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For instance, we have seen customers who encounter IVIVC issues with their formulations find ways to breathe new life into them through the use of alternative technologies, such as osmotic pumps, which provide zero order release profiles independently of digestive state.


What are some regulatory requirements manufacturers have to be aware of when formulating new controlled release products?


Ali: Abuse deterrent formulations (ADFs) or tamper resistant formulations (TRFs) have been a subject of continued debate in the industry and the agency has set forth a guideline for opioids and other controlled substance formulations. With the new landscape in ADF, the industry is using novel formulation technologies to derive dosages that meet the current challenges for the abuse. The formulation technologies such as hot met extrusion and lipid based formulations, have been used to prevent and alleviate the once readily available extractable drugs to difficult- to-extract drugs for sniffing, snorting, and injecting. For non-opioids, and conventional drugs, the industry has been using the commercially available and approved excipients including cellulosic and vinylacetate and gums due to their abilities to control and deliver drugs, and hence, alleviate the dose dumping and systemic toxicity.


Kyburz: During development of a modified release product, it is im- portant to show robust formulation and operational process ranges through implementation of Quality by Design (QbD) principles as out- lined in ICH guidelines: Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System. For both commercial immediate and controlled release products, the FDA recently redefined process validation to focus on a lifecycle approach with distinct design, qualification and continuous verification phases. The aim is to understand the source and risk of material and process variations via in-depth process development and process qualification, and appropriate control strategies based on statistical scientific evidence. These are especially critical for modified release dosage forms where raw materials and manufacturing variables have high impact. For products that are post-approval, the FDA SUPAC-MR guidelines streamline changes to the formulation, manufacturing process, and/or batch size for modified release dosage forms. While all SUPAC guidances are older than ICH and PV, it’s expected these rules will be updated to be consistent with current development and validation philosophies.


Another regulatory requirement is demonstration of drug release robustness to substantial amounts of ethanol. Certain CR technologies are intrinsically more robust – such as osmotic tablets, some matrix tablets, some MPs – but this factor must be designed into all CR dosage forms prior to key studies.


An additional focus of regulatory agencies is to require, or incentivize, pediatric drug formulation evaluations alongside conventional dosage forms intended for adults, including controlled release. For pediatric formulations, there is a heightened need for palatability, swallowability, ease of preparation and administration, and appropriateness for a wide range of pediatric ages.


Khot: Quality by Design (QbD) was previously viewed as optional, but it is now an absolute requirement. Formulators need to work closely with raw material suppliers to understand the sources of variability that could impact their product. The Dow-Colorcon Alliance offers a full library of QbD samples for matrix modified release, as well as technical support for other controlled release technologies.


Musakhanian: Many of the currently referenced oral CR dosage forms consist predominantly of polymers that serve as drug stabilizers and or sustained release matrices. The approach has its limitations. The high percentage of polymer needed to diminish the drug release is not amenable to high drug dosing. More importantly, the polymers may be subject of rapid hydration in the gastrointestinal tract due to pH, presence of alcohol, or food, leading to untimely burst release or dose dumping. Such risks may have grave consequences for potent drugs with narrow therapeutic index.


FDA continues to issue guidance documents aimed at ensuring drug safety and efficacy. With respect to controlled release dosage forms, the FDA may require additional studies. These include scientific evidence that the product performance does indeed match the claims being made. More importantly the innovator must demonstrate that the integrity of the dose in alcoholic and at times in acidic media is preserved. Since alcoholic beverage consumption may lead to a more rapid release of the drug impacting its safety and efficacy, a bioavailability study of the drug product when administered with alcohol may be needed.


Another concern with CR dosage forms is the potential variation in therapeutic response among patients. In a warning issued in September 2015, the FDA strongly cautions the health authorities about the dangers of administering the opioid analgesic Tramadol HCL to children aged 17 and younger.


Can you tell us about some new technologies that will debut in the next five years that will make the development of controlled released products easier and more efficient?


Dürig: New techniques to achieve gastro retention will increasingly facilitate the development of controlled release products for BCS class III drugs.


Novel highly functional polymers are under development that will facilitate more efficient development of controlled release matrix systems due to their ability to accommodate drugs with a wide range of characteristics and improved in vivo robustness, thus facilitating easier in vivo-in vitro correlation .


Finally adoption of GMP grade 3-D printing technologies has the potential to revolutionize controlled release device development. This technology allows the rapid development of novel device architectures and geometries that can enable novel drug delivery benefits.


Ali: The agency is focused on setting the standards for developing controlled release formulations − especially abuse deterrent formulations (ADF) to safeguard the patients, and public at-large. This is extremely critical as more opioids and pain killers going off patent are being developed. In this endeavor, the hydrogel are becoming more common, and the trend will continue because of the available range of excipients possessing the ability to hydrogel and control the release of drugs. For instance, polymers such as high molecular weight polyethylene oxides and polyethylene glycols will continue to play an important role. In other cases, polymers having the abilities for thermo-gelling will play an important role in controlling the release of small and large molecules. For instance, Poloxamer 407 (Kolliphor® P407) and other gelling enhancing excipients such as Poloxamer 188, hyaluronic acid, hydroxypropyl methyl celluluse, polyacrylic acid, serum albumin among others, will contribute significantly to new innovative drug delivery technologies such as the


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