Biocon’s Insulin Glargine gets approval in Japan

New Drug Approvals

Avik Das | TNN | Mar 28, 2016, 02.52 PM IST

BENGALURU: Biopharmaceutical company Biocon said it got approval from Japan’s health ministry to sell its biosimilar Insulin Glargine in the country.

The product, which is a ready-to-use, prefilled disposable pen with 3 ml of 100IU Insulin Glargine, is expected to be launched in Japan in the first quarter of 2017 with its commercial partner FUJIFILM Pharma Co. Ltd, Biocon said on Monday.

The move will help Biocon capture a significant share of the Japanese Glargine market, which is about $144 million and second largest market outside of North America & Europe.
“The Insulin Glargine approval in the highly regulated market like Japan, marks a huge credibility milestone for Biocon. We see this as a significant achievement in our journey of making global impact in diabetes management through our affordable biosimilar insulins,” chairperson and managing director Kiran Mazumdar-Shaw said.

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New FDA Guidance on Completeness Assessements for Type II API Drug Master Files

Since 1st October 2012, special regulations have been applying to the US Type II Drug Master Files. This year in February, the FDA published a new Guidance for Industry. Read here what the DMF holder has to consider when submitting data about the API Drug Master File.,15339,S-WKS_n.html

Since the coming into force of the “Generic Drug User Fee Act” (GDUFA) on 1st October 2012, special regulations have been applying to the submission to the FDA of a Drug Master Files for a pharmaceutical API (Type II DMF). The DMF holder must pay a one-time fee when authorising the reference of his/ her DMF in an application for a generic drug (Abbreviated New Drug Application, ANDA). Moreover, the DMF will undergo a completeness assessment through the FDA.

This year in February, the FDA published a Guidance for Industry entitled “Completeness Assessments for Type II API DMFs under GDUFA” which provides DMF holders with comprehensive information regarding the application for a Type II DMF. The document describes the criteria according to which the FDA performs a completeness assessment and which data are expected.

This completeness assessment does not replace the full scientific assessment to be executed at a later time. It serves to find out whether the data contained in the DMF are sufficient for the ANDA. In a completeness assessment, the following elements are examined:

  • Is the DMF active?
  • Has the fee been paid?
  • Has the DMF been previously reviewed?
  • Does the DMF pertain to a single API?
  • Does the DMF contain certain administrative information?
  • Does the DMF contain all the information necessary to enable a scientific review?
  • Is the DMF written in English?

The Guidance contains a checklist (Appendix 1) listing the criteria according to which the FDA performs the assessment. For the DMF holder, this list is helpful to check the completeness of his/ her data before submitting them to the FDA.

One essential element underlined in this Guidance is to pay the DMF fee in due time (at least 6 months prior to the submission of an ANDA). The FDA won’t continue to process the DMF as long as the fee hasn’t been paid. If the applicant of an ANDA references in his dossier a DMF for which a fee is due, the FDA will inform him. If the fee hasn’t been paid within 20 days after notification, the FDA will stop the further processing of the application.

When submitting a DMF, the form “FDA 3794″ (Generic Drug User Fee Cover Sheet) should be attached. It contains the minimum information required by the FDA to determine whether the DMF holder has satisfied his fee obligations.

After the successful completeness assessment of a DMF, a number will be attributed and posted on a publicly available API DMF list. The FDA has compiled all important information regarding DMFs Type I-V on the Drug Master File webpage. Here, you can also find the list of all active DMFs.

//////API Drug Master File, fda, type2

Second Revision of USP Chapter Injections and Implanted Drug Products (Parenterals)-Product Quality Tests

After the revision of the General Chapter on quality testing of sterile medicinal products in the US American Pharmacopoeia had already been announced last year in the USP 38-NF 33, the USP is planning a new revision. Read more about the revision of Chapter <1>.–1–Injections-and-Implanted-Drug-Products–Parenterals–Product-Quality-Tests_15090,15160,15266,Z-PEM_n.html

Last year already, the revision of the General Chapter on quality testing of sterile medicinal products was initiated in the USP 38 NF 33. The targeted official date for coming into force was the 1st May 2016. Now, the USP has announced that because of some comments received, there will be a further revision. This is due to the USP’s intention to support in Chapter 1 both existing monographs as well as new monographs to be developed. The new scope should now be focussed again to avoid confusion. The publication is striven for March 2016 as well as the adoption of the changes in the USP 40 NF 35. Furthermore, USP has announced that also the contents of General Chapters <2> to <5> will be examined.

