Contract Manufacturing For Highly Potent Active Pharmaceutical Ingredients

Contract Manufacturing For Highly Potent Active Pharmaceutical Ingredients

Highly potent active pharmaceutical ingredients (HPAPIs) represent a significant change in the way pharmaceutical innovators are using small molecules to deliver new patient therapies. This shift toward highly potent APIs has not only led to a pipeline of more effective medicines that require lower doses and lead to fewer side effects, but also to new manufacturing challenges.

Highly potent active pharmaceutical ingredients (HPAPIs) represent a significant change in the way pharmaceutical innovators are using small molecules to deliver new patient therapies. This shift toward highly potent APIs has not only led to a pipeline of more effective medicines that require lower doses and lead to fewer side effects, but also to new manufacturing challenges.

Approximately 25% of drugs currently in development worldwide are classified as highly potent with forecasts suggesting that their increasing therapeutic use is expected to drive the global market for HPAPIs by an estimated CAGR of 9.9% from 2012 to 2018 . While the majority of HP drugs are anti-cancer compounds (the oncology sector alone is expected to increase in value from $64bn in 2011 to $104bn in 2018 ), other HP products include therapeutics such as hormones, narcotics and retinoids.

Typical high potency active ingredients are hormones or cytostatic drugs: they may have a carcinogenic or mutagenic effect or cause genetic mutations if handled in relatively high quantities without suitable protection.

Each production phase has to be carefully evaluated as for its related risk; initial planning of production facilities should take into consideration all the measures needed to remove this risk. The analysis not limited just to the production plant, but it may concern also the warehouse management, cleaning processes and the maintenance of the equipment.

Over the past few years a steady stream of contract manufacturing organizations (CMO) have added high potency active pharmaceutical ingredient (HPAPI) production capacity. The expansions give biopharma executives charged with selecting HPAPI production partners an unprecedented number of options, but all this choice creates a problem — which CMO should you pick when each is touting similar technical capabilities?

When looking at CMOs from a purely engineering perspective this is a very tricky question. As an industry we now know what it takes to manufacture HPAPIs. The engineering controls, toxicity and potency evaluations, and containment strategies that make HPAPI production possible are well understood and in place at multiple CMOs.

Each manufacturer takes a slightly different approach to designing their plants and policies, but nonetheless their operations still address the same essential elements of HPAPI production.

The working environment is the sum of the room, the equipment and the people working in it.  According to regulatory guidelines, it is necessary to adopt suitable protections for the working space and the equipment, in order to facilitate as far as possible the free movements of the workers.  Starting from an OEB level of 3, protective measures have to be directly applied on the machines: they start to look different. The planning is aimed to keep separated the process area and the technical area containing the auxiliary apparatus needed to run the machines. Manual operations should be limited as far as possible. Glove ports and isolation barriers are used if it is necessary to allow access for the operator. High level of automatic control is also put in place. Cleaning systems are also completely automatized. Absolute air filtration is used to manage air movements between the external and interior of the isolator, a procedure that is involved at various degrees with all operations on powdered high potency ingredients.

On one level this is a positive for anyone tasked with picking a CMO for HPAPI production. Yet even though multiple manufacturers have the same basic technical capabilities, the services they provide are separated by far more than just timing, location and price. Sellers and procurement personnel of HPAPI services understandably focus their talks on production operations, but successful CMOs know manufacturing these demanding ingredients is a test of more than just engineering expertise. Producing HPAPIs is a mission for the whole company.

Figure 1 is an overview of a responsibly designed HPAPI production workshop:

Staff in quality control (QC), environmental safety, purchasing, human resources, and other teams all play a role in ensuring the smooth, safe operation of a HPAPI production plant. Most fundamentally, everyone working at a HPAPI production plant — regardless of whether they come into contact with the ingredients — must understand the risks. Company-wide health and safety training and standard operating practices (SOPs) are important to identify critical hazards and proactively prevent even the most unlikely of dangers inherent in producing HPAPIs.

