ICH guide line For stability study

ICH Q1A (STABILITY TESTING OF NEW DRUG SUBSTANCE & PRODUCT)


ICH Q1B (PHOTOSTABILITY TESTING FOR NEW DRUG SUBSTANCE & PRODUCT)

ICHQ1C (STABILITY TESTING OF NEW DOSAGE FORM)

ICH Q1E (EVOLUTION OF STABILITY DATA)

ICHQ3A (IMPURITY IN NEW DRUG SUBSTANCE)

ICH Q3B (IMPURITY IN NEW DRUG PRODUCT)

ICH Q5C ( STABILITY TESTING OF BIOTECHNONOLOGICAL/ BIOLOGICAL PRODUCT)

ICH QA2 GUIDE LINE FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

1. INTRODUCTION

1.1. Objectives of the Guideline

The following guideline is a revised version of the ICH Q1A guideline and defines

the stability data package for a new drug substance or drug product that is

sufficient for a registration application within the three regions of the EC, Japan,

and the United States. It does not seek necessarily to cover the testing for

registration in or export to other areas of the world.

The guideline seeks to exemplify the core stability data package for new drug

substances and products, but leaves sufficient flexibility to encompass the variety

of different practical situations that may be encountered due to specific scientific

considerations and characteristics of the materials being evaluated. Alternative

approaches can be used when there are scientifically justifiable reasons.

1.2. Scope of the Guideline

The guideline addresses the information to be submitted in registration

applications for new molecular entities and associated drug products. This

guideline does not currently seek to cover the information to be submitted for

abbreviated or abridged applications, variations, clinical trial applications, etc.

Specific details of the sampling and testing for particular dosage forms in their

proposed container closures are not covered in this guideline.

Further guidance on new dosage forms and on biotechnological/biological products

can be found in ICH guidelines Q1C and Q5C, respectively.

1.3. General Principles

The purpose of stability testing is to provide evidence on how the quality of a drug

substance or drug product varies with time under the influence of a variety of

environmental factors such as temperature, humidity, and light, and to establish a

re-test period for the drug substance or a shelf life for the drug product and

recommended storage conditions.

The choice of test conditions defined in this guideline is based on an analysis of the

effects of climatic conditions in the three regions of the EC, Japan and the United

States. The mean kinetic temperature in any part of the world can be derived from

climatic data, and the world can be divided into four climatic zones, I-IV. This

guideline addresses climatic zones I and II. The principle has been established that

stability information generated in any one of the three regions of the EC, Japan

and the United States would be mutually acceptable to the other two regions,

provided the information is consistent with this guideline and the labeling is in

accord with national/regional requirements.

2. GUIDELINES

2.1. Drug Substance

2.1.1. General

Information on the stability of the drug substance is an integral part of the

systematic approach to stability evaluation.

2.1.2. Stress Testing

Stress testing of the drug substance can help identify the likely degradation

products, which can in turn help establish the degradation pathways and the

intrinsic stability of the molecule and validate the stability indicating power of the

analytical procedures used. The nature of the stress testing will depend on the

individual drug substance and the type of drug product involved.

Stress testing is likely to be carried out on a single batch of the drug substance. It

should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.)

above that for accelerated testing), humidity (e.g., 75% RH or greater) where

appropriate, oxidation, and photolysis on the drug substance. The testing should

also evaluate the susceptibility of the drug substance to hydrolysis across a wide

range of pH values when in solution or suspension. Photostability testing should

be an integral part of stress testing. The standard conditions for photostability

testing are described in ICH Q1B.

Examining degradation products under stress conditions is useful in establishing

degradation pathways and developing and validating suitable analytical

procedures. However, it may not be necessary to examine specifically for certain

degradation products if it has been demonstrated that they are not formed under

accelerated or long term storage conditions.

Results from these studies will form an integral part of the information provided to

regulatory authorities.

2.1.3. Selection of Batches

Data from formal stability studies should be provided on at least three primary

batches of the drug substance. The batches should be manufactured to a minimum

of pilot scale by the same synthetic route as, and using a method of manufacture

and procedure that simulates the final process to be used for, production batches.

The overall quality of the batches of drug substance placed on formal stability

studies should be representative of the quality of the material to be made on a

production scale.

