[Ref. & Thanks: Pharmahelp Group of Google Plus]
WHO publishes New Version of Guide regarding the Principles of GMP
The draft for comment of this superordinated Guideline was already published in the middle of 2013 (we reported). Since then, nothing has fundamentally changed. Only changes to the following chapters have been made:
WHO publishes New Version of Guide regarding the Principles of GMP
The draft for comment of this superordinated Guideline was already published in the middle of 2013 (we reported). Since then, nothing has fundamentally changed. Only changes to the following chapters have been made:
1. Pharmaceutical quality system
(formerly "quality assurance")
2. Good Manufacturing practices for pharmaceutical products
7. Contract production, analysis and other activities
17. Good practices in quality control
Compared to the draft from 2013, the
new document contains an extended description of the pharmaceutical quality
system. In Chapter 1, the ultimate responsibility of senior management has been
strongly emphasized. Likewise, the aspect of qualification has been
complemented. In Chapter 2, the required review of processes has been extended
to the scientific aspect (so far only review based on experience only). 2. Good Manufacturing practices for pharmaceutical products
7. Contract production, analysis and other activities
17. Good practices in quality control
The Guideline "Good Manufacturing Practices for Pharmaceutical
Products: Main Principles" has been published as Annex 2 of the
Technical Report 986.
WHO publishes second
Draft on the Revision of its Process Validation Guideline
In April 2014 WHO published a first draft to revise their Non-sterile Process Validation Guideline. Comments to the first draft from April 2014 have now flowed into the second one. This is obvious at one point or another.
The table of contents and the scope have remained unchanged. Yet, the definition of process validation contains the life-cycle approach in the glossary already. Compared to the first draft, the new version now also explains the matrix approach or bracketing.
Still, the introduction mentions different possibilities for process validation (traditional vs. life-cycle approach vs. hybrid). A flow diagram "may" be helpful. At the end of the introduction, a flow diagram intends to illustrate the process validation life-cycle. Now, the diagram mentions "validate process" already at the process design stage.
The chapter on process design contains no major changes compared to the first draft.
In the chapter "process qualification", a risk assessment is required for the change in batch size from scale up to commercial batch size. Explicitly, manufacturers are requested to implement the new validation approach. However, it is mentioned that full implementation may take time. In the interim, the traditional approach or concurrent validation may be accepted. Also a hybrid approach (based on a scientific basis and risk management principles) may be an alternative.
Compared to the first draft, the chapters "continued process verification" and "change control" haven't changed significantly.
Conclusion: The second draft is considerably more stringent than the first one. The document is a bit of a mix of FDA's Guidance on process validation and EMA's process validation guideline where the terms used come from the FDA Guidance. Both documents are also listed under references. A few inconsistencies remain. The topics risk assessments, QRM, and risk-based approaches are seen in very different ways in the document. The chapter "background and scope" recommends a risk-based approach. Risk assessments are referred to as "should" requirements, QRM rather as "nice to have" ("when applying QRM..."). A flow diagram shouldn't be only named as "may" requirement. Naming process validation under process design in the flow diagram for the process validation life-cycle (background/objective) is against the definition in the glossary according to which process validation include the whole life-cycle. Moreover, mentioning concurrent validation as an alternative to the life-cycle approach could be misunderstood.
It is astonishing that ICH Q10 hasn't been referred to although some elements of this document (e.g. continuous improvement, product life cycle) have been used.
ECA SOP: Methods for the Identification of Trends in Production and QC
After the creation of an SOP on Out-of-Specification results, ECA Working Group on Analytical Quality Control's next objective is the elaboration of an SOP on methods for statistical process control with regard to the statistical evaluation of the variability of production processes. The analysis of trends in stability studies will also be part of this SOP. Moreover, the handling of Out-of-Expectation (OOE) results will be addressed in this SOP, too.
Among other things, the following methods and working examples will be considered:
In April 2014 WHO published a first draft to revise their Non-sterile Process Validation Guideline. Comments to the first draft from April 2014 have now flowed into the second one. This is obvious at one point or another.
The table of contents and the scope have remained unchanged. Yet, the definition of process validation contains the life-cycle approach in the glossary already. Compared to the first draft, the new version now also explains the matrix approach or bracketing.
Still, the introduction mentions different possibilities for process validation (traditional vs. life-cycle approach vs. hybrid). A flow diagram "may" be helpful. At the end of the introduction, a flow diagram intends to illustrate the process validation life-cycle. Now, the diagram mentions "validate process" already at the process design stage.
