International sourcing and global quality — a topic
of growing concern
The Industrial Pharmacy Section and the Laboratories
and Medicines Control Section jointly reviewed an important topic of growing
concern — the international sourcing and global assurance of active pharmaceutical
ingredients (APIs) and excipients. At a meeting on 5 September, 10 international
speakers, representing suppliers, purchasers and regulators, undertook
a comprehensive survey of different aspects of the subject.
Supply management
Hans-Jorg Seidel (Aventis, Germany) reviewed the
strategies available for management of supply chains, which he said was
“a core function within pharmaceutical business”. He examined the driving
forces, trade scenarios, and the complex pattern of international trade
blocs and free trade zones. He referred particularly to bilateral agreements
and the effect of reduction of world tariff barriers resulting from the
“Uruguay round”, which had aided a major increase in sales of pharmaceuticals.
“This sounds wonderful,” Mr Seidel said, “but the reality is different”,
because of the effect of “non-tariff” barriers, such as local surveillance,
regulations, content level for added value and reimbursement rules. These
hurdles had effectively forced manufacturers to open regional hub sites
for production and clinical trials. In the ASEAN (Association of South
East Asian Nations) region, Aventis had chosen Singapore as best fitting
its requirements. The basis for its decisions on sourcing were optimising
resources, reducing complexity, matching flexibility and customer needs,
and added value commitment. One outcome was for a company to undertake
formulation and packaging of established products on one site while keeping
their new strategic products at their “mother” site.
A supplier’s views
With regard to assuring quality when sourcing APIs
in the Pacific region, there were complementary supplier and buyer presentations.
From the supplier standpoint, W. I. Hong (Yuhan Chemical Industries, Korea)
said that at present API exports represented about one sixth of the Korean
pharmaceuticals market. His country had joined the World Trade Organization
in 1995 and had been recognised by OECD in 1996 as a “developed country”.
He suggested that Korea was at a stage where it could supply and contract
APIs and major intermediates — and even look to introduce new chemical
entities. He went on to describe the evolution of Good Manufacturing Practice
standards in Korea, referring both to APIs and to finished products. Meeting
common guidelines had facilitated exchanges of drugs between Korea and
other countries and bilateral agreements were sought with the United States,
the United Kingdom, Switzerland and Japan.
Mr Hong presented a detailed case study of GMP compliance
within his company and quoted examples for ensuring safety and quality.
He was confident that, ultimately, API quality assurance in Korea would
become fully compliant with International Committee on Harmonisation (ICH)
guidelines and it already operated satisfactory systems for managing supply
chains and customer relationships.
A buyer’s perspective
Anna Ng (GlaxoSmithKline, Singapore) emphasised
that certified GMP was a “non-negotiable” global requirement, yet it did
not necessarily guarantee quality. She rehearsed some customer expectations
where fitness for use had been challenged or there had been misunderstanding
of what had been supplied. She stressed that supplier’s changes in processing
might affect the purchasing specification or associated analytical method.
“It was important to prevent surprises,” she said, and instanced the need
to check suitability of packaging and the provision of tamper-proof closures,
and to monitor transport conditions that could affect stability of an
API. She had found it most useful to provide “technical terms of supply”
that reflected changes in control procedures, including critical process
and engineering parameters.
Mrs Ng believed that “not all is well” when relying
on purchasing specifications. One also needed to consider the impact of
unknown (or very low level) impurities on a sensitive process, non-compliance
with GMP arising from differences in interpretation and non-specified
attributes of the API which varied with its source. Her solution was for
the purchaser to “develop an alliance with the supplier to foster a co-ownership
of quality”. This involved four steps — choosing the right partner, developing
a quality assurance partnership, determining critical performance parameters
and evolving a joint quality improvement plan. Moreover, as part of the
quality culture within the purchasing company, she asserted, “It is not
sufficient to have good QA department: you must involve senior management
and production commitment” — because it was very much a people and motivation
issue. She summarised that, although accepting that market competition
was a business reality and cost containment a key issue, purchasers needed
to work in partnership with suppliers “to reduce the hidden cost of poor
quality”.
Excipient sources
Ray Marcuelo (United Laboratories, Philippines)
presented a buyer’s view for excipients and provided an impressive range
of sources in the Pacific basin for many of the commonly used ones. Excipients
had gained global attention because of their influence on the bioequivalence,
bioavailability and stability of dosage forms. She emphasised the prime
importance of safety and purity of excipients because any contamination
therein was most likely to be present in the dosage form. Mrs Marcuelo
iterated seven strategies in assuring quality. Three were based upon approval
mechanisms, impurity profile, and use of clinically relevant in-house
specifications, whereas three more reflected raw materials quality by
controlling significant changes of source, a “strong portfolio and audit
of GMP-certified suppliers”, and controlling incoming shipments. Her seventh
strategy proposed introducing a “more toxicity-based product clearance
test”.
