Fiocruz avança na tecnologia para vacina ( O Estado de S.Paulo )

Jornalista: Fábio Grellet

28/10/2014 - Dois pesquisadores da Fundação Instituto Oswaldo Cruz (Fiocruz), no Rio, criaram um método para desenvolver vacinas contra diversas doenças.

Essa tecnologia está sendo usada para buscar imunizadores contra a doença de Chagas e a aids e, no futuro, poderia até ser usada contra o Ebola.

A base do método é a vacina contra a febre amarela, usada desde 1937.

Como outras, ela previne a infecção usando vírus vivos atenuados, capazes de se multiplicar no organismo do paciente, mas incapazes de provocar a doença. A partir do contato com esses vírus inofensivos, as células de defesa do paciente aprendem a reconhecer o causador da doença e ficam prontas para uma infecção.

Os pesquisadores Myrna Bonaldo, chefe do Laboratório de Biologia Molecular de Flavivírus do Instituto Oswaldo Cruz (IOC/Fiocruz), e Ricardo Galler, do Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos/ Fiocruz),inseriram genes de outros micro-organismos no material genético dos vírus usados na vacina contra a febre amarela. Assim, criaram “vírus recombinantes”, capazes de “ensinar” as células de defesa dos pacientes a reconhecer, além da febre amarela,uma outra infecção.

Uma das pesquisas que usa esse novo método se refere à aids e é liderado pelo cientista David Watkins, da Universidade de Miami. O processo para registrar a patente do método como invenção brasileira foi iniciado em 2005 e encerrado em setembro nos Estados Unidos.

Segundo Myrna, a metodologia pode ser usada contra diversas doenças.

Há estudos, por exemplo, sobre o parasita Trypano soma cruzi, causador de Chagas.

Notícias– 27/10/2014 - CRF-SP - Conselho Regional de Farmácia do Estado de São Paulo

Butantã vai testar droga contra o câncer em humanos
25/10/2014 - O Estado de S.Paulo
O Instituto Butantã entrou na reta final para os testes clínicos - com humanos - de uma nova droga contra o câncer produzida a partir de uma proteína encontrada na saliva do carrapato-estrela (Amblyoma cajennense). Os experimentos feitos com camundongos e coelhos, inteiramente concluídos, mostraram que a proteína levou à regressão de tumores renais, de pâncreas e do tipo melanoma, além de reduzir metástases pulmonares derivadas desses tipos de câncer. 
De acordo com a coordenadora do estudo, Ana Marisa Chudzinski-Tavassi, o instituto está esperando autorização da Agência Nacional de Vigilância Sanitária (Anvisa) para iniciar os testes clínicos em humanos. “Confirmamos que a proteína ataca e mata as células cancerígenas sem oferecer risco às células saudáveis. Os testes pré-clínicos foram um sucesso e temos tudo pronto para termos um medicamento inovador para tratamento do câncer com menos efeitos colaterais”, disse.
Segundo ela, as pesquisas foram iniciadas há cerca de dez anos no Laboratório de Bioquímica e Biofísica. Mas o impulso definitivo aconteceu em 2013, com a construção de uma nova infraestrutura, exclusivamente voltada para o projeto, financiada com recursos de mais de R$ 15 milhões do Banco Nacional de Desenvolvimento Econômico e Social (BNDES). O instituto conseguiu também parceria com a indústria farmacêutica nacional para realizar os testes. Segundo ela, o modelo de pesquisa e desenvolvimento traçado pelo instituto é um marco para a ciência brasileira. “Graças à expertise do instituto e à estrutura do laboratório, conseguimos produzir a proteína em biorreatores dentro das condições exigidas pelos órgãos reguladores e adiantamos os testes de estabilidade e toxicidade.” 
Assim, segundo ela, foi possível levar a pesquisa até um estágio tão avançado que a indústria se sentiu confortável para fazer uma formulação e tocar os ensaios pré-clínicos. “Com isso, acredito que conseguimos criar um modelo de desenvolvimento de novos fármacos viável para o País”, disse. Transformar as pesquisas feitas na bancada dos laboratórios em produtos disponíveis no mercado, segundo ela, é um notório gargalo para a produção de novos medicamentos.
Saliva de carrapato. De acordo com Ana Marisa, o interesse inicial do laboratório no carrapato-estrela não tinha nenhuma relação com o câncer. Os cientistas queriam entender como a espécie, que se alimenta de sangue de animais, é capaz de impedir sua coagulação. “Analisamos uma série de substâncias na saliva do carrapato e encontramos uma proteína que inibia uma fase importante do processo de coagulação sanguínea. Como é difícil trabalhar diretamente com a saliva do animal, analisamos os genes envolvidos com a expressão dessa proteína e, com técnicas de engenharia genética, expressamos essa proteína em bactérias”, afirmou.
Durante os vários testes com a nova molécula - batizada de Amblyomin-X -, os pesquisadores notaram que, além de inibir a coagulação em células de vasos sanguíneos, ela matava células tumorais. “Testamos em culturas e células, em camundongos, depois em coelhos. O resultado era sempre o mesmo: as células normais permaneciam ilesas e as células tumorais morriam”, disse.
Utilizando marcadores biológicos, os cientistas acompanharam a trajetória da molécula no organismo dos animais. “Nos animais sem tumores, vemos a molécula dar uma volta e ser excretada. Nos que têm tumor, ela fica estacionada. Isso demonstra a baixa toxicidade da droga”, disse Ana Marisa.



