Detailed Requirements concerning the DOE in the Regulatory Submission Dossier: EMA’s and FDA’s Recommendations

The EMA has published together with the FDA a new question & answer (Q&A) paper at the end of 2014. This document answers questions on detailed requirements in connection with the documents concerning regulatory submissions. Among others it contains the answer to the question “What level of detail should be considered for design of experiments (DOEs) in a regulatory submission?

GMP News

In our News dated 18 February we reported on a question & answer (Q&A) paper which was published by EMA and FDA together at the end of 2014. This document answers questions on detailed requirements in connection with the documents concerning regulatory submissions. It also answers a question on the topic design of experiments (DOE).

The document answers the question “What level of detail should be considered for design of experiments (DOEs) in a regulatory submission?” as follows:

The level of detail should be commensurate with the significance of the outcome of the DOE to the selection of the product design, commercial manufacturing process and control strategy. According to the document a DOE to define operating ranges for an important unit operation would normally be considered of high significance. The information provided to the authority in such cases could include:

  • Type of experimental design and parameter ranges studied. As a supplement it is pointed out that justification for choice of design could be useful.
  • Tables summarizing inputs and outputs, including batch size.
  • Summary of parameters that were kept constant during the DOE.
  • Delineation of factors as scale dependent or independent, with justification (for example experimental results, scientific rationale, prior knowledge).
  • Description of main effects and interactions on response variables, including statistical significance of parameters (p-value).
  • Discussion of regression model validation parameters (such as output from ANOVA regression analysis, residual plots, etc.) if applicable.

Please also see the “Questions and answers on level of detail in the regulatory submissions“.




Design of Experiments Planning

Design of Experiments or short DoE is a process of designing experiments to understand and validate the relationship between a list of input factors and a desired output variable.

The article on DoE has already explained the importance and benefits of DoE, key terminologies like error, noise factors, correlation and interaction. This article will provide information that will be helpful to successfully plan a DoE.

The process of DoE has the following steps. We will look at details to be taken care at each step to successfully conduct a DoE.

Figure 1: Design of Experiments Planning Flowchart

The main purpose of Planning & Designing Experiments is to obtain maximum amount of information from a least or optimal number of experiments (runs) & trials.

Pre-Requisites of a DoE Planning

One must note the below points before designing & conducting Experiments.

    1. Define the Problem: One must confirm whether a DoE is really needed for the problem taken. One should evaluate whether the required result or information can be obtained from any other source, or any set of calculations. There may be constraints in availability of raw materials & equipment. Some experiments may be very costly and time consuming. Therefore, DoE must be chosen when it is absolutely necessary and there are no other alternatives available.
    2. Identify the objective of the study: There may be different objectives.
      1. Exhaustive Study: One might need to know the complete list of variables/factors affecting the response variable. For this, a full factorial design is needed. No factors or levels should be omitted while conducting experiments.
      2. Examine Specific factors: Sometimes, the business need will be to only validate the effect of a single or few parameters on the response variable. For this purpose, there is no need to conduct all the experiments.
      3. Screening: The business need might be to identify only the vital few variables that have the maximum impact on response variable. One must study the Signal to Noise ratio, trivial factors that are not needed.

The number and set of experiments and trials will vary depending on the requirement. One must first ascertain the objective of the study to choose the appropriate design.

While planning and designing experiments the below items should be considered.

Figure 2: Design of Experiments Planning Considerations

    1. First use a Design Matrix to identify all possible combinations of factors and levels. The Design matrix will help to identify all combinations and an experiment will be conducted for each row item.

Figure 3: Design of Experiments Planning Design Matrix

The above table illustrates a Design matrix for a design that has two factors with two levels each. Each Factor-level combination has a unique experimental setup, which is called a Run. At a minimum, one experiment should be conducted per run.

    1. Blocking of Variables/Factors: While organizing experiments, runs can be grouped in a specific order for the ease of conducting experiments. Runs with factors that are homogenous to each other are grouped as clusters and experiments may be conducted together or sequentially or combined, depending on the nature of variables. This process of grouping runs based on the behavior of factors is called as Blocking. One should look at opportunities for blocking to reduce time and effort. Blocking is also used to screen the effect of known sources of variation.
    2. Randomization of Runs: It is known that there are interactions between factors which create a combined effect on the output variable. In addition to this, there may be some uncontrollable influences like change in equipment, raw material etc. To reduce the effect of these uncontrollable influences, the experiments should be conducted in no particular order but random, so that the effects are minimized.
    3. Replication of Runs: Replication or repetition of experiments is done to dampen the effect of uncontrollable variation. Also it helps in acquiring precise estimation of response and to detect the S/N (Signal to Noise) ratio better. The number of trials depends on the precision of equipment. Therefore, it is necessary to conduct MSA before conducting DoE.
    4. Order of Experiments: Experiments can be conducted either sequentially or in parallel. Sequential approach is required, when the outcome of one experiment is required to modify the set-up of further experiments. Otherwise, if there is enough equipment and manpower, Parallel runs will reduce the time spent on conducting experiments.