On the USP website you will find further details regarding the revision of Chapter <1>.

///////USP 38-NF 33, revision of Chapter <1>, quality testing of sterile medicinal products, monographs, USP,  new revision

ECA releases Version 18 of GMP Guideline Manager

How to access ten thousand pages of GMP Guidelines from FDA, EMA, ICH, PIC/S, ICH, WHO and many other organisations worldwide? You can print them or purchase hundreds of booklets. Or, alternatively, you can take advantage of a software tool developed by the ECA Academy, allowing you to access to the most comprehensive GMP Guideline Database

How to access ten thousand pages of GMP Guidelines from FDA, EMA, ICH, PIC/S, ICH, WHO and many other organisations worldwide? You can print them or purchase hundereds of booklets. But this will cause a huge amount of paper. And it will be more than difficult to find a specific regulatory requirement in this comprehensive library.

For that reason the ECA Academy has started to set up the largest GMP Guideline Database of its kind worldwide already 18 years ago. And every year a new release is published with all updates. A software was developed to structure the Guidelines in two so called “Guideline Trees”.

1. Guideline Tree structured according to the issuing authorities (e.g. EU, FDA, ICH)

2. Guideline Tree structured according to GMP topics (e.g. GMP for Medicinal Products, GMP for APIs, sterile production, validation etc)

In addition to the two structured libraries the software also allows you to search for certain key words. You may search the entire database for a keyword like “validation”. But you can also limit the search to certain areas (e.g. search in FDA Guidelines only).

If you have no CD drive on your computer you can also access the GMP Guideline Manager via the ECA WebApp. When you register you will receive the login details to access the ECA members area. The same login details will work for the ECA WebApp. With this service you can access the full GMP Guideline Database from your smartphone or tablet via the internet.

The GMP Guideline Manager can not be purchased – it is only available for ECA Members at no costs! This service is unique and not offered by any other organisation. By participating in any of the ECA conferences or courses you become member of the ECA free of charge for 2 years. If you can not attend an ECA course you can also apply for ECA membership for only 190,- Euro via our webpage.

Please find more information about the GMP Guideline Manager 18.0 here.

///////ECA,  Version 18,  GMP Guideline Manager

Already 13 EMA GMP Non-compliance Reports in 2016 published

EudraGMDP is the central database for GMP and GDP compliance. Inspections which have been performed by any of the EU member state inspectorates are published in the database. Please get the details about the GMP non-compliance findings at 11 manufacturers in Europe and abroad.,S-QSB_n.html

EudraGMDP is the central database for GMP and GDP compliance. Inspections which have been performed by any of the EU member state inspectorates are published in the database. If the manufacturing or distribution site has been found in compliance with GMP and or GDP then a certificate is issued in the database as reference for other inspectorates. This information is also available to the public. A negative outcome will lead to a GMP or GDP Non-Compliance Report. In 2016 no GDP Non-Compliance Reports have been published until today but already 13 GMP Non-Compliance Reports until March 15th.

Among the companies concerned there are 5 Chinese, 3 French, 2 Spanish manufacturers as well as one each from Sweden, Romania and Poland. All Non-Compliance Report were either issued in 2016 (12) or updated in 2016 (1).

The GMP non compliance findings reveal severe deviations from EU GMP. In addition some companies are involved in falsification and data manipulations – a serious trend which can be observed in many international inspections (e.g. those performed by FDA, WHO). Data Integrity and falsification issues are highlighted in the findings below.


Overall, 18 deficiencies were observed during the inspection, including 2 Critical and 4 Major deficiencies: [Critical 1]Falsification of source of API (Thiamphenicol): Repackaging, relabeling and selling of purchased API from a non-GMP company (Zhejiang Runkang Pharmaceutical Co.Ltd.) as if manufactured in-house; [Critical 2] Praziquantel manufactured according to CP process/grade was released as USP process/grade without a full traceability of the testing activities ; [Major 1] The maintenance and the cleaning operations of the manufacturing line used for the production of Praziquantel (API) were found deficient; [Major 2] The pipes design of some equipment used for the manufacturing of Praziquantel, the handling of change related to these equipment and the instruction used for the transfer of the intermediate solution using nitrogen were found deficient ; [Major 3] The hoses used for unloading of solvent were not identified, had no cleaning status and were stored on a dirty floor of an area not mentioned in the general layout of the site; [Major 4] There was no procedure in place for audit trail and there was no effective audit trail in place to determine any change or deletion of the chromatographic raw data. The audit trial function including the administrator profiles was enabled for all the QC staff.