The chapter on process design contains no major changes compared to the first draft.
In the chapter "process qualification", a risk assessment is required for the change in batch size from scale up to commercial batch size. Explicitly, manufacturers are requested to implement the new validation approach. However, it is mentioned that full implementation may take time. In the interim, the traditional approach or concurrent validation may be accepted. Also a hybrid approach (based on a scientific basis and risk management principles) may be an alternative.
Compared to the first draft, the chapters "continued process verification" and "change control" haven't changed significantly.
Conclusion: The second draft is considerably more stringent than the first one. The document is a bit of a mix of FDA's Guidance on process validation and EMA's process validation guideline where the terms used come from the FDA Guidance. Both documents are also listed under references. A few inconsistencies remain. The topics risk assessments, QRM, and risk-based approaches are seen in very different ways in the document. The chapter "background and scope" recommends a risk-based approach. Risk assessments are referred to as "should" requirements, QRM rather as "nice to have" ("when applying QRM..."). A flow diagram shouldn't be only named as "may" requirement. Naming process validation under process design in the flow diagram for the process validation life-cycle (background/objective) is against the definition in the glossary according to which process validation include the whole life-cycle. Moreover, mentioning concurrent validation as an alternative to the life-cycle approach could be misunderstood.
It is astonishing that ICH Q10 hasn't been referred to although some elements of this document (e.g. continuous improvement, product life cycle) have been used.
ECA SOP: Methods for the Identification of Trends in Production and QC
After the creation of an SOP on Out-of-Specification results, ECA Working Group on Analytical Quality Control's next objective is the elaboration of an SOP on methods for statistical process control with regard to the statistical evaluation of the variability of production processes. The analysis of trends in stability studies will also be part of this SOP. Moreover, the handling of Out-of-Expectation (OOE) results will be addressed in this SOP, too.
Among other things, the following methods and working examples will be considered:
1. Investigation of trends for
statistical process control:
Statistical process control for continuous data:
a. Shewhart Charts
b. CuSum & Zone Charts
c. Post Mortem CuSum Analysis
2. Statistical process controls for discrete data: p and c Charts
3. Trend analysis for stability testing:
a. Simplified procedure
b. More complex procedure using the "Random Coefficients" approach.
Statistical process control for continuous data:
a. Shewhart Charts
b. CuSum & Zone Charts
c. Post Mortem CuSum Analysis
2. Statistical process controls for discrete data: p and c Charts
3. Trend analysis for stability testing:
a. Simplified procedure
b. More complex procedure using the "Random Coefficients" approach.
All delegates of the OOT Forum on 22 - 23 October 2014 in Prague,
Czech Republic, will receive the outline of the draft version of ECA Working
Group on Analytical Quality Control's SOP on OOE and OOT Results. The outputs
from the workshops at the OOT Forum will provide the scope for the content of
the draft guidance. The participants will receive the draft guidance after the
team has put it together sometime after the Forum as defined as the next
steps for this project.
New FDA Interim
Guidance for Human Drug Compounding Outsourcing Facilities
In the USA, the compounding of medicinal products was not regulated very well. The compounding of medicinal products can be outsourced to specific compounders (Compounding Pharmacies) bypassing the authority and GMP regulations. Also quantitative limitations don't play any role so that those compounders could produce at industrial scale and thus also win a substantial share of the medicinal products market.
So far, they have been in a sort of no man's land in the USA. Manufacturers of medicinal products are regulated at federal level by the FDA, whereas pharmacies - including also Compounding Pharmacies - face a respective heterogeneous regulation at the level of the 50 federal states. In 2002, the Supreme Court refused FDA's attempts to intervene with regulations.
The inglorious culmination of this situation was the case New England Compounding Center (NECC) in 2012. A steroid solution for epidural injection had a fungal contamination and had been administered to approx. 14,000 patients. About 50 patients died of meningitis and over 700 had to be treated against fungal infection.
In 2013, the regulations in the USA were adjusted - DQSA Pub. L 113-54 - to transfer to the FDA the monitoring of outsourced compounding facilities. The subsequent inspections with a lot of Warning Letters issued to the compounders (partly with outrageous quality deficiencies) clearly showed the consequences of inexistent inspections over many years.