The health and safety implications of manufacturing HPAPIs mean it is unwise for companies to rush into the sector. As well as taking the time to plan the technical infrastructure, CMOs should step back and look at their whole business before committing to HPAPIs. It is essential to implement training, risk assessment tools and an ethical commitment to protecting staff across the business to create a safe working culture and environment. If entry to the HPAPI sector is rushed, each of these little, non-manufacturing aspects of becoming a successful producer are at risk of getting lost in the shuffle.

In this scenario worker safety is put at risk and the likelihood of the client receiving an excellent service diminishes. The effect of inadequate ancillary teams is most obvious — and critical — when looking at the interaction between manufacturing staff and their peers in research and development. When a CMO is running smoothly laboratory-scale work done by the R&D team feeds directly into manufacturing operations. This synchronization allows a CMO to demonstrate chemical processes in a safe, small-scale environment and then use this knowledge to shape HPAPI production.

A logical Contract Pharma Services Approach to Assessing New Highly Potent Product Introduction:

The level of containment

The occupational exposure level (OEL) is the parameter upon which the decision is taken: an OEL value minor or equal to 10 mg/m³ calls for the implementation of more rigid risk containment measures.

See containment pyramid below:

OEL is just one among several different parameters available as international standards in order to measure and classify the toxicity of the active ingredients and of other chemical substances. Operational exposure limit usually refers to inhalation exposure and it is used as an indication of the maximal concentration of the substance in the air at working places that allows no risks for the health. OEL levels change for oral or parenteral exposure. Exposition time is calculated on the basis of eight hours per day (40/h per week) over the entire life span. International guidelines do not indicate a precise requisite as for exposure levels during production.

In assessing the containment challenge, consider three levels of protection:

• ·      Primary containment - equipment targets isolation of the product from the operators and the environment. Equipment is normally equipped with Clean in Place (CIP)/Wash in Place (WIP) and may be supplemented by flexible single use element for interventions.

          Below is suitable equipment for primary containment:

• ·      Secondary containment - includes use of separate processing rooms

          Room dedicated for handling HPAPIs:

• ·      Tertiary containment - refers to facility design such as dedicated, segregated suite(s), security access controlled, HVAC single pass air (safe change in room), double HEPA exhaust, pressure cascade and fogging shower.

Achieving this seamless overlap between R&D and manufacturing takes time, resources and planning though. Unless the units have complementary training and equipment, manufacturing teams will struggle to translate the lessons learnt by R&D in the laboratory to larger scale production. The effect of any disconnects between R&D and manufacturing are particularly pronounced when the latter encounters an unexpected chemistry-related challenge. Without compatible equipment an R&D team will struggle to quickly find a solution to manufacturing’s problem. A small issue can create a big delay.

Air flow control

Air flow is one of the more critical points that need to be considered in risk analysis. The bigger the scale of the operation, the greater is the quantity of air involved, thus requiring more stringent safety measures. The solution more widely used is the filtration of suspended particles using absolute filters, a highly complex technique to be put in place. 

A pressing machine, for example, moves a very small quantity of air as the pill is created: a simple aspiration system, with a limited filtering surface, is enough. Fluid belt machines, used for powder granulation and drying, are the more difficult to be managed, as they work with thousands of air cubic meters each hour. The air that could have become in contact with the HPAPI needs to be filtered before it can be eliminated. These filters have a surface of hundreds of thousands of square meters and they too need to be handled under containment.

The monitoring of the efficacy of containment is possible thanks to detection devices located close to critical points of the equipment or on the workers’ dressing.

Areas of importance related to containment and air flow control:

• Room pressure differentials designed for containment (with monitoring and verification), with the main HPAPI-handling area at negative pressure to surrounding rooms
• Airlocks and vestibules around manufacturing and laboratory spaces to provide gowning and degowning areas and proper pressure differentials
• Restricted access to ensure that only the necessary trained employees enter the HPAPI-handling areas
• HVAC (heating, ventilation, and air conditioning) systems designed for single-pass air—no return, with temperature, humidity, and particulate controls
• Misting showers as part of degown and exit vestibules to rinse personal protective equipment (PPE) and gowning prior to removal
• Filtration and capture of contaminants, with safe-change filters, both point source (within the isolator, ventilated enclosure) and the general HVAC exhaust system
• Preventive maintenance and change-control procedures to ensure that equipment and systems continue to operate properly and according to design specifications.