The above points will help in designing a perfect DoE plan that optimizes the number of runs and maximizes the data and information collected to meet the objective of the study.


Lupin and Celon Pharma partner for generic version of GSK’s Advair Diskus

New Drug Approvals

Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin

India-based drugmaker Lupin has signed an agreement with Polish biopharmaceutical firm Celon Pharma to develop a fluticasone / salmeterol dry powder inhaler (DPI).

Under the deal, Lupin will take the responsibility for commercialisation of the product, which is a generic version of GlaxoSmithKline’s (GSK) Advair Diskus.

Lupin CEO Vinita Gupta said: “We are very pleased to partner with Celon given their experience in the development and manufacturing of fluticasone/salmeterol DPI in Europe…………..

Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin, is based in the United States, but has been in India a lot in the past one year.

Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin,
Vinita Gupta

With an expanding role in Lupin’s universe, Vinita has been spending more time outside the US, at times taking her six-year-old son, Krish with her. “He is getting exposure at a much younger…

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New, aggressive form of HIV identified in Cuba

Atasteofcreole's Blog

In Cuba, a variant of HIV that is much more aggressive than other known forms of the virus has been documented. Patients infected with this new variant progress to AIDS so rapidly that they may not even know they are infected, with AIDS symptoms occurring within 3 years of infection.
HIV attacking cellHIV anchors itself to proteins on the membranes of cells before it is able to penetrate the cell.

If a person contracts multiple strains of HIVtypically by engaging in unprotected sex with multiple infected partners – then these strains can recombine into a new variant of HIV within the host. The new Cuban variant of HIV is one such recombinant version of the virus.

HIV anchors itself to co-receptors – proteins on the membranes of cells – before the virus is able to penetrate the cell. The first co-receptor that HIV anchors to is known…

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click below

  • a review on drug approval process for us, europe and india …

    This article focuses on drug approval process in different countries like USA, Europe and India. Keywords: MAA, USFDA, Drug approval, Clinical trial.

     click below

    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 …

    The regulatory scenario in India is changing very fast and DCGI is coming up with precise guideline on each topic. The documentation for product registration in India has become at par with US FDA and seems to objective of DCGI so that data generated in India is acceptable globally. Ever-changing laws and regulations are driving demand for regulatory affairs professionals to cater the current needs of industries for the global competition and who can help pharmaceutical companies to effectively bring their medical products to the Indian market. In today’s competitive scenario, the reduction of the time taken to launch the product is imperative and hence vital for company’s success.  This post will be helpful to all pharma manufacturer/importer, regulatory, preclinical, formulation scientists, and clinical trial professional who are involved directly or indirectly in new drug registration process. The post covers new drug including fixed-dose combination in India and import & registration by foreign manufacturer. Need integrated knowledge and broad perspectives which you need to effectively manage the regulatory process for approval of new drugs in India.

    key points

    1. Regulatory Overview in India
    2. Regulatory Dossier
    3. Chemical, Pharmaceutical Information and Animal Studies data
    4. Clinical Trial Requirement and Documentation
    5. New Drug Application: IND developed in India
    6. New Drug Application: Marketed in other countries, not approved in India
    7. New Drug Application: New Indication, Dosage form or route of administration
    8. New Drug Application: Fixed dose combination of two or more drugs
    9. New Drug Application: Approved in India within four year and PSUR
    10. Import and Registration

Approval of New Drug in India (7-10): When a company in India wants to manufacture/import a new drug it has to apply to seek permission from the licensing authority (DCGI) by filing in Form 44 also submitting the data as given in Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945. In order to prove its efficacy and safety in Indian population it has to conduct clinical trials in accordance with the guidelines specified in Schedule Y and submit the report of such clinical trials in specified format.

