New Drug Approvals

Home » Regulatory

Category Archives: Regulatory


Blog Stats

  • 4,302,872 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,821 other subscribers
Follow New Drug Approvals on



Recent Posts

Flag Counter


Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,821 other subscribers


DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

Personal Links

Verified Services

View Full Profile →



Flag Counter

QbD Presentations

Organizational Initiatives Towards Developing Greener Processes for Generic Active Pharmaceutical Ingredients
– Dr. Vilas H. Dahanukar, Chief Scientist-Process R&D, Integerated Product Development Organization, Dr. Reddy’s Laboratories Ltd., India

Image result for IGCW-2015


presented at

4th Industrial Green Chemistry World Convention & Ecosystem (IGCW-2015) on 4th – 5th December 2015


Image result for waitThe presentation will load below

Please scroll with mouse to see


Innovative Techniques, To Synthesize Breakthrough Molecules, See DOE On pae 4 onwards

Image result for waitThe presentation will load below


Quality by Design Questions to Consider How can we maximize the benefits to the industry and other stakeholders? How can we ensure that this will speed.


Quality by Design in Drug Product Development

Introduction to drug product development – setting the scene

  • Drug product development at a glance – from first in man to marketing authorization
  • Pharmaceutical QbD: Quo vadis?
  • Application of QbD principles to drug product development

Expectations from regulatory agencies

  • Regulatory initiatives and approaches for supporting emerging technologies
  • Concepts of Real Time Release Testing (Draft Annex 17 EU GMP Guideline)
  • Harmonization of regulatory requirements (QbD parallel-assessment FDA-EMA, ICH Q8 -> Draft Q12?)
  • Regulatory expectations: Lessons learned from applications so far

Knowledge Management

  • Knowledge Management (KM) System – Definition and Reason
  • Knowledge Management Cycle
  • Explicit and Tacit Knowledge – The Knowledge Spiral
  • Correlation between KM and other Processes
  • Enabling Knowledge Management
  • Knowledge Review – integral part of the Management Review (ICH Q10)

Quality Risk Assessment and Control Strategy

  • Objectives of Quality Risk Assessment (QRA) as part of development
  • Overview to risk assessment tools
  • Introduction of Process Risk Map
  • Introduction of risk based control strategy development

QbD Toolbox: Case studies DoE, PAT, and Basic Statistics

  • Value-added use of QbD tools – generic approaches and tailored solutions
  • Case studies and examples for different unit operations and variable problems

Reports and Documentation

  • Development Reports
  • Transfer protocols and reports
  • Control Strategy and link to the submission dossier

Wrap-up & Final Discussion
The concepts and tools used over the two days will be summarized and future implications and opportunities of applying QbD principles to process development will be discussed. Delegates will be given time to ask questions on how they can apply what they have learned to their own drug product development and manufacturing.

Workshop Process Risk Map & link to Control Strategy
Based on a risk assessment tool tailored to cover development needs, delegates will work on case studies of process development for a solid oral dosage form.
From QTPP and CQA to relationship analysis of process parameters and material attributes
Process mapping for integrated documentation of the development work
Process Risk Map as a tool for development-focussed risk assessment

Quality by Design in API Manufacturing

General framework and key elements of QbD for APIs – background and potential strategies

  • What is it all about?
  • What are the benefits?
  • When and how should you use it?
  • Practical examples with typical points of discussion

How to identify and control Critical Quality Attributes (CQAs) in API synthesis – a risk-based approach to developing a control strategy

  • Severity assessment of quality attributes
  • Impact levels for critical process parameters (CPPs) and critical material attributes (CMAs)
  • Considerations for the API Starting material
  • Design of an effective risk-based control strategy
  • Examples

How to provide information on the development of the API manufacturing process – dossier requirements

  • What should be done at which stage?
  • Which information is relevant for the dossier?
  • What are the key-points to be considered for APIs (NCE/Biotech) and their formulations
  • Typical questions from Authorities