Link:

Notícias– 27/10/2014 - CRF-SP - Conselho Regional de Farmácia do Estado de São Paulo

Update to EU GMP Chapter 6 – Quality Control | Inspired Pharma Training

UPDATE TO EU GMP CHAPTER 6 – QUALITY CONTROL

A new update to EU GMP Chapter 6 on Quality Control has been issued and came into operation on 1st October 2014. Here is a summary of the main changes from the previous version Chapter 6 Quality Control OLD. A copy of the new version can be found by clicking on the link: Chapter 6 Quality Control NEW.

The new chapter has a slightly stronger microbiological feel and there is a totally new section on the transfer of testing methods from one laboratory to another. These are also a number of other changes, all of which are highlighted below.

Principle:

No change from the previous version.

General (6.1 – 6.4):

No change from the previous version.

Good Quality Control Laboratory Practice (6.5 – 6.6):

A new requirement not to move laboratory equipment between high risk areas to avoid accidental cross-contamination. What a high risk area actually is is not defined!

There is also a requirement for the microbiological laboratory to be arranged to minimise cross-contamination (I guess cross-contamination of micro-organisms). This will probably be seen as a mixed blessing by Microbiologists. On the one hand they get their first mention in European Union GMP (EU GMP). On the other hand it suggests that, as is often the case, they are shut away in their own area, away from the rest of their Quality Control colleagues!

There is also a mistake that has gone un-noticed. Clause 6.6 cross-refers to “Chapter 7 – Contract Analysis”. This is an inaccurate reference to a now renamed chapter which is in fact called “Chapter 7 – Outsourced Activities”.This error doesn’t really matter – but it does show us that the Regulators are human and can make mistakes too!

On a final note whilst we are on this section, do note that Quality Control (QC) labs work to Good Quality Control Laboratory Practice (GQCLP) – the name of this section of the chapter. GQCLP is sometimes shortened to Good Control Laboratory Practice (GCLP). QC labs DO NOT work to Good Laboratory Practice (GLP). This is confusing, but in Europe GLP (Good Laboratory Practice) is concerned with toxicological studies on animals.

Documentation (6.7 – 6.10):

There is a new clause added here that you will be amazed was absent before. Clause 6.7 (iv) requires a procedure for dealing with investigating Out Of Specification (OOS) and Out Of Trend (OOT) results. Whilst I guess that every QC Lab on the planet already has such procedures, there was not, until now, a requirement to have such procedures.  In fact the words Out Of Specification and Out Of Trend were not mentioned in EU GMP at all! Clause 6.9 also requires the OOS or OOT procedure to be followed when investigating such occurrences.

They have also removed the specific requirement to keep QC related documentation and records for at least 5 years after Qualified Person certification (in effect batch release) or 1 year after expiry date. Instead the reader is simply cross-referred to EU GMP Chapter 4 (Documentation), where it states the same thing.

Sampling (6.11 – 6.14):

There is the first mention of a “sampling plan” at clause 6.12. Previously the chapter simply stated that “samples should be representative of the batch”. Now GMP required a specific “plan”, but there is no mention of what this plan should be based on. Organisations are likely to base the plan on risk. There is still no mention in GMP of the infamous ROOT N +1 sampling plan or any cross-reference to ISO 2859 (Sampling procedures for inspection by attributes). Both of these are commonly used in practice.

There is also a requirement (clause 6.13) to “manage and store samples correctly”. There is though no specific mention of a sample storage area, cupboard or cabinet (which are commonly used).  However, the requirement for a location to store samples can be found in EU GMP Chapter 3 (clause 3.27).

Testing (6.15 – 6.25):

There are many new requirements added to this section.

The first clause (6.15) covers the new requirement to ensure that if a test method has been validated elsewhere (such as by another organisation) then the current method used must still valid.

There is also a more stronger use of the word “trending” atclause 6.16. Many labs do trend analytical results, but until now GMP simply stated that “for some kinds of data … it is recommended that records are kept in a manner permitting trend evaluation”. This is not exactly a command is it? Now we have the wording “results of parameters identified as … critical should be trended”. Much more direct now I think you will agree.

There is no change to the list of items to be recorded by analysts in labs books or result sheets (clause 6.17)except that clause 6.17 (ix), which is new, now requires that the equipment used should also be recorded. I suspect that most organisations will simply record “critical” equipment used (such as what HPLC was used) and not every single item of equipment (such as a test-tube holder, Bunsen burner, microscope, etc.).