Other supporting data can be provided.

2.1.4. Container Closure System

The stability studies should be conducted on the drug substance packaged in a

container closure system that is the same as or simulates the packaging proposed

for storage and distribution.

2.1.5. Specification

Specification, which is a list of tests, reference to analytical procedures, and

proposed acceptance criteria, is addressed in ICH Q6A and Q6B. In addition,

specification for degradation products in a drug substance is discussed in Q3A.

Stability studies should include testing of those attributes of the drug substance

that are susceptible to change during storage and are likely to influence quality,

safety, and/or efficacy. The testing should cover, as appropriate, the physical,

chemical, biological, and microbiological attributes. Validated stability-indicating

analytical procedures should be applied. Whether and to what extent replication

should be performed will depend on the results from validation studies.

2.1.6. Testing Frequency

For long term studies, frequency of testing should be sufficient to establish the

stability profile of the drug substance. For drug substances with a proposed re-test

period of at least 12 months, the frequency of testing at the long term storage

condition should normally be every 3 months over the first year, every 6 months

over the second year, and annually thereafter through the proposed re-test period.

At the accelerated storage condition, a minimum of three time points, including the

initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is

recommended. Where an expectation (based on development experience) exists

that results from accelerated studies are likely to approach significant change

criteria, increased testing should be conducted either by adding samples at the

final time point or by including a fourth time point in the study design.

When testing at the intermediate storage condition is called for as a result of

significant change at the accelerated storage condition, a minimum of four time

points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-

month study is recommended.

2.1.7. Storage Conditions

In general, a drug substance should be evaluated under storage conditions (with

appropriate tolerances) that test its thermal stability and, if applicable, its

sensitivity to moisture. The storage conditions and the lengths of studies chosen

should be sufficient to cover storage, shipment, and subsequent use.

The long term testing should cover a minimum of 12 months’ duration on at least

three primary batches at the time of submission and should be continued for a

period of time sufficient to cover the proposed re-test period. Additional data

accumulated during the assessment period of the registration application should

be submitted to the authorities if requested. Data from the accelerated storage

condition and, if appropriate, from the intermediate storage condition can be used

to evaluate the effect of short term excursions outside the label storage conditions

(such as might occur during shipping).

Long term, accelerated, and, where appropriate, intermediate storage conditions

for drug substances are detailed in the sections below. The general case applies if

the drug substance is not specifically covered by a subsequent section. Alternative

storage conditions can be used if justified.

2.1.7.1. General case

Study Storage condition Minimum time period covered

by data at submission

Long term 25°C ± 2°C/60% RH ± 5% RH 12 months

Intermediate 30°C ± 2°C/60% RH ± 5% RH 6 months

Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months

When “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.

2.1.7.2. Drug substances intended for storage in a refrigerator

Study Storage condition Minimum time period covered

by data at submission

Long term 5°C ± 3°C 12 months

Accelerated 25°C ± 2°C/60% RH ± 5% RH 6 months

Data from refrigerated storage should be assessed according to the evaluation

section of this guideline, except where explicitly noted below.

If significant change occurs between 3 and 6 months’ testing at the accelerated

storage condition, the proposed re-test period should be based on the real time

data available at the long term storage condition.

If significant change occurs within the first 3 months’ testing at the accelerated

storage condition, a discussion should be provided to address the effect of short

term excursions outside the label storage condition, e.g., during shipping or

handling. This discussion can be supported, if appropriate, by further testing on a

single batch of the drug substance for a period shorter than 3 months but with

more frequent testing than usual. It is considered unnecessary to continue to test a

drug substance through 6 months when a significant change has occurred within

the first 3 months.

2.1.7.3. Drug substances intended for storage in a freezer

Study Storage condition Minimum time period covered

by data at submission

Long term - 20°C ± 5°C 12 months

For drug substances intended for storage in a freezer, the re-test period should be

based on the real time data obtained at the long term storage condition. In the

absence of an accelerated storage condition for drug substances intended to be

stored in a freezer, testing on a single batch at an elevated temperature (e.g., 5°C ±

3°C or 25°C ± 2°C) for an appropriate time period should be conducted to address

the effect of short term excursions outside the proposed label storage condition,

e.g., during shipping or handling.