Here are some examples of HEPA filtration systems designed for cleanrooms:

Unknown toxicity substances

New substances coming from the research labs often have a still incomplete toxicity profile. It is thus more difficult to establish definitive levels of exposure to be used for risk analysis. There are two opposite behaviors to face this issue: Big multinational companies can invest great sums for the production facilities: they ask for the maximal containment.  Other companies, often working at preliminary R&D on small quantities of substance (max 1 Kilogram) and without 24H production needs, consider the risk level to be lower, as time exposure is shorter. There are still some manual operations difficult to make safe as for the equipment is concerned: the choice is thus to protect the workers with an appropriate dressing.

The risk analysis

The attention of pharma industry toward the adoption of containment measures has increased in parallel to the increasing regulatory requirements.  A first phase, some years ago, saw an initial rush: any solution was suitable regardless to the type of the production. Many companies invested a lot of money without reaching the goal, time and costs of production also increased. A later phase saw a greater attention to risk analysis and a better planning of the containment strategy.

In the production of solid pharmaceutical products, for example, the critical steps are the manipulation of the pure active ingredient and the mixing phase coming before the definition of the final pharmaceutical form.  Steps where the manipulation of the active ingredient is higher or it takes a longer time are the more critical ones, as well as weighting procedures. For small quantities, the operation is completely segregated inside the isolator. Completely automated weighing machines are available for bigger quantities. The risk level progressively decreases as the active ingredient is diluted upon mixing with the excipients.

Simple solutions are also available, as for example disposable flexible isolators; they get wet and are discharged at the end of the production.  This type of solution is suitable for production facilities already in place, that were not built in order to facilitate containment of the product.

The so-called make-a-batch is a theoretical simulation of the entire production process that can help running a good risk analysis.  The simulation considers in deep detail each single step of the process, even the more “forgettable” ones, in order to better value their potential impact.

The Standardized Measurement of Equipment Particulate Containment guideline (SMEPAC) may help in the periodic monitoring of the efficacy of the containment measures adopted.

The type of production may also condition the modalities of containment.  There is no need for separation of production areas if the plant is fully dedicated just to one product; there is a greater tolerance also for the flows of materials and workers. In the case of a multi-product plant, there is need to consider the risk of cross-contamination: working environment should be partitioned in different areas, one for each process. Cleaning, too, becomes a critical operation to pay a great attention to.

A new containment-based production plant has to be validated using the standard validation procedures. There is still a debate open on the reliability of containment measures, after validation and over a long period of time.  Two are the key elements of a production chain, not only valid for the pharmaceutical industry. The future challenge shall combine high standard levels for production, plant’s flexibility and cost containment. An approach more aware toward containment is now available. The multi-disciplinary risk analysis asks for the participation of all internal functions, and even of suppliers of equipment and materials. Technical solutions are thus the most appropriate ones without being overestimated.

Personal protection equipment

Personal protection equipment is used to reduce the risk to enter in contact with dangerous substances. Personal protection equipment shall be used each time it is impossible to avoid the risk, or to reduce it, using preventive technical measures, collective protection equipment or different modalities of work organization. 

Assessing a CMO’s cleaning procedures

While the differences between R&D teams from CMO to CMO are subtle but far reaching, there is a very obvious distinction between how manufacturers approach cleaning and QC qualification. Faced with the task of preventing cross contamination, some CMOs simply eliminate cleaning as an issue by using dedicated equipment. This is a very effective way to mitigate the contamination risks posed by HPAPIs without having to develop robust cleaning methods. Some regulatory guidance favors the use of dedicated equipment, but this could change as authorities become comfortable with alternative models. The other option is to perform data-driven cleaning validations to enable a multiproduct HPAPI plant. In this model the CMO uses analytical tools to quantify the risk of cross contamination and subsequently determines a cleaning regime that ensures safe limits. Modern analytical technology is precise enough to handle this task and QC teams have the scientific understanding to convert the instrument readings into a safe cleaning strategy.  The International Society for Pharmaceutical Engineering (ISPE) showed how such a health-based risk assessment strategy can work in a document published in 2010.