The FDA has recently announced that it will regulate this area in the future in accordance with the cGMP. Until appropriate regulations have been developed, the FDA has - in the meantime - expressed its expectations for this transitional period in a Guidance for Industry - Current Good Manufacturing Practice - Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act. This Guidance is based on the 21 CFR parts 210 and 211 with regard to cGMP. The FDA has tried to take into consideration the differences between industrial medicinal products manufacturing and compounding, and to adjust the specific aspects of the compounders. The FDA has announced that it will focus its inspections efforts to the points which present the highest danger for patient safety. One should thus not be surprised - also in view of the past incidents - that these efforts will particularly address the securing of sterility. Decidedly, the following topics are addressed:
In the USA, the compounding of medicinal products was not regulated very well. The compounding of medicinal products can be outsourced to specific compounders (Compounding Pharmacies) bypassing the authority and GMP regulations. Also quantitative limitations don't play any role so that those compounders could produce at industrial scale and thus also win a substantial share of the medicinal products market.
So far, they have been in a sort of no man's land in the USA. Manufacturers of medicinal products are regulated at federal level by the FDA, whereas pharmacies - including also Compounding Pharmacies - face a respective heterogeneous regulation at the level of the 50 federal states. In 2002, the Supreme Court refused FDA's attempts to intervene with regulations.
The inglorious culmination of this situation was the case New England Compounding Center (NECC) in 2012. A steroid solution for epidural injection had a fungal contamination and had been administered to approx. 14,000 patients. About 50 patients died of meningitis and over 700 had to be treated against fungal infection.
In 2013, the regulations in the USA were adjusted - DQSA Pub. L 113-54 - to transfer to the FDA the monitoring of outsourced compounding facilities. The subsequent inspections with a lot of Warning Letters issued to the compounders (partly with outrageous quality deficiencies) clearly showed the consequences of inexistent inspections over many years.
The FDA has recently announced that it will regulate this area in the future in accordance with the cGMP. Until appropriate regulations have been developed, the FDA has - in the meantime - expressed its expectations for this transitional period in a Guidance for Industry - Current Good Manufacturing Practice - Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act. This Guidance is based on the 21 CFR parts 210 and 211 with regard to cGMP. The FDA has tried to take into consideration the differences between industrial medicinal products manufacturing and compounding, and to adjust the specific aspects of the compounders. The FDA has announced that it will focus its inspections efforts to the points which present the highest danger for patient safety. One should thus not be surprised - also in view of the past incidents - that these efforts will particularly address the securing of sterility. Decidedly, the following topics are addressed:
- Facility Design
- Control Systems and Procedures for Maintaining Suitable
Facilities
- Environmental and Personnel Monitoring
- Equipment, Containers, and Closures
- Components
- Production and Process Control (General Production and
Process Control / Aseptic Drug Processing)
- Release Testing
- Laboratory Controls
- Packaging and Labels
- Quality Assurance Activities / Complaint Handling
One interesting thing is that the
FDA itself isn't quite sure about certain aspects, whether its requirements
will be suitable for compounders. In the chapters "Components" and
"Laboratory Controls", an "Alternative Approach for Comment"
is respectively presented in the Guidance to both topics "Reducing the
Need for Laboratory Testing of Incoming Components" and "Minimize
Need for Facilities to Have an In-House Laboratory".
All in all, this is an interesting
development, and most of all has been a necessary evolution in the
regulation of compounders which comes a few years too late.
Sources:
Sources:
Saudi Food and Drug Authority publishes Drug Master File Guidance
This year in August, the regulatory authority of Saudi Arabia published a guideline entitled "Drug Master File (DMF): Guidance for Submission". The document describes the formal prerequisites to be fulfilled to ensure the successful submission of a DMF. The following elements have to be part of a DMF:
- Cover letter
- This letter shall include all technical-formal information like for
example the name of the API, trade name, name and address of both the
manufacturer and the DMF holder, registration or reference number.
- Letter of access:
authorisation to review and reference the DMF.
The same information as in the cover letter should also be indicated here. If the API is manufactured at different manufacturing sites, all sites have to be listed. - Formal requirements for the DMF: the DMF must be written either in English or Arabic.
Only one electronic-based copy - a CD - should be submitted. If the data
volume exceeds 750 MB, a DVD should be used.