2.1.7.4. Drug substances intended for storage below -20°C

Drug substances intended for storage below -20°C should be treated on a case-bycase

basis.

2.1.8. 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.

2.1.9. Evaluation

The purpose of the stability study is to establish, based on testing a minimum of

three batches of the drug substance and evaluating the stability information

(including, as appropriate, results of the physical, chemical, biological, and

microbiological tests), a re-test period applicable to all future batches of the drug

substance manufactured under similar circumstances. The degree of variability of

individual batches affects the confidence that a future production batch will remain

within specification throughout the assigned re-test period.

The data may show so little degradation and so little variability that it is apparent

from looking at the data that the requested re-test period will be granted. Underthese circumstances, it is normally unnecessary to go through the formal statistical

analysis; providing a justification for the omission should be sufficient.

An approach for analyzing the data on a quantitative attribute that is expected to

change with time is to determine the time at which the 95% one-sided confidence

limit for the mean curve intersects the acceptance criterion. If analysis shows that

the batch-to-batch variability is small, it is advantageous to combine the data into

one overall estimate. This can be done by first applying appropriate statistical

tests (e.g., p values for level of significance of rejection of more than 0.25) to the

slopes of the regression lines and zero time intercepts for the individual batches. If

it is inappropriate to combine data from several batches, the overall re-test period

should be based on the minimum time a batch can be expected to remain within

acceptance criteria.

The nature of any degradation relationship will determine whether the data

should be transformed for linear regression analysis. Usually the relationship can

be represented by a linear, quadratic, or cubic function on an arithmetic or

logarithmic scale. Statistical methods should be employed to test the goodness of

fit of the data on all batches and combined batches (where appropriate) to the

assumed degradation line or curve.

Limited extrapolation of the real time data from the long term storage condition

beyond the observed range to extend the re-test period can be undertaken at

approval time, if justified. This justification should be based on what is known

about the mechanism of degradation, the results of testing under accelerated

conditions, the goodness of fit of any mathematical model, batch size, existence of

supporting stability data, etc. However, this extrapolation assumes that the same

degradation relationship will continue to apply beyond the observed data.

Any evaluation should cover not only the assay, but also the levels of degradation

products and other appropriate attributes.

2.1.10. Statements/Labeling

A storage statement should be established for the labeling in accordance with

relevant national/regional requirements. The statement should be based on the

stability evaluation of the drug substance. Where applicable, specific instructions

should be provided, particularly for drug substances that cannot tolerate freezing.

Terms such as “ambient conditions” or “room temperature” should be avoided.

A re-test period should be derived from the stability information, and a retest date

should be displayed on the container label if appropriate.

PATENT

HISTORY :

The later part of the nineteenth century saw an increase in inventions in the field of art, process, method of manufacture, machinery, apparatuses and other substances by manufacturers who became very much interested that the inventions done by them should not be infringed by anyone else by copying them or by adopting the methods used by them.

In order to save the inventors the then British rulers enacted the Indian Patents and Design Act, 1911 . Since then due to substantial changes in the political and economic conditions of the Country , it was found desirable to enact a comprehensive law on the subject which would protect interests of both the inventor as well as consumer.

The Patents Act, 1970

The Patent Act, 1970 was therefore passed to amend and consolidate the existing law relating to patents. The Act extends to the whole of India. 

What is a Patent?

The term patent usually refers to a right granted to anyone who invents or discovers any new and useful process, machine, article of manufacture, or composition of matter, or any new and useful improvement thereof.

 In general the term of a new Patent is 20 years. From the date of filing.

INVENTION

The term invention according to the Patent Act has been defined as “a new product or process involving inventive step and capable of industrial application” where “inventive step” means a feature that makes the invention not obvious to person skilled in the art.

Inventions Not Patentable :

     I.        An invention which claims anything obviously contrary to well established natural laws.

   II.        The mere discovery of a scientific principle or the formulation of an abstract theory.

  III.        The mere discovery of any new property or new use of a known substance.

 IV.        A substance obtained by admixture resulting only in the aggregation of the properties of the components thereof or a process for producing such substance.