Process Evaluation and Design Space

  • Changing Validation Approach
  • Validation Life Cycle
  • Design Space Concept

Application of PAT in the API industry

  • PAT at development stages of a QbD-based development
  • PAT as part of the Control Strategy in a GMP environment
  • Practical examples of PAT implementations at a commercial scale in a GMP environmen

Control strategies – Case studies and examples

  • HA definitions
  • Why and When is a control strategy needed
  • Different types/elements of a control strategy
  • Practical examples


GDUFA: FDA’s new Guidance on Self-Identification of Generic Drug Manufacturers

Image result for Generic Drug User Fee Amendments

GDUFA: FDA’s new Guidance on Self-Identification of Generic Drug Manufacturers

FDA’s new Guidance requesting generic drug manufacturers who want to export to the USA to self-identify has recently been published in a finalised form. Read more here about what types of generic drug manufacturers are affected and which company data are required by the FDA.,S-RGL_n.html


The GDUFA (Generic Drug User Fee Amendments) is a legislative package which came into force in 2012 and entitles the US-American FDA to collect fees from generic drug manufacturers, who strive for a marketing authorisation for the American market. An annual fee has to be paid after the successful registration.

The core of the document is the obligation to “Self-Identify” for those companies that have to submit essential site-related information to the FDA. The details of this self-identification are set in a Guidance for Industry entitled “Self-Identification of Generic Drug Facilities, Sites, and Organizations” published on 22 September 2016 by the FDA in the finalised form.

The Guidance describes the following elements:

1. Which types of generic facilities, sites, and organizations are required to self-identify?

2. What information is requested?

3. What technical standards are to be used for electronically submitting the requested information?

4. What is the penalty for failing to self-identify?

Hereinafter, you will find a short summary of these four topics:

1. Companies that manufacture finished generic medicinal products for human use or the APIs for them, or both are required to self-identify as well as companies that package the finished generic drug into the primary container and label it. Besides, sites that – pursuant to a contract with the applicant (generic drug manufacturer) – repack/redistribute the finished drug from a primary container  into a different primary container are also required to submit a self-identification as well as sites that perform bioequivalence/bioavailability studies. Last but not least, the obligation to self-identify also concerns sites that are listed in the application dossier as contract laboratories for the sampling and performing of analytical testing.

2. Essential data are: the D-U-N-S number (a unique nine-digit sequence specific for each site / each distinct physical location of an entity), the “Facility Establishment Identifier, FEI” (an identifier used by the FDA for the planning and tracking of inspections) and general information with regard to the facility (company owner, type of business operation, contact data, information about the manufacture of non generic drugs).

3. The HLS standard (Health Level Seven Structured Product Labeling) requested for generic applications (ANDAs)  has to be also used for the submission of self-identification information. A detailed description of this standard can be found in the Guidance “Providing Regulatory Submissions in Electronic Format – Drug Establishment Registration and Drug Listing“.

4. Companies that fail to self-identify do not have to expect an explicit penalty. However, such a failure leads to two drawbacks: first, the likelihood of a site inspection by the FDA prior to approval is higher. The second drawback which is much more serious is that all the APIs or finished drugs from a manufacturer who hasn’t self-identified are deemed misbranded. For the FDA, such products are not allowed for importation in the USA.

To the satisfaction of the FDA, the regulations set in the GDUFA and the provisions laid down in the new Guidance represent a major contribution to an enhanced transparency in particular of complex supply chains.


//////////GDUFA, FDA,  new Guidance,  Self-Identification, Generic Drug Manufacturers

New WHO guidance on variations to multisource pharmaceutical products

The World Health Organizaton (WHO) recently published a new Annex 10 on handling of variations. Find out more about the new WHO general guidance on variations to multisource pharmaceutical products.


The World Health Organizaton recently published a new Annex 10: WHO general guidance on variations to multisource pharmaceutical products.