The requirements of clause 6.19 are not essentially new. These cover the use and control of reagents, solutions and reference samples. There is an additional sentence added through at the end of the clause, requiring that the controls used with such items should be commensurate with their use and available stability data. In other words – take care with such items, especially those which will really affect your results if they deteriorate.

There is also a new clause (6.20) covering the use of reference samples, stating that it is preferred if official compendial materials are used. These are, of course, more expensive to use than working standard, which labs may well produce for daily analysis.

Clause 6.21 also adds a bit of a microbiological feel to the whole chapter. I can only guess that in all previous updates of this chapter they forgot to ask the Microbiologist for input, as the wording suggest that the only laboratory of interest is the analytical one. In this clause the words “culture media” have been added with regard to the control of laboratory reagents and standards. Also, there is a need to record the date of opening of a reagent, standard or media. This would apply if the laboratory purchases a pre-prepared item rather than making it themselves.

The Microbiologist really must have been listened to in the wording of this new version of Chapter 6. New clauses 6.23 and 6.24 cover the use of preparation and use of culture media and the disposal of micro-organisms. However, when it comes to disposal of micro-organisms there is no mention of autoclaving or incineration!

On-going stability programme (6.26 – 6.36):

No change from the previous version.

Technical transfer of testing methods (6.37 – 6.41):

This is all new. Five lengthy clauses added here. As the name suggests these clauses cover the transfer of test methods from one lab to another. In essence, the new lab must ensure and document that their test method is equivalent to the previous one. If not, steps will need to be taken to fill any gaps.

This brings me to the end of this chapter. There are a number of changes, but as with other chapter updates, these changes are generally done anyway as best practice or common sense.

I would have thought that there would have been something added about the use of Laboratory Information Management Systems (LIMS). Many labs have these to record results, yet they are still not mentioned in GMP.  Perhaps, at a minimum, there is scope to add a requirement to double check the transfer of results from a lab book or result sheet onto a computer system. Maybe this is one for the next update?

If you are interested in any further information from us, including the range of GMP and quality management related training courses that we offer, then please get in touch.

Dominic Parry

Web source:

Update to EU GMP Chapter 6 – Quality Control | Inspired Pharma Training

Anvisa prioriza análise de novos medicamentos para hepatite C | Agência Brasil

Paula Laboissière - Repórter da Agência Brasil Edição: Marcos Chagas

A Agência Nacional de Vigilância Sanitária (Anvisa) informou que está avaliando novas moléculas para o tratamento de hepatites virais. A decisão, segundo o órgão, se deve às solicitações de informações recebidas pela agência sobre o procedimento de avaliação de novas terapias para o tratamento da hepatite C no Brasil.

Até o momento, segundo a Anvisa, foram adotadas medidas em relação a três processos de registro. A primeira foi o início da avaliação dos dados clínicos de um medicamento com o princípio ativo simperevir. Nos outros dois casos, foram aprovados pedidos de priorização de análise para medicamentos com os princípios ativos sofosbuvir e daclatasvir, ambos a pedido do Ministério da Saúde e de empresas solicitantes do registro.

“Esses pedidos de prioridade já foram aprovados dentro do que prevê a Resolução da Diretoria Colegiada RDC 37/2014, que disciplina as priorizações de análise de registro de medicamentos”, informou a agência.

A hepatite C é uma doença causada por um vírus e transmitida principalmente pelo sangue, mas também pelo contato sexual ou para recém-nascidos durante a gravidez. A enfermidade pode levar à lesões no fígado e até mesmo ao câncer hepático.

O Ministério da Saúde informou que os medicamentos em questão apresentam um percentual maior de cura, tempo diminuído de tratamento - 12 semanas - e a vantagem do uso oral. Os remédios também estão sob análise da Comissão Nacional de Incorporação de Tecnologias, no Sistema Único de Saúde (Conitec).

“Para que seja incorporado, os medicamentos devem obedecer às regras da comissão, que garantem a proteção do cidadão quanto ao uso e a eficácia do medicamento, por meio da comprovação da evidência clínica consolidada e o custo-efetividade dos produtos”, explicou a pasta. Depois de registrados na Anvisa e concluída a aprovação pela Conitec, a estimativa é que os novos medicamentos beneficiem cerca de 60 mil pacientes do SUS, nos próximos dois anos.

Atualmente 15,8 mil pessoas estão em tratamento para a hepatite C, na rede pública. O Brasil é um dos únicos países em desenvolvimento no mundo que oferece diagnóstico, teste e tratamento universal para as hepatites virais, em sistemas públicos e gratuitos de saúde. A definição do tipo de tratamento a ser seguido pelo paciente é feita pelo médico de acordo com o estágio da doença e as características de cada paciente.

* Matéria atualizada às 12h08 para acréscimo de informação.

fonte:

Anvisa prioriza análise de novos medicamentos para hepatite C | Agência Brasil

J&J Speeds Ebola Vaccine Development and Expands Production - Pharmaceutical Technology

J&J Speeds Ebola Vaccine Development and Expands Production - Pharmaceutical Technology

Johnson & Johnson is collaborating with WHO and others on clinical testing, development, production, and distribution of an ebola vaccine.

