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Creating Meaningful Protocols: Key Recommendations from FDA and EMA

Friday Nov 20, 2015

By: Mike Glacken  (mglackenatbptcdotcom)  , Senior Consultant

Early in my career I had a Sr. VP tell me, quite seriously, after I presented CMC timelines for a given project that “the problem with timelines, Mike, is that people expect you to keep them”. I had reason to recall this Captain Obvious moment recently when discussing with colleagues how to set acceptance criteria for a Process Performance Qualification (PPQ) protocol. Protocol authors seem to be afraid to set meaningful acceptance criteria in their protocols for exactly the same reason. Not that I can blame them. Failing acceptance criteria in a PPQ protocol will generate headaches.

However, validation philosophy has evolved greatly over the last decade or so. There have certainly been new guidance documents issued on the subject, from the FDA in 2011, to the EMA in 2014 and the PDA in 2013. A thoughtful reading of these documents provides some insight into how to generate more meaningful, yet generally achievable, acceptance criteria.

The FDA guidance document states that the PPQ protocol should contain:

  1. “criteria and process performance indicators that allow for a science- and risk-based decision about the ability of the process to consistently produce quality products” and there should be
  2. “a higher level of sampling, additional testing, and greater scrutiny of process performance than would be typical …”.

The EMA guidance document advises that controls during PPQ:

  1. “are expected to go beyond the routine control system as described in S.2.2 and S.2.4”,
  2. validation of the upstream process should “focus on the confirmation of consistency of performance indicators and quality attributes” while,
  3. validation of the downstream process should “confirm the clearance capability”, and
  4. demonstrate that the process is “able to consistently generate the targeted quality of process intermediates and active substance”.

This language certainly suggests that much more is expected than simply following the batch record and meeting batch drug substance (BDS) specifications.

In my role at BPTC, I recently reviewed a PPQ protocol with acceptance criteria that stated “All batch record ranges and IPCs must be met” and “The BDS from all conformance lots must meet specifications”, but little else. I wondered whether implementation of this protocol would be a valueless exercise. I had to ask “Don’t all commercial lots need to follow the batch record and produce BDS that meets specifications?” “Of course”, was the answer. I followed up with “Then what’s the purpose of the PPQ protocol?” The response was “That’s the way we have always written the acceptance criteria”. Unfortunately, almost all the PPQ protocols I’ve seen over the years were written the same way.

Given the above observation, how then should we set the acceptance criteria? While we want to make the criteria meaningful, we certainly do not want to fail. That’s something that Sr. VP apparently did not understand: I crafted those CMC timelines with the expectation that they would be met. The same must hold true for the acceptance criteria in PPQ protocols. This is a topic for another blog. I’d be interested in your opinion about how to improve PPQ protocols.


Top 3 COGS Drivers for Peptide Therapeutics

Wednesday Nov 11, 2015

By Terence Davidovits  (tdavidovitsatbptcdotcom)  

In the last few years, there has been a renewed interest in peptide therapeutics directed toward a wide range of indications, including diabetes, cardiovascular disease, HIV and cancer. Peptides, compared to other small molecule drugs, offer increased specificity while potentially offering greater metabolic stability and oral availability than protein biologics. These peptide therapies can be manufactured using either recombinant methods or chemical synthesis alone or in combination. Recently, innovative synthesis methods have been described for generating long peptides that can be classified as proteins. For example, Provence Technologies recently synthesized IL-10, consisting of 160 amino acids. The FDA classifies any peptide produced synthetically containing over 100 amino acids as a protein. This blog outlines the three elements that affect costs of producing a peptide therapeutic.

First, a critical factor in the cost of peptides made by chemical synthesis is the product yield per amino acid addition step. A high number of sequential synthesis steps to grow a peptide can prove detrimental to process economics. For example, even a 95% step yield repeated over 20 reactions gives a total product yield of around 36%. In addition, a similar yield challenge exists as the number of peptides to be linked together to form the final product increases. Therefore, gaining the highest possible overall yield is critical to achieving cost-effective processes for longer peptides. One option for longer peptides is to perform a hybrid synthesis where peptide fragments are produced using solid phase synthesis first, then joined using solution phase synthesis to generate the product. Two other significant variables to quantify when considering costs are the coupling reaction time needed per step and the raw materials required. In the case of chemical synthesis, costs are also dependent of whether the process utilizes solution or solid phase synthesis.

Second, costs for recombinant fermentation-based production depend on how much product is produced per batch and fermentor turnaround time. These two factors determine the length of time these batches will keep a manufacturing facility busy. The amount of product produced will depend on the size and number of fermentors used. Recombinant process costs also include downstream separation steps that differ depending on whether the peptide is held within the cells or excreted into the growth medium. Recombinant processes tend to require more up-front investment, but have better economies of scale.

Third, the scale of the manufacturing operation and market demand are key factors. Each of these parameters affects the major cost categories in COGS calculations as outlined in a previous BPTC blog written by my colleague Rick Stock. In many cases, it would be a worthwhile tradeoff to assess quantitatively which method is likely to be the most efficient before making a final manufacturing process selection. Early process development work could both inform the analysis and show how much development work remains for each case. Such an analysis is used to generate the metrics associated with a specific COGS target, and indicate which strategy would likely yield the lowest COGS.


