Blog

Leachables and Extractables in Biopharmaceutical Processing

With the burgeoning interest in the use of disposables for the production of modern biopharmaceutical products, the level of scrutiny surrounding the topic of Leachables and Extractables has moved into a higher gear. It seems that there is an endless amount of attention being paid to this topic because of the potential impact on patients receiving biopharmaceutical based therapies.

As a result there is a frantic level of regulatory activity as scientists attempt to predict and quantify whether there’s any regulatory impact, particularly as it relates to safety.

Although issues connected with Leachables and Extractables has been discussed for over 25 years, the recent trend towards the use of new disposable methods of production which includes; wave bags, disposable plastic bioreactor inserts and their myriad of associated tubing and samplers, means that the probability of some elastomer eluting from the components or alternatively some breakdown product washing off the material might be much greater.

With the potential for both Leachables and Extractables to have a marked effect on the quality and safety of protein therapeutics, the challenge is therefore on to find better testing methods to provide an adequate level of sensitivity and specificity that will assure both quality and safety concerns are met.

Similarly, provider companies are looking at newer materials that may not have the same potential contaminating profile which might reduce or minimize the problem.

With all this activity going on its often helpful to solicit the help of a consultant that is aware of the issue s to help guide a path forward.

In developing protein therapeutics that may be sensitive to contact with rubber and plastic components, the potential effect of Leachables over time can become a critical processing consideration. To help to address this issue, part of the modern approach is to use Risk Assessment and Risk Mitigation strategies to first quantify the extent of the potential risk and then to subsequently ameliorate possible negative outcomes that are identified. This is a really important step and should be planned carefully as it can save a lot of effort if it’s completed according to a well defined approach.

With the projected level of activity in using disposable production systems expected to increase markedly over the next 5-10 years, we can expect to see this area receive even more attention. Currently various industry associations are interfacing with the FDA to develop various standards to help to address these issues in order to prevent them from becoming a limiting condition to the application of this technology.

Venturing into the Bold World of Combination Products

- By Michael Hemenway

For a traditional medical device company contemplating a decision to develop a combination drug-device product, the question of whether or not to pursue this type of product should be weighed carefully.  While there might be a benefit to the patient from such a product, the benefit should be compelling and perhaps more importantly from a business perspective, the profit uplift from having a drug associated with the product should be large enough to more than offset the pre-clinical development and post-market costs associated with the pharmaceutical aspects of the product.  Developing and supporting a combination product brings more costs than the typical medical device company is prepared to bear or has even thought about, especially a smaller device firm.  A cursory “laundry list” of considerations that come into play include the following: drug-drug interaction study, drug-polymer interaction study, drug-packaging interaction study, biocompatibility studies, bioavailability, pharmacokinetics and pharmacodynamics studies, analytical method development and validation, drug product specifications development, initial pharmaceutical shelf life (stability) study, clinical evaluation, annual stability commitment, routine lot testing and retain samples storage.  Such a list does not even consider other items a regulatory agency might request after reviewing the PMA or 510(k) submission documents.  Welcome to the bold world of bringing a combination drug-device product to the marketplace!

Don’t keep failing, implement a LEAN Laboratory approach!

So your QC laboratory is failing to keep up with the manufacturing group.
Your number of samples is increasing and there are new products coming down the road which promises yet more samples.
Your laboratory analysts are working harder and longer hours just to maintain parity.
Overtime costs are exploding and errors are increasing which is leading to more and more laboratory investigations.
The pressure is mounting and there seems to be know light at the end of the tunnel.
What do you do?
First, have an experienced Lean laboratory consultant on your team. Second, work with them to develop a plan that will transform how you’re running the laboratory operations.
Third, make a commitment to integrate the QC laboratory as part of an overall operational strategy so that the laboratory is not an isolated function that’s exposed to changes in production priorities.
So what are some of the important factors that we need to consider in transforming the current situation to a Lean laboratory? Below is a short list of some of the more important features that you will need to build into the transformation plan.

• A process to provide a consistent leveled supply of samples
• A process that significantly reduces the lead times involved
• A process that reduces the level of work in progress
• A process that reduces the overall cycle-time for analysis
• A process that streamlines data processing

If these issues sound familiar to your situation and you want to implement a new approach don’t hesitate, pick up the phone and call us on 610-344-9218 now!

