Asia-Pacific Region Begins Adopting Lifecycle Approaches To Process Validation

Pharmaceutical manufacturers in India should be aware that inspectors may be looking to see that lifecycle approaches to process validation have been used in their systems with the country’s adoption of a WHO guideline on process validation. ASEAN is also about to issue guidance that tells manufacturers how to design a lifecycle approach to validating vaccine manufacturing processes.

Manufacturers need to be aware of new influences in the Asia-Pacific region that are driving regulatory adoption of the lifecycle approach to process validation pioneered in the US. The World Health Organization has joined other partners in the region in promoting this new approach – and it’s gaining adherents.

WHO joins Association of Southeast Asian Nations (ASEAN) and the Pharmaceutical Inspection Cooperation Scheme (PIC/S) in shaping the regulatory framework for process validation in the region.

Yet while progress is being made in advancing this approach, there are some challenges in implementing lifecycle validation in some markets. For example, some countries have adopted lifecycle validation but are not enforcing it, while some Tier I countries with mature GMP regulatory systems are not adopting lifecycle approaches. The pace of adoption also depends on whether there is a heavy presence of multinational companies in the region. Deep penetration of multinational companies in a region generally means greater adoption of lifecycle approaches there, with or without regulatory approval of lifecycle validation.

Maurice Parlane, principal and director of New Wayz Consulting Ltd. In Auckland, New Zealand, discussed these trends at the International Society For Pharmaceutical Engineering’s process validation conference Oct. 25 in Bethesda, Md. For the past four years Parlane has been involved with the Asia-Pacific ISPE affiliate council and has provided validation training in the region.

WHO Adopts Lifecycle Approach

Parlane said that WHO has begun helping to foment change in the region and drive the lifecycle approach to process validation with the publication last year of its guideline allowing for different approaches in process validation. The guideline states that “the lifecycle approach links product and process development, validation of the commercial manufacturing process and maintaining the process in a state of control during routine commercial manufacturing.”

The guidance is in a revised Appendix 7 to the WHO GMPs, which calls for a risk-based lifecycle approach to process validation and includes nonsterile products as well as sterile products and APIs. The document is called “Guidelines on Good Manufacturing Practices: Validation, Appendix 7: Non-Sterile Process Validation.” The guidance, despite its title, also applies to process validation for APIs and sterile products.

The guidance, said Parlane, is very similar to the process validation requirements spelled out in EU GMP Annex 15.

WHO member countries include Bangladesh, India, Indonesia, China, South Korea, Taiwan, Thailand and Vietnam.

He said that India has embraced the guidance and that it has had a strong impact there. “WHO guidances are viewed seriously because, largely speaking, it is a big brother type of thing and regulators want to keep the standard up for developing countries.”

Parlane said that at an ISPE Asia affiliates meeting last year a representative from WHO said inspectors will be using this guide when they inspect facilities. “Maybe the regulations will take a while to catch up but WHO is starting to look at some of these sites and is starting to think about lifecycle validation and asking questions about that.”

Forthcoming Guidance on Vaccines

In another new development, ASEAN is expected to release guidance soon that calls for a lifecycle validation approach for vaccine manufacturing. The guidance is meant to complement ASEAN’s existing document on lifecycle approaches for drug products.

ASEAN’s process validation guidance for drugs, adopted in July 2012, adopts the International Council for Harmonization’s lifecycle approach to process validation and incorporates various aspects of EU and FDA guidance on process validation. Referring to the ASEAN guideline, Parlane said that “Asia seems to lay behind but it was right on the cusp with everyone else.” (Also see "ASEAN Countries Make Progress in Harmonizing Pharmaceutical Quality Guidelines" - Pink Sheet, 28 May, 2015.)

The content of the guideline is expected to align with the content of WHO’s “Validation of Production Processes for Vaccines for WHO Prequalification Compliance Expectations,” issued in July 2013. ASEAN’s Consultative Committee for Standards and Quality Pharmaceutical Product Working Group is developing it.

PIC/S Annex 15 Uptake

Another force in the Asia-Pacific region that is helping to drive lifecycle validation of pharmaceutical processes is PIC/S, which has adopted the approach to process validation set forth in EU GMP Annex 15.