Johnson & Johnson (J&J) committed up to $200 million to accelerate and significantly expand the production of an Ebola vaccine program in development at its Janssen Pharmaceutical Companies. The company is closely collaborating with the World Health Organization (WHO), the National Institute of Allergy and Infectious Diseases (NIAID), and other key stakeholders, governments, and public health authorities on the clinical testing, development, production, and distribution of the vaccine regimen.

The vaccine regimen, which was discovered in a collaborative research program with the National Institutes of Health (NIH), combines a Janssen preventative vaccine with a vaccine from Bavarian Nordic, a biotechnology company based in Denmark. This combination vaccine regimen has shown promising results in preclinical studies and is now planned to be tested for safety and immunogenicity in healthy volunteers in Europe, the US, and Africa starting in early January. Janssen is targeting production of more than one million doses of the vaccine regimen in 2015. Of these, 250,000 doses are expected to be released for broad application in clinical trials by May 2015.

The regimen consists of two vaccine components that are based on AdVac technology from Crucell Holland B.V., which is part of the Janssen Pharmaceutical Companies, and the MVA-BN technology from Bavarian Nordic. The research collaboration for a monovalent vaccine targeting the Zaire strain of the Ebola virus is part of an ongoing development program for a multivalent vaccine against other virus strains that cause disease in humans, including Ebola and Marburg viruses.

As part of an overall commitment to advance innovations that address unmet medical needs worldwide, a team of dedicated experts has been assigned to focus on bringing this preventative vaccine to people in need. The commitment by J&J includes an equity investment in Bavarian Nordic to provide capital for the development, testing, and production of Bavarian Nordic’s vaccine. Janssen will take the lead in funding and developing both components of the combination vaccine regimen.

“Our goal to produce more than a million vaccines in the next few months is within reach,” says Paul Stoffels, MD, chief scientific officer of J&J and worldwide chairman, Pharmaceuticals. “Ebola is a significant and growing threat to the people of West Africa and it has the potential to impact people around the world. We are committed to bringing our science, technology, innovation, and resources to help prevent and treat this deadly disease.”

“In preclinical testing conducted in partnership with the National Institutes of Health, the combination vaccine regimen has shown complete protection against Ebola,” said Johan Van Hoof, MD, global head, Infectious Diseases and Vaccines, Janssen. “Using our PER.C6 high density cell production technology, we have been able to produce large quantities of the Janssen component of the vaccine regimen in testing batches, and we have already started production toward our goal to have these vaccines available for clinical testing in the next several months.”

In September, J&J and Bavarian Nordic first announced they would fast-track the development and clinical testing of the vaccine program, which features a prime-boost regimen in which one vector is used to prime and the other to boost the immune response.

The program has received direct funding from, and is also using, preclinical services from NIAID. Preclinical experiments conducted at NIH of the combination vaccine regimen demonstrated that when both vaccines were administered two months apart, complete protection was achieved against the Kikwit Zaire strain of Ebola, which is highly similar to the virus that is the cause of the current outbreak in Western Africa.

The emergence of Ebola in West Africa has strained the health care systems of Liberia, Sierra Leone, and Guinea. The company’s long tradition of disaster response has prompted support of Direct Relief International’s efforts in this area as well as the efforts of other relief organizations. J&J is also participating in the ongoing efforts by public health authorities, including the Centers for Disease Control and Prevention and WHO, to mount a coordinated world response to address the immediate needs raised by the Ebola outbreak. The company is also seeking to secure additional partners and resources to assist in its efforts to increase vaccine production and further speed up the clinical trial program.

Source: Johnson & Johnson

ABRADILAN - What`s news: A Johnson & Johnson

What`s news: A Johnson & Johnson

 23/10/2014 - Valor Econômico

A Johnson & Johnson, farmacêutica dos EUA, anunciou ontem que, em janeiro, começará a testar em humanos uma vacina contra o ebola e, em maio, pode ter 250 mil doses disponíveis se as autoridades aprovarem o remédio. A vacina está sendo desenvolvida em parceria com a empresa dinamarquesa de biotecnologia Bavarian Nordic. Outras farmacêuticas, como a britânica GlaxoSmithKline, também estão desenvolvendo vacinas contra o vírus.

ABRADILAN - What`s news: A Johnson & Johnson

The top 10 most expensive drugs of 2013 - FiercePharma

The price of Gilead Sciences' breakthrough drug Sovaldi has drawn all of the attention this year. By pricing it at $85,000 for a 12-week course, Gilead Sciences ($GILD) has been pilloried by politicians, payers and providers. But as EvaluatePharma points out, at that price Sovaldi barely makes it into the top 20 most expensive drugs, number 19 to be exact, just above Novartis'($NVS) Gleevec and just below GlaxoSmithKline's ($GSK)Mekinist.

Sovaldi is pricey, but if you want to talk about really pricey, then look at the 10 most expensive. The least of those, Celgene's ($CELG) Revlimid, ran $128,666 last year, the numbers ninjas at EvaluatePharma determined. The most expensive, Soliris, costs nearly $537,000.

Of course, debate about the appropriate price for drugs is ongoing. It costs a lot of money to discover and develop drugs, including the money that gets sunk into candidates that don't succeed. And because of the way the U.S. market works, it will have the highest prices that the market will bear.

Among the 20 most expensive drugs, only hep C fighter Sovaldi, Roche's breast cancer drug Kadcyla and Bristol-Myers Squibb's ($BMY) colon cancer drugErbitux are not orphans, drugs approved under a special program to motivate companies to develop treatments for conditions that usually have patient populations of fewer than 200,000. In the case of some rare diseases, like Maroteaux-Lamy syndrome, for which BioMarin ($BMRN) developed Naglazyme, the patient pool may be very, very small. EvaluatePharma says Naglazyme was prescribed to just 64 people in the U.S. last year.

Companies have programs to help patients pay for many of these drugs, and what is the alternative for patients? The burden of paying for some of these drugs eventually goes away, when patients recover, or die, but many of these drugs are for chronic conditions. Still, it is interesting to note that some of these prices rival the median price of homes in the U.S., which ran $265,000 for a new home in 2013 and $197,000 for an existing home. And for a home you can get a mortgage.

In this report, we give you the ins and outs on the 10 most expensive drugs. We are interested in your thoughts. You can contact Carly Helfand or myself or go to the FiercePharma LinkedIn group and start a discussion on whatever aspect of this fascinating topic you choose. -- Eric Palmer (email | Twitter)

The top 10 most expensive drugs of 2013 - FiercePharma

Indian firm, 26 others cited for failing to pay GDUFA fees

Indian firm, 26 others cited for failing to pay GDUFA fees

Indian firm, 26 others cited for failing to pay GDUFA fees

By Zachary Brennan+, 01-Oct-2014

Indian generic manufacturer Marck Biosciences has received a warning letter from the US FDA for failing to pay its annual facility fees for the past two years, which for foreign fixed-dose formulation facilities in 2014 was $235,152 .

http://www.in-pharmatechnologist.com/Regulatory-Safety/Indian-firm-26-others-cited-for-failing-to-pay-GDUFA-fees

GMP MANUAL Updates - Good Manufacturing Practice Updates

What is new?

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

 

GMP in Practice

Chapter 4 Facilities and Equipment

4.A Facility Planning

Facility planning occupies a prominent place when a facility is being designed. During this phase, all aspects of its later use must be taken into consideration and included in the facility requirements. These include, in particular, qualification procedures, materials, building and construction element requirements, hygiene requirements, cleaning capability, maintenance friendliness and special process requirements. A comprehensive and detailed implementation of this phase ensures an efficient overall project. (Thomas Peither)

4.B Materials

Different materials are required for the construction of facilities. At the same time, a distinction is made between construction materials and auxiliary materials. The author gives an overview on different types of stainless steel, their characteristics and explains their designation according to standards. Topics such as alloying, surface coating, welding techniques and corrosion are also addressed. Plastics are also often used in facility construction. Their manufacturing, classification and characteristics are discussed and the statutory requirements are explained. Sealing materials and lubricants are auxiliary materials. Here too, an overview on materials, characteristics, use and statutory requirements is given. (Ruven Brandes)

4.C Hygienic Design in Solids Handling

This chapter is still under revision and will be provided with the following update.

4.D System Controllers and Process Control Systems

In order to be able to control a process, quality-related process parameters must be measured using calibrated sensors. Checks are carried out as part of the operational qualification to ensure that parameters are kept within their limits by automatic control loops. When microprocessors or programmable logic controllers (PLCs) are used, this falls within the scope of computer validation. PLCs normally fall under Category 4 in accordance with GAMP 5 and must undergo qualification. The hardware/software functional requirements are described in the URS (user requirement specification). A thorough and efficient formulation of the URS/FS simplifies the actual qualification that follows. The scope of testing is determined by the operator during a risk analysis. The life cycle of a PLC is subject to the same requirements as the associated facility. PLC qualification can be carried out during qualification of the facility. (Rainer Röcker, Anton Steurer, Andreas Rösch)

4.E Technical Documentation

The term Technical documentation means compiling, organising and archiving technically relevant data and documents as well as providing them for information purposes. Generally, the requirements of the EU GMP Guidelines Part I, chapter 4 Documentation apply. The author discusses important contents of technical documentation and gives practical advice for managing, updating and archiving these documents, which are often very comprehensive and complex. (R. Brandes)

4.F Calibration

Process automation has become a widespread standard in modern pharmaceutical processes. As a consequence, approvals and other GMP-relevant decisions increasingly rely on the use of appropriate measurement technology, which means that the monitoring technology itself has to undergo regular function control. The author discusses statutory and normative requirements for calibration and presents the relevant contents of a calibration Master SOP. This includes identification of measuring points requiring calibration, definition of calibration intervals and selection of appropriate methods. The calibration hierarchy and the requirements for reference devices are explained. The chapter rounds up with practical advice for implementation and documentation of the calibration process. (Wolfgang Rudloff)

4.G Maintenance

Maintenance includes measures such as inspection, overhaul and repair and servicing. One of the main tasks of maintenance is to ensure the availability of machinery and facilities as needed with a minimum of product risk and maintenance costs. The author presents different maintenance strategies that should be considered when implementing a comprehensive maintenance concept: failure recovery, preventive maintenance, condition-based maintenance and predictive maintenance. Risk-based maintenance is used to make decisions about the selection of a maintenance strategy based on product and commercial risk. This type of maintenance is very effective when properly established and reduces maintenance costs. When considering the introduction of an electronic maintenance system, the cost-effectiveness of such a decision must be taken into account and the system introduced with caution. (Ruven Brandes)

4.H Cleaning of Facilities

Cleaning technology has a significant impact on the effectiveness of the cleaning process. Understanding of the process types and modes of operation is necessary when selecting effective processes and optimising them under practical conditions. The authors discuss advantages and disadvantages, capabilities and characteristics of CIP/WIP and COP processes. The design and development of cleaning processes is explained in detail. The chapter then focuses on the CIP cleaning technology. Single pass, single use and solution recovery systems are presented. Relevant aspects of GMP-compliant design and the resulting requirements for important functional elements, such as pumps, valves and nozzle heads are discussed. The chapter is completed by information on measuring technology. (Torsten Knöpke, Stefan Schneider)

4.I Containment (Personnel Protection) in Solids Handling

This chapter is still under revision and will be provided with the following update.

GMP Regulations

Chapter C: EU Directives and Guidelines

C.4 EU GMP Guide Part I – Basic Requirements for Medicinal Products

The European Commission has published the final version of the revised chapters 3, 5 and 8 of the EU GMP Guide. The deadline for implementation of all three chapters is 1 March 2015. For transparency reasons, we decided to provide you with both the current version of the chapters effective until 30 April 2015 and the revised version effective from 1 March 2015. The documents are listed successively.

C.4.3.1 Chapter 3 Premises and Equipment (effective from 1 March 2015)

In Chapter 3 Premises and Equipment only section 3.6 (Production Area) has been revised as part of the improved guidance on prevention of cross-contamination involving also Chapter 5.

C.4.5.1 Chapter 5 Production (effective from 1 March 2015)

The revised Chapter 5 Production also deals with the prevention of crosscontamination and refers to toxicological assessment (section 17–21). Changes were also introduced in sections 27-30, including a new section on the qualification of suppliers in order to reflect the legal obligation of manufacturing authorisation holders to ensure that active substances are produced in accordance with GMP. This also includes supply chain traceability. A new section 71 introduces guidance on notification of restrictions in supply.

C.4.8.1 Chapter 8 Complaints, Quality Defects and Product Recalls

This chapter was comprehensively revised. Extensive changes have been made to reflect that Quality Risk Management principles should be applied when investigating quality defects or complaints. The need to investigate and determine the cause of quality defects is emphasized. Additionally, appropriate preventative actions (e.g. root cause analysis, CAPAs) have to be put in place and quality defects should be reported to Competent Authorities.

C.5 Part II Basic Requirements for Active Substances used as Starting Materials

The European Commission has published a revised version of Part II of the EU GMP Guide. According to the EC this became necessary due to changes in various Annexes of the GMP Guide. Hence Part I can no longer be followed for active substances used as starting materials. The amendments canmainly be found in Section 1.2 (Scope) which now also clarifies the relationship between section 17 (Agents, Brokers, Traders, Distributors, Repackers and Relabellers) of Part II and the forthcoming guidelines on Good Distribution Practices for active substances for medicinal products for human use. The document came into operation on 1 September 2014.

C.8 EU GMP Guide Part III - GMP related documents

C.8.5.1 Importation of Active Substances for Medicinal Products for Human Use; Questions and Answers

Two new questions and their corresponding answers (Q&A 33 and 34) have been added to the new version of this document. The questions deal with GMP non-compliance statements superseding the corresponding written confirmations, if existing and the EudraGMDP database which lists all active substance manufacturing sites that received statements of GMP non-compliance.

C.18 Guidance for the template for the qualified person’s declaration concerning

GMP compliance of active substance manufacture “The QP declaration template” The EMA has published the long awaited Qualified Person (QP) declaration template and accompanying guidance concerning GMP compliance of API manufacture. The objective of this guidance and the Qualified Person (QP)declaration template is to emphasise the importance of providing a valid declaration, to harmonise the format for the declaration, to forestall questions during assessment and to enhance the efficiency of the regulatory process, including the timely processing of relevant regulatory submissions.

C.18.1 Qualified Person’s declaration concerning GMP compliance of active substance manufacture “The QP declaration template”

A QP declaration is required to be submitted with all applications for new marketing authorisations, renewals and submissions of relevant quality variations, concerning changes (addition or replacement) to the manufacturer of a starting material and/or to the registered manufacturer(s) of the active substance, finished product or batch importation/certification sites. The use of the QP declaration template is optional. Nevertheless, applicants are strongly recommended to use the template to facilitate the validation of regulatory submissions and their review.

Chapter D: USA: CFR and FDA Guidelines

D.1 Code of Federal Regulations

The Code of Federal Regulations is subject to an annual revision. With the current Update of the GMP MANUAL we provide the recent versions of

• 21 CFR 210 (chapter D.1.1)
• 21 CFR 211 (chapter D.1.2)
• 21 CFR 11 (chapter D.1.3)
• 21 CFR 4 (chapter D.1.5)
• 21 CFR 600 (chapter D.1.6)
• 21 CFR 606 (chapter D.1.7)

The date of these CFRs has been updated as of April 1, 2014. No further amendments were made.

• 21 CFR 820 (chapter D.1.4)

The list of definitions of 21 CFR 820 was extended.

Chapter F: PIC/S Guidelines

F.9-F.12 PIC/S PE 009-11: Guide to Good Manufacturing Practice for Medicinal Products

The changes made to the PIC/S GMP Guide take over the issues resulting from the transposition of the EU GMP Guide to the PIC/S GMP Guide and ensure a better harmonisation of the documents. In Part II a new subsection 2.2 has been added to section 2 Quality Management in order to introduce the principles of Quality Risk Management. Annex 2 regarding biological medicinal products for human use has been amended and Annex 14 regarding products from human blood or human plasma has been revised.

Source:

GMP MANUAL Updates - Good Manufacturing Practice Updates

GMP News: WHO publishes second Draft on the Revision of its Process Validation Guideline

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.  You can find the second revision draft in ECA's members' area.

GMP News: USP's New Requirements for Compendial Validation

GMP News: USP's New Requirements for Compendial Validation


USP's New Requirements for Compendial Validation

An interesting article from the USP on the future requirements for compendial validation has been published in the Pharmacopoeial Forum 39(6). This is the first General Chapter in a series of chapters which should introduce significant changes in the approaches to validation and its influences on compendial procedures. This new chapter <1200> will concentrate on the types of data expected by the USP to see if an analytical method can be accepted before it is included in USP/NF. Methods containing the data expected in the future  will be suitable for compendial applications. According to USP's "General Notices" 6.30, alternative procedures may be used as long as they have been validated or have been demonstrated to be equivalent to or better than the existing compendial procedure. The article lists the different parameters for compendial validation. Concrete propositions are made. Five standardised studies may be used to evaluate the acceptability of a new procedure: Specificity Accuracy Precision Range Detectability The USP wishes to get feedback to the propositions made in this article. You can find all information on the USP website of the Pharmacopeial Forum (PF).

Anvisa define composição de vacina contra a gripe para 2015 | Notícias | EBC

Anvisa define composição de vacina contra a gripe para 2015 | Notícias | EBC

Paula Laboissière - Agência Brasil

Resolução da Agência Nacional de Vigilância Sanitária (Anvisa) publicada hoje (17) no Diário Oficial da União define a composição da vacina contra a gripe que será usada no país no próximo ano. A composição da vacina contra a gripe é atualizada a cada ano, de acordo com os vírus circulantes, para garantir a eficácia do produto. A resolução, segundo a Anvisa, está de acordo com as recomendações da Organização Mundial da Saúde para o Hemisfério Sul.

Leia também no Portal EBC: 

Anvisa suspende venda e uso de lotes de vacina contra meningite

Lotes de medicamentos são retirados do mercado por determinação da Anvisa

De acordo com o texto, as vacinas influenza trivalentes a serem utilizadas no Brasil a partir de fevereiro de 2015 deverão conter, obrigatoriamente, três cepas (tipos) de vírus em combinação: um vírus similar ao influenza A/California, um vírus similar ao vírus influenza A/Switzerland  e um vírus similar ao influenza B/Phuket.

Ainda segundo a Anvisa, as cepas A/South Australia/55/2014, A/Norway/466/2014 e a/Stockholm são consideradas similares à cepa de vírus A/Swiesrland. Já as vacinas influenza quadrivalentes deverão conter os três vírus descritos anteriormente e um vírus similar ao vírus influenza B/Brisbane.

“As vacinas influenza a serem utilizadas no Brasil no ano de 2015 somente poderão ser produzidas, comercializadas ou utilizadas, se estiverem dentro das determinações e nas composições descritas nesta resolução”, informou a agência.

A Anvisa ressaltou que fica vedada a utilização de quaisquer outras cepas de vírus em vacinas influenza no Brasil, sendo que as que são atualmente comercializadas ou fabricadas fora destas determinações deverão ser retiradas do mercado. A resolução entra em vigor hoje.