  V.        A method of agriculture or horticulture.

Types of Patents :

     I.        An ordinary patent.

   II.        A  patent or addition for improvement in or modification of an invention for which a patent has already been applied for or granted.

  III.        A patent granted in respect of a convention application filled under section 135 of the Act.

A product patent for a medicine or drug as provided by the Patents(Amendment)Act, 1999

Procedure for getting a Patent

•      An application for an ordinary patent including for a product may be made by the person claiming to be the first or true inventor , his legal representative , or his assignee , either alone or jointly with any other person.

•      An application for the patent of addition may be made only by the applicant for original patent to which it is an addition, if the application for original patent is pending , or by the registered proprietor of such original patent if the patent has already been granted.

•      A convention application may be made by any person who has made the application for patent in respect of that invention in convention country , or by this assignee or his legal representative.

•      Every application for a patent should be for one invention only and should be made in the prescribed form and filled in the Patent office (Head office of Calcutta and Branch Offices at Chennai , Mumbai and Delhi ).

•      If the application is made by virtue of an assingnment, then the proof of the right to make an application should be furnished.

•      It must be stated in the application that the applicant is in posesion of the invention and the name of the owner claiming to be the true and first inventor must also be stated.

•      Every application must be accompanied by a provisional or a complete specification .

A complete specification is a document drawn in a prescribed form and contains the following :

     i.        A  full description of the invention and its operation or use and the method of performance.

    ii.        Disclosure of the best method of performing  the invention known to the applicant and for which he is entitled to claim protection.

3. A statement of claim or claims defining the scope of the invention for which protection is sought.

Intellectual property rights in India

As was the case with China, India too showed signs of resistance to quick enforcement of international intellectual property right (IPR) protection laws as demanded by the developed countries, particularly the US. China could get away on grounds that it is not a member of the World Trade Organisation (WTO), but India was required to comply. Under the terms of the WTO, India is required to implement WTO-standard IPR protection laws by 2005. It must be acknowledged that there has been remarkable progress in IPR protection the field of software and cinema products. India's general argument was that it does acknowledge in principle the case for strict IPR protection, but this can be done only in phases suited by its own ground reality. The reality is that absence of international IPR protection for some decades  has spawned employment for millions, so an overnight clampdown on IPR violators would foment social unrest. However, under pressure from its own domestic industry and the United States, India strengthened its copyright law in May 1994, placing it at par with international practice. The new law, which entered into force in May, 1995, fully reflects the provisions of the Berne Convention on copyrights, to which India is a party. Based on its improved copyright protection, India's designation as a "priority foreign country" under the United States' Special 301 list was revoked and India was placed on the "priority watch list." Copyright enforcement is also rapidly improving. Classification of copyright infringements as "cognisable offenses" expands police search and seizure authority. While the formation of appellate boards under the new legislation should speed prosecution, local attorneys indicate that some technical flaws in the laws, which require administrative approval prior to police action, need to be corrected. Trademark protection is considered good by the US authorities, and could be raised to international standards with the passage of a new trademark bill that codifies existing court decisions on the use and protection of foreign trademarks, including service marks. The bill was first introduced in 1995 but failed to win parliamentary approval. Passage of the trademark bill is expected in 1998. Enforcement of trademark owner rights had been weak in the past, but is steadily improving as the courts and police respond to domestic concerns about the high cost of piracy to Indian rights' holders. India's patent protection is weak and has especially adverse effects on international pharmaceutical and chemical firms. Estimated annual losses to the US pharmaceutical industry due to piracy are $450 million, but Indian authorities have a different point of view. India's patent act prohibits product patents for any invention intended for use or capable of being used as a food, medicine, or drug or relating to substances prepared or produced by chemical processes. Consequently, many drugs invented by foreign companies are widely reproduced. Processes for making drugs are patentable, but the patent term is limited to the shorter of five years from the grant of patent or seven years from the filing date of the patent application. Product patents in other areas are granted for 14 years from the date of filing. However, as a signatory to the Uruguay Round of GATT, including its provisions on Trade Related Intellectual Property Rights (TRIPS), India must introduce a comprehensive system of product patents no later than 2005. The Indian government has formed an advisory committee to recommend changes in the 1970 Indian Patents Act. A temporary ordinance for patent protection implementing the "mailbox" provisions of the WTO TRIPS agreement and providing for exclusive marketing rights was issued in December 1994. However, the ordinance lapsed and the parliament has yet to pass a new patent bill implementing the provisions of the ordinance. In July 1996, the U.S. initiated WTO dispute settlement procedures over India's failure to implement its TRIPS obligations. The final panel report on this case was issued in August 1997, and ruled that India had failed to meet its obligations under the TRIPS agreement. Indian officials have pledged to introduce another bill in parliament which, if passed, will put India in compliance with its TRIPS obligations. The bottomline is that India considers itself a responsible member of the WTO which suggests that international class IPR protection should be in place by 2005. Besides, given India's determination to emerge as a power in the global software industry, it is most likely that all IPR protection laws will be instituted and enforced by 2005. Note that Bill Gates, the chief executive officer of Microsoft Corporation, has distinguished India as a most promising base for software development. If such an IPR-conscious business leader like Gates is of this opinion, one can only conclude that India's IPR scene is no deterrent to foreign companies.