The manufacturer has not established a quality management system including adequate controls to ensure the accuracy and completeness of the critical records data.

S.C. IRCON SRL, Romania

During inspection a number of 34 deficiencies were found, out of which 4 were critical and 10 major. Critical deficiencies are related to the quality management system, qualification/validation activities, manufacturing and material management documents and quality control laboratories activity.

Agila Specialties Polska Sp. z o.o, Poland

29 major deficiencies were found in Agila Specialties which pose a risk of microbial and particulate contamination and could not assure the sterility of the final product. Most of these are related to: 1.) design and qualification of HVAC, laminar air flow system and clean areas, 2.) cleaning and maintenance of clean areas. 3.) manufacturing and batch releasing in the conditions not complying with GMP requirements 4.) change control. In December, 2014 the HVAC system of vials and prefilled syringes lines was significantly modified. Since January till July 2015, 49 batches were manufactured in that area without qualification after the change. During the inspection it was found that: 1) pressure differential between clean areas B and C grade were usually below 10 Pa (effective to < 0 Pa) and alarm (generated electronically, non-validated after the change of the system) has triggered at 0 Pa and after reversing the flow; 2.) laminar air flow system did not comply with requirements given in Annex 1; 3.) test of maximum permitted number of particles “in operation” does not perform properly; 4.) technical condition of clean areas and equipment show lack of proper and regular maintenance. In clean areas A/B grade contamination were found on the arm of the filling machine for prefilled syringes and difficult to clean equipment placed without proper SOP. In grade C e.g. crumbling insulation of pipes, peeling teflon on the ports of tanks and pumps, lack of labelling and mixed clean and dirty equipment, chipped glass accessories was found; 5.) the filtration process was not fully validated and during routine process a pressure difference to be used across the filter was not recorded; 6.) lack of confirmation of A grade in a lyophilizer working in a nitrogen atmosphere; 7.) design, installation and use of nitrogen system did not guarantee tightness and can cause contamination of the clean medium.


This inspection was performed in the framework of the CEP dossier for the manufacture of Metronidazole R1-CEP 2007-309-Rev 01. The inspection identified in total 24 deficiencies to EU GMP. One of them was categorized as critical and related to the Company’s Quality Assurance System for production of Metronidazole. 10 deficiencies were categorized as major and were related to: QA, Documentation, Supplier Qualification, Data Integrity, Out-of-Specification handling, Quality Control, Computerised System validation, Change Control.


The Company’s facility at No. 428 Yishui North Road, Fengshan Town, Luotian County, Huanggang City, Hubei Province, China was subject to a spot check, because this site is mentioned as an intermediate manufacturing site in CEP 2001-450 Metronidazole. The Company clearly stated in their introduction that the site does not follow EU GMP. The following observations were made and together categorized as critical: a. The manufacturing site and it’s equipment was found in a devastated state. b. Huge layers of dust and product indicated that no cleaning was applied to either the facility or the equipment, leading to an extreme risk of cross-contamination. c. The extremely bad shape of the facility and the equipment showed that no maintenance was in place. d. Almost none of the products seen was labelled. e. No batch manufacturing documentation could be seen. Reference: EU GMP Part II was found not implemented at the facility.


As a preliminary note, the starting materials repacked by the site were intended for pharmaceutical compounding activity in community pharmacies. The site did not distribute to the industry. Overall, 21 deficiencies were found, including 3 critical deficiencies and 5 major deficiencies: [Critical 1] Important risks of confusion in the repacking operations were identified. [Critical 2] Important risks of cross contamination in the repacking operations by substances of high pharmacological activity or toxicity were identified. [Critical 3] The active substances and excipients batches were not analysed as per the pharmacopoeial specifications. [Major 1] The release of active substances batches was deficient, notably in the absence of batch production records. [Major 2] Several risks of contamination in the sampling operations, notably cross contamination, were identified. [Major 3] The management of active substance suppliers was deficient, notably in the absence of written confirmation. [Major 4] Several risks of contamination in the repacking operations, notably cross contamination, were identified. [Major 5] The transmission of information to pharmacies was incomplete and confusing, notably regarding the analyses actually performed by the site. The inspection’s observations also apply to excipients, which are repacked and distributed under the same conditions as the active substances.

