients
and 2) change to alternative equipment of the same design and operating
principles of the same or of a different capacity
 Test documentation and filing documentation remains same as non release
controlling excipients
Level 2 changes
 Change in equipment to a different design and different operating principles
 Test documentation and filing documentation
 Remains same as non-release controlling excipients
Manufacturing process changes:-
 Changes involve the manufacturing process itself
 Validation studies should be conducted in case of process changes
 For purposes of categorizing the level of changes, process change may be
considered only to affect a release controlling excipients when both types of
excipients (i.e., non-release and release controlling) are present during the unit
operation undergoing a change.
Level 1 change:-
Test documentation:-
 Chemistry documentation
 None beyond application/compendial product release requirements
 Notification of the change and submission of the updated executed batch records
 Other documentation remains same as non-release controlling
Level 2 change:-
 This category includes process changes involving adjustments of equipment
operating conditions such as mixing times and operating conditions such as
mixing times and operating speeds outside of original approved application ranges
 Other documentation remains same as non-release controlling excipient
Level 3 change:-
 This category includes change in the type of process used in the manufacture of
the product, such as a change from wet granulation to direct compression of dry
powder

 Other documentation remains same as non-release controlling excipients.
13) Post marketing surveillance:-

About PMS procedure:-
 It should assign departments or position a responsible for performing a particular
function
 Manufacturer may find it helpful to a have report at the end of year, as well as
PMS tracking schedule and log
 This information could constitute feedback received from user
 Information obtained from PMS system should be communicated, at a minimum,
annually during a management review meeting which is top management’s
examination of the organization’s quality management system

Summary:-
 Post marketing surveillance (PMS) is the practice of monitoring the safety
of a pharmaceutical drug
 Device after it has been released on the market and is an important part of
the science of Pharmacovigilance
 Since drugs are approved on the clinical trials which involve relatively
small numbers of people who have been selected for this purpose
 Post marketing surveillance can further refine, or confirm or deny, the
safety of a drug after it is used in the general population by large numbers
of people who have a wilde variety of medical conditions
 Post marketing surveillance uses a number of approaches to monitor the
safety of licensed drugs, including spontaneous reporting databases,
prescription event monitoring, electronic health records, patient registries
and record linkage between health database
 Pre-licensure clinical, product, and manufacturing data are critical
foundation for evaluation safety and effectiveness
 However, post-licensure surveillance is essential to assure product safety
 Absence of complete diagnostic information
 Vaccines and other medical products have risk that may include rare series
adverse events not detected.
14) Outsourcing BA (bioavailability) and BE (bioequivalence) to CRO (contract
research organization)

What is outsourcing
 Outsourcing is the business practice of hiring a party outside a company to
perform services and create goods that traditionally were performed in house by
the company’s own employees and staff
 Outsourcing was first recognized as a business strategy in 1989 and became an
integral part of international business economics
 Outsourcing is generally done to reduce the costs and improving the efficient
resources within a company ex. Of outsourcing is bioavailability, bioequivalence,
R&D department. Etc

Typical services outsourced for BA-BE studies:-
 Bioanalytical studies
 Bioanalytical site selection and qualification
 Clinical study design
 Clinical protocol development
 Clinical site selection and qualification
 Clinical conduct
 Clinical monitoring
 Data management
 Pharmacokinetic analysis
 Statistical analysis
 Pharmacokinetic report writing
 Integrated ICH report writing
 Project management
 FDA/regulatory consultation
Advantages:-
 Improved customer service
 Increase productivity and efficiency
 Better people management
 Focus on core competencies
 Access to world class solutions
 Skilled expertise
 Cost savings

Key elements for success:-
 Communication at all levels between the CRO and the pharmaceutical
company
 Sensitivity to both the project specific requirements and timelines
 Flexibility to recognize and adjust to unexpected events throughout the project
timeline
Timing/ cost considerations:-
 Timing and costs are two major considerations that come into play when a
pharmaceutical company decides to outsource
 Timing is even more critical when a generic manufacturer intends to file an
ANDA with a paragraph 4 patent certification
 The first generic to file (as a paragraph 4) is entitled to 6 months of exclusivity
(i.e., no generic competition)

CRO (contract research organization):-
 A contract research organization (CRO) is an organization that provide support
to the pharmaceutical, biotechnology and medical device industries in the form
of research services outsourced
 It offers various pharmaceutical research that is essential for conducting
clinical trials, the ICH technical requirements for registration of
pharmaceuticals for human use
 (CRO) is an organization contracted by another company to manage and lead
to the companies trials, duties and functions
 Organizations and businesses that contract within CROs do so to acquire
specific expertise without hiring permanent staff
 CRO independent organization that steps into the development process once a
pharma company has identified a promising new molecule
 Example of CROs include:- quintiles, Covance, icon, zydus cadila and HMR
Summary:-
It is critical to the process of working effectively with CROs that client companies (and
the CRO) precisely define deliverables and expectations, assign a qualified project team,
and develop communications systems that work for both the CRO and client company
Tips for secure outsourcing:-
o Know what you are outsourcing
o Understand risk and dependencies
o Access outsourcer risk management level
o Ask about training and background checks of personnel level
o Ensure data is protected appropriately

15) Regulatory requirement for product approval:-
(Other non-active ingredients), then either press the mixture into pills and tablets or
prepare powders for solutions or filing of capsule, and finally, package the product for
the public or private market. The active pharmaceutical ingredient (API) forms the most
vital part of every formulated end product, and is an important part of the whole
pharmaceutical industry. The pharmaceutical companies follow certain guidelines and
benchmarks to set the relative strength of API in any medicine production. These
standards differ from one company to another cetrimide, chlorohexidine digluconate
solution and cetylpyridinium chloride are most popularly used active pharmaceutical

ingredients based in ankleshwar, Gujarat since 1996, the company is serving the global
market and has became one of the fastest growing specility chemical and pharmaceutical
company in India
16) Biologics and regulatory requirement for product approval:-

