As of September 2015, updated Requirements apply to the Application of a CEP!

As of September 2015, updated Requirements apply to the Application of a CEP!

The EDQM recently revised its certification policy. Read more here about what you now need to consider when applying for a Certificate of Suitability (CEP).–updated-Requirements-apply-to-the-Application-of-a-CEP!_9159,9255,9299,9300,S-WKS_n.html

The EDQM recently published a revised version of its certification policy document titled “Content of the dossier for chemical purity and microbiological quality“. The revision takes into account the new regulatory developments in Europe that are reflected in many revised and, to some extent, new guidelines of the EMA, ICH as well as in some revised general chapters and monographs of the European Pharmacopoeia (see the summary of these guidance documents under “References” at the end of the policy document).

The aim of the policy document is to provide CEP applicants with a guideline for preparing the authorisation dossier and for compiling all the documents required for this. The dossier is to be divided into 3 modules:

  • Module 1: The authorisation history of the products is to be described which contain the active ingredient for which a CEP application is submitted. The following declarations are also to be submitted:

    – a declaration of GMP conformity from all manufacturers involved in the manufacture of intermediate products and the final active ingredient,

    – a declaration from these manufacturers that they are willing to be inspected before and after being granted a certificate of suitability,

    – a declaration of the CEP applicant/holder about the use/non-use of material of human or animal origin. In cases where such material is used, compliance with the provisions of the EDQM Guideline “Content of the dossier for a substance for TSE risk assessment (PA/PH/CEP (06) 2)” should be demonstrated.

    – a commitment to provide the EDQM, upon request, with samples of the final active ingredient and/or its impurities,

    – a declaration to acknowledge the provisions of the Certification procedure and to agree to the exchange of assessment reports between the national competent authorities of the European Member States as well as the EMA experts.

  • Module 2: Part of this module (analogous to the CTD structure) is the Quality Overall Summary (QOS). The EDQM published a ready-to-use Word template for this. The template can be accessed on the EDQM website “Submit a new application” which contains the most important facts regarding the submission of a new application for a CEP together with links for the relevant documents. With the description of the active ingredient in the QOS, evidence must be provided that the pharmacopoeia monograph is suitable to control the quality of the active ingredient, particularly with regard to the impurity profile of the substance. Plausible justification is important for the cases where testing for possible impurities is omitted.
  • Module 3: Also this Module reflects the CTD structure, i.e. the content of subchapter 3.2.S.1 to 3.2.S.7 with further subdivisions corresponds to the content of a standard authorisation application for a medicinal product. Here are some examples of important points that must be considered in light of the regulatory developments:

    – A CEP that covers different grades of active ingredient (different physical properties, such as particle size or certain polymorphic forms) cannot be issued if these grades also have different limits for impurities and if different analytical methods of determination are required for their control. A CEP for different grades of freedom from pyrogens or bacterial endotoxins is only possible when the relevant monograph foresees this. Otherwise, separate applications must be submitted for grades of the active ingredient that do and do not contain pyrogens or endotoxins (“General properties“; 3.2.S.1.3).

    – Different production sites and manufacturing processes may only be described in one and the same application if it can be proven in a plausible manner that the quality (specifications and impurity profiles) of the relevant intermediate products and the final active ingredient is not significantly changed. Reprocessing steps are to be clearly described; reworking is not normally accepted (“Description of the manufacturing process and process controls“; 3.2.S.2.2).

    – The selection of the starting material is to be justified as per the regulations of ICH Q11 and the EMA Reflection Pager on Starting Materials (EMA/448443/2014). Single step synthesis is generally not accepted unless the starting material itself has a CEP (see EDQM Guideline “Use of a CEP to describe a starting material in an application for another CEP“). Testing for impurities including solvents, catalysts and reactants and absence of a possible carryover into the final product is to be described (“Control of materials“; 3.2.S.2.3).

    – Validation data for manufacturing sterile substances is to be submitted; the complete validation data (protocols and reports) is to be presented for the sterilisation process. Part 2 of the EU GMP guidelines applies to the manufacture of the active ingredient until immediately before the sterilisation stage; sterilisation and aseptic processing should be carried out according to Annex 1 of the guideline (“Process validation and/or evaluation” 3.2.S.2.5).

    – Testing for all kinds of impurities (reagents, catalysts, solvents, by-products etc.) and their potential sources are to be described, particularly if the monograph does not contain suitable test methods. Analytical data and a minimum of significant validation data (incl. LOD/LOQ values) are to be presented (“Impurities“; 3.2.S.3.2).

    – Data from formal stability studies are not normally required for active ingredients. However, when a retest period is requested to be mentioned on the certificate, these data must be collected and submitted as per the guideline “Stability testing of existing active substances and related finished products” and its Annexes (“Stability“; 3.2.S.7).