Disposables and Single –Use Systems: A Way to Drive Biomanufacturing from a Lean Perspective

Over the last ten years we’ve seen a massive change in the way we look to manufacture biopharmaceutical products. Increasingly the methods and technology that were in vogue through the late 1980’s and 90’s are being superseded by new disposable options.
There are several reasons for this including, but not limited to:
Better products and more adaptable materials of construction, lower upfront costs for facilities and equipment, the potential for greater flexibility of production (particularly for clinical trial material), lower financial barriers to entry for early phase companies that have limited capital and easy scalability for low volume products that are now available from high producing cell lines.
When one looks deeper into the interface between upstream and downstream processing, the opportunity for tighter integration is available and this cuts down waste due to non-added value holding periods, cleaning time and chromatography column regeneration time.
The potential for upfront lead time reduction is also a significant advantage that disposable solutions offer as well as the opportunity to eliminate process time associated with process cleaning and re-sterilization.
For multiple low volume products manufacturing, whether it’s associated with either clinical or commercial manufacturing, disposables offer the advantage of more rapid change-over and this is another area which provides the opportunity to develop a lean manufacturing strategy.
However, the story is not all rosy as there can be problems associated with operational implementation.
To help address this the assistance of a pharmaceutical consultant is often needed to provide good advice and support when developing a robust strategy for the lean manufacturing/biomanufacturing of your biopharmaceuticals.
If you like this blog, let us know.

NDC codes: National Drug Codes and How They are Assigned

The NDC code is a 10 digit code that is applied to uniquely identify products having a drug registry component. The number is a 3 segment number in terms of its construction and the various components correspond to sections responsible for the label, the product and the packaging.
The first section identifies the labeler code, is assigned by the FDA and it identifies any manufacturer (including re-packagers or re-labelers) or distributer (under their own name) of the drug or drug containing material.
The second section identifies the product code which includes the specific strength, dosage form and formulation for the company.
The third section identifies the packaging code and this corresponds to the package size and type. This part together with the product code is provided by the company filing the NDC application.
In practice NDC codes follow the following convention: 4-4-2, 5-3-2 or 5-4-1, where the second and third parts are determined by the operating convention within each individual company.
In practical terms then, should a packaging size change for the product and if the same product is manufactured in the same location, then the codes would change and a unique code would be required for that packaging configuration/size.
Similarly if the packaging size was the same but the formulation changed, then the code would also change to a new unique number for that formulation.
Changes in the product which force a change in the label would also trigger a change in the primary code used by the FDA.
So this is a complex process that may require the filing of many systems where a product may have several packaging configurations, several formulations and several label types.
Guidance through this process is best achieved by employing a pharmaceutical consultant who can objectively steer a clear path through the maize of paperwork and forms to provide a lean process for the most effective and efficient outcome.

Issues Connected with Device Combination Product Convenience Kits

The development of medical device combination product convenience packages continues to throw up interesting technical/regulatory challenges.
Inclusion of pre-sterilized syringes and other applicators as part of these products poses problems for manufacturers and distributors due to the possibility of post sterilization contamination and/or plastic leachables/extractables.
Most device convenience kits are ETO sterilized and this can leave ETO residuals on the applicators and syringes if they’re included in the paper convenience trays.
If manufacturers are to use these types of device combinations, then an alternative material of construction may be required to avoid this issue or possibly a modified sterilization cycle will be required which provides assurance of the removal of the sterilant.
As a first step testing is needed to quantify the extent of the problem. Only when the size of this issue is understood can a resolution be developed.
These are complex issues which often can be best addressed using the experience of a pharmaceutical consultant to structure a creative path forward.
Whatever the testing results however, manufacturers still need to know what their exposure is and the regulatory authorities will require evidence to show that practices are safe.

Do Start up Life Science Companies need Quality Management Systems?

