7 steps to solve regulatory issues

Managing regulatory obstacles is a key essential factor in expediting the approval of the products. Yet it can be daunting when we receive pages long of questions.

Let’s look at the general workflow for solving regulatory issues.

  1. Categorize the questions into either administrative or technical. This will enable us to allocate our time better in solving the issues.
  2. Understand the question asked. Often, we find ourselves scratching our head at the “impossible” question being asked and assumption kicks in. What I recommend is to digest the question asked and highlight the points that I do not understand.
  3. Clarify any doubts. Speaking to the regulator via the phone is a clearer way of communication than email. With the points answered by the regulator, do follow up with an email to summarise and affirm the discussion points.
  4. Review what was submitted. When analyzing the question, it is good to see the relation between what has been submitted and the missing point that it fails to address. It can also help greatly with communication to the manufacturer that is supporting you.
  5. Work out possible solutions. When brainstorming solutions, it is good to make reference of step 1 to 4 so as to ensure that we address the objective of the question.
  6. Communicate to the manufacturer . When we send out queries to request for support, we need to be able to explain and supplement what is required from their end. Taking the extra effort to make someone’s job easier to help you will greatly increase the efficiency and time in response.
  7. Implement timeline to achieve the close out date. It is a good practice to have some leeway time to review the responses provided. A good yardstick will be to review any lacking response 1 week before the close out date/deadline.

By following the 7 steps above, it can increase your efficiency in dealing with pages long of queries and will enable you to foresee what’s going to come for the next round of queries. Good luck.

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5 quick questions to check before regulatory filing of pharmaceutical products in ASEAN

To many of the principals out there, ASEAN remains one of the biggest untapped market . But yet, there are many “mysteries” surrounding the ASEAN’s regulations. for filing of pharmaceutical products. Common questions encountered are like: What are the regulatory requirements? What are the obligations as a marketing authorization holder? What business model would be most appropriate to work with? As such, many principals fail to understand the needs and hence misunderstanding arises with local partners. Based on experience, the easiest to start with would be to work on the regulatory dossier at hand. Regulatory dossier is like the set of legal documents that you have to prepare in order for you to get the “VISA” =product licence into the country.

Let’s come down to the top 5 questions to check your dossier against before filing:

  1. Do you have a PIC/S GMP? PIC/S stands for pharmaceutical international cooperation scheme and is a “international standard” for the pharmaceutical industry to follow with regards to manufacturing operations. Many of the ASEAN countries health authority follows this standard for pharmaceutical products. Having a PIC/S GMP(Good Manufacturing Practice ) can save you plenty of time from on-site inspection , hefty costs as well as the long waiting time arranged finally for the site inspection. Use the below link to check out whether the GMP issued falls under PIC/S: https://www.picscheme.org/en/members
  2. Do you have Zone IVb stability studies? ASEAN climatic zone lies in hot and humid region hence it is important the products are able to maintain their quality and efficacy throughout the shelf life proposed . At minimum, there should be about 12 months of real time data[(30 30°C/75%Relative Humidity (RH)] and 6 months of accelerated data( [(40 30°C/75%Relative Humidity (RH)] ) for two batches for non-critical dosage forms ( Immediate Release Solid Oral Dosage Forms such as capsule and tablets) and 3 batches of the above data for critical dosage forms( injectables, oral-modified dosage forms, sterile preparations) .
  3. What is the reference product used in Bioequivalence (BE) study? *applicable especially for filing generics product* Health Authorities in ASEAN prefer that the bioequivalence studies are conducted using the registered source in their own country. If not, bridging studies are often required which includes but not limited to comparative dissolution studies.
  4. Is your dossier arranged in ASEAN Common Technical Dossier (ACTD) format? ACTD format comprises of 4 part namely Part I: Adminsitrative documents, Part II: Quality [Chemical Manufacturing Control(CMC) portion lies], Part III: Non-clinical, Part IV: Clinical documents. The structure remains essentially similar to that of the International Council of Harmonization Common Technical Document (ICH CTD) format which have 5 parts. Certain country such as Singapore can accept the original ICH CTD format for filing and hence arrangement of the dossier is not required.
  5. Labelling: are you ready to adapt to the specifics requested for labelling? Some specifics include but not limited to individual registration number, specific wording in country’s own native language to be printed on carton as well as the Summary of Product Characteristics (SPC)/ Patient Information Leaflet(PIL) in country’s own native language.