But a provision is there in Rule – 122A of Drugs and Cosmetics Act 1940 and Rules 1945 that the licensing authority may waive certain trails if he considers that in the interest of public health he may grant permission for import of new drugs basing on the data of the trials done in other countries. Similarly there is another provision in Rule – 122A which says Section 2.4 (a) of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says for those drug substances which are discovered in India all phases of clinical trials are required. Section 2.4 (b) of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says that for those drug substances which are discovered in countries other than India; the applicant should submit the data available from other countries and the licensing authority may require him to repeat all the studies or permit him to proceed from Phase III clinical trials. Section 2.8 of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says that the licensing authority may require pharmacokinetic studies (Bioequivalence studies) first to show that the data generated in Indian population is equal to data generated that the clinical trials may be waived in the case of new drugs which are approved and being used for several years in other countries. abroad and then require him to proceed with Phase III trials.

In summary, the exact requirements of Clinical trials may change from case to case and depend on the extent to which licensing authority is satisfied about its safety and efficacy.

The process of approval of new drug in India is a very complicated process, which should meet necessary requirements along with NDA to FDA. The need of the present work is to study and document the requirements for the process of approval of new drug in India with emphasis on clinical trials as per Drugs Control department, Government of India.

New Drug Application NDA is an application submitted to the FDA for permission to market a new drug. To obtain this permission a sponsor submits preclinical and clinical test data to NDA for analyzing the drug information, description of manufacturing procedures. After NDA received by the agency, it undergoes a technical screening. This evaluation ensures that sufficient data and information have been submitted in each area to justify “filing” the application that is FDA formal review. At the conclusion of FDA review of an NDA, there are 3 possible actions that can send to sponsor:

Not approvable- In this letter list of deficiencies and explain the reason. Approvable – It means that the drug can be approved but minor deficiencies that can be corrected like-labeling changes and possible request commitment to do post-approval studies. Approval- It state that the drug is approved. If the action taken is either an approvable or a not approvable, then FDA provides applicant with an opportunity to meet with agency and discuss the deficiencies.






The Drug approvals in the US, Europe & India are the most demanding in the world. The primary purpose of the rules governing medicinal products in US, Europe & India is to safeguard public health. It is the role of public regulatory authorities to ensure that pharmaceutical companies comply with regulations. There are legislations that require drugs to be developed, tested, trailed, and manufactured in accordance to the guidelines so that they are safe and patient’s well – being is protected.




Quality by Design in Action 1: Controlling Critical Quality Attributes of an Active Pharmaceutical Ingredient

The importance of Quality by Design (QbD) is being realized gradually, as it is gaining popularity among the generic companies. However, the major hurdle faced by these industries is the lack of common guidelines or format for performing a risk-based assessment of the manufacturing process. This article tries to highlight a possible sequential pathway for performing QbD with the help of a case study. The main focus of this article is on the usage of failure mode and effect analysis (FMEA) as a tool for risk assessment, which helps in the identification of critical process parameters (CPPs) and critical material attributes (CMAs) and later on becomes the unbiased input for the design of experiments (DoE). In this case study, the DoE was helpful in establishing a risk-based relationship between critical quality attributes (CQAs) and CMAs/CPPs. Finally, a control strategy was established for all of the CPPs and CMAs, which in turn gave rise to a robust process during commercialization. It is noteworthy that FMEA was used twice during the QbD: initially to identify the CPPs and CMAs and subsequently after DoE completion to ascertain whether the risk due to CPPs and CMAs had decreased……….

Quality by Design in Action 1: Controlling Critical Quality Attributes ofan Active Pharmaceutical Ingredient

CTO-III, Dr. Reddy’s Laboratories Ltd, Plot 116, 126C and Survey number 157, S.V. Co-operative Industrial Estate, IDA Bollaram, Jinnaram Mandal, Medak District, Telangana 502325, India
Department of Chemistry, Osmania University, Hyderabad, Telangana 500007, India
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/op500295a
Publication Date (Web): January 21, 2015
Copyright © 2015 American Chemical Society
*Telephone: +919701346355. Fax: + 91 08458 279619. E-mail: (A.K.R.)., * (P.S.).

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USP Chapter Visual Inspection of Injections published

The long-awaited USP Chapter <1790> regarding the 100% visual control of injections has been issued in the Pharmacopeial Forum 41(1) for commenting. Read on.–1790–Visual-Inspection-of-Injections-published_40007,9087,9200,Z-PEM_n.html

The long-awaited USP Chapter <1790> regarding the 100% visual control of injectables has now been issued as a first draft in the Pharmacopeial Forum 41(1) for commenting.