So you may be a start-up or virtual life sciences company, but you still have a requirement to have a Quality System to develop your pharmaceutical/life sciences products. That’s true if you are a company that is regulated by the FDA and major international regulatory agencies that conform to ICH guidelines.
Although you’re not likely to be inspected as an early stage company, regulators still expect that developers of human products must be stage appropriate managed in terms of compliance expectations for the products they are developing and commercializing. So you just can’t leave it for later because you’re not going to be inspected. The regulatory agencies expect that you comply with the law even though they’re not necessarily checking up on you.
Modern regulatory agencies require companies to have Management Controls and a Quality Plan in place even when their product development is at an early stage.
As a result you can’t just leave it to your vendors and work off their systems.
This is a much misunderstood concept that is often overlooked because it takes time and expense to develop and put in place. However, given that it is the law, those ignoring the issues and failing to address the need are really jeopardizing their future business and products.
Companies intending to partner with large pharmaceutical companies will find that they can negotiate better terms if they have their compliance house in order. Large Pharma likes positive results and will pay for the convenience of an in-license, but if there are regulatory issues as a result of a lack of quality oversight they may be less inclined to pay top dollar as some of that amount may be needed to address regulatory short falls.
A better business & compliance approach is to do it right first time and to initiate a flexible and expandable Quality System strategy.
At SCG we offer a fully expandable and serviceable Quality System that’s been tried and tested over a number of years at start-up, clinical and commercial scale.
Developed from first principles using process mapping, our system is sensitive to the requirements of commercial rigor without stifling development for earlier stage situations.
Talk to us about our early start QMS package and reap the benefits of being in compliance right from the development inception. This is a must do for virtual or blended outsourced business models.

Shortened Lead Times as a Key Component of Lean Biomanufacturing

A significant driver in the improvement in bioprocess plants profitability relates to the reduction in non-value added lead times.

Cost of goods is related to both real manufacturing work time together with all other activities connected with servicing this piece of the process.

By their very nature, these activities are not value added and therefore provide a negative component in the overall cost of goods equation.

In responding to market sales, manufacturers want to keep their raw material inventory in check to minimize overhead costs, but must have sufficient on-hand to be able to provide a timely response to market demand. This is the dilemma of all manufacturers that are starting to build market share and increase their ROI.

Companies that can balance this equation and maintain short raw material lead times and truncated production runs with a low non-value added component will have a distinct competitive edge that will propel them to a market leadership position.

Companies that can effectively manage their capacity to produce only what’s required when the market demand calls for that product enjoy the real numerical benefits of the “pull” manufacturing methodology over those who cling to batch methodology where product is “pushed” out into the warehouse and kept as inventory.

However, the real benefit is the flexibility this brings to plant operations as the plant becomes more responsive and can be changed over to make the next product without any significant loss in time.

Attractive as this prospect is however, it does not come overnight and requires the investment of resources.

For the most attractive ROI, a best results coordinated strategy is often developed with the aid of experienced pharmaceutical consultants who will take a holistic approach, employing all the tools of Lean systems in concert, for the very best outcome.

Lean Product Change–Over in an FDA Regulated Environment

Some would argue that there is a conflict between the idea of lean practices and a highly regulated quality compliant environment. However, upon closer analysis this is not necessarily the case.
Both Lean and Compliance have very definite requirements to operate properly and it’s this discipline of implementation and execution that can bind both rather than separate them as “end-game” outcomes.
Compliance requires systematic control of elements connected to and driving manufacturing compliance functions, where as Lean requires similarly strict adherence to operating modalities that assure efficiency, repeatability and overall process capability.
Where much of the conflict appears to reside is in relation to how that execution is achieved.
However, with the advent of recent new guidance documents which include GMPs for 21st century, ICH Q8, Q9 & Q10, we’re seeing a more pragmatic approach to compliance that is more systematic and which lends itself to fit naturally with Lean concepts of implementation through the application of creative flexible approaches.
Our challenges as manufacturers are to find creative approaches to embrace this marriage of ideas which can be more compatible than many often believe are the case.

Reaching into Research and Development of a Supply Chain Strategy

Critical materials and suppliers are selected early in development. By the time Technology Transfer occurs for commercialization, it is often too late to make changes to these critical components without having to do additional testing or even repeating clinical trials. Regulatory authorities have made securing the supply chain a priority and have promised serious repercussions for companies and their management who do not manage risks to the supply chain. We propose developing a strategy for selection of raw materials and components and their suppliers early in the development cycle. The strategy should be based on risk management principles and the needs and demands of the commercial market. The strategy would consider the unique attributes of the material and suppliers balanced against the potential risks that may be encountered when manufacturing for the commercial market.

To read the full white paper, click on the following link:

Reaching into Research and Development for Development of a Supply Chain Strategy

Microsoft Word Document (.doc)