17) ANDA for generic drugs ways and means of US registration for foreign drugs:-
ANDA:-
A written request to the US food and drug administration (US-FDA’s CDER) office of
generic drug, to manufacture and market a generic drug in the United States.
Abbreviated new drug applications are “abbreviated” since they do not require the
applicant to conduct clinical trials and require less information than a new drug
application. If an ANDA is approved, the generic drug will be listed in the orange book,
which lists all medicines the FDA has found to be safe and effective.
Basic generic drug requirements are:-
 Same active ingredient
 Same route of administration
 Same dosage form
 Same strength
 Same condition for uses
 Inactive ingredient already approved in similar NDA
Main objective of ANDA
 To reduce the price of drug
 To reduce the time development
 To increase the bioavailability
Generic drug approval:-
In 1970 FDA established ANDA for review approval of generic version, before 1978
generic product applicant were required to submit the complete safety and efficacy

through clinical trial. Post 1978 generic product applicant were required to published
report of such trial.
Hatch Waxman act 1984:-
Hatch-Waxman act commonly known as “drug price completion and patent term
restoration act 1984” this act dealing with approval of generic drug.
General provisions of the act:-
 Maintaining list of patient
 Only bioequivalence study required
 No need clinical trial
 Para 1,2,3 and 4 certification
 Bolar provision
 Data exclusive period for new molecule entities
 Extension of the original patent term
Broad outline for ANDA:-
Product must meet appropriate standards of
 Identity
 Strength
 Quality and
 Purity
Efficacy and safety should be equivalent to brand product already established.
Information required for filing ANDA:-
 Product’s formulation
 Manufacturer’s procedure

 Control procedure
 Testing
 Facilities
 Dissolution profile
 Labeling
Patent certification:-
While filing an ANDA, the generic manufacturer is required to one of the following four
certifications.
The subject of the reference brand name listed in the ORANGE BOOK.
CERTIFICATION:-
 Para 1 certificate, there is no patent for the drug listed in the orange book
 Para 2 certificate, patent is listed but expired
 Para 3 certification, patent is listed, is valid but the generic wants approval to
market the drug once the pertinent patent expires
 Para 4 certificate, is the most critical of all and gives to almost all the anti-
competitive practices associated with the hatch-Waxman amendments of the EED
and C act
The Orange Book
The publication approved drug products with therapeutic equivalence evaluations
(commonly known as the orange book) identifies drug products approved on the basis of
safety and effectiveness by the food and drug administration (FDA) under the federal
food, drug and cosmetic act (the act) and related patent and exclusivity information.

18) Novel therapies obtaining NDA
Innovation drives progress. When it comes to innovation in the development of
new drugs and therapeutic biological products, FDA’s Center for Drug Evaluation
and Research (CDER) supports the pharmaceutical industry at every step of the
process. With its understanding of the science used to create new products, testing
and manufacturing procedures, and the diseases and conditions that new products
are designed to treat, CDER provides scientific and regulatory advice needed to
bring new therapies to market.
The availability of new drugs and biological products often means new treatment
options for patients and advances in health care for the American public. For this
reason, CDER supports innovation and plays a key role in helping to advance new
drug development.
Each year, CDER approves a wide range of new drugs and biological products:
 Some of these products are innovative new products that never have been
used in clinical practice. Below is a listing of new molecular entities and
new therapeutic biological products approved by CDER in 2020. This listing
does not contain vaccines, allergenic products, blood and blood products,
plasma derivatives, cellular and gene therapy products, or other products
approved in 2020 by the Center for Biologics Evaluation and Research.
 Others are the same as, or related to, previously approved products, and they
will compete with those products in the marketplace. See Drugs@FDA for
information about all of CDER’s approved drugs and biological products.

Certain drugs are classified as new molecular entities (“NMEs”) for purposes of
FDA review. Many of these products contain active moieties that have not been
approved by FDA previously, either as a single ingredient drug or as part of a
combination product; these products frequently provide important new therapies
for patients. Some drugs are characterized as NMEs for administrative purposes,
but nonetheless contain active moieties that are closely related to active moieties in
products that have previously been approved by FDA. For example, CDER
classifies biological products submitted in an application under section 351(a) of
the Public Health Service Act as NMEs for purposes of FDA review, regardless of
whether the Agency previously has approved a related active moiety in a different
product. FDA’s classification of a drug as an “NME” for review purposes is
distinct from FDA’s determination of whether a drug product is a “new chemical
entity” or “NCE” within the meaning of the Federal Food, Drug, and Cosmetic
Act.
The Food and Drug Administration (FDA)'s New Drug Application (NDA) is the
vehicle in the United States through which drug sponsors formally propose that the
FDA approve a new pharmaceutical for sale and marketing.[1][2]
Some 30% or less
of initial drug candidates proceed through the entire multi-year process of drug
development, concluding with an approved NDA, if successful.[1]
The goals of the NDA are to provide enough information to permit FDA reviewers
to establish the complete history of the candidate drug. Among facts needed for the
application are:[2]
 Patent and manufacturing information
 Drug safety and specific effectiveness for its proposed use(s) when used as
directed
 Reports on the design, compliance, and conclusions of completed clinical
trials by the Institutional Review Board
 Drug susceptibility to abuse
 Proposed labeling (package insert) and directions for use
Exceptions to this process include voter driven initiatives for medical
marijuana[3]
in certain states.

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