Regulators rethink how best to oversee quality issues

Patient safety demands strict quality controls for drug manufacturers, but increasing drug shortages have led to new initiatives by the regulatory authorities that aim to streamline the oversight of new drugs, production processes and facility inspections

The past few years have seen a high number of defects in pharmaceutical products and in their production processes, as witnessed by the recent rise in product recalls and regulatory warning letters. The increase is due, at least in part, to the development of ever more complex products and processes, particularly for biologics, and also because of increasingly stringent oversight by the regulatory authorities. In some cases, where manufacturers have been unable to afford the investment to bring their processes up to the required regulatory level, the consequence has been a shortage of certain drugs. Many countries also face a backlog of applications with regulatory authorities, who are struggling with the approval output required by the industry.

In a recent white paper1 the US Food and Drug Administration also noted that the number of post-approval supplements received for review had increased over the past decade, partly due to the FDA’s own practice of ‘locking in’ an applicant’s manufacturing process before it is fully optimised. The current regulatory framework is particularly burdensome for manufacturers that must submit supplements as they strive for process optimisation. As so many manufacturers are looking to introduce new inline process analytical techniques (PAT), to move from batch to continuous processes or from stainless to single-use equipment as well as to digitalise systems, the regulators are struggling to keep their oversight and practices updated accordingly.

The FDA recently embarked on a new strategy to strike the balance of maintaining safety without creating shortages in drug supply. The Office of Pharmaceutical Quality (OPQ) – a new single unit within CDER dedicated to product quality, which opened in January – is designed to create ‘one quality voice’ and improve quality oversight throughout the lifecycle of a drug product. The aim of OPQ, says the FDA, is to create a uniform drug quality programme across all sites of manufacture, domestic or foreign, and across all drug product areas – new drugs, generics and over-the-counter products.

According to the regulator, OPQ is strategically organised to streamline regulatory processes. Not only will it look to promote and encourage the adoption of emerging pharmaceutical technology to enhance pharmaceutical quality, it will also bring closer integration of review, inspection, surveillance, policy and research for the purpose of strengthening pharmaceutical quality on a global scale.

In its white paper, the FDA notes that the present regulatory review and inspection practices ‘tend to treat all products equally, in some cases without considering specific risks to the consumer or individual product failure modes’, which results in a disproportionate amount of regulatory attention devoted to low-risk products and issues. This approach is diverting resources needed for the assessment of high-risk products, it says, and it plans to look at new methods that would redress the balance.

Furthermore, the FDA says that it currently has no formal means for quality surveillance, except through inspections, and it lacks resources to comprehensively review annual reports and other data (recalls and Field Alert Reports), which may provide significant quality information. It says that past inspection findings have not been a reliable predictor of the state of quality as they often cannot cover all products and processes, but rely on a limited subset of representative products and processes, often without reference to the specifics in the approved application. Similarly, it says product review is often conducted based on pre-marketing data from exhibit or clinical batches. ‘There may be a significant disconnect between these data and the conditions under which the material is manufactured during commercial production,’ it says. As a consequence, the FDA is looking to transform product quality oversight from a ‘qualitative’ to a ‘quantitative and expertise-based assessment’.

To do this, the OPQ has been organised based on discipline and expertise, e.g. drug substance, drug product, microbiology, process and biopharmaceutics. It says structured risk assessment will be used to facilitate quantitative regulatory evaluations and will serve as a communication vehicle internally and externally. ‘This will increase the efficiency and effectiveness of quality assessments by focusing on the specific risks to the consumer and individual product failure modes,’ it maintains.

It is, of course, too early to report on any specific outcomes and improvements resulting from this massive shake-up.

European regulatory focus

On the other side of the pond, EU regulatory focus has been on the new GMP Annex 15: Qualification and Validation guidelines, due to come into force on 1 October 2015. In particular, these guidelines suggest that the qualification and validation may also be used as supplementary optional guidance for active pharmaceutical ingredients (APIs) as well as the finished product. It also puts special emphasis on risk management and, in view of the growing deployment of IT systems, includes a note on the need to validate the computerised systems used.

Pharmaceutical ingredients have seen increased scrutiny from several angles and oversight is moving further down the chain from APIs to excipients and raw materials suppliers.