She described significant approaches in the quality
assurance programme of her company, referring especially to creating a
“Partners for quality” programme with suppliers, and implementing an ISO
9002 certified and GMP compliant quality system. Suitably trained auditors
were able to assess whether controls existed, and were adequate, implemented
and effective. The “Partners for quality” programme, she said, was “a
necessity, not an option”. Her company experience had shown that trust
and openness between vendor and purchaser created a true commitment to
quality.
Counterfeit medicines are big business
Mike How (UK), on behalf Dr Mike Anisfeld (Globepharm,
US), presented a “no punches pulled” review of counterfeit starting materials.
Between 8 and 15 per cent of world-wide sales of all pharmaceuticals were
counterfeit and “no country was immune”. Reports were quoted that 47 per
cent of pharmaceutical products in Nigeria were below specification; many
antimalarials in South East Asia contained less than 25 per cent of active
ingredient and one third of one open-sale brand contained no active ingredient
at all. Even hi-tech products were not exempt: in the US in 2001, three
major cases involved drugs simulating somatropin and filgrastim products.
Counterfeiting often targeted the most vulnerable
section of the community and Dr Anisfeld’s paper cited some notorious
examples of sub-standard drugs in the 1990s. Then, 223 children died in
Bangladesh, 23 patients died in Argentina and 109 children died in Nigeria
(from contamination of glycerol with diethylene glycol). In Niger a meningitis
vaccine with no antigen led to around 2,500 deaths, and in Haiti 89 children
died from a locally made popular prescription syrup that had been contaminated
by an imported raw material used in its manufacture. A US Food and Drug
Administration investigation traced this component back through a series
of brokers from China, to Rotterdam and thence to Haiti, with an even
more convoluted routing of commercial invoices through six countries;
even the laboratory certificates of analysis supplied were counterfeit.
Dr Anisfeld’s paper also referred to the unfortunate
consequences in Brazil following illicit diversion of a Schering inactive
contraceptive comparator product that had been dumped after clinical trials
had been completed. He concluded that greed and corruption were the roots
of the problem “by permitting incompetent manufacturing, and a lack of
governmental controls and effective enforcement”. He commended final dose
manufacturers to “know their suppliers”, discourage purchasing from middle-men
and test every drum of incoming raw materials “because alleged country
of origin is no guarantee”. Mr How interposed that a sample must be representative
because unscrupulous suppliers could put best quality material on top.
Concomitantly, legislators were enjoined to enact strict legislation with
adequate punitive powers to punish those found guilty of counterfeiting
and to improve pay and training for government inspectors.
Dr Anisfield’s paper also criticised the World Trade
Organization’s “Market News Service” (MNS) website. This published monthly
information on brokers, prices and supplies — but none of the eight brokers
Dr Anisfeld contacted would reveal the actual source of their raw materials.
He urged the WHO to promote a recommendation of the independent review
by Davidson and Pogany in 1998, that MNS should discontinue advertising
undisclosed source supplies, and discourage endorsement of brokers that
did not purchase from manufacturers meeting the ICH quality guidelines
for GMP.
The WHO view of global strategies
Dr Sabine Kopp-Kubel (WHO) recognised an impressive
series of challenges in the increasing globalisation of commerce and trade,
free ports and large trade zones, international production and sources
of starting materials often involving third parties, cross-border promotion
and sale via the internet, multiple relabelling and repackaging, forwarding
companies and counterfeit drugs. The last three of these challenges frequently
involved “travelling documentation”, with a false name of origin and perhaps
accompanied by an unauthenticated certificate of analysis. She referred
to regional efforts to control enforcement and provide a supportive environment
through legislation. She described WHO guidelines for model legislation
for registration procedure and a network for authorities to alert problems,
including an update on discovered counterfeit drugs. WHO also provided
global norms in production, inspection, QC and storage, as well as an
international programme of selecting and adopting non-proprietary names.
She noted that an impurity profile could vary from
country to country. WHO commended test procedures and supplied a world-wide
network of reference materials. She agreed with earlier speakers that
good practice expected clear identification of the laboratory issuing
a certificate.