Svenska Bioforce AB, Sweden

During the inspection, 42 deficiencies were found. None of the deficiencies was critical but 17 were major. The 17 major deficiencies related to batch certification, Product Quality Review, change management system, deviation handling system, management responsibility, training, premises and equipment, documentation, line clearance, quality control, complaint handling, and cleaning validation. Re-inspection after implementation of CAPA is required in order to verify that the Pharmaceutical Quality System meets the requirements according to EU-GMP.


Overall, 14 observations were made, including 1 critical deficiency and 4 major deficiencies: [Critical] The management of semi-finished batches and of the mixing operations was deficient and conformity of the final batches to specifications, notably Ph.Eur. specifications, could not be guaranted. [Major 1] The site had been manufacturing an active substance without ANSM authorisation. [Major 2] The change control related to the suppression of one filtration step in the active substance manufacturing process was deficient. [Major 3] The manufacturing of the active substance had not been made using master production instructions and no batch production records had been established. [Major 4] No review of batch production records of critical process steps had been done before release of the active substance for distribution. 7 observations are related to lack of traceability, risks of contamination induced by the absence of cleanliness in the production environment, very bad condition of the production equipment and insufficient equipment cleaning procedures. The inspection’s observations also apply to the manufacture of pharmaceutical excipients and starting materials that are intended to be used as ingredients in cosmetics and medical devices, which are manufactured under the same conditions as the active substance.


Critical deficiencies a) Lack of an effective pharmaceutical quality assurance system b) Release of batches of medicinal products produced without completing all of the manufacturing protocols, without being checked quality assurance unit and without the approval of the technical director. c) Use in quality control a non-qualified chromatographic equipment, with operating faults and with an unvalidated computerized management system. As a result, the integrity, reliability, up-to-dateness, originality and authenticity of the data that are obtained cannot be guaranteed. d) Transfer of some of the final analytical quality controls of medicinal products to a third party, without appropriately transferring the control methods and without the authorization of the relevant health authority e) Manufacture of medicinal products using procedures that have not been appropriately validated or have not been periodically revalidated. f) Acceptance of results of repeated analytical controls and sterility tests of finished medicinal products without having undertaken an in-depth investigation to determine the root cause of a previously result obtained which was out of specifications. g) Although a visual inspection of injectable medicinal products reveals a high number of critical quality defects (the presence of visible particles) non deviations are opened and is not investigated. c) Do not do any quality control on a statistical sample of units of injectable medicinal products that have passed the visual inspection. Major deficiencies a) Do not do the annual quality product review of medicinal products manufactured. b) Deviations in the manufacturing processes are not investigated suitably and in-depth. c) The simulation of the aseptic manufacturing process is not performed every six months and samples used in the simulation are not incubated at the right temperature. c) The air treatment system in manufacturing areas is not properly qualified, as it is only checked when it is “at rest” but not “in operation”. e) Medicinal products are manufactured without full compliance with conditions established in the marketing authorisation dossier and/or without carrying out all the established process controls. f) Manufacturing and quality control documents of each batch of medicinal products manufactured are not filed correctly. g) The facilities have been modified considerably without the authorization of the relevant health authority h) Test of growth promotion of culture media, which are used in the sterility testing, in the simulation of the aseptic manufacturing process or in the environmental control of critical manufacturing areas, is not carried out. h) Do not analyse all of the specification parameters for raw materials used in the manufacturing.