Overall the provisions of the new certification policy document are rather extensive. As mentioned at the start, the pharmacopoeia authority has reacted to the increased requirements in the newly published and revised ICH and EU guidelines. The policy document is now applicable with no transition period, which means CEP applicants who submitted their application without knowing about this document may receive from the EDQM a particularly long list of deficiencies along with the request to submit the relevant information required.

EU: New GMP Implementing Act published

The EU Commission has published a new public consultation on an Implementing Act on GMP principles and guidelines for medicinal products for human use.

The EU Commission has published a new public consultation on an Implementing Act on Principles and guidelines on good manufacturing practices for medicinal products for human use.,9232,10335,Z-QAMPP_n.html

The reason is that once Regulation (EU) No 536/2014 on clinical trials becomes applicable, manufacture and import of Investigational Medicinal Products (IMPs) for the use in clinical trials carried out under that Regulation cannot follow GMP for IMPs set out in Directive 2003/94/EC. They then have to be manufactured or imported under regulations laid down by the Delegated Act or other specified regulation. It is therefore necessary that Directive 2003/94/EC is revised by a new Implementing Directive on principles and guidelines of good manufacturing practice for medicinal products for human use (without IMPs).

The EU Commission states that because “good manufacturing practice for medicinal products for human use already exists and is generally well-functioning, there is no need to reinvent the wheel”. So the GMP related consultation documents carry over elements set out in Directive 2003/94/EC relating to medicinal products for human use.  GMPs for advanced therapy medicinal products will be introduced with a new provision.

Generic drugs in the EU

Process of reviewing and assessing the dossier to support a medicinal product in view of its marketing (also called licensing, registration, approval, etc.), obviously finalized by granting of a document also called marketing authorization (equivalent: product license). This process is performed within a legislative framework which defines the requirements necessary for application to the concerned (competent) regulatory authority, details on the assessment procedure (based on quality, efficacy and safety criteria) and the grounds for approval or rejection of the application, and also the circumstances where a marketing authorization already granted may be withdrawn, suspended or revoked.NOTE [1]
The application dossier for marketing authorization is called New Drug Application (NDA) in the USA or Marketing Authorization Application (MAA) in the European Union and other countries, or simply registration dossier. Basically, this consists of a dossier with data proving that the drug has quality, efficacy and safety properties suitable for the intended use, additional administrative documents, samples of finished product or related substances and reagents necessary to perform analyzes of finished product as described in that dossier. The content and format of the dossier must follow rules as defined by the competent authorities. For example, since year 2003, the authorities in the United States, the European Union and Japan ask for the Common Technical Document (CTD) format, and more recently, its electronic version – the electronic Common Technical Document (eCTD).

Marketing Authorisation

The application is filed with the competent drug regulatory authority in the concerned country, which can be either an independent regulatory body or a specialized department in the ministry of health.
In accordance with local legislation, the resulting document allowing to the applicant to market the product may be more detailed (in addition to data identifying the product and its holder it may contain addresses of all manufacturing sites, appended labeling, artwork of packaging components, etc.) until a one-page document called certificate of registration (and containing minimal data identifying the product and its source).
Many generic drugs are now being prescribed and the trend is increasing. For example, in Austria, the number of all generics prescriptions has more than doubled from 11% in 2000 to 23% in 2010. However, many myths and questions about generic drugs remain and information may be difficult to come by. It is therefore not surprising, as we have discovered in recent years, that even physicians and pharmacists are not always fully up to date in their understanding of generic drugs. Some of their questions centre on issues such as: are generic drugs really as good as the original; are we really dealing with an adequately tested, high quality medicinal product.
Today, generic drugs present an equally well-tolerated and efficacious alternative to established medicinal products, which contain well-known, rigorously tested active ingredients. An established originator product undergoes expensive and protracted development (up to 15 years) with inherently high preclinical and clinical research costs in order to be given market approval. The development of generic drugs, on the other hand, is relatively quick and inexpensive, which allows generic drugs to be sold at a distinctly cheaper price. This is due to the waiving of new preclinical and clinical studies, aside from some bioequivalence studies. Their lower price however should not be equated with ‘cheap quality’. In fact, generic medicines undergo the same strict scrutiny by the European or national medicines authorities as reference products.
 This marketing authorisation validates the safety, efficacy, and quality of a generic drug.

What makes a generic medicinal product generic?

