Facility design requirements for high potency APIs

Amrit Karmarkar

Highly active chemical substances or drugs are one of the fastest growing segment of pharmaceutical industry. Different Indian multinationals such as Cipla, Dr Reddy’s Laboratories, Ranbaxy, Sun Pharma have set up their high potency active pharma ingredients (HPAPI) facilities across India. Handling, containment, manufacturing, facility design, machinery and regulatory requirements of these compounds are more stringent and different from conventional APIs. This review focuses on current market, machinery requirements, facility design aspects and handling issues.

Introduction

There is great demand for HPAPIs since the last 17 years. Advancements in clinical pharmacology and oncology, AIDS research has resulted in emergence of HPAPIs in market. Large numbers of HPAPIs are currently undergoing clinical trials and will soon reach commercialisation. Due to the potent nature of HPAPIs, there must be a keen eye on the evaluation of these compounds for toxicity. Also for manufacturing pharma products, safety and containment issues must be monitored. European Medicines Agency (EMEA) has taken the initiative so far to issue a concept paper regarding this type of drugs.

Indian scenario

The pharma industry is one of the booming industries in India. Current annual growth rate (CAGR) for this industry is 12-14 per cent according to McKinsey Report. The industry has seen a growth up from $1 billion in 1990 to $20-24 billion by 2015. Active pharma ingredients (API) manufacturing is the key business in India’s pharma sector. Nonetheless, India has around 75 US FDA approved manufacturing plants. HPAPIs are relatively the new segment in Indian pharma sector but due to demand of cytotoxic/anticancer drugs in India, the companies are setting up their plants in India. Carbogen Amcis, a Dishman Group company has set up 4300 sq m site at Ahmedabad in 2010 at the cost of $20 million which is in compliant with current good manufacturing practices (cGMP). This is an initial step by foreign companies to invest in India’s HPAPI market. Soon more companies will plan to set up their activities in India. Even, Indian multinationals like Cipla, Lupin, Dr Reddy’s Laboratories have set up their oncology drugs facilities in the country.

Overview of the global market

Global HPAPIs market is expected to grow at a CAGR of 8.4 per cent till 2015. Cytotoxic agents (oncology segment) market out of them is itself growing at a CAGR of 12.6 per cent globally. North America predominates the HPAPIs market in the world with a 45 per cent share. The US has a dominant share of 93 per cent out of them. A majority of the drugs in this region are from anticancer, hormonal, glaucoma, etc. Major players in the North American market are Teva, SAFC, Carbogen Amcis, Bristol Meyers Squibb, Asymchem, etc. Europe is second largest market with 35 per cent share in HPAPIs industry. Bristol Meyers Squibb, Lonza, Bayer, Boehringer Ingleheim, Sanofi Aventis, Carbogen Amcis are some of the companies leading the HPAPI market in Europe. However, in Australia, IDT is a leading player for HPAPI. In the Asian scenario, Japan, China and India are the most emerging markets. In total, it is estimated that more than 25 per cent of the drugs in clinical development pipeline are in this category.

HPAPI facility design

As HPAPIs can get access to body systems via inhalation, accidental injection, ingestion of contaminated foodstuffs or mouth contact with contaminated hands and dermal absorption; protection of personnel is the first criteria in facility design. Manufacturing HPAPI is a complex process, and involves manufacturing and processing in clean room operations with containment facilities. These processes are carried out at negative pressure to prevent materials from entering the environment, with workers wearing full protective gear.

It is advisable that containment equipment must be available throughout the process of HPAPI from bulk API production to product formulation. Containment device selection, setting targets, and verifying containment performance by factory acceptance test (FAT) and site acceptance test (SAT) are the key steps in achieving HPAPI production and processes. Use of airlocks, barrier isolators, transfer chambers, bagging devices, rapid transfer port, buck valves, split butterfly valves is helpful. For change room areas, systems such as mist shower or air shower are also used.