Chengdu Okay Pharmaceutical Co. Ltd., China

Overall, 21 deficiencies were observed during the inspection, including 5 critical and 10 major deficiencies. The critical deficiencies were observed in QC Dept. including calculation of impurities of Diosmin and there were no records of standard (used as a reference) for testing in-house standard. Also the data integrity was not guaranteed. In manufacturing Dept. presented measuring methods were inadequate to the results. The condition in clean area was not acceptable for final product. Critical deficiences: Testing of the final product: There was incorrectly way of calculation the impurities and Diosmin content. There were no records of prepared in-house HPLC standard. There was no confirmation of the conditions HPLC analysis. Computerized systems – documentation and control: There was found in HPLC system that the method was changed, without any savings of previous method. There were no logins and passwords to the HPLC system and no procedure for granting permission to access to the HPLC system. There was no register of persons authorized to access the HPLC system. On the same computer station there were two different HPLC software. Manufacturing documentation: Presented measuring methods of pH during the inspection time were inadequate to the results recorded in the batch report. Premises: Crude Diosmin drying was carried out in an area which did not provide the appriopriate coditions during the discharge from the dryer. Qualification of equipment: Some data of HVAC system qualification had been falsified. The major deficiencies were observed among others: in the warehouse, in the manufacturing documentation and in the production area.

Dongying Tiandong Pharmaceutical Co., Ltd., China

This serious Non-Compliance Report refers to a manufacturing site for Heparin. French Inspectors found 2 critical and 3 major deviations. Heparin manufacturing sites were involved in one of the largest counterfeit scandal ever. Therefore it is worrying that critical deviations in Heparin manufacturing have been found again. Read more in our GMP News Chinese Heparin Manufacturer again involved in Falsification and GMP Non-Compliance.


Here a manufacturing site for Investigational Medicinal Products (IMPs) is concerned. Overall 45 deficiencies, including 5 critical deficiencies and 17 major deficiencies have been detected. The following critical deviations in sterile production are listed in the agency report:

1) The implementation of exemption SOP for manufacturing operations which is not compliant to GMP principles, for example, Media Fill Test were performed with unqualified equipment.
2) The lack of sample area for incoming materials and their systematic use in quarantine status for manufacturing operations.
3) Appropriate measures in terms of monitoring locations, alert and action limits rationale, were not set for particle and microbiological monitoring in clean rooms grade A and B.
4) No protocol for clean rooms’ qualification was established and clean rooms classification didn’t fulfill ISO14644 requirements.
5) Some analytical methods and process were not validated for the clinical trial EudraCT : 2015-000845-21

All Non-Compliance Reports with the detailed address of the facilities and the product concerned can be found in the EudraGMDP Database.

///////////// 13 EMA,  GMP Non-compliance Reports, 2016 published, EudraGMDP,  central database

Zydus Chairman and Managing Director,Mr. Pankaj R. Patel won the prestigious ‘Gujarat Business Leader of the Year’ award at the CNBC Bajar, Gujarat Ratna Awards 2015-16

New Drug Approvals

IMG-20160312-WA0032.jpgZydus Group

Zydus Chairman and Managing Director,Mr. Pankaj R. Patel won the prestigious ‘Gujarat Business Leader of the Year’ award at the CNBC Bajar, Gujarat Ratna Awards 2015-16 from Hon’ble Chief Minister of Gujarat, Smt. Anandiben Patel at a glittering ceremony held at Hyatt, Ahmedabad.


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What are the current Rules for Supplier Qualification?

Supplier Qualification is more than auditing. Supplier qualification can be seen as a risk assessment tool. But what are the exact requirements for qualifying suppliers?,15099,15179,Z-QAMPP_n.html

Supplier Qualification is more than auditing. Supplier qualification can be seen as a risk assessment tool. It should provide an appropriate level of confidence that suppliers, vendors and contractors are able to supply consistent quality of materials, components and services in compliance with regulatory requirements. An integrated supplier qualification process should also identify and mitigate the associated risks of materials, components and services. But what are the exact requirements?

They are wide-ranging and complex. There are different directives and regulations for medicinal drug products for human or veterinary use and for investigational medicinal drug products. Certain requirements in different directives and the EU-GMP Guidelines define expectations. Here are some examples:

Article 8 of EU-Directive 2001/83/EC
“The application [of a marketing authorization] shall be accompanied […] by […] a written confirmation that the manufacturer of the medicinal product has verified compliance of the manufacturer of active substance with principles and guidelines of good manufacturing practice by conducting audits.”