The definition, according to Austrian drug law/the Medicinal Products Act as well as to EU Directive 2001/83/EC, is that a generic medicinal product ‘is a product which has the same qualitative’, i.e. kind of active substance, ‘and quantitative’, i.e. amount of active substance, ‘composition as the reference medicinal product’. For the sake of simplicity, the reference product is often also referred to as the originator. The different salts, esters, or derivatives of an active substance are considered to be the same active substance, unless they differ significantly in their safety and/or efficacy properties. In these cases, the manufacturer of a generic drug has to submit further proof of efficacy and safety.
The pharmaceutical form, which means the distinct way a product is to be administered, of the generic medicinal product has to be the same as for the reference medicinal product [1]. However, remarkably the various types of immediate release oral pharmaceutical forms, e.g. tablets, capsules and dragées, are considered to be one and the same pharmaceutical form. A patient prescribed with a particular medicinal product may therefore be prescribed either a film-coated tablet or a capsule of the same drug by his physician. This in itself does not pose a problem, as the galenic formulation may indeed be different, but the impact on the safety and efficacy profile of the whole product has been judged to be comparable during the approval procedure.

Are different compositions possible?

Differences in composition between the generic and reference medicinal product are possible, but only regarding the excipients, e.g. bulking agents, colouring agents; and not for the active substances. For example, corn starch may be used instead of lactose as an excipient. However, it has to be demonstrated by the applicant of the generic drug that these differences in composition do not influence the therapeutic efficacy and safety or how the drug is absorbed, distributed, metabolised or eliminated by the body, i.e. the drug’s pharmacokinetics must also remain more or less the same.
Bioavailability or bioequivalence trials need to be conducted in order to demonstrate the equivalence between the generic medicinal product and the reference medicinal product. Differences in the manufacturing process compared to the originator are allowed, but the same strict general quality criteria, e.g. controlled production under good manufacturing practice (GMP), apply to the production of the generic medicinal product as well as for the reference product.
Also a medicinal product can only be considered as the reference product if it has been granted market approval in at least one Member State of the European Economic Area. However, only the so-called originator can serve as the reference product in bioequivalence testing, but never another generic drug, as this would otherwise mean the allowance of a copy of a copy.

How soon can generic medicinal products appear on the market?

The applicant needs to provide proof that the originator product has been authorised for at least eight years, or that the originator company has issued a written informed consent stating that the generics company is permitted to apply for its generic drugs sooner. As a rule however, the earliest a generic medicinal product is allowed to go on sale is 10 years after the first European originator is granted marketing authorisation. This 10-year market exclusivity can be extended by an additional year if, during the first eight years, the marketing authorisation holder of the originator obtains an additional authorisation for one or more new relevant therapeutic indications [2]. Figure 1 shows the ‘8+2 (+1) Formula’ applicable to generic medicinal products entering the market.
Some originators, however, hold patents—in some cases up to 1,000 patents for one single product were found—which can further postpone the launch of a generic drug. Such delay in market access is therefore possible, even if the marketing authorisation has already been granted to the generic drug. Notably, some misuse of patent strategies was described in the final report of the 2009 sector inquiry of the European Commission for Competition [3]. In a sample of 219 molecules from 2000 to 2007 there were reportedly 1,300 patent-related out-of-court disputes related to the launch of a generics.
The number of patent litigations brought to court totalled nearly 700 cases in these seven years and the number of cases increased by a factor of four between 2000 and 2007. The report reached the conclusion that the behaviour and practices of originators contribute to generics delay as well as to difficulties in innovation itself because originators may even block each other.

What is a bioequivalence study?

Bioequivalence studies are often the demanded basis for granting marketing authorisation for a generic medicinal product. They are clinical studies conducted in accordance with Austrian drug law as well as to EU Directive 2001/20/EC and provide data to demonstrate bioequivalence between a test product, i.e. the generic medicinal product, and a reference product, i.e. the originator.
The rate and extent of absorption of the medicinal products and therefore the bioavailability of the active substance(s) are determined. It is a widely accepted regulatory assumption, even sometimes challenged by generics disputants, that equivalent plasma concentration time curves represent equivalent efficacy and safety. Therefore, if bioequivalence can be shown after the administration of the same molar dose, equivalence or assumption of so-called essential similarity of the two products in terms of efficacy and safety can be concluded.

What are the rules for conducting bioequivalence studies?

How exactly a bioequivalence study has to be conducted, and which requirements need to be taken into consideration, is laid out in detail in the European bioequivalence guideline, the revised version of which came into effect mid-2010. The guideline clearly specifies the requirements for the design, conduct, and evaluation of bioequivalence studies for all EU countries. Since 2001, when the first bioequivalence guideline was published, many additional aspects were identified which needed to be amended and improved. Minor issues were addressed in interim question and answer documents.
After a three-year preparation period, the comprehensively revised version of the guideline came into effect in August 2010. The comments and suggestions of over 50 expert organisations and associations were worked into the 22 draft versions. The revised version therefore now reflects the most up-to-date state of knowledge, which is essential in issuing harmonised and standardised marketing authorisations across Europe.
The aim of the guideline was to do away with the ambiguities of the past, which often led to lengthy discussions and differences in professional opinion between the countries and competent authorities of the EU. This also ensures the safety and efficacy of all generic drugs being granted marketing authorisation.