Editora: Denise Griesinger

Big Pharmas and API suppliers eyeing Brazilian Government deals says EMS

Big Pharmas and API suppliers eyeing Brazilian Government deals says EMS

Evaluating Cross-Contamination Risk of Highly Potent APIs - Pharmaceutical Technology

Evaluating Cross-Contamination Risk of Highly Potent APIs

Manufacturers using highly potent APIs must examine cross-contamination routes and determine acceptable limits.

Oct 15, 2014 By: Jennifer Markarian

Highly potent APIs present several challenges for finished-dosage drug manufacturing because they must be handled in a manner that both protects the drug product from cross-contamination and protects manufacturing personnel. Automation, process analytical technology that allows monitoring without operator contact, and disposable equipment are technologies that offer potential solutions to some of these challenges (1). No matter what equipment is used, however, manufacturers must first assess the risk of cross contamination and exposure.

Using shared facilities
A significant issue has been whether manufacturers can use shared facilities for manufacturing highly potent drugs. FDA regulations say that penicillins must be processed in dedicated, segregated facilities, and a 2013 FDA guidance added that beta lactams should also be segregated (2). Other products may be manufactured in shared facilities if precautions are taken to prevent cross contamination or mixups, noted Stephanie Wilkins, president of PharmaConsult US, in a presentation at Interphex 2014 (3).

The European Medicines Agency (EMA) has updated their GMP regulations, and the final version of Chapters 3 and 5 will come into effect March 1, 2015 (4, 5). The new regulations say that the outcome of a quality risk management process should determine the need for segregated facilities. The risk assessments should address modes of cross-contamination that could occur to be sure that certain thresholds are not exceeded. Dedicated facilities must be used if scientific data from the toxicological evaluation does not support a controllable risk (e.g., for penicillins or beta lactams), cannot control the risks to acceptable levels, or do not have an analytical method that is more sensitive than the relevant residue limits derived from the toxicological evaluation, noted Wilkins.

EMA does not yet have a final guidance for the toxicological evaluation. An EMA draft guidance on manufacturing in shared facilities (6), however, outlines how to determine threshold values or permissible daily exposures (PDEs) that can be used to set limits for unacceptable cross-contamination. Alternatively, the International Society of Pharmaceutical Engineering (ISPE) Risk-MaPP Baseline Guide provides guidance on how to determine acceptable daily exposures (ADEs) that can also be used to set the limits (7). These limits are more appropriate than previous limits, which may not be stringent enough to protect workers or product quality for highly potent compounds, said Wilkins.

Cross-contamination routes 
In a risk assessment, companies must examine various routes of cross-contamination. These routes include mixups, carryover, and mechanical or airborne transfer, Wilkins explained in her presentation.

An example of a mixup is a wrong label on a product. Mislabeling does occur. In September, 2014, for example, Baxter initiated a voluntary recall of one lot of injectable product due to a labeling error on a shipping carton (8).  

With shared equipment that is cleaned between different materials, material retained in equipment could be carried over into the next product, resulting in cross-contamination. The big change in regulations here, explained Wilkins, is using health-based limits based on ADE, acceptable daily intake (ADI), or PDE thresholds to determine what the limits should be for confirming that cleaning processes are effective to prevent retention and carryover. ISPE’s Risk-MaPP Baseline Guide offers a scientific, risk-based approach to determining and managing cross-contamination using ADE, which is similar to PDE (7).

Mechanical transfer can occur if residue escapes the process (e.g., a spill onto the floor), where it could be transferred, for example, by operators’ shoes or gloves. Airborne transfer can occur if residue escapes the process and is in the air, where it could be transferred through the air-handling system. Controls must be set to prevent cross-contamination through any of these routes, noted Wilkins in the presentation. In addition, the new EU GMPs now require a risk assessment of these controls to be able to confirm that these products can be safely manufactured in shared facilities.

References

1. C. Challener, "Technology Choices in Highly Potent Solid Dosage Manufacturing," Jul. 2, 2013,www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=817278, accessed Sept. 29, 2014.
2. FDA,Guidance for Industry: Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination (Silver Spring, MD, April, 2013).
3. S. Wilkins, "Using Shared Facilities for Manufacturing High Potency Finished Drugs," Presentation at Interphex (New York City, 2014).
4. European Commission,EudraLex Volume 4, Chapter 3: Premises and Equipment (Brussels, Aug. 13, 2014).
5. European Commission,EudraLex Volume 4, Chapter 5: Production (Brussels, Aug. 13, 2014)
6. EMA,Draft Guideline On Setting Health Based Exposure Limits For Use In Risk Identification In The Manufacture Of Different Medicinal Products In Shared Facilities, (Dec. 13, 2012).
7. ISPE, Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP), (Tampa, FL, Sept. 2010).
8. Pharm.Tech., "Baxter Initiates Voluntary Recall of Potassium Chloride Injection," http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=854254 accessed Sept. 29, 2014.

To hear a recorded interview with Stephanie Wilkins on this subject, watch PharmTechTV.

Web link:

Evaluating Cross-Contamination Risk of Highly Potent APIs - Pharmaceutical Technology