FIP Congress 2005
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In a symposium organised by the Board of Pharmaceutical
Sciences and the Industrial Pharmacy Section, issues surrounding
good chemistry, manufacturing and industrial practice were discussed.
Jane Nicholson reports
|
 The World
Congress of Pharmacy and Pharmaceutical Sciences was
organised by the International
Pharmaceutical Federation in association with the Syndicate
of Pharmacists of the Arab Republic of Egypt.
It took place in
Cairo from September 2 to 8, 2005 |
What good chemistry, manufacturing and control practice will be in
future
Speaking on “International trends in quality systems and risk
based management”, Michael Anisfeld, of Globepharm Consulting,
US, predicted that 10 years from now the Pharmaceutical Inspection Co-operation
Scheme (PIC/S) would probably be the global system for setting good manufacturing
practices (GMPs) and quality systems standards, and
for sharing inspection reports between countries. He listed the key international
GMP publications currently having the greatest impact on GMP developments
as being those of the US, Canada, the European Union and the PIC/S. He
described the Canadian guidelines on risk categorisation of GMPs as being
a commonsense approach to categorising GMP deficiencies according to
the risk they represent to the patient. The recently published document
from the US Food and Drug Administration — “Quality systems
approach to GMPs” — he found to be a revolutionary document
heralding a long overdue change to the FDA’s approach to GMP implementation,
bringing the FDA towards merging ISO concepts of quality, as expressed
in ISO 9000, with the FDA’s traditional GMP regulations for pharmaceutical
manufacture and its quality system regulations for medical device manufacture.
It indicates a significant change in agency thinking, and deeply impacts
on GMP concepts in the pharmaceutical industry, said Dr Anisfield.
He explained the concepts of product quality, including the new International
Conference on Harmonisation-proposed guideline on “Quality by design” (ICH-Q9),
which means designing and developing manufacturing processes during product
development to ensure product quality. Risk management is useful in establishing
specifications and process parameters, while risk assessment is useful
in determining the extent to which discrepancy investigations and corrective
actions need to be taken.
The concept of “Corrective and preventative action” (CAPA),
a part of the US medical device industry GMPs for about 35 years, was
proving from product quality and economical perspectives to be highly
useful to pharmaceutical manufacturers. Fixing a problem is no longer
good enough; manufacturers need to prevent defects and deficiencies from
happening again. A good CAPA programme requires analysis, investigation,
identification, verification, implementation, dissemination, management
review and documentation.
Change control focuses on managing change to systems, documentation and
processes to prevent unintended consequences. In a well-designed quality
system, effective change control plays a central role. As change and
continuous improvement is strongly encouraged by the regulators, manufacturers
are, under new FDA initiatives, empowered to make changes based on a
deep knowledge of their processes.
The FDA has developed a six system inspection model to expedite speed
and deep inspections to assess GMP compliance. The six systems inspected
by FDA during GMP inspections of pharmaceutical manufacturers include
review of the production, facilities and equipment, laboratory control,
packaging and labelling systems with the quality system at the epicentre
of the entire six-system package. When inspected, if any one system is
found to be inadequate then the entire company is considered out of control
and thus becomes a “high risk company” in the eyes of the
FDA.
Getting to quality means knowing, communicating and minimising the risk
to the patient; it involves defining management responsibilities, provision
of adequate resources, knowing the variability of manufacturing operations
and the evaluation of activities to provide constant improvement. Dr
Anisfeld stated that there needs to be constant communication between
management and staff and that senior management must be involved in the
evaluation of process
improvement.
The Australian and Canadian Authorities, and through them PIC/S, have
implemented the concepts of risk assessment in performing their GMP inspections.
These authorities have slightly different definitions of what are critical,
major and minor deficiencies. Such categorisation is extremely helpful
to the authorities and to the pharmaceutical manufacturer. Dr Anisfeld
noted that the Canadian authorities had developed a website (found via
a Google search on “Canada GMP risk”) listing hundreds of
examples of critical and major GMP deficiencies.
Mutual recognition
In response to a question on mutual recognition, an ex-FDA official
(Tom Leyloff) commented that US bilateral agreements have been drawn
up
between countries such as Sweden and Switzerland whose inspectorates
have established confidence in one another over many years. He pointed
out that the FDA will not accept multinational arrangements such
as those of the PIC/S because US federal law requires national legislative
agreements while in the US many manufacturing requirements were state-based,
rather than federal-based.
Pharmaceutical quality assessment
In his lecture on pharmaceutical quality assessment, Moheb Nasr, from
the FDA, described the new chemistry, manufacturing and controls review
paradigm in the 21st century. The FDA is responsible for protecting
public health in the US and regulates about 25 per cent of every consumer-spent
dollar every year. The Centre for Drug Evaluation and Research (CDER)
is the largest of the eight FDA offices and has approximately 2,200
employees. It is responsible for ensuring the safety and efficacy of
drugs and biologicals marketed in the US.
CDER review is divided by indication and discipline, creating a matrix
review environment. A multidisciplinary team is assigned to each drug
application and includes one or more chemistry, manufacturing and control
(CMC) reviewers.
A final report on GMP was issued in September 2004. The Office of New
Drug Chemistry has a new pharmaceutical quality assessment system (PQAS).
Its guiding principles are risk-based orientation, science-based policies
and standards, integrated quality systems, international co-operation
and strong public health protection. The new system should allow rapid
introduction of new technologies into manufacturing and expedite review
of applications without compromising quality. There will be dedicated
pre- and post-marketing divisions, pharmaceutical assessment leads who
will identify critical quality areas and develop the “big picture”,
assessment protocols and timelines, a new manufacturing science branch
and project management staff.
Key accomplishments to date have been the adoption of a quality systems
model, the development of quality systems guidance, the implementation
of a risk based management plan and the establishment of a risk-based
assessment to replace the current CMC review. Several science-based policies
such as aseptic processing and training programmes to support risk-based
regulatory decisions and continuous improvement have been instituted.
A Council on Pharmaceutical Quality has been established that will be
responsible for policy development and for the co-ordination and implementation
of plans.
The regulatory responsibilities include investigational new drug applications
(INDs), new drug applications (NDAs), post-approval CMC charges, the production
of annual reports, compendial standards evaluation and guidance and policy
development. The workload in 2004 was 879 INDs and 185 NDAs, 1,738 CMC supplements
and 2,422 annual reports.
The quality of applications varies widely, commented Dr Nasr. Many applications
lack adequate pharmaceutical development information and there is insufficient
scientific dialogue between the CMC reviewer and the applicant. The evaluation
of all CMC data is resource-intensive and in future rather than a single reviewer,
a pharmacist, engineer and chemist may review the CMC part of the applications
jointly.
Appropriately prepared summaries rather than data copied from laboratory notebooks
are needed. Reviews can help to generate a comprehensive application summary.
Late amendments submitted by the applicant often lead to delays. The objective
of the new PQAS is to facilitate innovation and continuous improvement throughout
the product life cycle and provide regulatory flexibility of specification
setting.
Companies want fast drug approvals and freedom to make changes so they need
to provide more science to back up the amendments, said Dr Nasr. The principles
of the new PQAS are to focus on critical quality attributes and their relevance
to safety and efficacy and to ensure product quality and performance. The quality
of the overall summary will be extremely important as will the integration
of the review and inspection. In response to a question on review times, Dr
Nasr said that an accelerated review will take six months and a standard review
will take 10 months. Challenges in daily practice
How to meet the challenges of GMP inspections in daily practice was the
subject of a presentation by Abdel-Aziz Saleh, of the World Health
Organization Eastern Mediterranean Regional Office (EMRO). One of the
WHO goals is to provide safe, effective and good quality medicines
for the poor and disadvantaged. The volume of locally produced products
is increasing in developing countries but most national authorities
lack the necessary infrastructure and competent personnel to develop
and run an efficient system of GMP inspection.
The EMRO has produced Arab guidelines on GMP. The WHO has provided
clear guidelines on the qualifications needed to staff an inspectorate
but the available facilities
and working conditions do not attract competent personnel to work in the government
sector, explained Dr Saleh. In Tunisia, government inspectors are working with
the universities to encourage job satisfaction and continuing education and
this may be a way forward for other countries.
Few countries have the funds to organise “on the job” training
in quality assurance and such activities depend on external donors and agencies
of the United Nations. There is an imbalance between the resources given to
the pre-marketing product registration assessments and the post-marketing activities,
said Dr Saleh. He has been struggling for five years to set up a suitable post-marketing
surveillance system in the 25 countries of the EMRO.
The regional network for drug regulatory authorities is being strengthened
through joint planning; electronic communication and regional GMP training,
said Dr Saleh. However, regional collaboration is needed not only in the areas
of product registration but also in the regulation of drug distribution channels.
There is no doubt that GMP and courses in quality systems should be part of
the core curriculum of undergraduate pharmacy education, he noted.
In the discussion which followed, informal debating groups between university,
government and technical staff in industry was recommended as a way of encouraging
the teaching of quality assurance. An industrial perspective
In a presentation entitled “Towards one worldwide harmonised manufacturing
practice standard for drug substances and drug products”, an industry
perspective was presented by Tom Sam. He observed that GMPs are not harmonised
and, in many countries, are not implemented. This was exemplified by
reports from China and the outcome of a UN project run by the WHO on
the pre-qualification programme for essential medicines. Shortages of
funds, rigid operational mechanisms, ideological resistance among manufacturing
staff and a lack of senior managers with any knowledge or awareness of
GMP have all led to problems. In these circumstances, it will usually
take a long time to reach compliance.
Differences in GMP lead to double standards and lack of mutual recognition
between agencies causes the industry costly duplication of testing and
regulatory inspections.
Dr Sam summarised the responses to a questionnaire he had distributed
to responsible staff in WHO and PIC/S and other GMP experts from developed
and developing countries. His findings were that harmonisation of GMP
is desirable and should cover both local and global manufacturers and
apply equally to internally and externally marketed goods. More than
one harmonised GMP system would be dangerous. However, the road to harmonisation
is important and the strategy and tactics employed will determine its
success or failure. Therefore, high level GMP core values need to be
established by all stakeholders including PIC/S, the ICH and the WHO,
concluded Dr Sam.
During the discussion period, it was suggested that members of FIP as
well as WHO could play a role in guiding the long process towards harmonisation
of standards. |
The
Pharmaceutical Journal