Are bioequivalence studies only used in the development of generic drugs?

Since the task of bioequivalence studies is to detect differences between formulations or pharmaceutical forms, they are indeed not only used as a basis for the licensing of generic medicinal products. In fact, originators may also use bioequivalence studies during their own development since the formulation first used in clinical trials is often not the same which later goes into large-scale market production. Bioequivalence studies are used in these cases to allow bridging of the results obtained in the clinical trials. The same principles in study conduct, data evaluation, and assessment of results by the authority are applied in such originator studies as in the above-described studies for generic drugs. Remarkably, essential similarity between an originator small-scale clinical trial product and a large-scale originator product later to be for sale has never been put in question by anyone. Considering media coverage sometimes casts massive doubt about generics and the way they are authorised, obviously there seems to be an unfounded contrast in the perception dependent on who—the originator company or the generics company—makes use of the bio – equivalence concept for the authorisation of one of their products. Assuming that the bioequivalence concept is valid and trustworthy for authorisation of a new originator product, the same should be applied to the authorisation of a generic drug.

Is the manufacturing quality the same for generic and originator products?

The same quality requirements apply to the manufacturing of generic drugs as for any other medicinal product. Production has to be performed in accordance with GMP and is strictly controlled by evaluating the manufacturing data and by inspections performed not only in Austria and the EU, but also all over the world including countries such as India and South Africa. As for any other medicinal product, quality deficiencies in individual batches are theoretically possible and therefore the Austrian Federal Office for Safety in Health Care as well as the other competent EU authorities closely monitor the quality of all authorised medicinal products on the market. This is achieved by the legal obligation of authorisation holders to inform the authority about every out-of-specification results or other problems in manufacturing and an additional quality-defect notification system involving all healthcare professionals. This guarantees that only high quality medicinal products are available, regardless of whether these products are originators or generics.

When is a generic drug granted market authorisation?

An Austrian or an EU marketing authorisation is only issued when the pharmacokinetic parameters of the generic drug are comparable to those of the reference product and bioequivalence has been successfully demonstrated.
Furthermore, the overall benefits of the generic medicine need to outweigh its risks (positive risk–benefit ratio) and its excipients and the manufacturing process must have been demonstrated to not negatively influence its safety and efficacy.
Last but not least, all internationally relevant quality standards and legal requirements have to be fulfilled before marketing authorisation can be granted.

Procedures for obtaining a marketing authorization

Authorization processes follow either a purely national procedure, with rules and requirements as per national legislation in force, as it occurs in most of countries worldwide, or should follow a centrally approval or a mutual recognition or decentralized procedure within the European Union.

Types of applications

The type of application may vary according to status of the active ingredient.
Thus, if the application concerns a new active ingredient (new active substance, new chemical entity, new molecular entity), one talks about a full application.
Once a new active ingredient authorized, any additional strengths, pharmaceutical forms, administration routes, presentations, as well as any variations (changes to the existing marketing authorization) and extensions shall also be granted an authorization or be included in the initial marketing authorization, being subject of an abridged application.NOTE [2]
Special consideration is to be given to application for authorization of biological products and biotechnology products,[1] homeopathic products, herbal drugs, radionuclide generators, kits, radionuclide precursor radiopharmaceuticals and industrially prepared radiopharmaceuticals; in such instances, requirements are specific, in the meaning that they are special, more or less detailed, as per the nature of active ingredient.

Validity of marketing authorizations

In most countries, a marketing authorization is valid for a period of 5 years. After this period, one should apply for renewal of the marketing authorization, usually by providing minimal data proving that quality, efficacy and safety characteristics are maintained and the risk-benefit ratio of the medicinal product is still favourable. However, in the European Union, after one renewal, the marketing authorization shall remain valid for an unlimited period, unless the competent regulatory authority decides otherwise.NOTE [3]
If the marketing authorization is not renewed in a due time as requested by the local legislation, in order to maintain the pharmaceutical product on a market, one can apply for re-authorization (re-registration). In such situations, the applicant may be requested to submit the whole items necessary for a full application.
Marketing authorization may be withdrawn, suspended, revoked or varied by regulatory authorities if under normal conditions of use the benefit over risk ratio is no more favorable, the product is harmful, or if it lacks therapeutic efficacy; also, one of the above actions can be taken if the qualitative and quantitative composition or other qualitative aspects (control) are not as currently declared.
Marketing authorization may be also withdrawn, suspended or revoked if the marketing authorization holder or its representative does not fulfill other legal or regulatory obligations necessary to maintaining of product on the market, as per the legislation in force.
Also, the marketing authorization is withdrawn in the EU if the product is not placed on the market within next 3 consecutive years after granting of authorization or if it is no more marketed for 3 consecutive years (so-called “sunset clause”).NOTE [4]