If you have checked more than 3 of the above(especially point 1,2 and 4) , you are about 80% ready to enter the market and cross the regulatory barrier. Hopefully this simple checklist can come into your mind when developing your business plan for the ASEAN market and raise some awareness for your meeting with your ASEAN partners.

Commercializing your product through regulatory classification

Healthcare industry remains to be one of the most regulated among all businesses. So how do small companies remain competitive in this regulated world? Today we will discuss about ways to maximize your product value through regulations.

We need to look closely at each category of classification: Medical Device, Drug Product, Cosmetics and supplements.

A medical device is a tool ( instrument, machine, diagnostic reagent, software and etc) that is intended to be used for diagnosis, prevention, monitoring and treatment of diseases.Usually a medical device would require a risk classification and grouping classification based on the intended use as well as the principle mode of operation. Class A(Class I /Class 1) Low risk device. Class B( Class IIa/Class 2 ) low-medium risk device. Class C (Class IIb/Class 2) moderate-high risk device. Class D (high risk/Class 3) high risk products. The technical requirements for a dossier in ASEAN would be a CSDT format which will consists of the following standard documentation such as but not limited to : Essential Principle Checklist, QMS certification(ISO 13485), Instructions for Use, Clinical and Non-clinical overview, and Risk Management.

Pros of registration as a medical device: Able to sell at higher price . Can open up more towards both the prescription and consumer market. Being innovative and unique allows you to stand out amongst competitor. Shorter registration lead time. Lower compliance cost. Sell a lot on consumable, technical servicing and parts. More route to open up for market trial before committing to registration.

Cons as a medical device: Small volume. Needs longer time to build a brand and requires heavy marketing. Invest in setting up a QMS which can be quite tedious for small company.

An example of such product is a perineal cold pad used for supporting wound healing after post healing procedures.( medical device) . It would be better to market the product as a medical device through gynecologist so as to build up the brand for you through prescription . Once the awareness of such product is high, it would be much easier to place it on the general drug stores to acquire sales volume without incurring shelving fees and even through online platform.

A drug product is a chemical/ biological entity that is presented in various dosage form to treat and prevent of disease. Drugs are classified according to their status as a prescription(Px/POM) , pharmacy(Rx/OTC) and a general sales list( products that does not require any professional advice). The technical requirement of a drug is much more extensive and typically would include but not limited to formulation studies, pharmaceutical development, manufacturing processes and controls, process validation studies, stability studies, bioequivalence studies, clinical and non clinical studies.

Pros of registration as a drug: Claims are backed by established human studies. Able to sell at a higher volume compared to other products . Marketing is not as extensive in terms of cost wise for well-established drug profile.

Cons of registration as a drug: requires a lot of clinical data and studies. Long registration time and cost. Need to compete a lot on relationship with healthcare institutions and good supply practice ( able to meet the demand of the clinic).

One such example is a intraarticular injection (med device/ drug). The intended use of an intrarticular injection : to replace the synovial fluid between the joints in osteoarthritis and rheumatoid arthritis. Active ingredient is a high molecular weight hyaluronic acid. However, some companies would prefer to register it as a drug product as it will be able to increase the prescription value for a doctor. Usually MNC follow this route and they will be established as a innovator in this area.

Smaller companies would register it as a medical device as it has a shorter lead time to bring in the products. It also creates branding awareness by being the first few products to be launched.

A supplement consists of a standalone or combination of vitamins, minerals and extracts which is used to support a physiological function of the body.Often the claims are based on general usage of the vitamins, minerals or extracted clinical papers. Technical requirements are usually the ingredient listing, packaging, manufacturing processes as well as supporting evidence of clinical claims.

Pros of registration as a supplement: Registration lead time might be shorter and registration requirements are not as extensive compared to the rest of the products. The claims are essentially based on well-established studies about the product as essential vitamins and minerals to support and sustain physiological functions.

