Asia-Pacific Roundup: Malaysia’s NPRA publishes guideline on nitrosamine impurities

Malaysia’s National Pharmaceutical Regulatory Agency (NPRA) has published a guideline on the control of nitrosamine impurities in pharmaceutical products, allowing product registration holders to submit files they created to meet requirements in Europe and the US to satisfy its demands.

NPRA’s text applies to all pharmaceutical products for human use that contain chemically synthesized active pharmaceutical ingredients (APIs) “including biological products except for non-scheduled poison, natural and health supplement products.” The scope of the guidance will expand to cover any products that are found to have issues related to nitrosamine impurities. NPRA has drawn on guidance from the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) to create its guideline.

The first main section lists risk factors related to the manufacture of APIs, finished products and good manufacturing practices. The risk factor section provides the same information as a question-and-answer document from EMA. NPRA has abbreviated some of the EMA responses, notably about the reaction of APIs or impurities with nitrosating agents in finished products during formulation or storage but has referred readers to the European document for more information.

Similarly, NPRA’s list of steps to mitigate the risk of nitrosamine impurities follows the same format as the European Medicines Regulatory Network. Malaysian and European officials both recommend a three-step approach that covers risk evaluation, confirmatory testing and the implementation of risk mitigation measures.

NPRA wants product registration holders to assess if their APIs or finished product could be at risk of nitrosamine impurities. If a risk is identified, the company should perform confirmatory testing as soon as possible. NPRA wants registration holders to use a “sufficiently sensitive” analytical method and take the purpose of testing into account. If an API or finished product contains impurities above the limit set by FDA and EMA, the company should submit a risk mitigation plan and propose regulatory actions.

The NPRA guideline goes on to discuss scenarios in which variation submissions are or are not required and explain that the agency may request risk assessments from companies seeking authorization of new products if they are not included in the registration dossier. NPRA will continue its surveillance program and perform periodic monitoring of commercial products to ensure nitrosamine standards are met.

NPRA has attached a frequently asked question (FAQ) document to the guideline that explains there is no timeline for the work and that registration holders are responsible for performing risk assessments “by considering the whole product’s lifecycle.” There is no fixed risk assessment format, the attachment states, and companies can use evaluations completed for EMA and FDA to meet Malaysian requirements. NPRA is equally accepting of the approaches proposed by EMA and FDA.

NPRA Guideline

Pakistan’s DRAP seeks feedback on draft guidelines for post-registration variation of drugs

The Drug Regulatory Authority of Pakistan (DRAP) has released draft guidelines on the post-registration variation of pharmaceutical and biological products for consultation, proposing major structural changes to the first version of the guidelines that it finalized last year.

According to DRAP, the draft retains “the essentials” of the previously published guidelines and has been “extended with new terminology of types of variations and documentation required to support a specific change.” DRAP is also proposing to recategorize certain major variations as minor variations that require prior approval before implementation and to end the need for approval of some minor variations.

The draft is “technically and structurally inspired” by the Association of Southeast Asian Nations (ASEAN) variation guideline and a World Health Organization (WHO) document on prequalified products. DRAP prepared the first version in light of the EU’s position.

The revised draft is dominated by a section that outlines what qualifies as minor variations needing notification, minor variations needing prior approval and major variations. For each type of variation, DRAP lists the change in a table and then provides information to clarify its position.

For example, a table states that companies only need to notify DRAP of minor changes in the manufacturing process of an immediate-release solid oral dosage form, semi-solid or oral solution. Subsequent bullet points clarify that the rule applies to changes such as the switch from manual to automated equipment for moving ingredients and the use of different equipment of the same design and operating principles.

Proposed changes to the type of variation include plans to reclassify updates to prescribing information as minor variations that need prior approval. While currently classed as a major variation, DRAP thinks a minor variation with approval is suitable for changes that are in line with the “labeling and prescribing information of the innovator products as approved by the Reference Regulatory Authorities designated by the Registration Board.” DRAP wants companies to submit the old label and justify their changes.

The guideline features new language on changes leading to a new product registration. DRAP explains that certain changes to the drug substance, such as switching to a salt or isomer form, and revisions to the dosage form, including moving from a liquid to a powder for reconstitution, require a submission to market a new product.

Other changes include new timelines for processing applications. The existing guideline only states that DRAP will take 90-120 days to assess major variation applications. In the draft, DRAP proposes a wait of 45 working days for minor variation approvals and 60 days for major variation approvals.

DRAP, which published the draft on 4 July, is accepting feedback for 14 days.

Draft Guidelines

HSA starts requiring ‘full-fledged registration’ to supply COVID tests in Singapore

Singapore’s Health Sciences Authority (HSA) has closed off the Pandemic Special Access Route (PSAR) for COVID-19 tests and begun requiring products to have “full-fledged registration” to be sold in the country. The new rules took effect on 1 July.

To support the transition, HSA directed manufacturers to two guidance documents on in vitro diagnostics and a summary of the validation requirements for the registration of COVID-19 tests. HSA has provided different sets of validation requirements for COVID-19 self-tests and professional use tests.

Tens of COVID-19 diagnostics including tests made by Abbott, Hologic and Roche are already listed in the Singapore Medical Device Register (SMDR).

HSA Notice, More

Other news:

Australia’s Therapeutic Goods Administration (TGA) has reminded sponsors to consider its nitrosamine guidance when preparing Category 1 prescription medicine registration applications. The guidance provides acceptable intake limits for nitrosamine impurities, and TGA expects sponsors to refer to the information to help them meet their regulatory obligations. TGA Notice

Asia-Pacific Roundup: Malaysia’s NPRA publishes guideline on nitrosamine impurities

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