  1. Jump up to:a b
  2. Jump up^ Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Official Journal of the European Union, L 311, 28.11.2001, p. 67.
  3. Jump up^ Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. L 136, 30.4.2004, p. 34.
  4. Jump up^ CMD(h) Agreement on Sunset Clause and its application to MAs granted in more than one Member State. Co-ordination Group for Mutual Recognition and Decentralised Procedures -Human, December 2006.
  1. European Medicines Agency. CPMP/EWP/QWP/1401/98 Rev.1. Guide line on the investigation on bioequivalence. Available from:
  2. European Commission. Guidance on elements required to support the significant clinical benefit in comparison with existing therapies of a new therapeutic indication in order to benefit from an extended (11 years) marketing protection period, 2007. Available from:
  3. European Commission Competition, EU Sector inquiry, 8 July 2009. Available from:
  4. Tschabitscher D, Platzer P, Baumgärtel C, Müllner M. Generic drugs: quality, efficacy, safety and interchangeability. Wien Klin Wochenschr. 2008;120:63-9.
  5. American Medical Association. Summaries and recommendations of Council on Scientific Affairs Reports. Generic drugs (CSA Rep 6, A-02). 2002 Annual Meeting of the American Medical Association. 2002:13-4.
  6. Henney JE. Review of generic bioequivalence studies from the food and drug administration. JAMA. 1999;282:1995.
  7. Nwakama PE. Generic drug products demonstrate small differences in bioavailability relative to brand name counterparts: review of approved ANDAs, FDA. 2005.
  8. Davit BM, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the FDA. Ann Pharmacother. 2009 Oct; 43(10):1583-97.
  9. Statement of the Austrian Society of Cardiology (ÖKG) regarding Clopidogrel-Generics. 2010. Available from:
  10. Consensus statement of Austrian Society of Biologic Psychiatry (ÖGBP), Generics and originators in psychiatry, 2008. Available from:

Intellectual Property (IP) Value Realization

IP-driven companies thoroughly and vigorously develop a Technology Value Realization (IP Commercialization) process to a level of sophistication such that they can predict with a reasonably high degree of accuracy the market success for their emerging technologies. This process links the stages of moving a technology with product potential to patent procurement/ management. In the four phases of technology commercialization, there are parallel patent value realization activities.

Bringing Patent Protected Technology to Market
The process begins in the Research & Development (R&D) labs where technology with product potential is identified. It is at this early point that the linkage with the patent process is formed.
Commercialization Process Patent Process
  I. Technology Analysis Process   I. Patent Search
  • Starts with an analysis of the technology followed by the development of a draft Technical Product Description
  • Patent searches are done for prior art
  • Provisional patents may be filed
  II. Market Opportunity Identification   II. Patent Application
  • Market opportunity identification
  • Competitive analysis
  • Draft Business Case
  • Final Technical Product Description
  • Initial patent value determination is made
  • Patent application is registered with the Patent and Trademark offices of the US (and other countries) for value added features
  • Patent Issued (or rejected)
  III. Market Actualization Planning   III. Patent Profit Planning
  • Most effective method(s) for value realization/commercialization are determined
  • Develop licensing strategies and Patent Licensing Agreements (PLAs)
  IV. Implementation   IV. Patent Management
  • Commercialization and appoint of a Product Manager (or market manager) to transition the technology into implementation and bring it to market
  • Associated patent(s) are then moved into Patent Management

Tuesday, 27 January 2015


The Paris Convention, signed in 1883 was one of the first IP treaties and now has over 170 signatory countries of which the US is one. The fundamental benefit of this treaty is that the filing date of a patent application filed in any one of the convention countries can serve as the priority date for patent applications filed within one year in any other member country. There are other treaties with similar reciprocal priority rights. The US, for example, has one with Taiwan.

The Paris Convention
As we discussed, the Paris Convention is an international treaty that allows applicants to file a first application in their home country. That application is referred to as a priority document or filing, and the date it is filed is called the priority date.
The priority filing starts a 12-month period within which a further application called a Paris Convention application (or a direct application claiming priority) can be filed elsewhere, claiming Paris Convention priority back to the priority date. To the extent that the content of the Paris Convention application is disclosed in the earlier priority document, it will be backdated to the priority date.
The advantages of using the Paris Convention are well known to those familiar with the patent process. The 12-month convention period lets the applicant seek funding, perform market research and turn an idea into a commercial product. All of these can be done following a single filing without risking a loss of rights in other countries.
If the Paris Convention didn’t exist, applicants would need to coordinate simultaneous filing in all countries that are of potential interest at the very start of the process. This would be complicated and costly, bearing in mind the need for translations in many countries.
– See more at:

The Paris Convention
As we discussed, the Paris Convention is an international treaty that allows applicants to file a first application in their home country. That application is referred to as a priority document or filing, and the date it is filed is called the priority date.
The priority filing starts a 12-month period within which a further application called a Paris Convention application (or a direct application claiming priority) can be filed elsewhere, claiming Paris Convention priority back to the priority date. To the extent that the content of the Paris Convention application is disclosed in the earlier priority document, it will be backdated to the priority date.
The advantages of using the Paris Convention are well known to those familiar with the patent process. The 12-month convention period lets the applicant seek funding, perform market research and turn an idea into a commercial product. All of these can be done following a single filing without risking a loss of rights in other countries.
If the Paris Convention didn’t exist, applicants would need to coordinate simultaneous filing in all countries that are of potential interest at the very start of the process. This would be complicated and costly, bearing in mind the need for translations in many countries.
– See more at:
The Paris Convention



A regulatory process by which a person/organization/sponsor/innovator gets authorization to launch a drug in the market, is known as drug approval process. In general, a drug approval process comprises of various stages: application to conduct clinical trials, conducting clinical trials, application to marketing authorization of drug and post-marketing studies. Every country has its own regulatory authority, which is responsible to enforce the rules and regulations and issue the guidelines to regulate the marketing of the drugs. This article will focus the similarities and differences in drug approval process of various regulatory bodies.



In the present scenario, countries have different regulatory requirements for approval of a new drug. The single regulatory approach for marketing authorization application (MAA) of a new drug product applicable to various countries (on the basis of single dossier) is utmost difficult. Therefore, the knowledge of exact and detailed regulatory requirements for MAA of each country should be known to establish a suitable regulatory strategy [1].

The new drug approval is of two phase process – the first phase for clinical trials and second phase for marketing authorization of drug. Firstly, non-clinical studies of a drug are completed to ensure efficacy and safety, and then application for conduct of clinical trials is submitted to the competent authority of the concerned country. Thereafter, the clinical trials can be conducted (phase I to phase IV). These studies are performed to ensure the efficacy, safety and optimizing the dose of drug in human beings. After the completion of clinical studies of the drug, then an application to the competent authority of the concerned country for the approval of drug for marketing is submitted. The competent authority review the application and approve the drug for marketing only if the drug is found to be safe and effective in human being or the drug have more desirable effect as compare to the adverse effect [2].

Even after the approval of new drug, government should monitor its safety due to appearance of some side effects, when it is used in larger population. The interactions with other drugs, which were not assessed in a pre-marketing research trial and its adverse effects (in particular populations) should also be monitored[3].

Drug Approval Process In Europe

In European Union (EU), the medical products were approved for marketing at the National level initially. The mutual recognization procedure was introduced in 1983 and a single national review in case of pharmaceutical/medicinal product for marketing authorizations in all EU’s countries was made feasible. The primary aim of this procedure was to create a united standard for product review among national regulatory authorities. In 1987, for high-technology or biologically derived products, the concertration procedure was established by directive 87/22, in which product assessment should be completed by Committee for Proprietary Medicinal Products (CPMP) besides the the normal national regulatory review. Further, in 1993, by council regulation (EEC) 2309/93, the concertration procedure was replaced with centralised procedure, by which all the high-tech and biologically derived product was reviewed and granted EU’s wide marketing authorization by the EU’s CPMP[12].

Similarly, the drug approval process in European countries is also accomplished in two phases: clinical trial and marketing authorization. A clinical trial application (CTA) is filed to the competent authority of the state to conduct the clinical trial within EU. The competent authority of that member state evaluates the application. The clinical trials are conducted only after the approval. The purpose and phases of clinical trials are similar as specified in FDA drug approval process[13]. Figure 2 represent the clinical trial authorization process in EU.

After completing of all three phases of clinical trial, marketing authorization application is filed including all animal and human data, its analyses, as well as pharmacokinetics, manufacturing and proposed labelling. In the EU’s countries, the company have a choice of following regulatory procedures:

Centralized Procedure

The Committee for Human Medicinal Products (CHMP) evaluate the applications received by the EMEA. In view of the applicant’s preference, CHMP contracts out assessment work in one of the member states (the “rapporteur”). After the complete assessment, the CHMP deliver opinion to EU Commission within 210 days. The EU Commission requests comments from other member states, if a positive opinion from CHMP is received. The other member states can respond in about 28 days. When a licence is recommended, a European Public Assessment Report (EPAR) is produced and marketing authorisation is issued. This authorisation is valid throughout the European Union and is for five years, however, the extension can be applied to the EMEA three months before the expiration of this period[14]. Figure 3 represent the centralized procedure for marketing authorization.

