EMA modernizing the Orphan designation process

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EMA modernizing the orphan designation process

On June 19, 2018, the European Medicines Agency (EMA) launched a new secure online portal for Orphan Designation (OD) applications. The portal, named ‘Iris’, provides a single window where applicants can submit and manage the information and documents related to their applications for orphan designation ref 1. This initiative is expected to reduce the time required to prepare and submit the applications. During the review process, applicants can check the status of their applications from any device and receive automatic notifications when the status of the application changes.

About Iris

IRIS is the online web portal through which applicants can apply to the EMA for orphan designation for a medicine. EMA plans to expand the scope of this portal to cover other regulatory and scientific procedures. This new process, which will become mandatory after September 19, 2018, for procuring orphan designation, requires the following steps to be completed before any activity relating to an orphan designation procedure can be carried out using the new IRIS Portal ref 2:

a) Both the Applicant and Sponsor of an orphan designation, or persons acting on their behalf, must have an active EMA user account and must be registered with IRIS user access roles of either ‘Orphan Industry Manager’ or ‘Orphan Industry Contributor.

b) The ‘Organization’ for which the OD application is being submitted must be registered in the EMA’s Organization Management System (OMS);

c) The ‘Substance(s)’ for which the application is being submitted must be registered and appear on the official EMA list of all substances, the European Union Telematics Controlled Terms (EUTCT) database;

d) Each new OD application must have a Research Product Identifier (RPI) – the process for requesting an RPI will be required before OD application.

About orphan drug designation

The European Medicines Agency (EMA) plays a central role in facilitating the development and authorization of medicines for rare diseases, which are termed ‘orphan medicines’ in the medical world. The medicine must fulfil following criteria for designation as an orphan medicine so that it can benefit from incentives such as protection from competition once on the market

It must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating;

The prevalence of the condition in the EU must not be more than 5 in 10,000 or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development;

No satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorized, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition.

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19/06/2018

Modernising the orphan designation process

EMA launches new submission portal today

The European Medicines Agency (EMA) has launched a new secure online portal for orphan designationExternal link icon applications.

The portal, named ‘Iris’, provides a single space where applicants can submit and manage the information and documents related to their applications for orphan designation. This is expected to reduce the time needed to prepare and submit the applications. During the review process, applicants can check the status of their applications from any device and receive automatic notifications when the status of the application changes.

Iris is part of a longer-term programme that aims to make the handling of product-related applications easier and utilises the domains of master data in pharmaceutical regulatory processes (SPOR).

Applicants will still be able to use the existing submission process until 19 September 2018. However, the Agency strongly encourages companies to start using the new portal from today.

In order to help applicants with the transition, EMA has developed two guidance documents. These step-by-step guides provide detailed instructions on how to use the new system and explain what has changed with its introduction.

EMA tested a pilot of the new system in March 2018 with 35 volunteers from 26 different organisations. Feedback from this test helped EMA to optimise the portal and showed high levels of satisfaction.

In future, the new system may be extended to include other procedures, taking user feedback and experience into account.

12 http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2018/06/news_detail_002976.jsp&mid=WC0b01ac058004d5c1

13 http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2018/06/WC500250762.pdf

Note- In order to help applicants with the transition, EMA has developed two guidance documents. These stepby-step guides provide detailed instructions on how to use the new system and explain what has changed with its introduction.

//////iris, ema, orphan designation process

Report from the EMA-FDA QbD pilot program

Image result for QBDReport from the EMA-FDA QbD pilot program

In March 2011, the European Medicines Agency (EMA) and the United States Food and Drug Administration (US FDA) launched, under US-EU Confidentiality Arrangements, a joint pilot program for the parallel assessment of applications containing Quality by Design (QbD) elements.

The aim of this program was to facilitate the consistent implementation of QbD concepts introduced through International Council for Harmonisation (ICH) Q8, Q9 and Q10 documents and harmonize regulatory decisions to the greatest extent possible across the two regions.

To facilitate this, assessors/reviewers from US and EU exchanged their views on the implementation of ICH concepts and relevant regulatory requirements using actual applications that requested participation into the program. The program was initially launched for three years. Following its first phase, both agencies agreed to extend it for two more years to facilitate further harmonization of pertinent QbD-related topics.

The program officially concluded in April 2016. During this period, the agencies received 16 requests to participate. One submission was rejected because the approach presented was not limited to QbD applications, and another application was not reviewed because it was never filed by the applicant.

In total, two Marketing Authorisation Applications (MAA)/New Drug Applications (NDA), three variation/supplements and nine scientific advice applications were evaluated under this program. One MAA/NDA was assessed under the parallel assessment pathway, with the rest following the consultative advice route. Based on the learnings during the pilot, FDA and EMA jointly developed and published three sets of Question and Answer (Q&A) documents.

These documents also addressed comments from the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), which participated as an observer, offering input to further facilitate harmonization. The objective of these Q&A documents was to generate review guides for the assessors/reviewers and to communicate pilot outcomes to academia and industry.

Additionally, these documents captured any differences in regulatory expectations due to regional requirements, e.g. inclusion of process validation information in the dossier. The following topics were covered in each of the three Q&A documents: –

Q&A (1) published on Aug 20, 2013 included the following topics: (a) Quality target product profile (QTPP) and critical quality attributes (CQA), (b) Criticality, (c) Level of detail in manufacturing process descriptions, and (d) QbD for analytical methods1 –

Q&A (2) published on Nov 1, 2013 on Design Space Verification, that included definition, presentation, justification (including potential scale-up effects) and verification of design spaces both for active substances and finished products2 –

Q&A (3) published on Dec 19, 2014 included the following topics: (a) Level of detail in the dossier regarding Risk Assessment (RA), (b) Level of detail in the dossier regarding Design of Experiments (DOE) and Design Space3 R

 

Additionally, the FDA-EMA pilot provided the agencies an opportunity to harmonize regulatory expectations for the following precedent-setting applications that were reviewed under the consultative advice pathway: – The first continuous manufacturing (CM) based application submitted to both agencies.

Based on the learnings from this application, the following areas related to CM were harmonized: batch definition; control of excipients; material traceability; strategy for segregation of nonconforming material; real-time release testing (RTRT) methods and prediction models; and good manufacturing practice (GMP) considerations for RTRT, validation strategy, models, and control strategy. – A post approval supplement that included a broad based post-approval change management plan/comparability protocol.

Both agencies were harmonized on the expected level of detail in the protocol and considerations for implementation of a risk based approach to evaluate the changes proposed in the protocol. In line with the scope of the QbD pilot program, joint presentations of key findings were publically presented and discussed with stakeholders at different conferences.

These included the Joint EMAParenteral Drug Association QbD workshop4 organized in 2014 which also included participation from FDA and PMDA.

Overall, it is concluded that, on the basis of the applications submitted for the pilot, there is solid alignment between both Agencies regarding the implementation of multiple ICH Q8, Q9 and Q10 concepts. The FDA/EMA QbD pilot program opened up a platform for continuous dialogue which may lead to further communication on areas of mutual interest to continue the Agencies’ support for innovation and global development of medicines of high quality for the benefit of patients.

Both agencies are currently exploring potential joint activities with specific focus on continuous manufacturing, additional emerging technologies, and expedited/accelerated assessments (e.g. PRIME, Breakthrough). Additionally, EMA and FDA are hosting experts from each other’s organisations to facilitate dialog and explore further opportunities.

References: 1. EMA-FDA pilot program for parallel assessment of Quality-by-Design applications: lessons learnt and Q&A resulting from the first parallel assessment http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/08/WC500148215.pdf

2. FDA-EMA Questions and Answers on Design Space Verification http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/11/WC500153784.pdf

3. FDA-EMA Questions and answers on level of detail in the regulatory submissions http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/12/WC500179391.pdf

4. Joint European Medicines Agency/Parenteral Drug Association quality-by-design workshop http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/events/2013/12/event_detai l_000808.jsp&mid=WC0b01ac058004d5c3

EMA publishes Q&A on Health Based Exposure Limits – Does the 1/1000 dose criterion come again into play in Cleaning Validation?

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In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. This publication triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now a draft of a Q&A paper from the EMA provides some concretisation.

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http://www.gmp-compliance.org/enews_05736_EMA-publishes-Q-A-on-Health-Based-Exposure-Limits—Does-the-1-1000-dose-criterion-come-again-into-play-in-Cleaning-Validation_15560,15661,15963,Z-VM_n.html

In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. As mentioned in the publication itself, this document triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now, the draft of a question & answer paper from the European Medicines Agency provides some concretisation of the guideline.

The document altogether comprises five pages with 14 questions and answers.

The questions – and even more the answers – are very interesting, as shown in question 1 already: Do companies have to establish Health Based Exposure Limits (HBELs) for all products?

The answer is: Yes, but there are references to question 2 and 4 (and their respective answers). Question 2 clarifies what products/active substances are considered as highly hazardous. There are, among others, 5 groups listed, which products should be classified as highly hazardous (e.g.compounds with a high pharmacological potency, daily dose < 1 mg/day (veterinary dose equivalent 0.02 mg/kg)). For highly hazardous substances the answer yes in question 1 is expected. Even more interesting is the link to question and answer 4: Can calculation of HBELs be based on clinical data only (e.g. 1/1000th of the minimum therapeutic dose)? And the answer is yes, but only at designated circumstances. This means the products should have a favourable therapeutic index (safety window) and the pharmacological activity would be the most sensitive/critical effect.

Some further clarification regarding LD 50 is provided in Question 5 and the respective Answer: The use of LD 50 to determine health based limits is not allowed.

There are also more questions and answers regarding Veterinary Medicinal Products, the inspection of the competence of the toxicology expert developing HBELs, Occupational Exposure Limits, cleaning limits, Investigational Medicinal Products and paedric medicinal products and about Cross Contamination. Details will follow.

The document is still a draft and the industry has the opportunity to comment it until the end of April 2017. Let´s see what the final version will bring.

Please also see the draft Questions and answers on implementation of risk based prevention of cross contamination in production and ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’on the EMA website.

At ECA´s Cleaning Validation Course, 9-10 February 2017 in Heidelberg, Germany the EMA Q&A draft will also be discussed.

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///////////EMA, Q&A , Health Based Exposure Limits, 1/1000 dose , criterion,  Cleaning Validation,

EMA issues new Guideline on “Chemistry of Active Substances”

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The new EMA “Guideline on the chemistry of active substances” represents the current state of the art in regulatory practice and fits into the context of the ICH Guidelines Q8-11. Find out what information regarding active substances European authorities expect in an authorization application.

http://www.gmp-compliance.org/enews_05704_EMA-issues-new-Guideline-on-%22Chemistry-of-Active-Substances%22_15982,15721,S-WKS_n.html

A medicinal product authorization application requires comprehensive information on origin and quality of an active substance. What information is required was defined in two Guidelines so far: the Guideline “Chemistry of Active Substances” (3AQ5a) from 1987 and the “Guideline on the Chemistry of New Active Substances” from 2004. Because both Guidelines’ content do not take into account the ICH Guidelines Q8-11 issued in the meantime and do thus not meet the current state of the art in sciences and in regulatory practice, the EMA Quality Working Party (QWP) developed an updated document  entitled “Guideline on the chemistry of active substances” (EMA/454576/2016), which was issued on 21 November.

The new Guideline describes the information on new or already existing active substances required in an authorization dossier. In the context of this Guideline “already existing” ingredients are those that are used in a product already authorized in the EU.

In detail the information and data regarding the substance have to be included in the following chapters of the CTD:

3.2.S.1: Nomenclature, information on the structural formula, pharmacological relevant physicochemical properties.

3.2.S.2: Information on the manufacturer(s), contractor(s), testing facilities etc.; description of the manufacturing processes (schematic representation with flow diagram as well as narrative); where appropriate detailed information on alternative manufacturing processes, for recovering of solvents and for routine reprocessing. Information with regard to re-working should not be included in the authorization dossier.

3.2.S.2.3: Information for controlling the material used during the manufacture and for its specification (incl. identity test). This paragraph is more comprehensive in the new Guideline compared with its predecessor and takes into account the requirements of the ICH Guideline Q11. This Guideline comprises requirements for the following materials: materials from biological sources, those used for the chemical synthesis of starting materials, materials from herbal origin, excipients like solvents (incl. water), reagents, catalysts etc.

3.2.S.2.4: Information on critical process steps (the Guideline comprises examples for these critical steps) as well as on quality and control of isolated intermediates within the synthesis steps. All information has to be provided with the appropriate justifications.

3.2.S.2.5: Information on Process Validation

3.2.S.2.6: Information on the development of the manufacturing process. Here all changes have to be described that were performed during the various phases (pre-clinical, clinical, scale-up, pilot and possibly production phase) of the process for new active substances. For already existing active substances available in production scale no information on process development is needed.

3.2.S.3: Information on Characterisation. Comprehensive information on the elucidation of the structure of the active substance, its physico-chemical properties and its impurities profile have to be provided. Further, the mutagenic potential of degradation products has to be considered. The analytical methods have to be described and their suitability has to be justified.

3.2.S.4: Information on the control of active substances. The analytical procedures and their validation have to be described. Data for the analytical method development should be provided if critical aspects of the analysis regarding the active substance’s specification need to be clarified. Analytical data are necessary for batches for pre-clinical and clinical studies as well as for pilot batches which are not less than 10% of the maximum production scale. The substance’s specification and its control strategy have to be justified on the basis of data from the pre-clinical and clinical phase and, if available, from the production phase.

3.2.S.5: Information on reference materials. If no Chemical Reference Substances (CRS) of the European Pharmacopoeia – counting as completely qualified reference standards – are used, comprehensive information on the analytical and physico-chemical characterization are required even for established primary standards.

3.2.S.6: Information on Container Closure System. Here a brief description is sufficient. However, if a Container-/Closure System is critical for the substance’s quality, its suitability has to be proven and justified. A reference to stability data can be used as supporting information.

3.2.S.7: Information on Stability. A detailed description of the stability studies carried out and the protocol used as well as a summary of the results are expected. Information on stress studies and conclusions on storage conditions and re-test dates or expiry dates are also to be made. This does not apply to substances monographed in the European Pharmacopoeia. If no re-test period or expiry date of batches on the production scale is available at the time of submission of the application, a stability commitment has to be attached with a post-approval stability protocol. The analytical methods have to be described.

The Guideline’s provisions also apply to an Active Substance Master File (ASMF) or to a Certificate of Suitability (CEP). They apply to active substances that have undergone development in a “traditional” way or according to the “enhanced” approach. The provisions of the ICH Guidelines Q8-11 have to be taken into account.

The Guideline is not applicable to active substances of herbal, biological and biotechnological origin as well as to radiolabelled products and radiopharmaceuticals.

The Guideline “Guideline on the chemistry of active substances” (EMA/454576/2016) becomes effective six months after issuing, which means in May 2017.

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EMA/ FDA Mutual Recognition Agreement on drug facility inspections moving forward

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EMA/ FDA Mutual Recognition Agreement moving forward
A possible agreement between the EMA and the US FDA on mutual recognition agreement on drug facility inspections could already be signed in January 2017.

http://www.gmp-compliance.org/enews_05650_EMA–FDA-Mutual-Recognition-Agreement-moving-forward_15642,15660,15656,Z-QAMPP_n.html

A possible agreement between the European Medicines Agency EMA and the US Food and Drug Administration FDA on mutual recognition of drug facility inspections could already be signed in January 2017. This is noted in a report of the EU Commission: “The state-of-play and the organisation of the evaluation of the US and the EU GMP inspectorates were discussed. In light of the progress achieved, the conclusion of a mutual recognition agreement of Good Manufacturing Practices (GMPs) inspections by January 2017 is under consideration.”

But, according to the Commission, some issues are still not resolved – like, for example, the exchange of confidential information and the inclusion of veterinary products in the scope of the text.

The “Report of the 15th Round of Negotations for the Transatlantic Trade and Invesment Partnership” summaries the 15th round of negotiations for the Transatlantic Trade and Investment Partnership (TTIP) from 3rd to 7th October 2016 in New York.

////////EMA, FDA,  Mutual Recognition Agreement, drug facility inspections

EMA reviews Medicines manufactured at U.S. Company

Following the issuance of two Non-Compliance Reports for two sites of the US based company, EMA has started a review of medicines manufactured by Pharmaceutics International Inc., USA.

The European Medicines Agency (EMA) has started a review of medicines manufactured by Pharmaceutics International Inc., USA. This follows the issuance of two Non-Compliance Reports for two sites of the US based company after an inspection in February 2016 conducted by the MHRA (the medicines regulatory agency in the United Kingdom) which highlighted several shortcomings in relation to good manufacturing practice (GMP).

Pharmaceutics International Inc. manufactures the centrally authorised medicine Ammonaps (sodium phenylbutyrate) and is also the registered manufacturing site for some other medicines that have been authorised through national procedures in the European Union (EU).

This inspection which was a follow-up to an inspection in June 2015 aimed to assess whether corrective measures agreed previously had been appropriately implemented. It found that shortcomings remained, which included insufficient measures to reduce the risk that traces of one medicine could be transferred to another (cross-contamination), as well as problems with the way data were generated and checked and deficiencies in the systems for ensuring medicines’ quality (quality assurance).

EMA’s Committee for Medicinal Products for Human Use (CHMP) will now review the impact of the inspection findings on the products’ overall benefits and risks and make a recommendation as to whether any changes are needed to their marketing authorisations.

There is no evidence that patients have been put at risk by this issue. However, as a precautionary measure, medicines from this site will no longer be supplied to the EU unless they are considered to be ‘critical’ to public health. Criticality will be assessed by national medicines regulatory agencies for their territories, taking into account alternatives and any impact of shortages on patients. In case where a medicine manufactured at this site is considered not critical in a member state it will no longer be supplied in this member state and any medicine remaining on the market will be recalled.

Source: EMA Press Release

Pharmaceutics International Inc., USA

/////////// EMA,  Medicines,  manufactured, U.S. Company, Pharmaceutics International Inc., USA

EMA publishes Q A on data required for sterilized primary packaging materials used in aseptic manufacturing processes

The European Medicines Agency, EMA, recently published questions and answers on what data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process. Read more about “What data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process?“.

http://www.gmp-compliance.org/enews_05330_EMA-publishes-Q-A-on-data-required-for-sterilized-primary-packaging-materials-used-in-aseptic-manufacturing-processes_15303,15493,15615,Z-PKM_n.html

The European Medicines Agency, EMA, recently published questions and answers on quality of packaging materials (H+V April 2016):

“3. What data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process?
Terminal sterilisation of the primary packaging, used subsequently during aseptic processing of the finished product, is a critical process and the sterility of the primary container is a critical quality attribute to ensure the sterility of the finished product. Both need to be assured for compliance with relevant Pharmacopoeial requirements for the finished product and product approval.

The site where sterilisation of the packaging materials takes place may not have undergone inspection by an EU authority and consequently may not hold an EU GMP certificate in relation to this activity1. When GMP certification is not available, certification that the sterilisation has been conducted and validated in accordance with the following ISO standards would be considered to provide an acceptable level of sterility assurance for the empty primary container:

  • I.S. EN ISO 20857:2013 Sterilization of Health Care Products – dry Heat – Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 20857:2010);
  • I.S. EN ISO 11135:2014 Sterilization of Health-care Products – Ethylene Oxide – Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 11135:2014);
  • I.S. EN ISO 17665-1:2006 Sterilization of Health Care Products – Moist Heat – Part 1: Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices, and, ISO/TS 17665-2:2009 Sterilization of health care products — Moist heat — Part 2: Guidance on the application of ISO 17665-1;
  • I.S. EN ISO 11137-1:2015 Sterilization of Health Care Products – Radiation – Part 1: Requirements for Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 11137-1:2006, Including 1:2013);
  • I.S. EN ISO 11137-2:2015 Sterilization of Health Care Products – Radiation – Part 2: Establishing the Sterilization Dose (ISO 11137-2:2013);
  • I.S. EN ISO 11137-3:2006 Sterilization of Health Care Products – Radiation – Part 3: Guidance on Dosimetric Aspects.

It is the responsibility of the user of the manufacturer of the medicinal product, to ensure the quality, including sterility assurance, of packaging materials. The site where QP certification of the finished product takes place, and other manufacturing sites which are responsible for outsourcing this sterilisation activity, should have access to the necessary information to demonstrate the ongoing qualification status of suppliers of this sterilisation service. This should be checked during inspections. The Competent Authorities may also decide, based on risk, to carry out their own inspections at the sites where such sterilisation activities take place.

Dossier requirements:

The following details regarding the sterilisation of the packaging components should be included in the dossier:

1. The sterilisation method and sterilisation cycle;
2. Validation of the sterilisation cycle if the sterilisation cycle does not use the reference conditions stated in the Ph. Eur.;
3. The name and address of the site of sterilisation and, where available details of GMP certification of the site. Where the component is a CE-marked Class Is sterile device (e.g. sterile syringe), confirmation from the manufacturer that the component is a Class Is sterile device, together with a copy of the declaration of conformity from the Notified Body will suffice.

In the absence of GMP certification or confirmation that the component is a CE-marked Class Is medical device, certification that the sterilisation process has been conducted and validated in accordance with the relevant ISO standards should be provided.
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1Sites located in the EU which perform sterilisation of primary packaging components only are not required to hold a Manufacturer’s/Importer’s Authorisation (MIA). Sites located in the EU, which carry out sterilisation of medicinal products, are required to hold a MIA in relation to these activities.”

Source: European Medicines Agency – Quality of medicines Q&A: Part 2 – Packaging.

///////////EMA,  Q&A, data, sterilized primary packaging materials,  aseptic manufacturing processes

EMA’s new Draft Guideline on the Sterilisation of Medicinal Products, APIs, Excipients and Primary Containers

For medicinal products administrated in sterile form, the process to reduce the microbial level is a critical manufacturing step with regard to quality. The EMA has recently published the draft of a guideline on that topic which contains a range of clarifications. Read more about the coming requirements on sterilisation of medicinal products, APIs, excipients and final containers

see

http://www.gmp-compliance.org/enews_05350_EMA-s-new-Draft-Guideline-on-the-Sterilisation-of-Medicinal-Products–APIs–Excipients-and-Primary-Containers_15435,S-WKS_n.html

As referred to in the European Pharmacopoeia, the procedure for terminal sterilisation of a medicinal product, an API, or an excipient is generally the method of choice. Yet, this might be difficult in many cases for product stability reasons. That’s why other microbial reduction processes can be used like sterilising filtration or aseptic processing. So far, there has been some uncertainty about these methods and their acceptance in a marketing authorisation procedure or a variation application, and about which data have to be submitted.

EMA’s new draft guideline entitled “Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container”  from April 2016 contains clear provisions with regard to the acceptance of alternative sterilisation processes by the European authorisation authorities. Those provisions apply to chemical and biological medicinal products for human and veterinary use as well as the respective APIs and excipients, but aren’t applicable for immunological veterinary medicinal products.

The document describes the requirements on sterilisation of medicinal products, APIs, excipients and primary containers, as well as on the choice of the method of sterilisation. Besides, the document contains two decision trees for the selection of the sterilisation method for products in diverse galenic forms.

Please find hereafter a summary of most important aspects in this chapter:

Manufacturing of sterile medicinal products
The conditions and physical parameters for the following processes are described in detail:

  • Steam sterilisation
  • Dry heat sterilisation
  • Ionisation radiation sterilisation (here reference is made to the Note for Guidance “The use of Radiation in the Manufacture for Medicinal Products“, ISO 11137 and Ph. Eur. Chapter 5.1.1)
  • Gas sterilisation (with ethylene oxide,  ethylene chlorhydrin, etc.)
  • Sterile filtration
  • Aseptic processing

Basically, the following rules apply to all processes:

  • The choice of the sterilisation method has to be justified.
  • The method must be validated.
  • The method described in the corresponding general monograph of the European Pharmacopoeia has to be used. All deviations have to be justified.
  • The procedures for all sites (including outsourced activities) where sterilisation is performed have to be documented (CTD module 3, chapters 3.2.P.2 and 3.2.P.3).

Manufacturing of sterile APIs and excipients
The document clarifies that the requirements laid down in Part II of the EU GMP Guide are only applicable for the manufacture beginning with the starting material up to the finished API, immediately prior to sterilisation. The sterilisation step performed on the API is considered to be a step in the manufacture of the medicinal product. As a consequence, each manufacturing establishment which performs sterilisation of an API requires a manufacturing authorisation, a GMP certificate and thus aQualified Person too. This also applies to establishments which manufacture sterile excipients. APIs and excipients with a Certificate of Suitability (CEP) are also covered by this regulation.

Selection of the sterilisation method
The following principles apply:

  • According to Ph. Eur., general chapter 5.1.1, the terminal sterilisation step should be made in the final container whenever possible.
  • When sterilisation by heat is not possible because of temperature sensitivity of the product, alternative methods or aseptic processing may be used if they are properly validated. Terminal steps for the reduction of the microbial level are also possible as long as they are not used to compensate for poor aseptic manufacturing practice.
  • A change (shortening) in shelf-life or storage conditions caused by the terminal sterilisation step is not in itself a reason to allow aseptic processing unless the new storage conditions or shelf-life would cause problems or restrictions in the use of the product.
  • An increase in impurity levels or degradation products upon terminal sterilisation doesn’t directly lead to the acceptation of aseptic processing. The risks induced by an increased level of impurities should be balanced with the risks induced with an aseptic manufacturing method (e.g. characteristics of the degradation products vs. posology of the medicinal product). Attempts performed to determine sterilisation conditions to give acceptable impurity levels and to simultaneously achieve a microbial reduction of at least 10-6 have to be described in the quality dossier.
  • Under specific conditions, aseptic processing may be accepted even if terminal sterilisation of the product itself would be possible, e.g. in the case of eye drops in polyethylene containers enabling administration of single drops or pre-filled pens. Here, terminal sterilisation of the product would destroy the final container.
  • The considerations for the choice of the container should be described in the dossier also in the case of heat-sensitive final containers. Here, the search for materials which come through terminal sterilisation has priority. For example, polypropylene is more resistant than polyethylene. The choice for the final container has to be justified.
  • Large volume parenterals should be terminally sterilised whenever possible.

In general, the regulatory authorities will expect a detailed justification for the selection of the sterilisation method or the aseptic processing in the form of a benefit/risk analysis.

The essence of the requirements described in the chapters of this guideline can be found in the two decision trees for sterilisation of products in diverse administration forms (aqueous liquid; non-aqueous liquid, semi-solid, dry powder).

The deadline for comments on this Draft Guideline Sterilisation of the medicinal product, active substance, excipient and primary container ends on October, 13th 2016.

///////////////EMA,  new Draft Guideline, Sterilisation of Medicinal Products, APIs, Excipients and Primary Containers

EMA publishes finalised Process Validation Guideline for Biotech Products

Approximately two years ago the EMA published a draft guideline on process validation for the manufacture of biotech products. Now the final guideline has been published under the title “Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission“.

READ

http://www.gmp-compliance.org/enews_05342_EMA-publishes-finalised-Process-Validation-Guideline-for-Biotech-Prodcts_15435,15373,15298,15250,Z-VM_n.html

Approximately two years ago the EMA published a draft guideline on process validation for the manufacture of biotech products. Now the final guideline has been published under the title “Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission”.

The scope of the guideline is to provide guidance on the data to be included in a regulatory submission to demonstrate that the active substance manufacturing process is in a validated state. The guideline focuses on recombinant proteins and polypeptides, their derivates, and products of which they are components (e.g. conjugates). But it is explicitly mentioned that the principles could also be applied to vaccines or plasma-derived products and other biological products, as appropriate.

Process validation is mentioned as life cycle, comparable to Annex 15 and to the EMA guideline on process validation for finished products . Also comparable to both, the guideline offers a traditional or an enhanced  (with reference to ICH Q 11) approach to process validation. A combination of both approaches is possible as well. This “hybrid approach” is in line with the other new European process validation guidelines, too.

Process validation is divided into two parts:

  • process characterisation, where the commercial manufacturing process is defined

and

  • process verification, where the final manufacturing process as established based on process evaluation studies performs effectively in routine manufacturing.

Process characterisation itsself is also divided into two parts:

  • process development, which includes studies to reach a potential design of a future manufacturing process

and

  • process evaluation which includes studies on small and/or commercial scales, providing evidence that the complete manufacturing process has been appropriately designed to design the full operating ranges of the manufacturing process.

It is explicitly mentioned that subsequent to succesfull process validation product quality and process performance must be maintained in a state of control during routine production. This ongoing process verification is normally not part of submission data, with the exception of e.g. niche products, which could not be fully validated at the time of the regulatory submission.

There is no number of validation runs mentioned in this guideline and concurrent validation could  be considered only in exceptional circumstances (e.g. medical need is mentioned) and after consultation with the regulatory authorities.

Please find further information in the “Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission”

/////EMA,  publishes,  finalised,  Process Validation Guideline,  Biotech Products

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.

http://www.gmp-compliance.org/enews_05224_Already-13-EMA-GMP-Non-compliance-Reports-in-2016-published_15159,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.

MINSHENG GROUP SHAOXING PHARMACEUTICAL CO. LTD, China

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.

DESARROLLOS FARMACÉUTICOS BAJO ARAGÓN, S.L., Spain

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.

HUBEI HONGYUAN PHARMACEUTICAL CO., LTD. , China

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.

HUBEI HONGYUAN PHARMACEUTICAL CO., LTD. (Facility 428) , China

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.

SAS JARMAT « LABORATOIRE ADP », France

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.

CARGILL FRANCE, France

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.

FARMA MEDITERRANIA, S.L., Spain

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.

THERAVECTYS – VILLEJUIF, France

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

What are “complex manufacturing processes”? A recent reply from the EMA

https://33.media.tumblr.com/1ccca0c990f7ce76796c2c2b35cb7f49/tumblr_noi3n89RZi1ur8m7ho1_500.gif

 

 

Sometimes a clear definition of terms is crucial in the communication between authorities and pharmaceutical companies. Find out what the European Medicines Agency EMA defines as “complex manufacturing steps” and what authorisation holders providing a variation application need to consider.

http://www.gmp-compliance.org/enews_05072_What-are-%22complex-manufacturing-processes%22-A-recent-reply-from-the-EMA_9371,15219,S-RGL_n.html

 

The Variations Regulation (EC) no. 1234/2008 of the European Commission defines the procedure for variations of existing marketing authorisations. The “detailed guidelines for the various categories of variations“, which were published in the consolidated version in August 2013 in the European Official Journal, explain the interpretation and application of this Variations Regulation.

Although the “detailed guidelines” describe a number of scenarios of possible variations in some detail, there are formulations in the Guideline text which require clarification due to their blur. The EMA adopted such a case in a recent update of itsquestions and answers collection “Quality of Medicines Questions and Answers: Part 1” to concretise the case through a statement.

It is about the term “complex manufacturing processes”, which is used in two scenarios associated with type II variations (found in the “detailed guidelines” p 40ff):

  • Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product (Guideline change code B.II.b.1)

    c) Site where any manufacturing operation(s) take place, except batch release, batch control, and secondary packaging, for biological/immunological medicinal products, or for pharmaceutical forms manufactured by complex manufacturing processes.
  • Change in the batch size (including batch size ranges) of the finished product (Guideline change code B.II.b.4)

    d) The change relates to all other pharmaceutical forms manufactured by complex manufacturing processes .

The EMA now clarified this term as follows:

  • Guideline Change Code B.II.b.1: Complex manufacturing processes are given when the understanding of the relation between quality characteristics of the product and its in vivo efficacy is lacking. This is often the case in innovative medicines such as products of nanomedicine.
  • Guideline Change Code B.II.b.4: Complex manufacturing processes are those which contain one or more sub-steps, where a scale-up can lead to problems.

In both scenarios, the approving authority will decide on a case by case basis. If the applicant submits the variation as a Type IB, he must provide a valid justification that the production process is not “complex”. However, in doubt the authority may upgrade the variation to a Type II. Therefore, the EMA recommends that the applicant clarifies the situation with the authority before submitting the variation

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
25/02/2015

http://www.gmp-compliance.org/enews_4652_Detailed-Requirements-concerning-the-DOE-in-the-Regulatory-Submission-Dossier-EMA-s-and-FDA-s-Recommendations_9184,7307P,9059,Z-VM_n.html

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“.

 

 

basics

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.