Article 46 of EU-Directive 2001/83/EC
“The holder of a manufacturing and/or import authorisation shall at least be obliged […] to use only active substances, which have been manufactured in accordance with GMP for active substances and distributed in accordance with GDP for active substances and … to ensure that the excipients are suitable for use in medicinal products by ascertaining what the appropriate GMP is.”

Article 46b of EU-Directive 2001/83/EC
“Active substances shall only be imported if they have been manufactured in accordance with standards of good manufacturing practice at least equivalent to those laid down by the European Union”. This can be shown by a written confirmation, or the exporting country is included in the so called white list, or a waiver has been granted.

EU-GMP Guidelines Chapter 5:
5.25 “The purchase of starting materials is an important operation which should involve staff who have a particular and thorough knowledge of the supplier.”
5.26 “Starting materials should only be purchased from approved suppliers …”
5.40 “…printed packaging materials shall be accorded attention similar to that given to starting materials.”

The revised Chapter 7 of the EU-GMP Guidelines describe the responsibilities of the Contract Giver when it comes to contract manufacturing and testing. He needs to assure the control of the outsourced activities, incorporating quality risk management principles and including continuous reviews of the quality of the Contract Acceptor’s performance. Audits are a helpful tool to asses the “legality, suitability and the competence of the Contract Acceptor“. The new Chapter 7 was obviously designed to intensify the control of Contract Acceptors by the Contract Giver and extend those controls to subcontractors.

The holder of the manufacturing authorisation is responsible for the supplier qualification by law but in fact the supplier qualification is one of the duties of the Qualified Person (which can be delegated) as defined in Annex 16 of the EU-GMP Guidelines. The QP of the marketing authorisation holder is responsible for certifying the drug product for the market place and is now being held accountable to ensure that all aspects of the supply chain have been made under the appropriate GMPs. However, according to Chapter 2 of the EU-GMP Guidelines, the heads of Production, Quality Control and Quality Assurance share the responsibility of approving and monitoring suppliers of materials (2.9).

So how to proceed? At the beginning of a supplier qualification process, the regulatory requirements regarding the type of material, component or service and the type of product (human/veterinary drug product or IMP) should be identified and specified. Audits, if required, should be planned and executed. The compliance of the selected supplier(s) with the requirements and user requirement specification should be demonstrated. The scope of an audit should cover this. But a successful audit is not the end of the qualification process. After finalising the contract, the compliance of the selected supplier(s) with the applicable requirements should be evaluated periodically. Changes at the supplier´s site (for example manufacturing process etc.) that pose a particular risk to the compliance with the requirements should be assessed. There needs to be a mechanism in place so that any change made by the supplier which could have an impact on the GMP status or the production or testing parameters have to be agreed to before any such changes are implemented. A supplier must also notify the contract giver immediately upon discovery of any deviation/non-conformance/complaint that may have an impact on the services provided. Those need to be assessed and respective actions need to be defined.

The use of Brokers:
Some raw materials are only available at reasonable costs if purchased through an intermediary, i.e. a Broker. If the material is critical to the process, e.g. an API or a key excipient this can give an added complexity to the process and this must be fully investigated with the Quality and Regulatory units being involved, before any orders are placed.


FDA Guideline on Dissolution Testing

The FDA has presented the draft of a revised guideline on dissolution testing for immediate release. Under certain conditions, the tests can now be standardised. Read on to get more information about FDA’s Guideline on Dissolution Testing.,Z-QCM_n.html

In August 2015, the FDA published the draft of a guideline on dissolution testing for immediate release solid oral dosage forms. It is planned that after its finalisation, a part of this guideline will replace the current guideline from August 1997.

The Biopharmaceutics Classification System (BCS) distinguishes 4 different classes of APIs depending on their  solubility and permeability.
On the basis of this classification, a decision can be taken for determining when bioavailability or bioequivalence studies are required, or when a successful in vitro-in vivo correlation (IVIVC) is likely.

The BCS proposes that, for certain medicinal products which contain a high soluble API, dissolution testing can be standardised. Due to their high solubility, medicinal products in the BCS classes 1 and 3 have a relatively low risk with regard to the impact on dissolution, provided that the in vitro performance meets or exceeds the recommendations given.