Quality Assurance of Pharmacy Education

Background

As the practice of pharmacy has become more complex and more accessible and as medical therapies have been used in more and diverse patients, patient safety and accountability for outcomes of therapy have become a greater focus of attention. Consumers and governments are demanding higher standards and seeking assurances of quality. Likewise, greater attention is being paid to the quantity and quality of pharmacist and pharmaceutical human resources, including the systems in place to assure the quality of education and training and the ongoing competence of practitioners. Consequently, many countries are introducing, expanding or undertaking major reform of pharmacy education. Such developments must be accompanied by robust systems to assure the quality of the educational structures, processes and outcomes; the latter primarily being graduates who are competent and capable of performing safely and effectively in their practice setting and contributing to the delivery of healthcare.

Introduction 

To promote and facilitate international dialogue and collaboration in the area of quality assurance of pharmacy education, the International Forum for Quality Assurance of Pharmacy Education was established in 2001. It operates under the auspices of the Academic Section of the International Pharmaceutical Federation (FIP), primarily as an informal network of individuals interested in the quality assurance and quality advancement of pharmacy education. The Forum has identified that countries seeking to establish or improve their quality system would benefit from an internationally‐developed and adopted QA framework. The Quality Assurance Project Team of the Pharmacy Education Taskforce was convened to continue the development of this “global framework”. The framework incorporates core principles and elements considered essential for an effective approach to quality assurance.

The objectives of the Quality Assurance Project Team are to: 1. Validate and further develop the Global Framework for Quality Assurance of Pharmacy Education. 2. Examine accreditation and quality assurance models and systems in country case studies 3. Provide guidance for the development of national and regional quality assurance systems

What makes a good Regulatory Affairs professional?

Most regulatory professionals are graduates in a scientific discipline – commonly life sciences or pharmacy – although increasingly biotechnology-based degrees are valuable. Some choose to have an additional legal qualification, and TOPRA offers an MSc in Regulatory Affairs for those who wish to gain a formal professional qualification in the discipline.The ability to tackle data in a wide range of scientific areas and to quickly grasp new concepts and complex technical information is vital.

Communication skills are very important.Analysing issues and presenting both written and oral evidence before a panel of experts such as scientists, pharmacists, doctors and lawyers who run the government agencies require considerable understanding of both legal and scientific matters. An attention to detail is a pre-requisite.

How do Regulatory Affairs professionals relate to other professionals?

The very nature of the task to be done brings regulatory personnel into contact with almost every discipline within the industry. This may include scientists such as pharmacologists, toxicologists, analytical chemists, pharmacists, medical doctors, veterinarians, engineers, physical chemists and statisticians.

That being said, the work is by no means confined to science but extends to the interface with and appreciation of advertising,marketing,legal,patent and manufacturing skills.

An ability to liaise closely with every kind of specialist is a crucial part of the job. Not only must there be the ability to use and assimilate information provided by such specialists, but also to present that information to regulatory authorities and feed-back their opinions to the rest of the company and appraise staff about the current thinking of the regulatory bodies.

In short, the regulatory specialist is central to the business and has the opportunity to interact with a wide range of specialities and extend his or her knowledge while doing so.