The new chapter is comprised of the following sub-chapters:
1. Scope
2. Introduction
3. Typical Inspection Process Flow
4. Inspection Life-Cycle
5. Interpretation of Results
6. Inspection Methods and Technologies
7. Qualification and Validation of Inspection Processes
8. Conclusions and Recommendations
9. References

This new informative chapter is applied to the manual, the half-automatic and the fully-automated inspection of parenterals. It mainly aims at controlling particles (>50 µm), but also comprises indications to further defects like cracks in primary containers or poorly fitting stoppers. In Chapter 2 there are also general statements regarding the patient risk due to particulate matter with regards to the size and type of the particulate impurity and the patient’s condition or age. It is interesting that this is expanded in Chapter 4 where possible particle sources (stopper, glass, silicon etc.) are mentioned together with the request to prevent any generation of particles. The Sub-chapter 4.2.1 aims at avoiding of intrinsic particles already in product development – e.g. through the prevention of glass delamination, by choosing appropriate formulations and according stability studies. Supplementary, Chapter 4.3 is dedicated the removal of particles, e.g. by washing primary containers and the associated particle depletion studies.

As already described in the USP Chapter <790> the AQL testing is supposed to be part of the evaluation of a batch. For that purpose samples are drawn from the good proportion of the tested batch according to defined sampling plans. These samples are then tested again to evaluate the quality of the preceeding 100% control. The AQL limits named exemplarily in Chapter <17990> are more strict, though, as those in the ECA Best Practice Paper for the visual control.

Some practical tips are contained in Chapter 5. For instance, it is suggested there to enhance the illumination to 10.000 Lux and to possibly screen the containers from the back when testing brown glass or plastic containers as a visual control for these containers is difficult to conduct.

Chapter 7 (Qualification/Validation of inspection processes) is mainly directed towards the manual visual inspection. It comprises tips for the creation of test sets and the qualification as well as the re-qualification of personnel. The application of Knapp tests for determining the detection rates is also mentioned there. However, there are only very few tips for the fully-automated inspection, and there are no details referring to the qualification or re-qualification of fully-automated inspection processes.

The draft of the new Chapter <1790> is available online on the USP website. You will only need to register, which is free of charge, though. The deadline for comments is the 31 March 2015.

Falsified Results of Analysis at Indian Pharmaceutical Manufacturer


Indian pharmaceutical manufacturers increasingly attract attention by breaching GMP rules. In a further case the analysis results not complying with the requirements were deleted and the batch was released for the US market. Read more.,9087,9200,9122,Z-PEM_n.html


Indian pharmaceutical manufacturers increasingly attract attention by breaching GMP rules. We recently reported on theunannounced FDA inspections in India as one of the consequences of this practice. In a further case the analysis results not complying with the requirements were deleted and the batch was released for the US market. An employee of Sun Pharmaceutical Industries Ltd. in Vadodara, India simply deleted analytical data of an HPLC testing on impurities of an antibiotic that did not comply. The next day another sample was tested, considered to be fine and the batch was released. This incident took place three years ago.

This fundamental GMP violation of data integrity has become known only now. The FDA’s computer forensics experts found traces of a total of 5031 deleted data records in the chromatography system. A senior QC Manager commented that they often made pre-tests and rejected the results before starting the final analysis. This practice is completely inacceptable not only according to FDA understanding. The FDA talks about the regular deletion of undesirable analysis results and about retesting the products without initiating an investigation as required and without documenting the problem. And this is no isolated case.

Similar irregularities concerning the data integrity were found at the site of the Indian producer Ranbaxy who had to pay a penalty in the amount of 500 Mio US Dollars. A responsible at the Indian government announced that India has had good manufacturing practices for the manufacture of drugs for years but that the laboratory guidelines to manufacturers entered in force only in 2012. He continued that usually it would take some years for new regulations to be complied with nationwide. In the case described a ban on exports had been imposed against the company Sun already two months earlier. The underlyingreport by Bloomberg states that at least 12 Indian pharmaceutical companies were affected by such a ban on exports in the last year. One of these cases concerns the Indian company Smruthi Organics Ltd., for instance which also manufactures an antibiotic. During an FDA inspection the inspectors noticed already in 2013 that batches of active ingredients that did not comply with the specifications were blended with passing batches in order to meet the requirements (= missblending). The relating batch documents had been destroyed.