If these conditions are met, the new guideline will provide concrete provisions regarding the methods which can be standardised: USP apparatus 1 (basket method) or 2 (paddle method) with fixed parameters for stirring rate, medium and temperature. For this, the permitted limits for the specifications are laid down. In addition, the possibility is granted that, under certain conditions, disintegration testing can be used as alternative method.

You can access the complete document of the FDA “Dissolution Testing and Specification Criteria for Immediate Release Solid Oral Dosage Forms” here.

The new Elemental Impurities Database for Excipients – ECA offers a meeting at no costs

A step-wise integrated risk-based approach to determine a control strategy for according to ICH Q3D has to consider data from all kinds of potential sources for elemental impurities in particular from excipients. Read more about the newly created Elemental Impurities Database as a valuable support for performing risk assessments for drug products.

The new ICH Q3D Guideline on Elemental Impurities strongly advocates the use of risk assessments in order to define a final control strategy. Specific challenges appear when risks associated with production equipment, packaging material and excipients have to be determined, and quantified. In particular the contribution of elemental impurities from excipients is not easy to assess due to their big variety and the lack of information from excipient vendors.

Quite recently a pharma consortium started an initiative which aims to collect and share data from pharmaceutical excipients by establishing a database. This Elemental Impurities (EI) Database provides information required for performing a comprehensive risk assessment of a drug product with respect to elemental impurities. Interested companies can contribute to this database by providing information about excipients and may also benefit from this database by taking out information needed for their risk assessments.

The “Impurities Workshop” from 14-16 June 2016 in Heidelberg, Germany provides a comprehensive and practical oriented review of impurities analysis and characterisation in drug substances and drug products. Part III of the workshop on 16 June 2016 is specifically dedicated to Elemental Impurites. In the subsequent post-Conference Workshop on 17 June 2016 the above mentioned EI Database will be explained. The following questions will be discussed:

  • What is the procedure of providing data for the Database?
  • How can information be obtained from the Database?
  • What has to be considered in terms of confidentiality when data will be received or submitted to the Database?

This post-Conference Workshop is free of charge. It ideally complements the previous parts of the “Impurities Workshop” and can be booked in combination with either Part III or all Parts of the “Impurities Workshop”. As we expect a high interest in this post-Conference Workshop participants joining the “Impurities Workshop” (one day or all three days) will be registered first


Fraud and Major GMP Violations at API Manufacturers in India and China


Two Non-Compliance reports to API manufacturers from the Far East  published in the EudraGMDP database reveal once more that basic requirements laid down in the ICH Q7 Guideline are not implemented. Read more details about those Non-Compliance Reports.,15339,S-WKS_n.html


The Non-Compliance reports in the Eudra-GMDP database of the European Medicines Agency (EMA) are – to a certain extent – the European counterpart of FDA’s Warning Letters. These reports are first drawn up then put in the database after a GMP inspection performed by a representative of the European national competent authorities at an API or medicinal product manufacturer showed serious GMP deficiencies. Similar to Warning Letters, the consequences of Non-Compliance reports are for the companies concerned critical, e.g. withdrawal of the GMP certificate or product recalls.

Two Non-Compliance reports issued at the end of last year concerned API production sites in China and India.

Regarding the Chinese manufacturer “Minsheng Group Shaoxing Pharmaceutical Co. Ltd“, GMP inspectors from the French competent authority found 2 critical and 4 “major” deficiencies. Those deficiencies are summarised below:

  • Falsification of source of starting materials: the starting materials supposed to have been manufactured in-house actually came from an external non GMP-compliant supplier and have been repackaged and relabelled accordingly (critical deficiency).
  • The API manufactured according to the Chinese Pharmacopoeia was wrongly and intentionally released as USP quality; there was no traceability of the testing activities (critical deficiency).
  • The cleaning and maintenance operations of the manufacturing line were insufficient (major).
  • Deficient equipment design (pipelines); non-compliant transfer of the intermediate solution using nitrogen; non-compliant change management with regard to equipment (major).
  • Hoses were lying on a dirty floor of an area not mentioned in the general layout of the site. Those hoses were unidentified and their cleaning status was unclear (major).
  • Audit trail function in the chromatographic system was deactivated; there was no procedure in place for audit trail (major).

By the way, the inspection of the Chinese manufacturer performed by the French authority was part of the prequalification programme of the WHO which means that it had been initiated by the manufacturer himself within the framework of his application for the inclusion of his products in the list of prequalified pharmaceutical APIs of the WHO.

