Dissolution Concepts and Applications

Addressing Compliance Concerns During Dissolution Method Development, Validation, and Transfer

By Gregory P. Martin and Vivian A. Gray

Dissolution is an important test for pharmaceutical products. Dissolu­tion is the only test that addresses product performance. While most dissolution tests are used for quality control purposes, there are several potential applications for dissolution methods that are vital during the entire product lifecycle. These include activities such as aiding in formulation selection, developing a correlation between in vitro data and in vivo data (IVIVC), or justifying post-approval product changes. Dissolution method development should be linked to the intended purpose of the method. Once method conditions have been established and an understand­ing of method ruggedness generated, the method must be validated. When sufficient data have been generated with the validated method, a specification can be proposed. The product dissolution specifica­tion will ultimately require regulatory approval. Over the lifetime of the method (from development to pro­duction to site transfer to generic product), there are likely to be multiple changes to both the drug prod­uct and the testing laboratory. With each change, the validity of the method may be challenged and must be reestablished.

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Guidelines for using the Test for Bacterial Endotoxins

In September, the European Directorate for the Quality of Medicines & HealthCare (EDQM) published in Pharmeuropa online the information about their  new policy for bacterial Endotoxins, which was approved by the Ph. Eur. Commission at its 149th Session in June 2014. Amongst others they announced for existing monographs:

"BET specifications are kept in individual monographs for substances for pharmaceutical use. Existing limits remain in individual monographs to maintain the use of well-established limits.

In order for the policy to be applied, the following changes are proposed to existing Ph. Eur. texts:

General chapter 5.1.10 is expanded with further considerations regarding the setting up of limits.

General monograph Substances for pharmaceutical use"

In consequence it is up to the users of these EP chapters to determine whether compliance to BET is needed or not for a given substance. Where a test is included in the monograph with no specific limit, it is up to the user to set the limit for the substance, based on the following considerations: use of the substance (route of administration, patient population); calculation according to the formula given in general chapter 5.1.10; process capability; or any other considerations raised by the competent authority.

Recently, on 26 September, a revision of Chapter "5.1.10. Guidelines for Using the Test for Bacterial Endotoxins" was issued and open for comments until 31 December 2014. The revision now includes possible alternative methods to the Limulus amoebocyte lysate (LAL) test, like testing with recombinant factor C.

Following a short overview of the additions and changes:

"The monocyte-activation test (2.6.30) is a suitable method to be used to rule out the presence of non-endotoxin pyrogens in substances or products."

"Hence, the analyst who wishes to implement a test for bacterial endotoxins or to replace the pyrogen test by a test for bacterial endotoxins has to demonstrate that a valid test can be carried out on the substance or product concerned; this may entail a procedure for removing interference"

"Replacement of the rabbit pyrogen test required in a pharmacopoeial monograph by an amoebocyte lysate test, or by other methods such as the monocyte-activation test or a test using recombinant factor C as a replacement for the amoebocyte lysate, constitutes the use of an alternative method of analysis and hence requires demonstration that the method is appropriate for the given substance or product and gives a result consistent with that obtained with the prescribed method as described in the General Notices"

The additions under paragraph 13. "Replacement of Methods prescribed in Monographs" are of particular importance. In section 2, you can find information about the replacement by methods not described in the PH.EUR:

"The use of alternative reagents such as recombinant factor C as a replacement to the amoebocyte lysate eliminates the use of live animals. Replacement of a rabbit pyrogen test or a bacterial endotoxin test prescribed in a monograph by a test using recombinant factor C or any other reagent as a replacement of the amoebocyte lysate is to be regarded as the use of an alternative method in the replacement of a pharmacopoeial test, as described in the General Notices: “The test and assays described are the official methods upon which the standards of the Pharmacopoeia are based. With the agreement of the competent authority, alternative methods of analysis may be used for control purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance with the standards of the monographs would be achieved if the official methods were used. In the event of doubt or dispute, the methods of analysis of the Pharmacopoeia are alone authoritative.”

The complete revision can be found in Pharmeuropa, Issue 26.4.

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Safety in the workplace

Safety In The Workplace/Occupational Health And Safety
An excerpt from the GMP MANUAL
By Dr. Michael Hiob

Good practical knowledge of the workplaces and processes used in the company and regular communication with personnel are a prerequisite for professional and efficient preventive healthcare. The assessment of the working conditions should be carried out in close cooperation with the expert for safety in the workplace.

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GMP MANUAL Update No. 19

What is new on GMP MANUAL Update No. 19 ?  [Date: 9 October, 2014]

GMP in Practice

New Chapters:

• Chapter 4 Facilities and Equipment
• 4.A: Facility Planning
• 4.B: Materials
• 4.H: Cleaning of Facilities

Updated Chapters:

• Chapter 4 Facilities and Equipment
• 4.C Hygienic Design in Solids Handling (formerly 4.L, still under revision)
• 4.D System Controllers and Process Control Systems (formerly 4.C and 4.K)
• 4.E Technical Documentation (formerly 4.F)
• 4.F Calibration (formerly 4.G)
• 4.G Maintenance (formerly 4.H)
• 4.I Containment (personnel protection) in Solids Handling
  (formerly 4.J, still under revision)

GMP Regulations

New Chapters:

• Chapter C EU Directives and Guidelines
• C.18 Guidance for the template for the qualified person’s declaration concerning GMP compliance of active substance manufacture “The QP declaration template”
• C.18.1 Qualified Person’s declaration concerning GMP compliance of the active substance manufacture “The QP declaration template”

Updated Chapters:

• Chapter C EU Directives and Guidelines
• C.4 Part I Basic Requirements for Medicinal Products
  C.4.3.1 Chapter 3 Premises and Equipment (entry into force 1 March 2015)
  C.4.5.1 Chapter 5 Production (entry into force 1 March 2015)
  C.4.8.1 Chapter 8 Complaints, Quality Defects and Products (entry into force 1 March 2015)
  C.5 Part II Basic Requirements for Active Substances used as Starting Materials
  C.8.5.1 Importation of Active Substances for Medicinal Products for Human Use – Questions and Answers Version 5.0
• Chapter D.1 Code of Federal Regulations
• D.1.1 21 CFR Part 210
• D.1.2 21 CFR Part 211
• D.1.3 21 CFR Part 11
• D.1.4 21 CFR Part 820
• D.1.5 21 CFR Part 4
• D.1.6 21 CFR Part 606
• D.1.7 21 CFR Part 606 
• Chapter F PIC/S Guidelines
• F.9 PIC/S PE 009-11 GMP Guide Introduction
• F.10 PIC/S PE 009-11 GMP Guide Part I
• F.11 PIC/S PE 009-11 GMP Guide Part II
• F.12 PIC/S PE 009-11 GMP Guide Annexes

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GMP Updates_October 2014

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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).

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:

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.

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:

• 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:

Guidance for Industry - Current Good Manufacturing Practice - Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act

Guidance - Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act

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.

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"
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:

• 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

HPLC Solutions #122

How to Measure Noise (Part 1)
By John Dolan

This installment of HPLC Solutions begins a series on different measurements that we make on chromatograms. Measuring the baseline noise generated by an HPLC system may seem like a singularly boring subject. But if you think about it, noise can be a critical factor in the results of our analytical work. It is directly related to the limit of detection and limit of quantification, it can be used to determine the health of the detector, noise is a great diagnostic tool for problems, and can be a limiting factor in the precision of a method.

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