Decentralised Procedure

In order to obtain marketing authorizations in several member states, the centralised procedure is not mandatory; in such case the decentralized procedure is to be used. An application is submitted to competent authorities of each of the member states, where a marketing authorization is to be sought. The information like quality, efficacy, safety, administrative information shall be submitted and a list of all Concerned Member States (CMSs) and one member state to act as Reference Member State (RMS). A draft assessment report on the medicinal product is prepared and the CMSs and the RMS validate the application within a time frame of 14 days. The RMS prepare draft summary of product characteristics, labeling and package leaflet within 120 days. This report can be approved within 90 days. However, if a medicinal product is supposed to cause potential serious risk to public health, CMS(s) will inform to other CMS, RMS and applicant and further decision in this regard is taken within 30 days. Within 60 days of the communication of the points of disagreement, all member states reach to an agreement on the action to be taken. After reaching to an agreement of the member states, the RMS records the agreement and informs to the applicant. However, if the member states could not reach an agreement, then CHMP intervenes and take a final decision keeping in view of the written or oral explanations of the applicant[15,16,17,18]. Figure 4 represent the decentralized procedure for marketing authorization in EU.

National Procedure

This type of authorization is granted on country-by-country basis by the competent authorities, in each member state. Products only intended for one market and not obliged to use the centralized procedure[19].

Mutual Recognition Procedure

The mutual recognition procedure (MRP) is similar to the de-centralized procedure with some differences. The mutual recognition procedure is applicable to medicinal products which have received a marketing authorization in any member state whereas the decentralized procedure is applicable to those products which were never approved in any member states of the European Union. The MRP is used to obtain marketing authorizations in various several member states. The evaluation of application by RMS can be taken within 90 days instead of 120 days (in decentralized procedure)[20]. After the grant of marketing authorization, the product can be marketed, which may be called as Phase IV trials, wherein new uses or new populations, long-term effects etc. can be explored[21].



1.Hörner A., Comparison of a global submission of new biological entity and a new chemical entity – strategic decisions and criteria for implementation (2005) (assessed on March 09th 2010).

2. Ng R., Drugs: from Discovery to Approval (2004)

3.Wang H., Wang C.,Yu W., Hsu S, Huang Y, Lin Y., Leu Y. And Lee C. “From Pharmacovigilance to Pharmacovigilance Planning–The System Building for Safe Medication” Journal of Food and Drug Analysis. 2007; 15:377-386.


11.Meadows, M. The FDA’s Drug Review Process: Ensuring Drugs are Safe and Effective (2002). (assessed on December 14th 2009).

12.Boas V.M.I. and Tharp P.C.,“The Drug Approval Process in the U.S., Europe, and Japan” J Managed Care Pharm 1997; 3: 459-465.

13.Commission Directive 2005/28/EC: Laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products…. (assessed on May 13th 2010).

14. (assessed on May 13th 2010).

15. Ghalamkarpour A., Marketing Authorization Procedures in the European Union – Making the Right Choice (2009).… (assessed on May 11th 2010).

16.…. (assessed on October 21st 2009).

17. European Commission: The Notice to Applicants; Volume 2A; Procedures for marketing authorisation-2005,…(assessed on May 21st 2010).

18. Marketing Authorization Procedures in the European Union – Making the Right Choice (assessed on May 27th 2010).

19.Davis H., An overview of the licensing process as it applies to medicinal products in the UK on May 13th 2010).

20.European Commission: Notice to Applicants: Volume 2A; Procedures for Marketing Authorisation; Chapter 2; Mutual Recognition (assessed on May 08th 2010).

21. (assessed on May 19th2010).

Clinical Trial Authorization Process of EU

Figure 2: Clinical Trial Authorization Process of EU

Centralized Procedure for Marketing Authorizat

MAA-Marketing Authorization Application, EMEA-European Medicine Evaluation Agency, EU-European Unionion in EU

Figure 3:Centralized Procedure for Marketing Authorizat

Decentralised Procedure for Marketing Authorization in EU

CMS(s)-Concerned Member State(s), RMS-Reference Member State, CHMP-Committee for Human Medicinal Products

Figure 4: Decentralised Procedure for Marketing Authorization in EU

Analytical chemistry ebook download

InTeOp | 2012 | ISBN: 9535108375 9789535108375 | 154 pages | PDF | 8 MB

The current text deals with several, very important topics of modern, Analytical Chemistry, such as analytical method validation in biotechnology today, principal component analysis, kinetic methods of analysis using potentiometric and spectrophotometric detectors, the current status of Analytical Chemistry and where it may move in the future, peptide and amino acid separations and identification, and several other, related topics in this growing and increasingly important area of Chemistry, in general.



