Welcome to our Asia Regulatory Roundup, our weekly overview of the top regulatory news in Asia.
TGA Steps up Initial GMP Inspections After Adopting Risk-Based Approach
The Therapeutic Goods Administration (TGA) of Australia has increased initial inspections of drug manufacturing plants at home and overseas. TGA reported double-digit increases in the number of initial inspections of local and foreign firms in the back half of last year following the introduction of a risk-based approach.
In the six months starting 1 July last year, TGA conducted 16% more initial inspections of Australian manufacturers of medicines and biologicals than it did in the comparable period of 2015. The rise in initial certifications of overseas manufacturers was even steeper. TGA performed 25% more such certifications in the second half of 2016 than it did in the final six months of the previous year. The agency said processing times have improved significantly.
The trends stem from the adoption of a risk-based approach, which has caused TGA to focus on initial inspections rather than re-inspections of facilities that have consistently complied with good manufacturing practices (GMPs) over a period of time. TGA bases its inspection schedule on whether a company’s compliance was deemed basic, satisfactory or good at the last assessment. Manufacturers that achieve a string of good ratings are subject to reduced-scope inspections at wider intervals than other companies.
TGA reported the inspection data in its half-yearly performance snapshot. The report also included a comment on processing times for high-risk medical devices, which lengthened to up to nine months last year because of delays to the start of clinical assessments. TGA has since enacted “a range of strategies” it thinks will cut the wait time for assessments.
Other notable developments include a jump in the number of targeted reviews of complementary medicines. TGA initiated 235 such reviews based on data collected during random compliance reviews in 2015 and 2016. In the second half of 2015, TGA began 89 of these reviews. TGA cited the increase in targeted reviews as the cause of the 8% year-on-year increase in the proportion of medicines with verified compliance breaches.
TGA has adopted the new ways of working against a backdrop of an ongoing heavy workload. The prescription medicine unit approved 156 Category 1 and 665 Category 3 applications — including 23 new chemical entities — over the reporting period.
“While this represents a slight decrease against the equivalent period in 2015, where 193 Category 1 and 685 Category 3 applications were approved, many applications, particularly related to cancer medicines, are increasingly more complex in nature,” TGA wrote in its report.
TGA Revises Guidance on Stability Testing of Biological Medicines
TGA has revised its guidance on stability testing for prescription medicines. The changes primarily affect a section on the specific requirements for biological medicines, which now features advice on the role of stability data in validating shipping methods and supporting manufacturing changes.
Neither shipping nor manufacturing variations were featured in the section on biological medicines TGA published in 2013. The revised document published this week features close to 1,000 words on the two topics.
TGA has used the new subsections to detail the role stability data play in indicating what duration and magnitude of temperature excursions are acceptable during shipping. The agency expects manufacturers to provide real-time data to support their proposed shipping methods, justify how the proposal represents the “worst case shipping scenario” and validate the containers for use in such conditions. TGA wants real-time data showing what happens when a drug is kept outside optimal conditions and then returned to the desired environment for the rest of its shelf life.
If a biological medicine is to be brought to market after being exposed to a temperature excursion, TGA wants to see data to support its release. Ideally, the agency wants manufacturers to include results from a temperature cycling study, in which three batches of commercial-scale product are exposed to extreme conditions — such as six weeks outside temperature range for products shipped by sea — and then put through stability tests.
TGA has looked to the European Union for insights into how to approach stability testing, but in the case of biological medicines the geography of Australia means it faces some problems that do not apply to other parts of the world. The shipping policy is shaped by the knowledge that drugs travel lengthy distances across the equatorial region to reach Australia, increasing the risk of temperature excursions of sufficient size and duration to affect product quality.
The new guidance also features revisions to existing sections and the addition of advice on stability data and manufacturing variations. TGA wants manufacturers to perform real-time stability studies to assess whether a product’s shelf life has been affected by process changes with the potential to alter protein structure, purity, impurities profiles and potency.
India Continues to Struggle to get FDC Manufacturers to File Phase IV Protocols
The Drug Controller General of India (DCGI) has yet again asked manufacturers of fixed-dose combinations (FDCs) to submit Phase IV clinical trial protocols. DCGI Dr. GN Singh said “most” companies are yet to file protocols, despite receiving two requests to do so last year.
Singh wrote to manufacturers of FDCs in June and September of last year to ask them to submit protocols for Phase IV trials designed to show their products are safe and effective. Yet, despite the letters following years of regulatory pressure to generate data on FDCs, many manufacturers are yet to comply with the request. Singh’s language has changed slightly — in the previous letter he said “hardly any” firms had complied — but the message is the same.
As in the previous letter, SIngh said the correspondence “may be treated as regulatory reminder for further necessary action,” but made no mention of what sanctions companies will face if they continue to ignore the requests.
The ongoing refusal to comply with the request means Indian officials have now spent more than four years trying to resolve the FDC situation by getting manufacturers to run Phase IV trials. Over that period, the Central Drugs Standard Control Organization (CDSCO) moved to ban 344 FDCs it felt lacked supporting safety and efficacy data, but has struggled to eradicate the problems created by years of FDC manufacturers bringing their products to market through a regulatory backdoor.
NPPA Widens Stent Overcharging Probe to Cover 30 Hospitals
The National Pharmaceutical Pricing Authority (NPPA) of India has expanded its stent overcharging probe to cover 30 hospitals. NPPA is advancing the investigations in parallel to attempt to make all hospitals detail the price and brand of the cardiac stent used when billing patients for procedures.
In the weeks since capping the price of bare metal and drug-eluting stents, NPPA has received and started investigations into overcharging complaints against 30 hospitals. At the last count, three of the hospitals under investigation had supplied NPPA with either a detailed reply or clarification. NPPA is examining the responses in parallel to taking other actions.
The complaints have alerted NPPA to the failure of hospitals to “specifically and separately” detail the brand and cost of the stent used when billing patients. NPPA views this as “serious non-compliance” and has told hospitals to correct their practices.
NPPA has also scheduled meetings with stent makers, including Abbott and Boston Scientific, and medical device trade groups.
NPPA List, Hospital Memo, Manufacturer Meeting, More