In June the UK Medicines and Healthcare products Regulatory Agency (MHRA) announced that counterfeit and unlicensed medicines and devices worth £15.8m had been seized in the UK as part of a global operation. The seizures – the biggest haul recorded to date in the UK – included large quantities of illegally supplied and potentially harmful slimming pills, erectile dysfunction, anaemia and narcolepsy tablets as well as unlicensed foreign medicines.
Picture courtesy of the MHRA

On 12 January 2015, the ICH Q3D Guideline on elemental impurities in pharmacuticals was integrated into the European Medicines Agency (EMA) scientific guidelines. The guideline was developed with the aim of providing a global policy for limiting metal impurities qualitatively and quantitatively in drug products and their ingredients. It, too, advocates the use of a risk-based approach to assessing the potential presence of elemental impurities in products.

In some of the fast-developing Asian markets, recent regulatory scrutiny and changes are reportedly hindering business growth. China’s Food and Drug Administration (CFDA), for example, is still facing a significant backlog of regulatory approvals, and some industry commentators suggest that its rigid approval structure combined with a lack of regulatory staff is holding back the commercial development of its innovative biotech R&D. In May, the CFDA also decided to raise the registration fees imposed on pharmaceutical drugs and medical devices.

Growth in both the Chinese and Indian sectors has been hurt by recent warning letters and by delays in FDA approvals, as the US safety body overhauls its review process. In addition, some smaller companies are struggling with the level of investment needed to meet the latest regulatory requirements.

The region still suffers from a high number of counterfeit products. According to the Indian Express2, India’s central drug regulator, The Central Drugs and Standard Control Organisation (CDSCO) has started the country’s biggest sampling drive to gauge more accurately the extent of counterfeit drugs on the market. Some 50,000 samples are thought to have been extracted for checking across the country over recent months and a report is expected within the next six months. Another rumour in the Indian press3 suggests that India’s Ministry of Health is proposing to change the regulator’s name to the Central Drug Administration (CDA) and will triple the agency’s staff over the next decade.

Counterfeit drugs, product tampering and adulteration remain a safety problem throughout the world. In a global market, the solution demands global initiatives – such as a requirement to give products a unique identifier that enables a drug’s authenticity to be checked against a central database. However, meeting the various nations’ different serialisation deadlines is the headache faced by many manufacturers. The EU’s deadlines for the 2011 Falsified Medicines Directive has compliance dates due in 2016 and 2017, for example.

India recently decided to harmonise its regulatory serialisation requirements with those being introduced in the other regions. The country’s Directorate General of Foreign Trade announced in March that from July 2015, all drugs with a manufacturing date on or after 1 April 2015 are exportable only if both the tertiary and secondary packaging carry barcoding as applicable, and if the relevant data as prescribed by DGFT is uploaded on its central portal5. The Global Trade Item Number (GTIN), batch number, expiry date and unique serial number has to be available on the primary packaging in human readable form.

While the requirement to include the data in a barcode has been exempt, the timelines for companies to install equipment and comply were deemed by many as short. New technologies for providing serialisation take time to implement and test but are now widely marketed. A recent report by Allied Market Research4 put growth forecasts for the joint anticounterfeit pharmaceutical and cosmetics packaging market at a compound annual growth rate (CAGR) of 15.7% during the period 2015–2020. According to the report, E-pedigree authentication technology will be the fastest-growing segment among RFID anticounterfeit technologies market, which is estimated to grow at a CAGR of 21.5% during 2015–2020.

Going digital

Data integrity is another area where greater regulatory attention is likely to fall in future. Many laboratory, production and quality processes are increasingly being computerised, removing the need for manual recording and human error, and thus improving quality. However, use of digital systems also requires that they meet certain quality standards and checks.

The UK MHRA updated its GMP Data Integrity Definitions and Guidance for Industry6 in March, following recent feedback from its members. This reminds manufacturers that data integrity is fundamental in a pharmaceutical quality system. The document provides MHRA guidance on GMP data integrity expectations for the industry and states that manufacturers and analytical laboratories are expected to design and operate a system that provides an acceptable state of control based on the data integrity risk, and which is fully documented with a supporting rationale.





4. “Global Anti-Counterfeit Pharmaceutical and Cosmetics Packaging Market-Industry Analysis, Size, Growth, Trends, Opportunities, and Forecast, 2014-2020”F



In June the UK Medicines and Healthcare products Regulatory Agency (MHRA) announced that counterfeit and unlicensed medicines and devices worth £15.8m had been seized in the UK as part of a global operation. The seizures – the biggest haul recorded to date in the UK – included large quantities of illegally supplied and potentially harmful slimming pills, erectile dysfunction, anaemia and narcolepsy tablets as well as unlicensed foreign medicines. Picture courtesy of the MHRA