The document is “intended to serve as a guide for establishing national requirements for the regulation of post-approval changes.” Proposed categories and reporting procedures are provided. Modifications may be justified in light of risk-benefit and legal considerations specific to each national medicines regulatory authority (NMRA).

The guideline can be used with respect to changes to the quality sections of product dossiers and should be read in context with the Guidelines on submission of documentation for a multisource (generic) finished product: quality part as well as other related WHO guidelines or applicable national guidelines.

The guideline emphasizes that “even well-resourced agencies find it difficult to evaluate all the pharmaceutical changes that are made to all products.” Therefore, “a shift towards increased self-assessment of changes by the marketing authorization (MA) holder” has been observed. In this context “it is necessary, to define those changes that can be made without the NMRA´s prior approval (self-assessable changes) and those that require prior approval based on an understanding of the risk and how best to manage the risk.”

Description of the reporting categories are discussed in section 5 of the Annex:

  • Notifications: They can be made for changes to the product that may have no potential or minimal potential to have a negative impact on the quality, safety and efficacy (QSE) of a finished pharmaceutical product (FPP). Implementation of such variations may be possible without prior approval by the NMRA (e.g. submission of these variations as annual notifications).
  • Minor variations: Changes with moderate or negative impact on the QSE. Such changes must be submitted to the NMRA with all required documentation prior to implementation. The MA holder may implement the change if no objection has been issued within a specific time period by the NMRA.
  • Major variations: They have a significant potential to have a negative impact on the QSE. A major variation should be reviewed and approved by the NMRA prior to implementation of the change. To increase the efficiency NMRAs may accept grouping of variations under specific circumstances (see also FDA´s new policy regarding grouping of CMC changes).
  • Editorial changes: They typically need not to be submitted and can be included as a notification together with a subsequent variation concerning that part of the dossier.

Certain changes can be so fundemental that they require a submission of a new dossier. Examples of such changes are:

  • Change of the API to a different API,
  • Inclusion of an additional API in a multicomponent product,
  • Removal of one API from a multicomponent product,
  • Change in the dose and/ or strength of one or more APIs,
  • Change from an immediate-release product to an extended- or delayed-release dosage form or vice versa,
  • Change from a liquid to a powder for reconstitution or vice versa,
  • Changes in the route of administration.

For any change in the SmPC, patient information leaflet (PIL)  and/or labels the NMRAS should be notified and submission of the revised product information and/or labelling is expected as per country-specific requirements.

Proposed recommendations on the regulatory procedures for the reporting of changes to the NMRA are discussed in section 8 of the Annex:

  • General: It is essential that different branches of the NMRA interact and exchange information effectively. They should, for example, discuss whether a change may require a GMP inspection or may be reviewed during the next routine inspection.
  • Presubmission meetings: Procedures should be established to allow MA holders the opportunity to obtain advice prior to submitting variations.
  • Proposed documentation for minor variations: Basic information like
    – covering letter,
    – application form,
    – a list of subsections of the current dossier affected by the change(s),
    – a list and description of each change, reason for change(s) and the date each change was implemented,
    – relevant summary of data from studies and tests performed,
    – copies of the updated subsections of the original dossier,
    should be included as part of the immediate or annual notification, where prior approval is not required.
  • Proposed documentation for variations requiring prior approval: Additionally to the documents mentioned under “minor variations”:
    – replacement of the relevant subsections of the dossier in accordance with the acceptable dossier format for the NMRAs concerned, with the proposed changes clearly annotated,
    – copies of the SmPC, PIL and labels, if relevant,
    – registration status and date of the proposed change(s) in other countries and/or agencies that have already approved the variation(s), especially the country of origin and the reference agencies.
  • Review procedures: NMRA should adopt a risk-based review strategy for assessment, concentratiing most effort on those changes considered to carry the greatest risk. NMRA may consider whether it will rely on decisions and/or assessment reports made by other national authorities or prepare its own full assessment report or use a combination of those approaches.