Cons of registration as a supplement : Limited medical claims. Have to check on the maximum and minimum and restricted ingredients that can be registered in the country . Similar competitors. Heavy marketing.

Let’s take a example of a food supplement which is intended to maintain good digestive system ( supplement/drug) . Such supplement is usually prevalence in the market so it’s better to register a higher category to give an edge that the product has clinical backings to it hence this will build your brand at a higher level than the rest of the competitors. Will increase consumer confidence.

A cosmetic product means any substance or preparation intended by its manufacturer to be placed in contact with the various external parts of the human body such as the skin epidermis, hair, nails, lips and external genital organs or with the teeth or the mucous membranes of the oral cavity with a view exclusively or mainly to cleaning them, perfuming them, changing their appearance, correcting body odours, protecting them or keeping them in good condition. (taken from ASEAN Consumer Information Handbook on Cosmetic Product). Cosmetics products are categorized mainly as low risk or high risk (applied around the eye area or mouth area). The technical requirements would usually be a product information file consisting of the formulation, manufacturing process, relevant certification, and packaging.

Pros of registration as a cosmetic product: shorter registration lead time and technical requirements. Cost is lower to bring in the product.

Cons of registration as a cosmetic product: Heavy marketing and brand building. Short product cycle. Many competitors.

Let’s take for example a sunblock ( cosmetic / medical device)that comes with a high SPF which is claimed to prevent the formation of melatonin or control the production of melatonin . It would better to register as medical device since you would be able to use the prescription market to give you a higher brand value.

Regulatory classification can definitely put your product at an edge over your competitor if you are able to first evaluate and understand the intended market audience, the awareness of the market on the condition and how you want to position your product in the long run . By considering the above strategy of categorization as well as the analysis of the pros and cons it would assist you to align your product supply with the market demands and manage your product life cycle better.

What is a ASEAN CTD ?

In my previous blog, we shared briefly on 5 points to look out for when preparing a dossier for submission. In the process of compilation of documents, you often hear your Southeast Asia partners mention about a specific format for submission which is the ASEAN CTD.

So what is ASEAN CTD?

ASEAN CTD stands for ASEAN Common Technical Documentation. It is a collaboration among ASEAN countries to unify common technical requirements and to simplify submission process across ASEAN countries for pharmaceutical products. It is also available as ASEAN CSTD- Medical Devices, ASEAN Product Information File-Cosmetics and so forth. Think of it as a similar approach of having a organized, structured and simplified framework to access to different countries in the region just like how European Union does it. The success of European union is what ASEAN hope to achieve soon down the road.

In European countries, ICH guidelines and format are used for submission of pharmaceutical products to the various health authorities amongst the countries. In ASEAN countries, we follow the ASEAN regulations as well as the ASEAN CTD format for submission. ICH has 5 modules as compared to ASEAN CTD which has 4 parts. The slight difference is in the organization of the documentation into the different parts stated.

ASEAN CTD consists of 4 parts namely : Part I: Administrative Documents, Part II :Quality Documents, Part 3 :Non-Clinical Documents and Part IV :Clinical Documentation. Each part has sub sections divided into Section A, Section B, Section C, Section D and Section E.

In Part I , it consists of the application forms, official letters of authorization, official certificates such as GMP, Manufacturing Licence, Certificate of Pharmaceutical Product (CPP) as well as packaging of the product to be marketed. This is how the section will look like:

Part II focus on the Chemistry Manufacturing Control portion of the active ingredient and the finished product. Information such as Quality Overall Summary(QOS), formulation, manufacturing process, in-process controls, validation, analysis and stability comes in.

Part III will have the non-clinical overview, written summaries and tabulated summaries.Part IV consist of the clinical overview, clinical summary, clinical reports and literature references.

Although most ASEAN countries follows the ASEAN CTD Format, however Part 1 requirements will still differ from country to country in terms of such as labelling, application form and official certificates required

Hopefully this simple write up has given you some clarity on ASEAN CTD. Good luck for submission!