In the context of this DMF Guideline,
there is another important document entitled "Guidance for Submission"
published by the SFDA in March 2014 in the updated version 4.0. The document
contains further technical details about the storage media to be used for all
submissions made to the SFDA, e.g. security requirements, password and virus
protection, etc. These requirements should also be considered for the
submission of Drug Master Files.
Further regulations and guidelines of the Saudi Authority relevant for authorisation can be found on the website of the SFDA
EU GMP Inspectors find 26 GMP Deficiencies at Chinese API Manufacturer Hebei Dongfeng Pharmaceuticals
EU GMP Inspectors from the competent authority in Romania identified several GMP deviations during a GMP inspection at HEBEI DONGFENG PHARMACEUTICAL Co., Ltd, Mingjiao Road Western Yongnian County, Handan, 057 150, China. As a consequence, a GMP Non-Compliance Report has been issued and entered into the European database EudraGMDP.
Further regulations and guidelines of the Saudi Authority relevant for authorisation can be found on the website of the SFDA
EU GMP Inspectors find 26 GMP Deficiencies at Chinese API Manufacturer Hebei Dongfeng Pharmaceuticals
EU GMP Inspectors from the competent authority in Romania identified several GMP deviations during a GMP inspection at HEBEI DONGFENG PHARMACEUTICAL Co., Ltd, Mingjiao Road Western Yongnian County, Handan, 057 150, China. As a consequence, a GMP Non-Compliance Report has been issued and entered into the European database EudraGMDP.
The products concerned are
doxycycline hyclate and doxycycline monohydrate. According to EudraGMDP, a
total of 26 deficiencies were found during the inspection. Six of them were
rated as major:
1) not fully implemented Quality
Assurance system
2) problems related to the documentation management
3) deviation related to material management and qualification of the approved supplier
4) risk of contamination in the production area
5) risk of contamination and cross-contamination of testing samples
6) data recording and integrity in the QC laboratory not in compliance
It is very interesting to
see that for the first time the GMP Non-compliance Report also
lists known customers of the API manufacturer. The report states:
"Known customers Doxycycline hyclate: Sintofarm, Industria, P.S.P.
,Chemifarma, Zetercoop Italy; Ofichem, ORFFA, ALC Netherlands; Divasa Spain;
Wins Czech Republik, Remedica Cyprus, Farmabase Brasil, many others in rest of
the world. Doxycycline monohydrate: only local market. Finished dosage forms:
only local market" 2) problems related to the documentation management
3) deviation related to material management and qualification of the approved supplier
4) risk of contamination in the production area
5) risk of contamination and cross-contamination of testing samples
6) data recording and integrity in the QC laboratory not in compliance
European manufacturers of medicinal products are not allowed to use the APIs concerned from Hebei Dongfeng Pharmaceuticals.
Source: EudraGMDP
ICH endorses new
Working Groups on Clinical Trials
The ICH Steering Committee approved the establishment of four new ICH Efficacy Expert Working Groups:
The ICH Steering Committee approved the establishment of four new ICH Efficacy Expert Working Groups:
- E6(R2) EWG will work on the development of an Addendum
to the current E6(R1) Guideline on Good Clinical Practices
The approach is to enable
implementation of innovative approaches to clinical trial design, management,
oversight, conduct, documentation, and reporting that will better ensure human
subject protection and data quality.
- E11(R1) EWG will work on the development of an Addendum
to the current ICH E11 Guideline on Clinical Investigation of Medicinal
Products in the Pediatric Population
This Addendum is proposed to address
new scientific and technical knowledge advances in pediatric drug development.
- E17 EWG will develop a new Guideline on General
Principle on Planning/Designing Multi-Regional Clinical Trials (MRCTs)
The goal is a harmonised
international Guideline to promote conducting MRCT appropriately, especially
focusing on scientific issues in planning/designing MRCTs. This new Guideline
will complement the guidance on MRCTs provided in ICH E5(R1) Guideline and
facilitate MRCT data acceptance by multiple regulatory agencies.
- E18 EWG will develop a new Guideline on Genomic
Sampling Methodologies for Future Use
Although ICH E15 Guideline describes
definition of sample coding, there is currently no harmonised ICH Guideline on
genomic samples collection in clinical trials or other studies. Harmonisation
across regions on this topic will maximise the information gathered from the
studies for e.g., sample collection and analysis (including ethical
considerations) and facilitate implementation of pharmacogenomics for the
benefit of all stakeholders.
Source: ICH Newsroom
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