Cleaning Validation and Analytical methods used for detection of residue

Cleaning Validation and Analytical methods

The specificity and the sensitivity of the method used for detection of contaminants after cleaning process are of great importance.
If the residues of previous product or the cleaning process is not detected in the analysis, which doesn’t mean that it is completely absent, it may be a case where the sensitivity of the analytical method and the limits may not be able to trace them in present concentration in the sample. The poor sampling method may be a cause of the absence of residue after cleaning as well. Therefore it is advisable that the analytical method must be challenged with different combination of sampling methods which are particularly used to demonstrate that the contaminant residue can be removed from an equipment surface at the level of 50% and 90% etc .Cleaning process evaluation and production in process quality control tests.
In process quality assurance tests can be used as tools to evaluate the efficacy of cleaning process, some of the indirect test like conductivity of last wash water can be used to predict and monitor the cleaning process. There must be a correlation between the in process test used to monitor effectiveness of cleaning, and during validation these tests should document that the the equipment not cleaned completely fail the in process tests employed. good manufacturing practices

Test for Total Organic Carbon (TOC) (TC ) for evaluation of efficacy of cleaning process:

Yes ! We can set this one of the test for evaluating cleaning effectiveness . in US FDA’S publication of the inspection guide on cleaning validation in 1993, a number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues.

Total Organic Carbon (TOC) (TC ) will be an acceptable method for monitoring residues routinely and for cleaning validation. To make this test TOC to be functionally suitable, we should first establish with suitable study that a substantial amount of the contaminating material(s) is of organic origin which contains carbon that can be oxidized by conditions applied in TOC test. This is an important exercise because some organic compounds cannot be reliably detected using TOC.

Test for TOC may be used to for direct surface sample testing as well as indirect (rinse water) sample testing. In both cases. As TOC does not identify or distinguish between different compounds containing oxidizable carbon, any detected carbon is to be therefore attributed to the target compound(s) for comparing with the established limit. Thus, a pharmaceutical manufacturing firm should limit ‘background’ carbon (i.e., carbon from sources other than the contaminant being removed) as much as possible. If TOC samples are required to be stored for long periods of time before analysis, a pharmaceutical manufacturing firm should verify the impact of sample storage time on accuracy and limit of quantization.

What are the References for above discussion:

21 CFR 211.67: Equipment cleaning and maintenance.
21 CFR 211.160(b): General requirements (Laboratory Controls)
USP 643 Total Organic Carbon
Guide to Inspections of Cleaning Validation, 1993



Laboratory Validation / Analytical Method Validation. Laboratory Validation is a process that is employed to ensure that laboratory test data and results are consistent, accurate and precise. The validation process for test methods, as well as the instrumentation that is used to perform the analysis, have IQ, OQ and PQ protocols. There are eleven main principles to the PQ laboratory test validation protocol. These points are to be applied to each and every laboratory test that is critical to the pharmaceutical manufacturing process as well as the stability program and any process validation. Not all of the eleven principles may apply to each type of testing that is performed, however, a thorough review must be done in order to ensure a complete protocol has been written. VCI’s experience with a broad range of analytical methods can make your laboratory validation project run flawlessly.
The eleven PQ principles are listed below:

  • Specificity
  • Linearity
  • Accuracy
  • Precision
  • Robustness
  • Range
  • Detection Limit (LOD)
  • Quantitation Limit (LOQ)
  • Ruggedness
  • Selectivity
  • System Suitability

Cleaning Validation. This validation is used to show proof that the cleaning system consistently performs as expected and provides scientific data that consistently meets pre-determined specifications for the residuals.

The cleaning validation process must be written into protocols and standard operating procedures which are detailed and specific for the different pieces of equipment and instrumentation used by the facility for each type of drug product produced. Other protocols and SOP’s are also required based on the type of product manufactured or process used (such as a batch or bulk process or shared versus dedicated equipment).

A final report on the cleaning validation system will attest that the studies and data prove that the process is in control and cleans as expected. This report will also detail when and why revalidation needs to take place. Call on VCI to help you clean up your cleaning validation backlog.

Hazard Analysis and Critical Control Points (HACCP). The HACCP process is a prevention-based food safety system. These HACCP programs are to be designed to prevent the occurrence of potential food safety problems. The system appears to be simple at first glance, however, it requires a methodical, systematic approach. A pre-requisite to a well-developed and implemented HACCP system must be a solid current Good Manufacturing Practices (cGMP) program as well as strongly committed management.

USP Defers Implementation of Elemental Impurities Provisions

USP Defers Implementation of Elemental Impurities Provisions
USP defers implementation date to work closely with ICH Q3D. USP will also form a new advisory group for implementation of the new general chapters on elemental impurities.
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FDA Issues Draft Guidance on Contract Manufacturing at (

The draft guidance describes how quality agreements can be used to delineate the responsibilities of contract manufacturers involved in the cGMP manufacture of APIs and finished drug products.

May 28, 2013
By: Patricia Van Arnum
FDA has issued draft guidance, Contract Manufacturing Arrangements for Drugs: Quality Agreements, which describes the agency’s current thinking on defining, establishing, and documenting the responsibilities of each party (or all parties) involved in contract cGMP manufacturing of drugs.