For more Information please see the new Annex 10 – WHO general guidance on variations to multisource pharmaceutical products.

//////////////Annex 10,  WHO general guidance, multisource pharmaceutical products.

APIC is working on an enhanced ICH Q7 How to do Guide

Acting on the publication of the ICH Q7 Q&A Document in June last year APIC has decided to elaborate another revision of its “ICH Q7 How to do Document” taking into account these Q&As. Here you will get to know why this upcoming How to do Document is a valuable support for API and API intermediate manufacturers regarding the practical implementation of the ICH Q7 What to do principles.


The first edition of the “How to do Document – Interpretation of the ICH Q7 Guide” was published by APIC shortly after the ICH Q7 Guideline appeared as Step 4 document in November 2000. In the meantime it has undergone a numer of revisions and the current version of the How to do Document to be found on the publications section of APIC’s website is an update from August 2015 (version 8). This document was written by experts from the European Industry (CEFIC APIC) and is essentially an interpretation of “how to” implement the requirements of the ICH Q7 Guide based on practical experience.

On the occasion of the publication of the ICH Q7 Questions & Answers Document in June 2015 another revision of APIC’s How to do Document was necessary. APIC is currently working on this new revision (version 9) taking into account the new ICH Q7 Q&A Document which will be incorporated into the How to do Document as a new chapter 21. In this chapter each Question/Answer of the Q&A document is examined and commented with respect to its practical implementation. The following example illustrates what these practical comments look like:

ICH Q7 Q&A – Question
For dedicated equipment, is ‘visually clean’ acceptable for verification of cleaning effectiveness, (i.e., no expectation for specific analytical determination)?

ICH Q7 Q&A – Answer
‘Visually clean’ may be acceptable for dedicated equipment based on the ability to visually inspect and sufficient supporting data from cleaning studies (e.g., analytical determination to demonstrate cleaning effectiveness) [ICH Q7, Section 12.76]. Equipment should be cleaned at appropriate intervals (e.g., time or number of batches) to prevent build-up and carryover of contaminants (e.g., degradants or objectionable levels of microorganisms) so that they do not adversely alter the quality of the API [ICH Q7, Sections 5.23, 12.7].

Comment in APIC’s How to do Document
“dedicated equipment” can be defined in various ways such as:
– a reactor that is used solely for 1 API process
– a reactor used for different intermediate steps of the same API.
– a reactor used for different steps in the same intermediate or API
– a reactor solely used for 1 stage in 1 process
Whatever definition is used it should be documented and justified.
When visual inspection is applied following points should be considered:
– adequate lighting
– fully dried
– difficult to clean spots visually inspectable
– use of cameras, endoscopy
– limit of detection of visual cleanliness
– dirty hold time / clean hold time
– Campaign length

While the purpose of the ICH Q7 Q&A Document is to clarify some equivocal issues of the ICH Q7 Guideline the comments of APIC’s ICH Q7 Q&A How to do Document intend to give support on an even more practical level. So after its finalisation and publication later this year the API industry will have another very useful document available which facilitates the implementation of the ICH Q7 principles.

At the pre-Conference Session to the 19th APIC/CEFIC European Conference on Active Pharmaceutical Ingredients on 22 November 2016 in Barcelona APIC will launch the ICH Q7 Q&A How to do Document as a stand alone document. All participants will receive a copy.

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.


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


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.



///////External GMP,  Audit Reports,  API manufacturers

Should Equipment Status Identification Labels be retained with the Batch Record?

Should Equipment Status Identification Labels be retained with the Batch Record?

Keeping equipment status identification labels with the batch record provides additional confirmation during the review process. But is it required?,15179,15156,15355,Z-QAMPP_n.html

Keeping equipment status identification labels with the batch record or other files is often done to provide additional confirmation during review of the record. It supports verification that certain equipment was cleaned before usage for manufacturing. But is it required?