Secondly, the inspection of the Indian company “AstraZeneca Pharma India Ltd.” was carried our by inspectors of the Swedish competent authority. The GMP deviations observed are summarised below:

  • The manufacturing process of the API was not sufficiently validated (major).
  • The documentation routine was not GMP-compliant (major).
  • Data integrity wasn’t assured (major).
  • Design and maintenance of the equipment was insufficient (major).

The GMP deficiencies discovered in both production sites concern essential GMP requirements for the manufacture of APIs as laid down in the ICH Q7 Guideline and in the EG GMP Guide Part II since already 16 years. Unfortunately, GMP inspectors from European authorities, the EDQM and the FDA are – again and again – confronted to such GMP deficiencies, mainly in Indian and Chinese manufacturing sites.


///////// gmp Violations, API Manufacturers, India,  China

Which External GMP Audit Reports may be used?

We are often asked about the acceptance of third GMP audits at API manufacturers. The background for this is that more and more organisations offer such audits. Now, the question is what do you have to pay attention to?,15099,15274,15179,Z-QAMPP_n.html

We are often asked about the acceptance of third GMP audits at API manufacturers. The background for this is that more and more organisations offer such audits. Now, the question is what do you have to pay attention to?

It is essential to clarify who gave the order: has the audit been initiated from another pharmaceutical company? From the auditor himself/ herself or the organisation behind? Or from the API manufacturer?

Audits (and their reports) which have been initiated by the API manufacturers or their traders have to be viewed in a critical light. Also audits performed by the auditor – i.e. the audit organisation requires closer examination and analysis. Especially possible conflicts of interest have to be clarified.

At best, a contract audit is requested by one or several medicinal product manufacturers who buy themselves a product from the API manufacturer. If the API manufacturer is the customer, then the independence of the auditor has to be clearly demonstrated. In such a case, it is absolutely necessary to obtain a confirmation from the auditor in writing.

Acceptance, Accreditation and “Conflict of Interest”: what should you keep in mind?

A medicinal product manufacturer can basically perform an audit himself or let it perform by a so-called Third Party. Commonly, the medicinal product manufacturer assigns a consultant who has experience in the performance of audits. Yet, – here again – a few elements should be considered because the external auditor will be acting for the pharmaceutical company as if he were an own employee. The important thing here is to choose an auditor who knows the processes which have to be audited. If for example a biopharmaceutical API i.e. the manufacturer has to be audited, the auditor should have relevant experiences in biopharmaceutical processes. The auditor should also confirm that he/ she hasn’t been acting as a consultant in the area to be audited for at least the last 2 years. This should help to avoid eventual conflicts of interest. For this, a documented confirmation is helpful but often forgotten. The qualification of the GMP auditor is an essential aspect. You should require a CV of the auditor (education, work experience, audit history and audit trainings) and qualify him/ her. The execution by an accredited body doesn’t play any role. Accreditation is of no significance in pharmaceutical law.

Purchasing audit reports later:

More and more audit reports are available for purchase. In principle there is no objection to the purchase of an audit report. However, the same rules apply as those concerning the initiation of an audit. In any case, the auditors must be independent. This must also be confirmed in writing. You should check whether the audited products are the products which are also relevant for your supplier qualification. The audit of another product is quite unhelpful. The audit report should contain concrete information about the product-specific processes and procedures. This is the only way for the customer to decide on the basis of the available information whether the supplier can be suitably qualified.

Important: an audit report is only a part of the supplier qualification!

Audit reports are the main focus of interest. However, it is often forgotten that audit reports are only a part of the supplier qualification but a central one. Audit reports contain a description of the GMP situation on the audit day(s). The real assessment of the results is done by the customer – for example by a quality unit or the Qualified Person. Beside the audit report, further data should be consulted like the experiences with the supplier and the assessment of the products delivered. How valuable is an audit report with a good GMP rating when repeated deviations from the specifications are observed in the course of withdrawal of samples? The assessment of further information like for example inspection reports of the FDA which are generally accessible through the Freedom of Information Act, or EDQM’s database with the list of CEPs of API manufacturers which have been withdrawn because of GMP deficiencies. All these data should flow into a risk analysis to be used to qualify (or not) a supplier.

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