Following the path established by ISPE allows CMOs to provide an extra layer of reassurance by showing clients exactly how they scientifically mitigate risk during changeover. The data-driven cleaning model also supports larger-scale manufacturing. Vessels that are too big to justify using for one HPAPI become viable when a multiproduct strategy is adopted. Use of such vessels can benefit both the CMO and its clients, but it is vital that anyone considering choosing a service provider that uses data-driven cleaning thoroughly investigates the potential partner.

The safe, successful running of a multiproduct facility requires a suitable risk-management strategy and top-tier toxicological expertise. Working with a CMO that has failed to establish the necessary cleaning and QC expertise and processes can lead to delays and, worse still, regulatory problems. To avoid these potential pitfalls while still realizing the benefits of working with a multiproduct plant, sourcing teams must establish the CMO meets certain standards before entering into a contract. This is just one of the important steps biopharma companies should take when choosing a CMO for HPAPI manufacturing.

What to look for in a HPAPI CMO

Price and capacity are understandably high on sourcing teams’ lists of questions when choosing a CMO, yet prioritizing these factors at the expense of other areas is a risky strategy. A CMO that submits the lowest bid but ultimately fails to deliver a product to agreed timelines is not the most cost-effective HPAPI provider. Equally, identifying a CMO with impressive engineering controls and technical capabilities is just one piece of the assessment process. A track record of success and evidence of a long-term, company-wide commitment to HPAPI production are equally important.

Assessing intangible factors like organizational commitment can seem daunting, but there are ways to check how focused a company is on HPAPIs. If a CMO is outsourcing analytical and toxicology work, for example, it is an indication the business is yet to fully commit to HPAPI production. As well as raising a red flag with regards to company-wide commitment, heavy reliance on third parties should prompt questions about how quickly the CMO can work with their vendor to fix a problem. CMOs that lack an in-house toxicology team may take longer to implement a change to evaluation processes.

By questioning the CMO and conducting an environmental, health and safety (EHS) audit sourcing teams can assess whether the provider’s track record and capabilities suggest it is likely to be a reliable partner. The evaluation process takes time, but some CMOs provide a shortcut for clients by undergoing assessment by an independent consulting company, such as SafeBridge. After passing an assessment by the consultants a CMO will receive certification showing the whole organization reaches certain standards, as well as advice as to how it can further improve its operation.

A lack of certification is not an indication that the CMO is substandard. Some CMOs rely on equally rigorous in-house assessments and policies. If the CMO has a track record of success and meets the organizational criteria discussed in this paper, there is no reason to think it will not be a reliable partner just because it lacks SafeBridge certification. The presence of a certificate simply shows an independent expert has already asked the important questions and been satisfied by the answers. As such, it can be a reassuring, time-saving tool for HPAPI sourcing teams tasked with selecting a CMO.

Summary

The demanding nature of HPAPI manufacture — and the level of investment this necessitates — makes outsourcing an attractive, cost-effective option for biopharma companies. These same demands make it particularly important to pick the right partner too though. Cost savings from working with a CMO can be wiped out quickly if the service provider’s failure to manage cross contamination leads to a recall. In light of these risks, sourcing teams should tread carefully when choosing a CMO, taking their time to pick a partner that has a company-wide commitment to HPAPIs and a track record of success. A CMO that has taken a similarly measured, diligent approach to entering the HPAPI sector is likely to be a reliable partner. Entering the HPAPI sector is about more than just installing the technical capabilities, it is a long-term process that reshapes all the groups working within the CMO. Service providers that take this holistic approach are best placed to meet your supply needs while also protecting the health of their employees and the environment.

Even if the decision to outsource is clear, the choice of partner is a crucially important of the decision. The service provider’s record of compliance with global regulatory and safety standards, as well as experience and capacity for producing HPAPI drug products, are good indicators that the service provider will be able to expeditiously bring a molecule to market and maintain supply of the product over time. The prospective partner needs to assess the service provider’s global experience, expertise and track-record in the manufacture of HPAPI compounds and be assured that their systems and procedures in place will allow for the safe and effective manufacture of the compound in question.