Yet Parlane pointed out that being a member of PIC/S does not automatically mean a country will adopt Annex 15. Parlane said that there has still been no major uptake on Annex 15 in the region. This situation is unchanged from a year ago where he also reported slow uptake. (Also see "Uptake on Annex 15 Slow in the Asia-Pacific Region" - Pink Sheet, 20 Nov, 2015.)

He said that only four PIC/s member countries have adopted Annex 15 – Malaysia, Singapore, Taiwan and Thailand. Yet he pointed out that just because a country adopts Annex 15 does not necessarily mean that it will be enforced. For example, while regulators in Malaysia have adopted the current version of Annex 15, they are not enforcing it. “They are using the lifecycle validation code but essentially it doesn’t really stick in their country. The regulatory framework says that you should do this but the industry doesn’t. It is not a criticism; it is just the way it is.”

He also noted an interesting contradiction: some Tier 1 countries with mature GMP systems have not yet adopted Annex 15, including Australia, Indonesia, New Zealand and Hong Kong, which are using outdated versions of the annex. He said that “even though the Australian regulator was what you would call a Tier 1 regulator, their legal framework does not mandate Annex 15 at this point in time and this is an important point to consider about Asia.”

Parlane said that PIC/S is wielding more influence in the region and that more of its inspectorates are joining PIC/S. By last year, for example, inspectorates of 18 Asia-Pacific countries had joined PIC/S. This year, 19 of the 24 Asia-Pacific countries “have been influenced by PIC/S” with inspectorates that are either members or applicants, or are simply following the guidelines.

He said that in the Asia-Pacific region, the following countries have PIC/S member pharmaceutical inspectorates: Australia, New Zealand, Singapore, Malaysia, Indonesia, Taiwan, Japan, South Korea, Hong Kong and Thailand. New members are Hong Kong, which joined Jan. 1, and Thailand, which became a member on Aug. 1. Inspectorates of the following countries have expressed interest in joining PIC/S: China, Brunei, Bhutan, Vietnam, India and the Philippines. Parlane said that India has shown no interest in joining. The following countries are using their own PIC/S GMP guides: Myanmar, Cambodia and Laos.

The following countries follow the PIC/S GMP guide: Argentina, Australia, Indonesia, Malaysia, New Zealand, Singapore, South Africa, Taiwan, Ukraine, Hong Kong and Thailand.

PIC/S aims to harmonize GMP standards and guidance documents among pharmaceutical inspection authorities by training competent authorities, in particular inspectors, assessing and reassessing inspectorates, and facilitating the cooperation and networking for competent authorities and international organizations, according to its website.

GMP Maturity And MNC Presence Big Factor In Uptake

Parlane said that GMP maturity and the presence of multinational companies in the area are also two determinants of whether the lifecycle approach to process validation will be adopted, with or without a regulatory structure in place.

Japan and Singapore are very mature markets with the presence of multinational companies from the US and the EU being a major influence. “Fundamentally process validation in the region is driven by multinational companies and not regulations. They either have local affiliates in the area or CMOs that are either being dragged in or are being proactive.”

Remaining Challenges Noted

Parlane said that there are regional influences – cultural barriers as well as language barriers – that may constrain the pace of adoption of lifecycle process validation, particularly for local firms that are not making products for export.

For example, there are different perceptions of risk, with a higher risk threshold in Asia than in Europe or the US. “They will climb up a 10-foot tower of scaffold of bamboo. Their tolerance for risk is different. They have a different risk paradigm.”

Another factor to be considered is the value proposition and whether it is worth it for government to push for lifecycle process validation, which may improve safety and quality of drugs produced for local consumption, but can result in higher drug costs. “You have to wonder what the government’s motivation is. Something costing 10 cents a dose and if you push really hard it will go up to $10.00. At the end of the day, the government has to make sure that the medicines are out there.”

There are also language barriers and trying to impart information on how to statistically sample products on the manufacturing floor to operators. “How do you convey this in a language that could be understood on the shop floor in Thailand? How do you explain statistics?”

He also said that these changes are “coming really, really fast and a lot has happened in four years.” He said that “if we push too hard and too fast we may unintentionally create divergent GMP systems when we want to harmonize – or worse, encourage resistance or reduced capacity in the CMO networks. We have to be careful of how fast to push. We don’t want reduced capacity, and I wonder if we are already starting to see this in China.”

The challenge for regulators is to set the bar at the right height for the market, he said. “The regulations are clear and we are driving the bar high. But we have to set the right bar for the market.”

From the editors of Gold Sheet.