QbD and Quality Systems Challenges Ahead as Cell Therapy Moves Forward

Monday Oct 19, 2015

By David Broad

As someone who worked on CAR-T cells and cell-based vaccines in the 1990’s, it was exciting to learn while attending the recent IBC Cell Therapy Bioprocessing and Commercialization conference that some of these cell-based therapies are moving towards commercialization. Marc Better (Kite Pharma) and Bruce Levine (U. Penn.) presented stunning clinical data on the use of anti-CD19 CAR-T cells for the treatment of various forms of hematological cancers. These results are the outcome of a better understanding of T cell biology, an improved conditioning of patients, and the appropriate choice of clinical indications. Levine also indicated his colleagues are turning their attention toward solid tumors. Similarly, Bluebird Bio representatives presented impressive data on the treatment of Beta thalassemia using genetically modified CD34+ cells.

Various presenters described some of the commercialization challenges associated with cell-based therapies. These challenges included the control of starting and raw materials, comparability strategies, and appropriate potency assays. Critical starting materials, such as patient apheresis samples, need to be generated using stricter quality standards to minimize variability. Apheresis use to produce a critical raw material does not necessarily have to be GMP, nevertheless suitable controls will be required. For example, an analysis of bone marrow isolates showed a 3-log variation in number of isolated CD34+cells/Kg at the same clinic. These differences appear to arise from individual patient variations as well as subtle differences in isolation methodology.

Critical raw material quality standards for such starting materials as plasmids and cell lines used in vector manufacture and the vector itself need to be adequately controlled. Consequently, there is a need to ensure that suppliers of these materials have adequate Quality Systems in place, that the facilities are adequate to meet these standards and that there are specifications and limits in place. Similarly, controls need to be in place for all ancillary materials, e.g. growth factors, media, bags, etc. Such controls are particularly critical for cell-based products due to the potential carryover of contaminants into the product. A USP risk-based approach for this quality control process was described.

Comparability studies are particularly challenging for cell-based products because there may be no suitable animal models to correlate efficacy with perceived CQA’s. In addition, the mechanism of action of these cells is not always fully understood. In such cases, clinical data is sometimes required as well as a matrix approach to comparability in terms of risk assessments, certificates of analysis results, and process validation documentation. Comparability studies on patient specific products present a unique challenge. One common approach is to split a patient’s cells into two volumes and process these samples in parallel using the processes to be compared. Further, careful consideration needs to be given to the mode of statistical analysis employed as well as how many cell-processing replicates need to be performed. To add further complications, often a source of patient cells is unavailable and normal donor cells must be used. In an ideal situation, at least some initial experimentation would show that patient and normal donor cells are equivalent.

There were two major take-away messages from this conference. First, great strides are being made in cell-based therapies and patient outcomes are extremely encouraging. Second, companies are moving forward with commercialization plans and need to adapt QbD and Quality Systems approaches to address novel safety and efficacy issues associated with such products. Establishing a clear QbD and Quality Systems strategy as early in product development as possible is paramount to assure that cell-based therapy companies maintain momentum across the regulatory approval process.


Two-Day Training Course: Introduction to Biopharmaceutical Manufacturing

Thursday Oct 1, 2015

Drs. Sheila G. Magil, Senior Consultant, and Frank Riske, Senior Consultant, will be leading a training course entitled, Introduction to Biopharmaceutical Manufacturing, during at the annual BioProcess International Conference and Exhibition to be held at the Hynes Convention Center in Boston, MA from October 26-27, 2015. For more information about this course or other BPTC training programs, please contact Al Doig  (adoigatbptcdotcom)  .


11 New Monoclonal Antibodies in Regulatory Review Spells Bright Future Ahead

Thursday Sep 17, 2015

By Al Doig  (adoigatbptcdotcom)  

Since the approval of Orthoclone OKT3 in 1986, the therapeutic monoclonal antibody industry has experienced three decades of continuous growth. Today there are over 40 market approved MAb products in the US and EU, having combined sales of over $75 billion in 2013. Our recent article entitled Monoclonal Antibody Targets and Indications, identifies three important industry trends based on an analysis of a bioTRAK® dataset. First, a number of the products currently in late stage development are focused on novel targets suggesting that the number of indications that will be successfully treated with MAb therapeutics is likely to grow. Second, several late stage development programs are focusing on developing improved antibody products against known molecular targets. These programs may yield “biobetters” for indications such as asthma, leukemia, non-small cell lung cancer, and multiple sclerosis. Third, there are 24 biosimilar development programs chasing the blockbuster revenue streams of six established innovator products.

As of July 1, 2015, there were 11 new MAb products under regulatory review for market approval either in the US and/or EU. In addition, two biosimilars have MAA applications under review; one a biosimilar to etanercept (Enbrel), and the other a biosimilar to infliximab (Remicade). Another 22 biosimilars are in Phase 3 development suggesting a competitive marketplace just over the horizon. An analysis of 62 MAb products in Phase 3 development finds autoimmune diseases and cancer to be the indication areas receiving the most development attention. However, approximately 1/4 of the MAbs in Phase 3 are for the treatment of indications outside these areas and include cardiovascular, neurological, and orthopedic diseases for which no approved MAb products currently exist.

MAbs as therapeutic agents continue to be viewed as attractive platforms for new drug development by industry. As the biopharmaceutical industry continues to grow, the number of molecular targets and therapeutic indications that can be treated with MAb products will undoubtedly increase. Many products that are currently in late stage development are focused on novel targets, confirming that the number of indications that will be treated successfully with MAb therapeutics in the future will be larger than today. In addition to antibodies in development against novel targets, several late stage development programs focus on developing improved antibody products against known molecular targets and these programs may yield “biobetters” for indications such as asthma, leukemia, non-small cell lung cancer, and multiple sclerosis. The result of both of these important trends –growth in indication areas treated by MAbs and growth of biosimilars – is likely to be an increase in the demand for manufacturing capacity to produce monoclonal antibodies.