Following are three ways by which HPAPI facility and processes can be set up:

Full containment technology

In this design method, sampling of active and transfer can be done by disposable, low cost charging bag. Excipients can be dispensed using dispensing isolator. Containment sifter with compact airlock sieve allows sifting of ingredients of formulation. Pot processor or integrated granulation system can be used and blending can be carried out in-line with granulation to avoid exposure. Containment tablet press with ‘wash in place’ facility or wash offline mode with exchangeable compression module technology (GEA) can be used. Auto-coater with discharge using split butterfly valve and clean in place facility can be used. Packaging can be done with isolator operation.

Containment using isolators

Here isolators are used for creating controlled environment for manufacturing activities. Sampling of actives is done in isolators and excipients are dispensed using dispensing isolators with split butterfly valves. For material handling across all the process intermediate bulk containers (IBC) with containment valves can be used. All granulation and compression machines will be stored inside isolator for manufacturing activities. Closed transfer of tablets will be done to coating area wherein coating machine is also fitted inside isolator. Barrier systems can also be used for packaging.

Combination of first two methods (cost effective)

This might be a cost effective approach for manufacturing HPAPIs. Here sampling is done in the isolator and double bagging can be used while material transfer. Sifter can be installed within isolator or the containment sifter can be used directly. Granulation and blending can be done in single pot processor. Wash in place and wash offline tablet press can be used for manufacturing tablets and using closed transfer system they can be transferred to coating area wherein auto-coater or coater in isolator will be installed. Packaging can be done in isolator.

For all processes, document transfer enclosure must be there to allow paperwork in processing to be handled in contained way so that powders are not transferred onto documents. This prevents contamination to individuals that are not protected. This system has a set of glove sleeves, bag in bag out canister, space to store plastic bags, and stainless steel frame. Document transfer enclosures of Dover Pac are popular in industry.

Important considerations for HPAPI facility

a. Personnel considerations: Basic requirements of manufacturing activity is use of standard operating procedures (SOPs), regular review of materials safety data sheet (MSDS), and use of personal protective equipment (PPEs). Gloves appropriate for the chemical being handled and double gloves must be used for handling HPAPIs. American Society for Testing and Materials (ASTM) designates chemotherapy gloves capable of resistance of permeation by chemotherapy should be preferably used. Gowns or coveralls must be used. These should have properties like lint free, low permeable, closed front, long sleeves, and elastic/knit closed cuffs. Cuffs of these gowns must be tucked under gloves. Safety glasses and N95 HEPA masks must be used. Powered air purifying respirators (PAPR) are the choice in the manufacturing or processing of HPAPIs. PAPRs are battery operated, consists of a half or full face piece, breathing tube, battery-operated blower, and particulate filters (HEPA only).

b. Protective goggles: Protective goggles help in preventing exposure of HPAPIs to eyes. These goggles are flexible and are made of scratch proof material with anti fog coated lens. Key feature of these is they can also fit on your spectacles.

c. Waste disposal facilities: Sufficiently large and leak proof waste disposal containers with specially made plastic bags of high density must be available in every area of manufacturing plant including store. All HPAPI waste must be stored into these containers or bags.

d. Emergency washing: Whenever exposure of highly potent compound happens to any person in the working area especially when eyes and skin are exposed, it may cause irritation, skin burn or any other potential hazard may occur. To prevent this, emergency washing facility must be used. These can be plumbed or portable washing units that can use isotonic saline flushing solution for washing.

e. Use of air and mist showers: These are only one-way rooms. Air showers installed at entrance of cleanroom help in minimisation of particulate matter entering into cleanroom area. HEPA jets can be used and contaminated air is drawn through bottom of unit, filtered and recirculated. Room for collection of protective clothing is necessary near air shower. In mist shower, highly pressurised water is spread on protective suit of person to drain the powder material in cleanroom area. This prevents passing out of hazardous material (HPAPIs) from circulating in air while de-gowning process. Mist showers are more advisable in industrial processing than air showers.

Conclusion

Due to demand in the market many companies are planning to set up their HPAPI facilities across different countries of world. Facility design of HPAPIs is always challenging as it includes many issues related to containment in every process. High use of containment guarantees safety to personnel working in the clean room area. Proper facility design with use of SOPs, training of operators, containment equipments, process isolation, facility design, personal protective equipment, and cGMP activities will help to prevent potential hazard during HPAPI production.