Application of new analytical technology
Ken Leiper (Benson Associates, UK) emphasised that
the validation of emerging and even traditional analytical techniques
used in increasingly novel applications was presenting major new challenges
for industry and regulatory agencies alike. He portrayed a product life
cycle from inception through manufacture to marketing against the time
base of licensing and concomitant changes in technology and regulatory
expectation. All along this axis “we must rely on timely analysis”, he
said. He affirmed that method validation would be critical for measurement
integrity, product performance, successful regulatory approval, timely
technology transfer, and the control of development, regulatory and compliance
costs. Nevertheless, “evidence from GMP inspection reports,” he said,
“continues to suggest that there is still a significant gap” between the
standards of method robustness and the methodology delivered. He quoted
some “horror stories” that could be found in publicly available reports
of FDA inspections, wherein non-compliances were frequently traceable
to erroneous or unvalidated test results or issues involving reference
standards.
Management of change of sources
Dr Peter Trindler (Roche, Switzerland) discussed
the “complex business” of managing source changes for APIs by “maximising
benefits but minimising risks”. Risks increased in line with the diversity
of choice and widening expectations of customers and regulators. He noted
that products for different markets involved a great diversity of authorisations,
requirements and timelines. Criteria for managing change involved assessing
potential impact on quality, safety and efficacy in intended use, properly
calculated costs and benefits and proper tuning of site logistics. He
recommended treating all cases of source change as an evolving project.
Up front, his model required senior management support, followed by team
evaluation of the impact on quality and time scales. When a final decision
was taken to proceed, they would recheck compliance and negotiate contracts,
and then have to satisfy regulators. He accepted that a pre-appraisal
inspection sometimes helped but it added expense and was time-consuming
and, in any event, “source changing can be very prolonged — perhaps three
years where a product is required in 35 countries”. Dr Trindler concluded
with expectations that the source of APIs will be an ongoing phenomenon
and that regulators would “refocus on change control systems” and compliance
in validating the effects of change. He foresaw the value of extended
modern communication technology and purchasing through “e-commerce”, while
new partnerships would be forged, with greater mutual acceptance by authorities.
GMP inspection of manufacturers
Charles Edwards (FDA, US) recalled the first on-site
inspection outside the US was in 1955. Since then, more than 4,000 inspections
had been undertaken in 62 countries, covering the production and control
of products to be exported to the US. If corrections were not promised
or made by the company, the FDA might send a warning letter, notifying
potential legal action. He explained that although about 70 per cent of
the international drug inspections covered APIs, these were based on Food
and Drug Administration guidance because FDA GMP regulations (from 1963)
applied only to dosage forms. The current active pharmaceutical ingredients
guide had not been updated because in 2001, in a major change of policy,
they decided officially to adopt the ICH Q7A GMP guide. Dr Edwards said
that coverage of APIs by the FDA had been an integral part of their “pre-approval”
inspection (PAI) process since the early 1990s. The FDA reviewer combined
the on-site PAI inspection findings with the application documents to
reach a final decision on approval of the new drug application or abbreviated
new drug application.
Another important development was the Mutual Recognition
Agreement that the FDA had signed with the European Union in May 1998.
“Observed inspections” carried out in 2001 would determine which EU member
states had regulatory systems equivalent to those of the FDA and could
thereafter carry out inspections in their own and other EU countries accepted
as equal to a FDA inspection.
Although the number of GMP warning letters to international
firms had declined, he noted that common deficiencies still appeared in
the control laboratory, with records and reports, and with manufacturing
process controls. He hoped that wider use of the ICH Q7A guide should
lead to a more uniform and consistent approach to the production of high
quality APIs.
A Singapore view on inspection
Chong-Hock Sia (Heath Sciences Authority, Singapore)
rehearsed the evolution of the concept of GMP in the US and Europe and
then turned to local experience. In Singapore, between 1960 and 1986,
there had been some government-based medicines production, but establishment
of the Beecham synthetic penicillin plant in 1973, and local generic production
after 1986, had led the government to become a regulator instead. Singapore’s
Medicines Act 1987 had embraced WHO GMP guidelines and subsequently Singapore
became the first Asian member of the Pharmaceutical Inspection Convention
(PIC) and made bilateral mutual recognition agreements with EU states,
Canada and Australasia.
Mr Sia said that traditional Chinese medicines had
been licensed since 1999 and the formal structure of the HSA had been
created in spring 2001. He discussed the structure of the HSA and in particular
the role of the manufacturing and quality unit, and then went on to describe
the current GMP inspection system, for which risk assessment dictated
the pattern and frequency. Thus, if the product of risk and acceptability
was high, then a revisit took place within two months, whereas, if low,
perhaps two years might elapse. Looking forward, he foresaw priority areas
to be biotechnology products, contracted-out testing, good distribution
practice, and “levelling up” of control for traditional Chinese medicines
through starting materials, processing, packaging and quality control.
Mr Sia said that the challenge was “to function effectively in the rapidly
changing environment of a knowledge-based economy, against the backdrop
of globalisation and a life sciences revolution”.
— Contributed by Professor Geoffrey Phillips, a former secretary of
the LMCS Section.
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