The U.S. Food and Drug Administration FDA has answered this question in an Q&A Document. Assuming each major piece of equipment has a unique “Cleaning and Use Log” that is adequately retained, these “quick reference” equipment labels can be discarded according the agency. FDA sees “no value in the retention of such labels in addition to the required equipment log or batch record documentation. The labels serve a valuable, temporary purpose of positively identifying the current status of equipment and the material under process. Any status label should be correct, legible, readily visible, and associated with the correct piece of equipment. The information on the temporary status label should correspond with the information recorded in the equipment cleaning and use log, or the previous batch record for non-dedicated equipment.”

However, as said before, it might be useful keeping these labels in a batch record. Many companies are doing so; not because it is a requirement but it is a helpful and reliable practice.



Revised Ph. Eur. Chapter on Raman Spectroscopy introducing PAT

The revised General Ph. Eur. Chapter on Raman Spectroscopy (2.2.48) comes into operation on April 1, 2016. The Chapter now includes hand-held devices and adaption to PAT purposes. Find out more about the revised  Ph. Eur. Raman Spectroscopy chapter.,15386,Z-PDM_n.html

The revision of the General Ph. Eur. Chapter on Raman Spectroscopy (2.2.48) comes into operation on April 1, 2016.

The revised Chapter has been published in Ph. Eur. Supplement 8.7. It has been completely rewritten to include now available handheld devices and adaption to Process Analytical Technology (PAT). Raman Spectroscopy has received more and more attention in pharmaceutical industry. Hand-held instruments are suitable for rapid identification purposes for example in the incoming goods control of raw and packaging materials.

Hand-held instruments require different tolerances for wavenumber scale verification than benchtop models. Therefore, an inter-laboratory study was organized and the results have been published in a corresponding paper titled “Rationale for the update of the European Pharmacopoeia general chapter 2.2.48. Raman Spectroscopy” in Pharmeuropa Bio & Scientific Notes 2015.

In addition, the chapter has been revised to focus more on the potential use of Raman Spectroscopy in a PAT environment. Raman Spectrometry is increasingly used for PAT and chemical imaging applications. Therefore, a chapter on Chemical Imaging is also under elaboration. The draft chapter on Chemical Imaging will be published for public consultation in Pharmeuropa 28.2 (April 2016).

For more information please visit the Newsroom on the EDQM website

///////////////Raman Spectroscopy,  PAT

When can a Chemical Substance be qualified as a “New Active Substance”? The New Reflection Paper of the EMA gives Information

When can a Chemical Substance be qualified as a “New Active Substance”? The New Reflection Paper of the EMA gives Information


A chemical structure with a therapeutic moiety for which no authorisation dossier has been submitted so far and which is – from a chemical structure point of view – not related to any other authorised substances is per se a “NAS” (New Active Substance). But what about a physiologically active molecule present for example in different salts or esters? In which cases do the different derivatives of an effective substance have the NAS status?

The EMA provides clarification to these questions in a new Reflection Paper which was published on 19 January this year. The document entitled  “Reflection paper on the chemical structure and properties criteria to be considered for the evaluation of new active substance (NAS) status of chemical substances” describes the criteria according to which isomers, mixtures of isomers, complexes, derivatives, esters, ethers, salts and other solid forms of  physiologically active molecules can be classified as “NAS “. If an applicant claims the NAS status of a substance to the regulatory authority in the centralised (CP) or decentralised procedure (MRP/DCP), the authority will first check whether the claim is justified. Afterwards – in case of a positive decision – the usual review of the application dossier will be performed.

The applicant can refer to the criteria described in this Reflection Paper to substantiate his/ her claim of a NAS status. In general, the evidence has to be brought for the derivative in question that it differs significantly  in properties with regard to efficacy and /or safety from the already approved active substance.

The scope of this Reflection Papers covers neither biological and biotechnological active substances nor active substances to be included in radiopharmaceuticals.


%d bloggers like this: