EMA publishes Q&A on Health Based Exposure Limits – Does the 1/1000 dose criterion come again into play in Cleaning Validation?
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.
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.
///////////EMA, Q&A , Health Based Exposure Limits, 1/1000 dose , criterion, Cleaning Validation,
Apr 13, 2014 – Thailand has its own drug registration format and also follows. ASEAN CTD. … Transparency in the regulatory authorities of member countries.
THAILAND PHARMACEUTICAL REGISTRATION AND APPROVAL
The Thai FDA (TFDA), one of several agencies under the Ministry of Public Health (MPH), is the regulatory body administering drugs in Thailand. The Drug Control Division of the TFDA is responsible for registration, licensing, surveillance, inspection and adverse event monitoring for all pharmaceuticals and pharmaceutical companies in Thailand. Foreign pharma companies dominate the Thai drug market. Due in part to trade negotiations, regional harmonization and positive economic trends, the pharmaceutical market in Thailand is predicted to double by 2022.There are several versions of the Drug Act currently in effect, and the Thai government is working on a revised version with updated regulations. Under the current laws, pharmaceuticals are categorized as either traditional or modern medicines, with different applications and oversight. Modern medicines are subdivided into three categories, each of which has separate registration requirements. Licenses currently do not require renewal.
FIRST ASEAN COUNTRY WITH A NATIONAL eCTD PROGRAM
Thai FDA intends to accept dossier in eCTD format: The Drug Regulatory Authority of Thailand (Thai FDA) has initiated the acceptance of Pilot eCTD from October 2014.Read More
Step to be followed to submit eCTD application
Regulatory Scientist at Kinapse
A) Prepare Application to get a eSubmission Identifier for every application issued. A request to the THAI FDA online service should be submitted to obtain an eSubmission identifier which will require following details.
- Licensee Number
- Description of Application
- Dosage Form
- INN or Generic Name
- WHO ATC Code
- Sequence Type
- Application form
- CPP (In case of Importer)
The eSubmission Identifier will be issued within 10 days of application. The Applicant must then make an appointment for submission within 30 days.
B) Prepare valid application along with validation reports as per country (Thailand) specific requirement with regional eSubmission Identifier provided.
The M1 requirements to be kept in consideration while compiling the Submission.
- Enhanced granularity for each sections
- Country code is not required in filenames
- Information relating to orphan market is not mandatory
- For LCM (Life cycle management) submissions the Operation attribute should be “Replace” in Tracking Table
- Validation report should be submitted along with the sequence
- 1.3.1 Product Information has been broken down into three specific sections for Labelling, SPC and the Package leaflet. No other product types are expected. If one file is submitted for this section, it should be submitted under 220.127.116.11 Labelling.
- 18.104.22.168 Package Leaflet has been broken down into language sections for English, Thai and Other languages.
- It is recommended that separate files should be submitted for each language.
- Applicants can re-use the content submitted in other regions (including STF).
- The identifier is a combination of a letter and seven digits.
- Working documents are not needed and do not need to be provided within the eCTD framework for Thailand
- Section 1.5.2 “Information for Generic, ‘Hybrid’ or Bio-similar Applications” has been broken down into three sections and given a section number to make expectations and cross referencing clearer.
- Only one file should be provided for 1.6 Environmental Risk Assessment. It is not allowed to provide content in both 1.6.1 and 1.6.2.
- During lifecycle, 1.8.2 Risk management plan should always use the lifecycle operator replace.
C) Dispatch Activity Delivery of the application at Thai FDA in CD/DVD (make an prior appointment with HA at firstname.lastname@example.org
Thai FDA has proposed a set of media formats to be used while submission of eCTD
- (CD-R) i.e. Compact Disc-Recordable
- Digital Versatile Disc-Random Access Memory (DVD-RAM)
- Digital Versatile Disc-Recordable (DVD+R/-R) recorded
Future Aspect-Import: The eCTD will be validated and imported into the THAI FDA Review System
Feedback: Application feedback (if there are problems experienced during the upload) and review of application by Thai FDA
Ensure that you do not use. 1. Double-sided discs 2. Re-writable disc (protection, authenticity and Stability of information cannot
Ensure that you do not use:
- Double-sided discs,
- Re-writable discs (protection, authenticity, and stability of information cannot be guaranteed)
- Compressed or zipped files (except for validation reports)
In the beginning of 2015 the FDA has published a draft guideline about GMP for Combination Products. Now the final version has been published. What are the differences between the draft and the final version of the FDA Guideline for Combination Products?
In the beginning of 2015 the FDA has published a draft guideline about GMP for Combination Products. Now the final version has been published. What are the differences between the draft and the final version? In the following you will find an overview:
The final guideline has expanded to now 59 pages (draft: 46 pages). And also the number of footnotes increased from 85 (draft) to 147 (final).
In the table of content there are one new subchapter (II B Quality and Current Good Manufacturing Practice) and one new chapter (VII Glossary). Subchapter III C was expanded to definitions and terminology. In the following the table of content is listed:
A. Definition of a combination product
B. Quality and Current Good Manufacturing Practices
C. Overview of the final rule
D. The role of the lead center and other agency components
III. General Considerations for CGMP Compliance
A. Demonstrating compliance
B. Investigational products
C. Definitions and terminology
D. What CGMP requirements apply to a product or facility?
E. Control of changes to a combination product
IV. What do I need to know about the CGMP requirements specified in 21 CFR 4.4(b)?
A. Provisions from the device QS regulation specified in 21 CFR 4.4(b)(1)
B. Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2)
C. Combination products that include biological products and HCT/Ps
V. Application of CGMP requirements to specific types of combination products
A. Prefilled syringe
B. Drug-coated mesh
C. Drug Eluting Stent (DES)
VI. Contact Us
In the introduction it is explicitly stated, that “The final rule did not establish any new requirements”. In a footnote the guideline gives an explanation why the term “legacy” combination product has not been used.
In the new subchapter II B (Quality and Current Good Manufacturing Practice) the guideline mentions, that “the core requirements embedded in these regulations provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. This includes establishing a strong quality management system, using appropriate quality raw materials, establishing robust manufacturing and control procedures based on sound design principles, and detecting and investigating product quality deviations. In addition, these regulations call for ongoing assessment of systems and the implementation of corrective actions where appropriate”.
The final document introduces in Section C the new term “CGMP operating system”. This means the operating system within an establishment that is designed and implemented to address and meet the current good manufacturing practice requirements applicable to the manufacture of a combination product. A clarification about constituent parts of cross-labeled combination products is also implemented. Further, there is a new passage about the choice of the GMP-approach (QS regulation vs drug CGMPs) also regarding a streamlined approach and for companies manufacturing different products. Completely new is the passage with the title “Documentation of CGMP Approach”. Here you can also find hints that manufacturerers with products that have been on the market since before GMP for Combination Products (21 CFR 4) came into operation, have to be compliant too. The guideline requires that the information about the “CGMP operating system” should be shared with FDA investigators in the beginning of an inspection.
In the “Demonstrating compliance” subchapter (III A) there is additional information about crossreferenced approaches (21 CFR 820 vs 21 CFR 211 and vice versa). For investigational products (III B) you can find more detailed information about exemptions from part 820 regarding 21 CFR 820.30 (Design).
In the Definition and terminology section (III D) there are amendments regarding container closure aspects and kits. Section III D (What CGMP requirements apply to a product or facility?) details the responsibility of the owner of a combination product and CAPA procedures in shared facilities.
In section III E. (Control of changes to a combination product) information for single entity and co-packed combination product manufacturers has been amended. The passages in IV A (Provisions from the device QS regulation specified in 21 CFR 4.4(b)(1) with regard to 21 CFR 820 about Management Responsibility, Design Controls, Purchasing Controls and CAPA have been extended – including examples – and “modernised”. Terms like quality oversight and QTTP are now mentioned there. Vice versa the passages with regard to 21 CFR 211, 211.84. 211.103, 211.132, 211.137, 211.165, 211.166, 211.167, and 211.170, (IV B Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2)) have also been extended – likewise with examples – and have been “modernised” as well (e.g. parametric release is mentioned).
In the example about prefilled syringes (V A) one can find an amended passsage about Design Controls and a new section about Design History File. In the example about drug-coated mesh (V B) there has also been included a new section about Design History File. In the drug eluting stent example (V. C) there are amendments in the section about 21 CFR 211.184, 21 CFR 211.103 and 21 CFR 211.170. Furthermore all examples comprise editorial changes.
Completely new is the chapter VII (Glossary). The number of references (Chapter VIII) increased to 31 (draft: 19).
There are a lot of changes from the draft to the final document. One chapter (Glossary) and a subchapter ( Quality and Current Good Manufacturing Practices) are new, but there are also new passages and amendments in the final document. Helpful are the examples that have been integrated.
Please also see the Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products for more details.
GMP’s for Early Stage Development of New Drug substances and products
|Description||range of colour|
|identification||conforms to a reference spectrum|
|assay||97–103% on a dry basis|
|impurities||NMT 3.0% total, NMT 1.0% each|
|mutagenic||follow EMA guidelines (pending ICH M7 guidance)|
|inorganic||follow EMA guidelines (pending ICH Q3D guidance)|
|residual solvents||use ICH Q3C limits or other justified limits for solvents used in final synthetic step|
|water content||report results|
|solid form||report results|
|particle size||report results|
|residue on ignition||NMT 1.0%|
“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
Chapter 5 of the EC GMP Guide for the area of production was updated last year. This chapter contains concrete information about the conditions when testing and sampling of APIs and excipients can be reduced. Read more here about the sections 5.35 and 5.36 of the EU GMP Guide.
Chapter 5 of the EC GMP Guide for the area of production was already updated last year. However, not everybody really knows that it contains concrete information about the conditions when testing and sampling of APIs and excipients can be reduced. Particularly sections 5.35 and 5.36 include requirements and thus show possibilities for a reduction.
Basically, the manufacturers of finished products are responsible for every testing of starting materials as described in the marketing authorisation dossier. Yet, part of or complete test results from the approved starting material manufacturer can be used, but at least their identity has to be tested – as described in the in the marketing authorisation dossier.
If one chooses to outsource the testing activity to the supplier, this has to be justified and documented. Moreover, a few additional measures have to be fulfilled, like:
- Particular attention should be paid to the distribution controls (transport, wholesaling, storage, delivery) to ensure that ultimately the test results are still applicable to the delivered material.
- Performance of risk-based audits at the sites executing the testing and sampling of starting materials to verify the GMP compliance and to ensure that the specifications and testing methods are used as described in the marketing authorisation dossier.
- The certificate of analysis of the manufacturer/supplier of the starting material should be signed by a designated person with appropriate qualifications and experience. The signature confirms the compliance with the agreed product specification.
- The medicinal product manufacturer should have adequate experience in dealing with the starting material manufacturer – including assessment of batches previously received and the history of compliance before reducing own, internal testing.
- At appropriate intervals, the medicinal product manufacturer or another approved contract laboratory has to carry out a full analysis to compare the test results with the results of the certificate of analysis of the material manufacturer or supplier, and thus to check their reliability. In case of discrepancy, an investigation has to be performed and appropriate measures taken. The certificates of analysis cannot be accepted until those measures are completed.
You can access the complete Chapter 5 “Production” of the EU GMP Guide here.
////////Opportunities, Reducing, Sampling, Testing, Starting Materials, EC GMP Guide
New EDQM’s Public Document informs about the Details required in a New CEP Application for already Referenced Substances
A Policy Document recently published by the EDQM describes regulations for referencing already existing CEPs in an application for a new CEP. Read more about how the certificates of an intermediate or starting material have to be used in new applications for a CEP.
When applying for a Certificate of Suitability (CEP) for an API, detailed information has to be provided regarding the synthesis stages, the starting material and the intermediates. In the event that the starting materials or the intermediates are already covered by a CEP, the EDQM has recently published a “Public Document” entitled “Use of a CEP to describe a material used in an application for another CEP”. The document contains regulations on how to reference the “CEP X” of a starting material or an intermediate in the application for the “CEP Y” of an API. The requirements for both scenarios are described as follows:
- CEP X belongs to an intermediate or a starting material within the synthesis route of a substance Y for which a CEP is submitted.
1. The submission must make clear that X is really an intermediate or a starting material and is covered by a valid CEP (“CEP X”). A copy of this CEP X has to be attached.
2. The complete specification described in the CEP X must be the basis for the release of the intermediate or the starting materials X for use in the synthesis of Y.
3. The lifecycle of CEP X is directly coupled with the lifecycle of CEP Y. For example, a revision of CEP X also triggers a revision of CEP Y so that the revised CEP X has to be included to the revision application of CEP Y.
4. If the CEP X looses its validity (e.g. due to expiry or withdrawal) the application for CEP Y has to be updated, for example the CEP of a substance from an alternative source has to be submitted.
5. The application for CEP Y has to include complete details about the supply chain and/ or about all the manufacturing sites involved in the process described on CEP X.
Details about all manufacturing sites involved in the process described in the CEP X will also be mentioned in the annex 1 of the new CEP Y when X is an intermediate for the synthesis of Y. However, this doesn’t apply when X is the starting material for the synthesis of Y.
Please see the Public Document “Use of a CEP to describe a material used in an application for another CEP” for further details.
////////// EDQM, Public Document, New CEP Application, already Referenced Substances
Dr. Amrendra Kumar Roy
We would like to share our ~13 yrs of practical experience in the field of product development using statistical tools. But first, what compelled us to pursue six-sigma. Most of us started our career as a process chemist after completing PhD and it was during those initial days we realized the importance of “first time right” during commercialization. This enabled not only first mover advantage but also ensured timely and un-interrupted supply of our products into the market. Another aspect of the process development is its robustness, which ensures sustainable margins in whatever products we manufacture. Above achievement was possible only because of the…
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